UNITED STATES OF AMERICA FOOD AND DRUG ADMINISTRATION ... · CENTER FOR DEVICES AND RADIOLOGICAL...

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Professional Video Associates, Inc. 2515 Saint George Way Brookeville, MD 20833

301-924-1556

UNITED STATES OF AMERICA

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

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CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

MEDICAL DEVICES ADVISORY COMMITTEE

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ORTHOPAEDIC AND REHABILITATION DEVICES PANEL

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April 20, 2016 8:00 a.m.

Hilton Washington DC North

620 Perry Parkway Gaithersburg, Maryland

PANEL MEMBERS: RAJKUMAR D. RAO, M.D. Panel Chair MAUREEN FINNEGAN, M.D. Voting Member S. RAYMOND GOLISH, M.D., Ph.D., M.B.A. Voting Member JEREMY GILBERT, Ph.D. Voting Member BRENT BLUMENSTEIN, Ph.D. Temporary Voting Member JOHN KELLY, IV, M.D. Temporary Voting Member STEPHEN LYMAN, Ph.D. Temporary Voting Member TY SUBHAWONG, M.D. Temporary Voting Member JAMES BAILEY, M.D. Temporary Voting Member GLENN PFEFFER, M.D. Temporary Voting Member JAMES HECKMAN, M.D. Temporary Voting Member JOHN CARRINO, M.D. Temporary Voting Member JEFFREY PAGE, D.P.M. Temporary Voting Member DEBRA MCCALL, B.S., M.B.A. Patient Representative KATHY TRIER, Ph.D. Industry Representative YUSEF A. SAYEED, M.D., M.P.H., M.Eng. Consumer Representative CDR S.J. ANDERSON, M.P.H. Designated Federal Officer

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FDA REPRESENTATIVES: MARK MELKERSON, M.S. Director, Division of Orthopedic Devices Office of Device Evaluation ERIC PAHON Press Contact FDA PRESENTERS: JEMIN DEDANIA, M.S., RAC Biomedical Engineer/Senior Lead Reviewer Restorative and Repair Devices Branch Division of Orthopedic Devices Office of Device Evaluation LAURENCE COYNE, Ph.D. Branch Chief, Restorative and Repair Devices Branch Division of Orthopedic Devices Office of Device Evaluation ALVIN VAN ORDEN, M.S. Division of Biostatistics Office of Surveillance and Biometrics

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SPONSOR PRESENTERS: TIMOTHY J. PATRICK President/CEO Cartiva, Inc. TIMOTHY R. DANIELS, M.D., FRCSC Professor, University of Toronto Head, Division of Orthopaedic Surgery St. Michael's Hospital Toronto, Canada DEBORAH J. MOORE Vice President, Regulatory, Quality and Clinical Affairs Cartiva, Inc. JUDITH BAUMHAUER, M.D., M.P.H. Professor and Associate Chair of Orthopaedic University of Rochester Medical Center MARK GLAZEBROOK, M.Sc., Ph.D., M.D., FRCSC Professor of Orthopaedic Surgery Dalhousie University Halifax, Nova Scotia, Canada SPONSOR ADVISORS: GREG MAISLIN, M.S., M.A. Biomedical Statistical Consulting PETER EVANGELISTA, M.D. Brown University DAWN LISSY, M.B.E. President/Founder Empirical Testing Corp.

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OPEN PUBLIC HEARING SPEAKERS: PAUL VOORHORST, Ph.D. Vice President of Clinical Research Depuy Synthes Joint Reconstruction, Mitek and Power Tools on behalf of the Orthopedic Surgical Manufacturers Association GAIL BUTT Patient NANCY SCHMELTER Patient JOHN O'MEARA Patient JANET GEISBERGER Patient

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INDEX PAGE

CALL TO ORDER - Rajkumar D. Rao, M.D. 7 PANEL INTRODUCTIONS 7 CONFLICT OF INTEREST AND TEMPORARY VOTING STATUS STATEMENTS - CDR S.J. Anderson, M.P.H. 10 SPONSOR PRESENTATION Introduction - Timothy J. Patrick 14 1st MTP OA, Device Description - Timothy R. Daniels, M.D., FRCSC 16 Study Timeline, Preclinical Study, Study Design - Deborah J. Moore 21 Study Results - Judith Baumhauer, M.D., M.P.H. 32 Risk/Benefit Considerations - Mark Glazebrook, M.Sc., Ph.D., M.D., FRCSC 46 Conclusions - Timothy J. Patrick 50 Q&A SPONSOR 51 FDA PRESENTATION Introduction, Device Description, Regulatory History, and Nonclinical Studies - Jemin Dedania, M.S., RAC 73 Clinical Background, Study Overview, Safety Assessments, and Effectiveness Assessments - Laurence Coyne, Ph.D. 75 Statistical Review - Alvin Van Orden, M.S. 89 FDA Summary (Benefit-Risk Assessment) - Laurence Coyne, Ph.D. 102 Q&A FDA 106

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INDEX PAGE

OPEN PUBLIC HEARING Paul Voorhorst, Ph.D. 126 Gail Butt 130 Nancy Schmelter 132 John O'Meara 134 Janet Geisberger 137 PANEL DELIBERATIONS 142 FDA QUESTIONS Question 1 198 Question 2 204 Question 3 209 Question 4 215 Question 5 222 Question 6 227 Question 7 236 SUMMATIONS Sponsor - Deborah J. Moore 248 Sponsor - Judith Baumhauer, M.D., M.P.H. 251 FINAL COMMENTS Industry Representative - Kathy Trier, Ph.D. 252 PANEL VOTE 253 ADJOURNMENT 262

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M E E T I N G

(8:00 a.m.)

DR. RAO: Well, good morning, everyone. And welcome. I'd like to call this meeting

of the Orthopaedic and Rehabilitation Devices Panel of the Medical Devices Advisory

Committee to order.

My name is Raj Rao. I'm Chair of this Panel. I am a Professor of Orthopaedic Surgery

and Chair of the Department of Orthopaedic Surgery at George Washington Hospital in

Washington, D.C.

I note for the record that the voting members present constitute a quorum as

required by 21 C.F.R. Part 14. I would also like to add that the Panel members participating

in today's meeting have received training in FDA device law and regulations.

For today's agenda, the Panel will discuss, make recommendations, and vote on the

information regarding the premarket approval application for Cartiva Synthetic Cartilage

Implant, sponsored by Cartiva, Incorporated.

Before we begin, I would like to ask our distinguished Panel members and the FDA

staff seated at this table to introduce themselves. Please state your name, your area of

expertise, your position, and your affiliation. And we'll begin on this side of the table.

DR. TRIER: My name is Dr. Kathy Trier, and I am the global VP of regulatory and

clinical affairs with Corin USA. My background is previously nursing and then biostatistics

and also clinical research methods. I taught at the university for a significant number of

years, and then most recently, I've been with industry. Oh, I should add that I serve on the

Panel as the Industry Representative.

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DR. RAO: Thank you, Dr. Trier.

DR. SAYEED: Dr. Yusef Sayeed, Chief Resident, Occupational Medicine, West Virginia

University. I serve as the Consumer Representative on this Panel. My medical specialties

are in musculoskeletal medicine and musculoskeletal ultrasound.

MS. McCALL: Debbie McCall. I'm the Patient Representative. I'm the Chair of the

Healthy Heart Alliance. I'm a volunteer for StopAfib.org. I'm also a patient researcher and

scientist.

DR. PAGE: My name is Jeff Page. I am a podiatrist by training, currently serving as

the Dean of the Arizona School of Podiatric Medicine on the campus of Midwestern

University.

DR. CARRINO: Good morning, my name is John Carrino, a musculoskeletal

radiologist at the Hospital for Special Surgery, and I work there as the vice chairman.

DR. HECKMAN: James Heckman, orthopedic surgeon and Clinical Professor of

Orthopaedics at Dartmouth-Hitchcock Medical Center.

DR. FINNEGAN: Maureen Finnegan. I am a general orthopedist at UT Southwestern

in Dallas.

DR. GILBERT: I'm Jeremy Gilbert. I am a Professor of Biomaterials in the Department

of Biomedical and Chemical Engineering at Syracuse University, Editor-in-Chief of the

Journal of Biomedical Materials Research Part B, and I'm here as a biomaterials expert.

CDR ANDERSON: Commander Anderson. I'm serving as the Designated Federal

Officer for this Panel. I'm representing the FDA and the United States Public Health Service.

Thank you.

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DR. KELLY: John D. Kelly, IV. I'm the Director of Shoulder Sports Medicine,

University of Pennsylvania, but I still perform foot and ankle surgery.

DR. LYMAN: Stephen Lyman. I am a clinical epidemiologist at the Hospital for

Special Surgery, and an Associate Professor of Health Policy at Weill Cornell Medical

College. My areas of expertise are study design analysis and health policy, health

economics, survey design, and such things.

DR. BLUMENSTEIN: Brent Blumenstein, a biostatistician working out of Washington,

D.C.

DR. GOLISH: I'm Raymond Golish. I am a practicing orthopedic surgeon and the

Chief of Spinal Surgery at Jupiter Medical Center in Palm Beach, Florida. I'm the chair of the

AOS Biomedical Engineering Committee.

DR. SUBHAWONG: I'm Ty Subhawong, Assistant Professor of Musculoskeletal

Radiology at the University of Miami.

DR. BAILEY: James Bailey. I am an orthopedic surgeon with a special interest in

spine and toe joint replacement, practicing in Birmingham, Alabama.

DR. PFEFFER: Glenn Pfeffer, Los Angeles, at Cedars-Sinai. I am an orthopedist and

director of the Orthopaedic Foot and Ankle Center.

MR. MELKERSON: I'm Mark Melkerson, Director of the Division of Orthopedic

Devices with the FDA, background in mechanical and biomedical engineering.

DR. RAO: Thank you, all. And good morning and welcome to all of you one more

time.

Members of the audience, if you have not already done so, please sign the

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attendance sheets that are on the tables outside the doors.

Commander Anderson, the Designated Federal Officer for the Orthopaedic and

Rehabilitation Devices Panel, will make some introductory remarks now.

CDR ANDERSON: Thank you.

The Food and Drug Administration is convening today's meeting of the Orthopaedic

and Rehabilitation Devices Panel of the Medical Devices Advisory Committee under the

authority of the Federal Advisory Committee Act (FACA) of 1972. With the exception of the

Industry Representative, all members and consultants of the Panel are special Government

employees or regular Federal employees from other agencies and are subject to Federal

conflict of interest laws and regulations.

The following information on the status of this Panel's compliance with Federal

ethics and conflict of interest laws covered by, but not limited to, those found at 18 U.S.C.

Section 208 are being provided to participants in today's meeting and to the public.

FDA has determined that members and consultants of the Panel are in compliance

with Federal ethics and conflict of interest laws. Under 18 U.S.C. Section 208, Congress has

authorized FDA to grant waivers to special Government employees and regular Federal

employees who have financial conflicts when it is determined that the Agency's need for a

particular individual's services outweighs his or her potential financial conflict of interest.

Related to the discussions of today's meeting, members and consultants of this Panel

who are special Government employees or regular Federal employees have been screened

for potential financial conflicts of interest of their own as well as those imputed to them,

including those of their spouses or minor children and, for purposes of 18 U.S.C. Section

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208, their employees [sic]. These interests may include investments; consulting; expert

witness testimony; contracts/grants/CRADAs; teaching/speaking/writing; patents and

royalty; and primary employment.

For today's agenda, the Panel will discuss, make recommendations, and vote on

information regarding the premarket approval application sponsored by Cartiva,

Incorporated, for the Cartiva Synthetic Cartilage Implant. The device is indicated for

treatment of degenerative and post-traumatic arthritis in the first metatarsophalangeal

joint in the presence of good bone stock along with the following clinical conditions: hallux

valgus or hallux limitus, hallux rigidus, or an unstable or painful metatarsophalangeal joint.

Based on the agenda for today's meeting and all financial interests reported by the

Panel members and consultants, no conflict of interest waivers have been issued in

accordance with 18 U.S.C. Section 208.

Dr. Kathy Trier is serving as the Industry Representative, acting on behalf of all

related industry, and is employed by Corin USA.

We would like to remind members and consultants that if the discussions involve any

other products or firms not already on the agenda for which an FDA participant has a

personal or imputed financial interest, the participants need to exclude themselves from

such involvement and their exclusion will be noted for the record.

FDA encourages all other participants to advise the Panel of any financial

relationships that they may have with any firms at issue.

A copy of this statement will be available for review at the registration table during

this meeting and will be included as a part of the official transcript. Thank you.

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I will now read the Appointment to Temporary Voting Status Statement.

Pursuant to the authority granted under the Medical Devices Advisory Committee

Charter of the Center for Devices and Radiological Health, dated October 27th, 1990, and as

amended August 18th, 2006, I appoint the following as voting members of the Orthopaedic

and Rehabilitation Devices Panel for the duration of this meeting on April 20th, 2016:

Drs. John Kelly, Stephen Lyman, Ty Subhawong, James Bailey, Glenn Pfeffer, James

Heckman, John Carrino, Jeffrey Page, Brent Blumenstein.

For the record, these individuals are special Government employees who have

undergone the customary conflict of interest review and have reviewed the material to be

considered at the meeting.

This has been signed by Dr. Jeffrey Shuren, Director of the Center for Devices and

Radiological Health, on April 12th, 2016.

Okay. For the duration of the Orthopaedic and Rehabilitation Devices Panel on

April 20th, 2016, Ms. Debra McCall has been appointed as a Temporary Non-Voting

Member also. For the record, Ms. McCall, a patient representative, serves as a consultant

to the Cardiovascular and Renal Drugs Advisory Committee in the Center for Drug

Evaluation and Research. This individual is a special Government employee who has

undergone the customary conflict of interest review and has reviewed the material to be

considered at this meeting.

The appointment was authorized by Jill Hartzler Warner, J.D., Associate

Commissioner for Special Medical Programs, on March 23rd, 2016.

Okay, thank you.

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Before I turn the meeting back to Dr. Rao, I'd like to make a few general

announcements.

Transcripts of today's meeting will be available from Free State Court Reporting,

Incorporated. Telephone: (410) 974-0947.

Information on purchasing videos of today's meeting can be found on the table

outside the meeting room.

Handouts of today's presentations are available at the registration desk.

The press contact for today's meeting is Eric Pahon, and he is standing up and

waving in the back. Thank you, sir.

I would like to remind everybody that members of the public and the press are not

permitted in the Panel area, which is the area beyond the speaker's podium. I request that

reporters please wait to speak to FDA officials until after the Panel meeting has concluded.

If you are presenting in the Open Public Hearing session and have not previously

provided an electronic copy of your slide presentation to the FDA, if you brought one or

have not signed in, please arrange to do so with Ms. AnnMarie Williams at the registration

table.

In order to help the transcriber identify who is speaking, please be sure to identify

yourself each and every time that you speak.

Finally, please silence your cell phones and other electronic devices at this time.

Dr. Rao.

DR. RAO: Thank you, Commander Anderson. Your medical pronunciation gets better

with each meeting.

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(Laughter.)

DR. RAO: We will now proceed to the Sponsor's presentation. I would like the

Sponsor to approach the podium, please.

I will remind public observers at this meeting that while the meeting is open for

public observation, public attendees may not participate except at the specific request of

the Panel Chair.

The Sponsor will have 90 minutes to present. And we will hold your toe to the line,

whether it's fused or whether it's got a device in it.

(Laughter.)

DR. RAO: You may now begin your presentation.

MR. PATRICK: Well, thank you. Hello and good morning. I'm Tim Patrick, CEO of

Cartiva, Incorporated. On behalf of the company, I'd like to thank the Panel members for

your commitment and time to be with us here this morning. We'd also like to thank the

Food and Drug Administration, who we've worked with interactively for the past 8 years on

study design, conduct, and analysis. Most importantly, we would like to thank over 200

patients who participated in the clinical study, some of whom we'll hear from this

afternoon.

I'd like to provide some background on the foot and ankle surgeon presenters as you

review the agenda for this morning. All three surgeons are current or former board

members of the American Orthopaedic Foot and Ankle Society. Dr. Baumhauer, the study

principal investigator, is past president of that organization. These three surgeons, all

professors of orthopedics, collectively have experience treating thousands of patients,

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thousands of cases of first metatarsophalangeal joint arthritis, arthritis of the great toe, and

we appreciate their willingness to share their surgical expertise with the Panel this morning.

Here's a review of the some of the additional representatives who are with us here this

morning, as well.

First MTP arthritis is the most common arthritic condition in the foot, and there are

approximately 100,000 surgeries in the U.S. each year to treat this condition for patients

who have moderate to severe disease. Medical devices used to treat these conditions

generally fall into two categories, those for fusion procedures and those for motion-

preserving procedures. All of these devices are Class II 510(k) medical device cleared.

The most common surgical procedure for this condition is a fusion where the motion

is prevented in the joint with plates and screws. Fusion does a fine job of reducing pain, but

it does so with the sacrifice of normal motion, and it's irreversible. There are dozens of

FDA-cleared motion-preserving devices, yet none of these have a proven track record.

In this X-ray, the implant has loosened and will require revision. This points out

several of the biggest limitations of the existing motion-preserving alternatives to fusion.

First of all, a lot of bone is removed. Wear debris can cause bone loss, and revisions to a

fusion can be very difficult. Resolving these limitations is why we developed the Cartiva

Synthetic Cartilage Implant.

In this image you can see the Cartiva synthetic implant. I've got a sample, and I

would like, Mr. Chairman, if it's okay with you, if we could pass a sample around so that the

Panel could view this product. Is that okay?

(Off microphone response.)

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MR. PATRICK: Okay. The Cartiva implant is pressed into the metatarsal head, and it

provides a cartilage-like bearing surface. This provides a new, durable, elastic, low-friction

bearing surface where the damaged cartilage was replaced. The implant is made of a

biocompatible polymer that is widely used in a number of FDA-cleared and approved

devices such as contact lenses, implantable nerve cuffs, and permanent embolic injectable

microspheres. It's the first use of this biomedical polymer in an orthopedic application.

More than 4,000 patients have been implanted with Cartiva where it's commercially

available, safely relieving symptoms of pain and preserving function for patients with MTP

arthritis.

The Cartiva implant is the best-studied alternative to fusion, ever. It's the largest

study that's ever been done, with over 200 randomized treated patients. It's the best study

that's ever been done. The American Orthopaedic Foot and Ankle Society recognized

Dr. Baumhauer and her colleagues with a Roger Mann award as the best clinical study

presented in 2015 in Foot and Ankle.

And importantly, it's the only product in this category that we're aware of that's

regulated by the FDA as a Class III medical device, FDA's highest standard for medical

devices.

I would now like to introduce Dr. Tim Daniels, Professor of Orthopaedics at the

University of Toronto and a Cartiva clinical investigator.

DR. DANIELS: I'm Dr. Tim Daniels. I'm an advisor to the company, and I am being

reimbursed for my travel and time here today. I do not hold any equity interest in the

company and have no financial interest in the outcome of this meeting.

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I'm a full professor at the University of Toronto. I've been involved with the Cartiva

implant from its inception. I was the first surgeon in North America to implant this device. I

have three patients where we used the Cartiva, one of which you will meet today. But prior

to involvement in the study, I've done over 75 implants, and I've yet had to take an implant

out, with a maximum of 9-year follow-up. We have looked at our mid-term and long-term

results for the patients in Canada that have the Cartiva implant.

As Tim Patrick mentioned, this implant is used for degenerative arthritis of the first

metatarsophalangeal joint. I would just like to point out that hallux valgus greater than 20

degrees was an exclusion criterion for this study.

The first metatarsal is twice the size of any of the lesser metatarsals because of its

importance. The dorsiflexion of the proximal phalange depresses the metatarsal head. It

tightens the plantar fascia, part of what we call the windlass mechanism. In short, it's very

important for stabilization of the medial arch and transfer of forces from the hind foot/mid-

foot through to the forefoot in the stance portion of gait.

Unfortunately, first metatarsal osteoarthritis is a very common entity. One in 40

people suffer from this disease, 2.2 million in the U.S., and there is a high predominance in

the female population. The etiology is still yet to be worked out. What we do know is that

trauma is not a common cause of arthritis in this joint.

When this joint becomes arthritic, it becomes painful, it becomes stiff. New bone is

formed, called osteophytes, which can rub on the shoe. Patients start to place weight more

through the lateral part of their foot, and it's not uncommon for them to present with other

pathologies such as Morton's neuroma. They gradually decrease their physical activities --

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running, ascending slopes, crouching -- even walking distances are gradually diminished,

and eventually come to a surgeon, looking at options to relieve pain in this area.

In this study, we're using the Coughlin scale. This has both clinical and radiographic

components. Essentially, the arthritis gets worse as you go up this grade. The fourth grade

has a strong clinical component with pain with even small amounts of motion at the joint.

Treatment options, as Tim Patrick had mentioned, include total joint replacement,

hemiarthroplasty -- both of these options involve bone resection -- fusion. And today I'm

talking to you about the Cartiva implant.

I have never done a total joint replacement for the first MTP joint. These devices are

available to me. I have refused to do this procedure because of the bone resection. My

personal belief is that I'm not going to offer a surgical option to a patient where there's not

a good salvage. And this is why I've looked at the Cartiva implant: It's bone sparing, and it's

motion sparing.

The problem with the total joint replacements is not only is it difficult to obtain or

maintain range of motion, but they do not have the capability of accepting the forces that

go through the normal bones in that area, leading to transfer metatarsalgia. They tend to

loosen; they tend to fail. And the problem is when you take them out, you're dealing with a

large amount of bone loss. The patient often is subjected to iliac crest bone or allograft

bone plates, long periods of non-weight bearing. And for this reason, I have not performed

these procedures.

The AOFAS, on their website, indicated that there is insufficient long-term studies to

support total joint replacement use in this area. Many of the current toe implants suffer

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from loosening and early failure, requiring another surgery. This is one reason why fusion

has remained the standard of care. As surgeons, we know that it's reliable in terms of pain

relief. The problem is, is that patients don't like the stiffness, and this is why we look at

alternatives.

When I talk to my patients about fusion, very often eyebrows get risen, their eyes

widen, and they might even sit back, and I spend a lot of time talking about the fact that

even though they're going to lose motion in that area, that if the pain relief is sufficient,

they will function okay.

Other than the stiffness, which the patients don't like, my patients don't like, there

are always potential things that can go wrong with surgery, such as non-union, mal-union,

or prominent hardware. Adjacent joint arthritis in the IP joint can also occur.

And here's an example of a patient who had a fusion and later presented with hallux

valgus interphalangeus and arthritis of the IP joint.

I'd like to talk to you a little bit about the device. It is a single-construct implant. It's

8 to 10 mm in size. It's very hydrophilic. It's composed of 60% saline. It needs to stay

moist. It's biocompatible, and it works as a press fit. There's no bony in-growth. It has

compressive capability or compressive modalities very much like cartilage, and it provides a

smooth gliding surface. The wear of this material is low. This is not silastic. And you'll get

more information on this later.

This is the instrumentation, including a drill bit, introducer, placer, and K-wire. In

this video, I'll discuss with you the instrumentation and the procedure. A dorsal approach is

used to the first metatarsal joint. There are often large bony osteophytes, and these are

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removed, but it's important to maintain the normal spherical shape of the metatarsal head,

both from a mechanical perspective but also to allow bone to accept the implant. The

extensor hallucis longus tendon is taken to the side. The joint is exposed. Debridement is

performed. The surgeon identifies where he wants to put the implant. A K-wire is

introduced, and then the reamer is used to create a receptive area for the Cartiva implant.

There is a bit of a learning curve in terms of how to appropriately debride the joint, but it's

not a steep learning curve.

Then the surgeon puts it in the introducer, and the implant is introduced. This is a

second learning curve; again, not steep, but it involves a push with the palm and

stabilization of the introducer as the implant is inserted. We like to have it approximately 1

to 1.5 mm prominent. And now, when the patient dorsiflexes and plantar flexes their toe,

they are gliding on this smooth surface, the Cartiva implant, as opposed to bone or hitting

up against the osteophytes.

A further debridement of the joint is performed, again maintaining a good rim of

bone around the implant for stability. Options, such as a Moberg osteotomy, are still

available to the patient if this is deemed to be necessary.

This is an example of the typical defect that we see in the metatarsal head, and here

the Cartiva implant has replaced that defect and appropriate debridement has occurred.

In the operating room, when you dorsiflex the first toe, because if the spherical

shape of that metatarsal head has been maintained, one can see depression of the

metatarsal head with dorsiflexion of the first metatarsal, which is recreating the normal

biomechanics of that joint.

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The postoperative care is straightforward. The patient requires simply a sandal or

something similar to accommodate the dressings for 10 to 14 days. When the sutures are

removed, they're encouraged to dorsiflex to improve the range of motion of their first MTP

joint. They like that. They like the sense of being able to move that joint again and to work

on retaining range of motion. This is a bit different with fusion, where we protect weight

bearing for up to 5 to 6 weeks as the bone is consolidating.

I'd like to ask Debbie Moore to come up to talk about the study itself.

MS. MOORE: Thank you, Dr. Daniels.

Good morning. I'm Deborah Moore. I'm the Vice President of Regulatory and

Clinical Affairs for Cartiva, and this morning I will be reviewing with you the regulatory

history, our preclinical testing, as well as the study design phase for the clinical trial.

The study timeline is illustrated here. Cartiva has been fortunate to have the benefit

of extensive feedback from FDA throughout the study and PMA process. Cartiva has had

five in-person meetings with FDA, as denoted by the blue triangles on this diagram. The

company first met with FDA prior to the start of the study in 2009 to review the study

protocol and feedback on design of a study. It was very important for us to design a study

that met FDA requirements and would support a PMA application. In general, the Sponsor

and FDA were in agreement with key aspects of the study design, which I will review in

greater detail in a moment.

We initiated the study in Canada and the UK in late 2009 for the following reasons:

The Cartiva implant was approved outside the United States and had already been used in

approximately 2,000 patients, demonstrating no safety concerns, and we had a protocol

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that we believe reflected FDA's major study design considerations. We then submitted an

IDE in 2009 with extensive preclinical testing, including wear and particulate testing.

However, FDA had requested additional wear testing that required the design of a new test

fixture for the toe model. I don't know how many of you have done wear testing, but it

does take a very long time. We needed to establish the protocol with FDA. We had to build

the fixture. We had to generate wear particles. And then we had to run the test and

analyze the data. By the time the preclinical testing was completed, study enrollment at

our OUS centers was complete.

Cartiva also met with the Agency to discuss the generalizability of the study results

and the statistical analysis plan before the lock of the database and analysis of the results.

So let's take a closer look at the preclinical testing.

As I mentioned, extensive preclinical testing was conducted both on the implant and

the instrumentation to support our IDE. The typical testing that you would expect to see for

this type of orthopedic device was conducted. Since the device was involved in new

material in orthopedics, there was focus on material safety, biomechanics, implant studies,

including a 1-year large animal study. The testing was conducted and successfully passed all

acceptance criteria in support of our IDE application. As I stated previously, FDA requested

additional wear particulate and implant study testing. That was conducted and also passed

and met the acceptance criteria.

These studies demonstrate that the material was biocompatible and safe. The wear

rate was low, and the device was able to withstand the physiological loads that we had

anticipated for this particular application. And most importantly, there was no local or

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systemic toxicity that was demonstrated in either the wear particulate model or the large

animal model. This information has been reviewed by the Agency, and there are no

outstanding questions related to any of the preclinical testing presented today.

I would now like to review the MOTION study design. We knew from the beginning

that the study was to support a PMA, and so it was conducted with the same standards of a

U.S. IDE trial from the start. The study was conducted in adherence to good clinical practice

and ICH guidelines. And specifically, all centers had ethics approval, which is the same as an

IRB approval in the United States.

Informed consent was in compliance with 21 C.F.R. Part 50 and ICH guidelines, and

informed consent was obtained from all subjects prior to enrollment and administration of

any study procedures.

The study sites were carefully selected to ensure they were familiar with FDA and

PMA clinical study requirements, and many of our MOTION study Canadian clinicians were

involved in a PMA that had been recently approved by the orthopedics group and FDA. The

study also had U.S. oversight by the overall study PI and medical monitor,

Dr. Baumhauer, who has extensive experience with FDA clinical studies.

The study was designed to support a PMA and also to be generalizable to the U.S.

patient population. We had demonstrated that the study was generalizable with regards to

the following aspects: the demographics, the prior treatment, the postoperative care.

Cartiva met with the Agency in August of 2011 to review the generalizability of the data,

and FDA agreed that there were no differences between the OUS and U.S. condition, the

conduct of the MOTION study, and adherence to applicable regulatory standards.

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In addition, there was a high study compliance, complete and consistent adverse

event reporting, and exceptional follow-up. Over 97% of patients were followed at 2 years,

resulting in minimal missing data.

The MOTION study is a randomized, prospective study. The control for the study

was fusion, and subjects were randomized in a 2:1 fashion. So for every two Cartiva

subjects, one subject was randomized to fusion. This was designed to address enrollment

issues that had been observed in other fusion studies where subjects often want to avoid

fusion. A total of 236 subjects were enrolled at very qualified and experienced sites in the

UK and Canada. All subjects were then followed for 24 months.

At each site, prior to randomization, the sites were allowed to treat two patients to

ensure that they were adequately familiar with the procedure, and those will be referred to

as roll-in patients throughout our discussion today.

As I mentioned previously, FDA has been very helpful and willing to work with the

company over the years to provide feedback and study design, and we're in general

agreement on most of the points raised and have substantially adopted their feedback.

Where we're in general agreement with the FDA is outlined here.

One of the key aspects that FDA requested in our discussions was the incorporation

of a composite study endpoint that included pain, function, and safety, which we did, as

well as include follow-up out to 24 months.

Another area of discussion was which functional component was appropriate to

include in the composite endpoint. After the PMA was submitted, FDA recommended that

we use the Activities of Daily Living Subscale rather than the Sports scale, both of which we

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collected, and are in agreement that the Activities of Daily Living is a better measure for the

intended population, and we will be presenting the results according to both definitions

today.

There is one area that there's been continued discussion with the Agency, and that is

with respect to our choice of the 15% non-inferiority margin. The company's choice of 15%

non-inferiority was decided in concert with expert clinical input and was determined to be a

clinically acceptable difference.

FDA then requested that we either suggest a lower margin or provide clinical

justification, and we provided justification that based on the benefits of range of motion,

shorter recovery, rehabilitation -- shorter rehabilitation as well as less bone loss, that that

was clinically justified.

The differences highlighted in our study design do not affect the study conduct or

the data that was collected, and they're only related to the analysis of the results, and we

will be prepared to present those results today.

The key eligibility criteria is highlighted here. In the clinical study, the

subject/patient selection criteria were developed specifically to address the underlying

clinical problem, with key eligibility being OA grade and a subject's baseline score and pain.

Subjects were excluded that did not have any bilateral osteoarthritis -- and that was

from a pure study design perspective -- as well as any condition or previous procedure that

resulted in significant bone loss or poor quality bone were excluded.

This highlights the study assessments that were collected. All assessments were

collected at baseline and through all visits through 24 months. The key efficacy outcome

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measures were pain and function, which were used according to validated patient-reported

outcome measures. In addition to that, we looked at range of motion, SF-36. We captured

radiographs on all subjects that were evaluated by an independent core group. We also

looked at function with a foot function index, captured patient satisfaction and all adverse

events.

The study employed a composite endpoint that was discussed when developed with

the FDA consideration looking at both safety and efficacy and assessed clinical performance

using validated tools. The composite endpoint included pain and function that were based

on validated outcome measures with known and well-established minimally clinical

important differences, or MCIDs, in the literature. Pain was captured using a validated VAS

score. And for function, we used the FAAM (Foot and Ankle Ability Measure), including

both the Sports and the Activities of Daily Living Subscales. This is the only validated foot

function measure with an established MCID in the literature.

The composite also looked at safety, which included freedom from subsequent

secondary surgical interventions and also from radiographic failures that were based on

FDA guidance for orthopedic devices as well as other prior PMA-approved devices.

And a composite endpoint, such as the one chosen by Cartiva, has substantial value

in clinically interpreting the results. It looks at whether or not an individual subject has

clinically meaningful results in each of several different measures. It then classifies the

subjects as success or failure. And in order for an individual subject to be an overall

success, that subject must have clinically meaningful results in all four of the prongs of the

primary endpoint.

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For the MOTION study, the composite endpoint was pre-specified and defined in the

protocol as follow: For pain, we determined greater than 30% for VAS; FAAM Sports was

determined to be less than 9, as indicated in the literature; and they had to have freedom

from radiographic failures and SSSIs, which I will define in a moment.

Following the submission of our PMA, the FDA then asked for additional analyses

using a revised composite endpoint, which Cartiva performed. The FDA's revised composite

endpoint is defined here and is very similar to our previously defined endpoint. FDA

requested that we look at efficacy at 24 months for both pain and function and that we use

the FAAM ADL assessment rather than FAAM Sports since that better reflects the general

patient population. Since we had collected data at 24 months, this was not a problem. We

performed the analysis, and we will present that here today. There were no changes to the

definition of a safety prong.

The adverse event reporting was a very important aspect of our study. We wanted

to ensure that all complications and adverse events, device related or otherwise, were

captured and reported to FDA. Adverse event reporting was done by the site investigator in

which they classified the severity, the relatedness, whether or not the event was considered

to be anticipated, unanticipated, and whether or not it was serious.

We ensured that there was a medical monitor that provided oversight during the

course of the study, and that was done by Dr. Baumhauer, who also served as the study PI.

She ensured that safety was evaluated on a periodic basis, and in particular looked at any

serious adverse event, ensured that they were handled appropriately and correctly, that

there were not any additional safety issues, and she had the ability to terminate the trial if

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there were any safety issues identified during the course of the study.

During the development of the study, FDA requested that SSSIs, or secondary

surgical interventions, be defined in accordance with FDA guidance for orthopedic devices.

In that guidance, subsequent surgical interventions are defined as follows:

A revision is a procedure that adjusts or in any way modifies or removes part of the

original Cartiva implant or arthrodesis hardware configuration, with or without a

replacement of the component.

A removal is a procedure where the original Cartiva implant or arthrodesis hardware

is removed, with or without replacement, due to, for example, mechanical failure, device

fracture, displacement, pain, or infection. Any SSSI in either treatment arm was predefined

in the protocol, and all were considered study failures on a primary composite endpoint.

As noted in FDA's questions, after the PMA was reviewed and unblinding of the data,

FDA has questioned the appropriateness of the definition of the SSSIs for fusion patients

only.

All secondary surgeries, whether performed at index level or not, were evaluated

during the course of the study and at the conclusion of the study. None were determined

to be safety failures, other than those already captured by the predefined endpoint for

procedures of the first MTP joint.

The radiographic endpoint was pre-specified in the study protocol as well.

Radiographic failures were considered by our clinicians to be those events that were

clinically important and capture the major complications typically associated with respect to

hemiarthroplasty and arthrodesis procedures, as reported in the literature and consistent

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with previous PMA studies. The radiographic failures for the study were defined differently

for the two groups, as necessary, given the differences in the procedures for the control

and the Cartiva groups. This is analogous to how other motion-preserving devices, such as

the STAR, were designed.

For Cartiva failures, they were defined as avascular necrosis, device displacement, or

device fragmentation. For fusion, mal-union or non-union, hardware failure or were

observed on radiograph were also considered failures. And all radiographs, as I mentioned,

were reviewed by the independent core lab.

The statistical analysis plan was also pre-specified and included in the protocol. It

was reviewed with the Agency both in early interactions in 2009, but also again before we

locked the database and performed the analysis. We used a statistically justified sample

size that accounted for a 20% dropout. We used a composite endpoint with safety,

effectiveness, and radiographic success because that is the best way to look at a motion-

preserving device compared to fusion. This was requested by FDA, which we agreed. And

FDA has accepted similar composite endpoints and other motion-preserving devices with a

fusion control.

The non-inferiority margin was pre-specified and was based on what was the

clinically acceptable difference. It was developed in concert with expert clinical input to

reflect the benefits of the device and adequately capture the important benefits of

maintaining motion of the MTP joint. A 15% margin has precedence in orthopedics for

another motion-sparing device, the STAR Ankle.

The STAR Ankle is the only other FDA-approved orthopedic device in the foot and

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ankle space comparing a novel motion-preserving device to fusion. There are some

significant parallels I would like to review between the STAR Ankle and Cartiva study. Both

studies are motion-preserving devices that have a fusion control. Both studies have a

composite endpoint including safety, effectiveness, and radiographic outcomes, with

radiographic criteria specific to the treatment group, as clinically warranted, given the

differences between a motion-preserving treatment and fusion.

There are some important differences as well. The most significant difference is that

the STAR composite endpoint incorporated range of motion. This was a distinct advantage

for STAR. In contrast, in our study, it does not include range of motion in its composite

since there's no applicable validated measure that incorporates range of motion. And

according to the SSED for the STAR Ankle, the non-inferiority margin for overall success and

safety was 15%, which is the same for our study. This margin allows for the ability to detect

whether there are clinically significant differences between the groups while also

considering the benefits of motion and an easier recovery.

And I think one thing that's important to understand is the timing. The Panel

meeting for the STAR Ankle was in 2007, and at that meeting there was no discussion by the

Panel or FDA regarding the 15% non-inferiority margin. Shortly after, we developed and

designed our study for the MOTION study and, for the clinical reasons stated, felt that 15%

was clinically appropriate.

It's also important to note that even though we did have a 15% margin pre-specified,

you will see in the results presented by Dr. Baumhauer that the margin observed in our

clinical trial was nearly 10%.

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The analysis populations are outlined here. Intent to treat was all randomized

subjects. Modified intent to treat are all randomized and treated subjects. And the mITT

completers was treated subjects with all available follow-up.

The primary analysis that was pre-specified was the intent to treat with last

observation carried forward. Supporting analyses were the mITT and per-protocol analyses,

which included any subjects that had major protocol deviations, were excluded from the

mITT.

Missing data in the primary analysis was addressed with two sensitivity analyses.

We looked at multiple imputation and a tipping point analysis.

After the PMA was submitted, FDA requested, and we were in agreement with FDA,

that the primary analysis would be the mITT populations. The supportive analyses again

were the per-protocol population as well as an additional per-protocol group that was

defined according to FDA's recommendations for looking at eligibility criteria. Missing data

was limited but was also addressed with a tipping point analysis. There was statistical

oversight, and an analysis was done by an independent statistician throughout the study.

So, in summary, the study was conducted according to a pre-specified protocol with

clinically meaningful and validated outcome measures. The study was conducted with the

same standards as a U.S. IDE trial with U.S. oversight and extensive data monitoring.

We had a prospective, randomized study with validated endpoints and success

criteria that was designed with FDA and clinician input.

The radiographic review was conducted independently by a core lab. A medical

monitor was also independent and reviewed all safety events, including the radiographic

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findings that went into the primary endpoint. There was independent statistical oversight

for analyses, and there was exceptional follow-up with minimal missing data.

So thank you very much. And at this point I'll turn it over to Dr. Baumhauer, who will

provide you an overview of our clinical study results.

DR. BAUMHAUER: Good morning. I'm Judy Baumhauer. I'm an orthopedic surgeon.

I am a professor and Associate Chair of Academic Affairs at the University of Rochester. I

am an advisor to the company, and I'm being reimbursed for my time and travel here. I do

not hold any equity interest in the company, and I have no financial interest in the outcome

of this meeting, but I am delighted to share with you the results of this study.

Each and every one of these items will be addressed during this session.

A total of 236 patients were enrolled in the MOTION study. Twenty-two of these

patients were roll-in subjects, and 17 patients withdrew prior to randomization, and the

remaining 197 were randomized 2:1 between Cartiva and fusion. These 197 formed the

intent-to-treat population.

One hundred and thirty-two patients were randomized to Cartiva; 2 withdrew after

randomization, leaving 130 who received the Cartiva implant. Sixty-five patients were

randomized to fusion; 15 withdrew, leaving 50 subjects who were fused. I'll discuss the

reasons for these 15 subject withdrawals in greater detail in the next slide. These 180

treated subjects formed the modified intent-to-treat population. The safety population

consisted of those 180 randomized treated subjects plus those 22 subjects treated in the

roll-in group, for a total of 202 patients in this population. There was excellent follow-up at

24 months, with only one Cartiva subject lost to follow-up and three fusion patients,

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resulting in 176 completers. Only two of the 130 subjects randomized to the Cartiva

withdrew, as I mentioned, prior to treatment. However, 15 subjects randomized to fusion

withdrew prior to surgery. The vast majority stated that they had hoped to obtain the

Cartiva implant. This truly emphasized that patients are interested in preserving their joint

motion.

All protocol deviations were reported, documented, and monitored throughout the

study. Methodology was reviewed with the Agency in January 2015, prior to categorizing

specific deviations as major or minor. The medical monitor, me, blinded to the data,

evaluated the types of deviations that could have an impact on the primary endpoint per

ICH guidelines and consisted of eligibility and impact on 24-month assessments.

This table provides all protocol deviations. These deviations are really quite typical

for this type of multicenter clinical trial with over 200 patients and 2-year follow-up. Most

were very minor. As you can see, the majority of these deviations, 210 of them, were for

study visits outside the strict follow-up visit window of plus or minus 2 weeks. This window

is much more narrowly defined than in FDA's recommended follow-up windows, as

described in the FDA guidance for orthopedic studies for 12- and 24-month visits. That

window is plus or minus 2 months.

The next most common deviation, 21% of deviations, was the use of another imaging

method other than the protocol-specific X-ray, and/or following the subject at an

unscheduled visit where the surgeon determined imaging or an assessment was really not

necessary. A total of four deviations were considered major. Two of the major deviations

were for patients who had their 24-month follow-up visit outside the 2-month window in

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FDA guidance. And two subjects had eligibility deviations, which could have impacted the

outcome. One was a mid-foot osteoarthritic not documented at baseline, and the other

was a low VAS Pain score at baseline.

The baseline characteristics for the modified intent-to-treat and the intent-to-treat

populations were really similar. The demographics of the subjects who dropped out after

randomization had comparable demographics to those subjects that were treated in the

study. As a consequence, at baseline, the Cartiva and the fusion groups maintained very

well balanced in terms of baseline covariates in the modified intent-to-treat analysis set.

Baseline characteristics in this slide are shown for the modified intent-to-treat

population, and this is our primary analysis population. I do want to call your attention

again to distribution. Great toe arthritis is more common in women, which is seen in both

the Cartiva and the fusion groups. The mean age for these subjects is the mid-50s, again,

very typical for great toe arthritis. And also note that these patients were experiencing a

significant amount of pain prior to surgery, with an average VAS score of nearly 70.

As was mentioned, the Coughlin osteoarthritic grading scale was used to grade each

of these subjects. Grade by group is presented here. The treatment groups had similar

osteoarthritic grades, with the majority of patients treated being in Grade 3.

According to the pre-specified composite endpoint that's listed here, non-inferiority

was met in the intent-to-treat population, the primary analysis, and the modified intent-to-

treat population. Specifically, in the modified intent-to-treat population, it was 80%

responders for both the Cartiva and the fusion groups. The FDA also requested that we

analyze the data using a revised endpoint incorporating the Foot and Ankle Ability Measure

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Activities of Daily Living Subscale, and looking at efficacy at 24 months. Nearly 80%

achieved success in the Cartiva group and similarly in the fusion group. Again, the lower

bound confidence interval that could be seen for the earlier modified intent-to-treat

component was nearly 10%. This is a very high rate of success.

Similar high rates of success were found for all per-protocol populations. The

success rates are essentially identical for the Cartiva and the fusion groups for all

populations. There was no clinically meaningful difference between these groups.

These are the results for the four prongs or components that make up the composite

endpoint. With the composite endpoint as the primary endpoint, these prongs are

considered secondary endpoints. The fusion rate of each prong is reported here for Cartiva

and fusion.

The Visual Analog Scale for Pain is a validated scale and widely used to assess pain.

Nearly 90% of the patients in the Cartiva group had greater than 30% improvement in pain

at 24 months. As expected, this was slightly less than the proportion of subjects in the

fusion group, but as we've noted, the fusion group had the expense of their entire joint

motion whereas Cartiva maintained motion. Having nearly 90% of the subjects in the

Cartiva group with clinically significant reduction in pain is a very strong outcome.

The FAAM Sports or ADL scores are also validated measures and widely used in foot

and ankle clinical scales or studies. Nearly all, about 98%, of the subjects in both groups

either maintained or improved their function as measured by the FAAM ADL at 24 months,

as denoted here. When we look at the radiographic and secondary surgical intervention

groups, there were no radiographic failures in the Cartiva group compared to 10% in the

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fusion group, which consisted of non-unions and hardware failures. There was a similar

number of subsequent secondary surgical interventions in both the Cartiva and the fusion

groups, representing 10% and 12%, respectively. The details of these interventions will be

discussed in a subsequent slide.

But if we look at these individual endpoint components, we can see that Cartiva

performs quite well and similarly to the fusions for all four components, with nearly an 80%

to 100% success rate in all four components for both groups.

Cartiva and the fusion achieved high rates of success, an 80% success for both

Cartiva and the fusion group. Cartiva met both the pre-specified and the FDA-requested

composite endpoints for the primary and sensitivity analyses. Greater than 88% of the

subjects in both cohorts were successes in each of the four individual prongs. There were

low and comparable incidences of secondary surgical interventions at 10% and 12%. And

there were few radiographic failures in both groups. Non-inferiority was achieved for all

analyses.

I'll now discuss the safety of the Cartiva implant. I'll be describing all adverse events,

treatment emergent adverse events, serious adverse events, and radiographic failures in

both groups.

Nearly the same percentage of patients in both groups experienced any adverse

event, any treatment emergent adverse event, and any serious adverse events. The

majority of the adverse events were classified as mild or moderate by the investigator.

There were no unanticipated treatment emergent events. Importantly, there were no

incidences of device migration, synovitis, bone destruction, device fragmentation, or any of

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those things that we saw for complications for other cleared hemiarthroplasty devices in

complaints to the FDA.

For the primary safety comparison, we're looking at the treatment emergent adverse

events, which are defined as the adverse events that are either device or procedure related.

This is the most appropriate comparison when considering the overall safety profile for the

two groups, given that the Cartiva is motion-retaining surgery and the fusion is motion-

sacrificing surgery.

Here are the details for all treatment emergent adverse events, which are similar

between the two groups. While pain at the implant site was the main observed difference

between the groups with 10.5% for the Cartiva versus 0% for the fusion group, the majority

of implant site pain was moderate or mild. The fusion group subjects had more reports of

medical device complications and non-unions, with an overall incidence of 12%.

It's important to recall that there's a 3:1 ratio of Cartiva to fusion in this study as the

roll-in subjects are added to the safety component arm along with the randomized subjects.

Therefore, it's important to look at the incidence and not the absolute numbers, as you will

see in the FDA presentation.

This slide shows serious treatment emergent adverse events resulting in secondary

surgical site interventions. First, there were no unexpected types of serious treatment

emergent adverse events. The majority of all -- the overall rates of these events were

similar between groups. Again, implant site pain was higher in the Cartiva group. Fourteen

patients, of Cartiva patients, resulted in the removal of the implant and a successful

conversion to the fusion of the joint.

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The arthrodesis patients had non-unions and hardware failures resulting in

complications reported as a medical device complication requiring reoperation, including a

revision arthrodesis or hardware removal.

Overall, Cartiva patients had comparable rates of secondary surgical site

interventions compared to the fusion group. Ten percent of randomized Cartiva patients

and 12% of the fusion patients had the secondary surgical interventions. This leaves 90% of

the Cartiva and 88% of the fusion patients free of secondary surgeries. Less than 10% of the

Cartiva patients required implant removal, and all of these patients that did have this

removal were successfully converted to a fusion. As pre-specified in the protocol, any and

all secondary interventions for either group, regardless of seriousness, were considered

failures in the primary endpoint.

Although perhaps considered minimally invasive, one Cartiva patient, categorized as

a reoperation, included an osteoclasis manipulation to break up scar tissue, not even an

incision. However, it was considered a failure. Similarly, for the fusion surgeries performed

on the first MTP joint, hardware is often not routinely removed. However, if the patient is

clinically symptomatic due to prominence or shoe or skin irritation, that hardware is

removed, and therefore these hardware complications resulting in removal were

considered failures.

The total Cartiva safety population with secondary surgical intervention rate was

11.2, very similar to the fusion group of 12. As I mentioned, 14 Cartiva patients underwent

removals of their implant and the reason for those, 12 were related to pain, one was due to

fibrosis, and one was due to progressive arthritis involving the sesamoids. The mean time

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to removal was 390 days. There was no infection, no inflammatory reactions, no

mechanical failures. There was no implant wear upon inspection of the removed implant.

The mean VAS was 9, and the FAAM ADL score was 88 in those patients who were

converted to a successful fusion. Those values are very similar to the index fusion values

that we saw in the study.

This slide addresses the pre-specified radiographic failures. FDA asked a question

about using different criteria for radiographic failures for these two groups. We believe

that the criteria used needs to be relevant to the clinical risks for these two different -- very

different procedures. And using the literature and clinical input, pre-specified radiographic

failure criteria was defined and listed here. There were no radiographic failures in the

Cartiva group. However, there was 10% failure in the fusion group, namely, non-unions and

symptomatic fractured hardware.

The FDA had some questions about whether or not the secondary surgical

interventions for symptomatic hardware removals should be considered failures. They are

painful events, and they required secondary surgical intervention. The mean time to

removal was 220 days. The radiographic failures were symptomatic non-unions,

demonstrated by the absence of bony bridging and loosening, screw loosening around the

hardware. There was one patient who had fractured hardware and radiolucency.

Fusion failures are consistent with FDA definition for removal or revision failures.

Symptomatic non-union is a fusion failure. This is consistent with other studies of

orthopedic and spine devices saying a non-union is a failure. The hardware removals

required in the study were due to painful events or prominent hardware. A secondary

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procedure that is required for these removals does introduce the risk of infection, nerve

injury, and often leads to activity restrictions during their recovery to allow for wound

healing. These treatment failures were clinically appropriate, as pre-specified in the

protocol, to be labeled as failures.

In summary, there's a similar percent of subjects with both adverse events in both

groups. The majority of adverse events in both groups were mild to moderate. There was

comparable rates of device- and operative-related events, with a low rate of serious

adverse events.

Cartiva avoided all failure modes that were commonly seen with other first MTP

implants reported in literature. Pain at the surgical site adverse event generally resolved,

and all serious pain adverse events were failures. There was a low rate of secondary

surgical interventions for both groups. And when the Cartiva implant was removed, it

resulted in a successful fusion.

In addition to these predefined radiographic failures, we asked the independent

radiologist to make any comments on the images as they categorized these radiographic --

as they categorized these into radiographic observations as bony reactions, radiolucency,

and heterotopic ossification. Each of these observations were reviewed and evaluated, and

none were clinically meaningful for the Cartiva implant group. We'll discuss each

observation here.

Radiolucency was more common in the fusion group than the Cartiva group.

Radiolucency in the fusion subjects primarily resulted in study failures for non-union or

fractured hardware. The radiolucency in the Cartiva implants had no impact on clinical

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outcomes or secondary surgical interventions. The bony reactions were divided into

erosions, cystic changes, and loss of cortical white line and osteolysis. Bony reactions, in

general, can be caused by bone remodeling, typical to variations of increase or decrease in

loading or surgical stimulation of the bone surfaces. Where observed, they were

nonspecific and not related to the implant.

These radiographic observations were not correlated to clinical symptoms nor an

indicator of success or failure in the study when we looked at the composite endpoint. As

we can see with imaging of the spine and many other areas of the musculoskeletal system,

radiographic observations may be present and have no meaningful clinical impact.

To that point, here's a bar graph with subjects with bony reactions in dark blue and

those subjects without bony reactions in light blue. For the composite endpoint and each

individual assessment of pain, function, and subsequent secondary surgical intervention,

they all experienced very similar rates of success as those regardless of these radiographic

observations. From a safety perspective, these findings did not lead to an increase in

secondary surgical interventions or adverse events. As I often say, treat the patient, not the

X-ray.

There was no radiographic evidence that heterotopic ossification findings were

related to the device. The findings are capsular in nature and similar to reactions shown in

other surgical procedures involving surgical stimulation of the bone and surrounding

tissues. All 12 Cartiva patients with Class III heterotopic ossification were responders on

pain, function, safety, and overall clinical composite success. There were no study failures

or non-responders in any component of the primary endpoint for those findings of Class III

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heterotopic ossification. Again, when you look at the primary composite endpoint and the

components of the primary endpoint on the same graph, where those with heterotopic

ossification are in dark blue and those with no heterotopic ossification are in light blue,

there's no difference between these groups. From a safety perspective, these findings did

not lead to any increase in secondary surgical interventions or adverse events. These

radiographic findings of heterotopic ossifications were not correlated to clinical symptoms

or any evidence of a lack of success.

Now I'd like to shift from safety to the effectiveness of the Cartiva implant. I'll be

describing secondary effectiveness outcomes other than the primary composite endpoint.

This will include the dichotomized components of the primary endpoint over time, as well

as look at pain and function as continuous measures. You'll see that the Cartiva was

effective in reducing pain, maintaining function, and that Cartiva patients were very pleased

with their outcomes.

This slide depicts the median VAS Pain score for the Cartiva and fusion groups over

time. The median is a good measure of central tendency for a population that is not

influenced by outliers. Pain reduction was dramatic in both groups, where the median VAS

was about 70 at baseline in both groups and decreased to less than 5 mm at 24 months in

both groups. With only a 3 mm difference in median scores between the two study arms at

24 months, this is not a clinically meaningful difference.

This graph demonstrates the mean VAS Pain scores. Again, the graph shows that the

Cartiva patients demonstrated substantial reductions in pain at every follow-up visit from 2

weeks post-op through 2 years, with less and less pain at each visit. There is a dramatic

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reduction in mean pain for the Cartiva group from just less than 70 at baseline to 15 at 24

months. That's nearly an 80% reduction in mean pain of the Cartiva patients. Many

patients are willing to trade off a low level of pain for extra mobility that the Cartiva device

provides, as demonstrated by the patient satisfaction scores that we'll see shortly.

Before I talk about the functional results, I want to briefly discuss the Foot and Ankle

Ability Measure outcomes instrument. The FAAM ADL and Sports scores are validated

measures. They are a general assessment of foot and ankle function. It's probably the best

tool available for assessment of function, but it does not discriminate for the first MTP joint.

The individual questions on this particular scale are not validated by themselves.

Substantial functional improvement was seen in both groups for both the means and

medians. The Cartiva subjects improved and maintained their motion, while the fusion

subjects improved with loss of their motion. The literature supports that loss of the great

toe motion can lead to gait disturbances, alteration in weight bearing, and subsequent

degeneration of adjacent joints, as Dr. Daniels showed with the IP joint arthritis example.

A very high percentage in both groups (98% in the Cartiva group, 97% in the fusion

group) were FAAM ADL successes at 24 months. The criterion of maintenance was used for

the primary endpoint because subjects were not required to have a functional deficit at

entry at baseline. While the primary endpoint threshold was maintenance, most subjects

observed significant improvement in FAAM ADL scores and far exceeded this threshold.

This can be observed if you look at the percent of subjects achieving an improvement of

greater than 8 points, the minimally clinically important difference denoted by the scale.

If we look at the median scores for FAAM ADL, this figure shows comparable

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improvement in function between these two groups. The Cartiva patients had identical

functional scores at 12 and 24 months as assessed by this score. The FDA had concerns

about the level of functional improvement observed, and they stated that there's a

substantial difference, but that is not the case observed here. Both groups achieved high

levels of functional improvement that's durable over time.

This figure shows that there was substantial improvement in FAAM ADL function in

both groups, with a mean of 55 to 60 at baseline improving to 90 to 95 at 24 months in both

groups. The 5-point difference at 1 and 2 years is not clinically meaningful.

The Foot Function Index-Revised is another validated foot function score that's

commonly used in foot and ankle. The Foot Function Index-Revised scores demonstrate

substantial durable improvement and function in the implant group. These values continue

to improve over time. The 7-point difference at 1 year, decreasing to 5 points at 2 years,

again is not clinically meaningful.

The SF-36 physical functioning subscale is a global health status measure of physical

function and is not specific for the foot or ankle. But again, we see substantial durable

improvements in both groups over time.

With a fusion, the joint is fixed statically at approximately 15 degrees of dorsiflexion.

The fusion group experiences no motion. This is known to be associated with changes in

gait, altered foot mechanics, and shifting of motion responsibilities to adjacent joints, with

the potential for arthritis and changes in static and dynamic balance amongst other

problems that we've seen cited in the literature.

These are the mean dorsiflexion values for patients in the Cartiva group. The fusion

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group has no motion, and they have to adjust for that lack of motion by shifting their weight

on their foot. The Cartiva shows an increase in baseline motion that is durable over time.

Postoperatively, all patients were asked if there were activities that they were able

to resume after surgery. As you can see, the Cartiva patients were able to resume a much

longer list of activities. Motion at the MTP joint is quite important for activities such as

soccer, volleyball, sailing, yoga, and as one patient reported, standing on their toes. As a

clinician, if I asked -- if a patient came to me with great toe arthritis and needed surgery and

yet wanted to return to one of these activities, I would have a long conversation because I

wouldn't be clear, with a fusion, that they'd be able to do so.

When we were designing this study, we looked for but could not find a validated

outcomes tool to assess hallux in a phalangeal joint. However, patients know there's real

benefits to maintaining their joint motion.

These are the functional results at 6 weeks. At the earlier time point you can see a

higher percentage of patients in the Cartiva group with clinically significant improvements

in all of these measures, demonstrating an earlier return to function, which can translate to

earlier return to work or other activities.

Subjects were asked to provide a global assessment of their satisfaction with

surgery. As you can see, approximately 80% of patients in both groups gave a favorable

assessment at both 12 and 24 months.

Investigators were asked to provide a global assessment of their satisfaction with

surgery, and there's no clinically meaningful difference between the groups at 12 or 24

months, essentially equivalent. In addition to the various measures we've already

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examined, the patient experience is very important. The patients were asked, would you

have the procedure again? Most subjects in the Cartiva group responded that they would

have the surgery again, compared to the fusion groups. These differences were more

pronounced among female patients, where 85% of the Cartiva subjects said they'd have the

procedure again, compared to 75% of the fusion subjects.

So, in summary, 88.8 -- nearly 90% of Cartiva subjects achieved substantial and

clinically meaningful improvement in pain similar to fusion at 24 months. Nearly 90% of the

Cartiva patients improved in function similar to fusion. The Cartiva patients showed

increased dorsiflexion that was durable over time. Eighty-six percent of the Cartiva patients

said that they would have that procedure again when asked at 24 months. Again, these

results were clinically significant, and durable improvement was seen over time. Cartiva is

not clinically inferior to fusion. It provides an excellent alternative to patients wanting to

maintain their motion.

Now I'd like to turn it over to Dr. Glazebrook, who will talk about risks and benefit

considerations.

DR. GLAZEBROOK: Good morning. My name is Mark Glazebrook. I am a Professor of

Orthopaedic Surgery and an orthopedic surgeon at Dalhousie University in Halifax, Nova

Scotia. I devote 80% of my working time to clinical care and 20% of my working time to

research. I'm a consultant for Cartiva. I am paid for the hours worked, I am reimbursed for

travel, and I have received research funds to conduct the study at my institution. I have no

equity in Cartiva, and I have no financial interest in the outcome of this study. As a MOTION

investigator, I am a member of the MOTION study, and I was the highest enroller in the

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MOTION study.

When I introduce a new technology to my patients, I weigh the risks and benefits on

their behalf. I'd like to share with you the risks and benefits that I weighed for Cartiva. The

risks would include continued pain and lack of function, need for secondary surgery, and

device-related adverse events. The benefits would include clinically significant pain relief

and functional improvement; improved range of motion; reduced surgical and recovery

time; and an option if the procedure should fail, essentially burning no bridges; lack of

material-based risks; and finally, best available evidence.

With respect to pain and function improvement, both groups were clinically

successful. The fusion cohort was slightly better. There was a slightly improvement --

slightly larger improvement in pain relief in the fusion cohort. This came at a cost of joint

destruction, loss of motion, and a non-union rate of 11%. Indeed, relief of pain came at a

cost of joint destruction in the fusion group.

With respect to repeat surgery, there was an equal incidence of repeat surgery in

both groups. Cartiva had no device malfunction, no migration, and no dislodgment. Cartiva

removal for persistent pain occurred in 14 subjects. This removal and conversion to a

fusion was no more difficult than the index procedure, and the outcomes were equally

good.

With respect to adverse events and radiographic observations, treatment emergent

adverse events were weighed. This was equal in both cohorts. Radiographic observations

were also made in the Cartiva group that were not clinically significant. Indeed, there was

no mechanical failure, no fragmentation, no synovitis, and no joint destruction. With

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respect to pain relief and function at 24 months, both Cartiva and the fusion cohort had

significant pain relief clinically improved. Eighty-nine percent of subjects in the Cartiva

group had pain and activity of daily living improvement that was significant. This resulted in

an 80% success in the composite index. This is non-inferior to the fusion cohort.

Motion is something that's desired by all patients. Cartiva patients were happy with

their ability to wear shoewear, heel rise, bend their toes, and do sports and other activities

that required bending their toes. My fusion patients were unhappy with the ability to wear

shoewear and to do certain activities.

For example, my fusion patients would tell me that they can do all activities

necessary; however, they have to make alterations when they do these activities. When

they walk up an incline, they tell me they have to externally rotate their foot to do this.

They feel not normal when they have a fusion. This was not the case in the Cartiva group.

This is probably why most of the patients, at a higher rate, wished to have the Cartiva

procedure done again, compared to the fusion cohort. In fact, one of my patients asked for

a second Cartiva procedure on the contralateral limb after the study was completed. This

patient is now 5 years out and runs marathons on a consistent basis, at a time much faster

than mine, of course.

(Laughter.)

DR. GLAZEBROOK: More patients would indeed prefer to have a repeat surgery with

Cartiva than with the fusion cohort. With respect to recovery, there was a faster recovery

noted at 6 weeks. This resulted in better ADLs, sports, and a better health-related quality

of life. Patients with Cartivas did not have to wear a cast. They are able to drive a car

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quicker, and they were able to wear normal shoewears. In essence, people got back to a

more normal life quicker, which is what we all want to do, get on with life.

The surgical time was also faster for Cartiva. The average time to do a Cartiva

procedure was 35 minutes, almost twice as fast as a fusion. This results in benefits for the

hospital financially, for the surgeon efficiency in patient care, and most importantly for the

patient. The decreased anesthesia time will likely translate into less exposure to morbidity.

Cartiva uses minimal bone resection. In this illustration here, you can see, when

compared to its competitor, there's 50% less bone loss and shortening. In our study, 14

patients had to have the Cartiva removed for persistent pain. This procedure was no more

difficult than the index procedure. I did one of these, and it was a straightforward fusion

exactly the way I would do a normal fusion. The outcome of these patients, as discussed

earlier, was equal as well. It didn't burn a bridge.

Cartiva has no material issues. There's no bone loss, there's no implant loosening,

there's no dislodgment. Cartiva lacks these problems, and these problems are what a

surgeon really worries about. Pictures like this are what scares me away from arthroplasty

and brought me to arthrodesis over the years. This new implant brings new technology that

I feel confident to provide for my patients. Indeed, Cartiva is not silicone. There's no

synovitis, there's no bone loss, no implant fracture, no dislodgment, like you see here in

these pictures. For this reason, I can offer it to my patients.

Most important to me is evidence. I do a lot of time doing evidence-based research.

The first study I did in this area was a look at the options for surgical treatment of end-stage

hallux rigidus. What I noted in my publication was that most of the literature available to

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support surgery for hallux rigidus was poor. Almost all Level 4 and 5 studies. Only one

other level study exists that is at a very low quality, and I would suggest it's a Level 2.

Indeed, thanks to the FDA's rigorous standards, this study was done. The MOTION study is

now the standard of care. It's the best available literature to support this implant, and

currently it is the best available evidence in the literature on the treatment of hallux rigidus

with surgery.

So, in summary, I would suggest that the risks are outweighed by the benefits.

Cartiva is effective in pain relief. It improves function, preserves motion, and most

importantly for a surgeon, burns no bridges. This is why I recommend Cartiva as an option

to fusion in my clinical practice, and it's my hope that soon the people of America will have

this same option.

Thank you very much.

MR. PATRICK: Tim Patrick, Cartiva.

Just a few important things that we have not been able to touch on up until this

point. First of all, a post-approval study. We've had 12 sites and over 20 foot and ankle

orthopedic surgeons who participated in the MOTION clinical study. We think it's probably

the largest great toe arthritis database that's out there today, and those physicians are very

enthusiastic about continuing to follow those patients.

Under principal investigator Judy Baumhauer's leadership, the ethics approval

process that is required to follow these patients up to 7 years is in process, and we will

intend to follow the same assessments that we've reviewed today on an annual basis.

The other topic we wanted to talk about is training. And like any responsible

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orthopedics company, we will also implement a physician training program. We think it's

important that we do everything we can to ensure the best possible clinical outcomes for

the patients.

Finally, just in summary, the Cartiva MOTION study provides Level 1 clinical evidence

of median pain reduction of over 90%, of median functional improvement of over 60%. The

patients had an improved range of motion, and if required, they could be easily converted

to a successful fusion. We believe that Cartiva is an important new option for patients with

first metatarsophalangeal arthritis who want to maintain motion in the joint.

We appreciate the time of the Panel members this morning. We also appreciate the

time of the FDA. We know that a lot of time and dedication is required to set this meeting

up. And that concludes the Cartiva presentation.

Thank you.

DR. RAO: Thank you very much, Mr. Patrick, Ms. Moore, Dr. Daniels,

Dr. Baumhauer, and Dr. Glazebrook.

Does anyone on the Panel have a brief clarifying question for the Sponsor at this

time? Please remember that we will also have time for Sponsor questions during the Panel

deliberation session in the afternoon. But if you have brief questions right now, this is a

good time to do that.

I'd also like the AV folks to get Dr. Blumenstein's slide ready. There's a slide

Dr. Blumenstein wanted to ask a question off of. The slide has been previously presented to

the Sponsors, and they're aware of this slide.

Let me start with Dr. Golish.

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DR. GOLISH: Thank you, Mr. Chairman.

A brief clarifying question is we've heard presentations from a number of surgeons

today, but please clarify. Though the company has had IDEs at some point in the past, the

current clinical data we're looking at today, your pivotal data from a clinical trial are all

from OUS sites and not done under IDE.

MS. MOORE: Debbie Moore.

That is correct. An IDE was submitted at the time. It was not approved because we

had additional preclinical testing that needed to be completed. So the study was conducted

all outside the U.S., in the UK and in Canada, but according to the same standards that

would be applied in the U.S. So again, with ethics approval, IRB approval with the same

standards, and also with a protocol that had been reviewed and discussed with the Agency,

including, as I discussed, their considerations.

DR. RAO: Dr. Kelly.

DR. KELLY: Yes. I'd like to address this to Dr. Baumhauer as someone that I respect

as a clinician. Dr. Baumhauer, I noticed to me an inherent flaw potentially is the lack of

using cheilectomy as a control. It's a procedure I still use and has, in my experience, good

results. So two questions. Why wasn't that considered as a control? And number two, is a

cheilectomy performed during the time of implantation? Because obviously there's a spur

there and you do remove it. And how can you minimize the effects of cheilectomy on the

product success rate?

DR. BAUMHAUER: Thanks for asking the question. So a cheilectomy procedure was

not used as a control because each -- for the entrance criteria for the study, each individual

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patient had to be considered a fusion candidate to be enrolled in this study and not a

cheilectomy candidate. So those patients had more significant symptoms that would

warrant a fusion and not an isolated cheilectomy.

The second issue -- and I'll let my counterpart clinical guys answer up. But as Tim

Daniels had commented, for the procedure, although they do like sort of an

osteophytectomy, they take away the bony spurs, they leave the cortical brim to contain

the implant.

You guys want to add to that?

DR. GLAZEBROOK: So that's a great question, and it poses concerns for this

technology, but it's easily answered. When you do a cheilectomy -- and I teach this to my

fellows and residents -- you take at least a third of the joint. If you take a third of the joint,

you can't put a Cartiva in. There's no room left. So you cannot do a proper cheilectomy in

the study. Indeed, you do an osteophytectomy. You nibble away the edges of the bone,

but you leave a large portion of the bone. So, in essence, a cheilectomy cannot be done. So

if you're concerned that this is presenting a confounder to this data, I would suggest the

very fact that you can't do a proper cheilectomy would reassure you that that's not the

case.

DR. RAO: I'll get to you in a second, Dr. Sayeed.

Could we have Slide 19 up, please, from the Sponsor's presentation? Slide 19. Just

to expand on Dr. Kelly's question, I'll have you come up again, Dr. Glazebrook. If you look at

the osteophyte resection here that Dr. Kelly is kind of tangentially referring to, is there a

way that we can be certain that any benefit that might have accrued from the device is from

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the device implantation and not from the resection of the osteophytes, whether you call it a

cheilectomy or whether you call it an osteophytectomy?

DR. GLAZEBROOK: Yeah, for sure. When you do a total knee replacement, when you

do a total hip replacement, you remove osteophytes. A cheilectomy is not a removal of

osteophytes. We have done removals of osteophytes like this in the past on patients; they

have failed. The literature has told us, if you're going to do a cheilectomy, you remove a

third of the joint, at least. That is where all the wear is.

So in my opinion, and I think in the opinion of the literature, this osteophytectomy is

not going to give a substantial improvement in pain. I think we can be assured that most of

the improvement in pain, because of the wear in the central portion of the cartilage, can be

attributed to the implant itself rather than this osteophytectomy.

DR. RAO: Dr. Pfeffer.

DR. PFEFFER: Would this be reasonable? I'd like to ask several questions of the

Sponsor.

DR. RAO: Excuse me, is this connected to this specific point we're talking about?

DR. PFEFFER: No.

DR. RAO: Then let me hold off for a second because Dr. Sayeed had a question.

DR. SAYEED: I have a question regarding the material science. In terms of the load

and the shear modulus, what is the type of stress that this cartilage can take? And my

second question is in terms of toxicology. Are there any nanoparticulate matter in the

implant? And can you give us the toxicology data?

MS. MOORE: So toxicology data specifically, I'm not sure I understand the question.

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DR. SAYEED: Are there any chemical substrates that can cause any type of toxic

reaction --

MS. MOORE: Oh.

DR. SAYEED: -- both locally and systematically?

MS. MOORE: I understand. So as I mentioned, we did extensive implant material

characterization. We did biocompatibility where we looked at it for if there are any

chemicals that were leaching out of material and tested that. We also did a 1-year animal

implant study where we showed no toxicological impact on the implant. We also did a wear

particulate study. So we had wear debris on a micrometer range, where we injected it into

a rabbit model and followed that for 6 months and also looked at the toxicology of those

implants to assure that there was no inflammatory reaction associated with it.

With respect to the loading of the material, we tested the device so that it was a

worst -- you know, more than worst-case scenario in the wear testing, worse than a normal

load that's typically expected during the walking gait in the joint.

DR. SAYEED: Can I follow up?

DR. RAO: You have a quick follow-up?

DR. SAYEED: Yeah. What is the load stress that this cartilage can undertake? And

what's the repetitive outcomes?

MS. MOORE: Sure. So we looked at extreme loads of 24 MPa, which is about six

times what the peak load was -- 24 MPa, megapascal -- and we looked at that out to 5,000

cycles, both in fatigue testing and wear testing. Does that answer your question?

DR. SAYEED: Yes.

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MS. MOORE: Thank you.

UNIDENTIFIED SPEAKER: Five million.

MS. MOORE: I'm sorry, five million cycles.


DR. PFEFFER: You've asked us to pose simple questions, but nothing's simple.

Would it be appropriate to pose some questions to the Sponsor that they might then be

able to think on over lunch and come back with a more excellent answer to? Or would you

rather --

DR. RAO: That would be just great. That would be fine. Go ahead and pose the

question now, and if they can give us a quick answer, they will give it to us now. If not --

DR. PFEFFER: No, I'd actually rather not have a quick answer. I don't think there are

any quick answers that will benefit this Panel.

DR. RAO: Okay.

DR. PFEFFER: I think a very thoughtful answer will be the most helpful. First of all,

this is a superb study, Judy, Tim, Dr. Glazebrook. Sorry, she shall be last named. You did a

wonderful, wonderful job, and you should be proud of your work and everyone should be

proud of you. The company did an excellent job.

I have some things that I just can't get my head around, though, that don't have a

simple answer, and it's following up on the other issues. And I see that one of our Panel

members asked this question indirectly earlier in the meeting. So these are the bigger

issues that I see, the 30,000-foot issues.

You've included Grade 2 Coughlin candidates in this. I know of no literature that

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supports doing a fusion in a Grade 2 Coughlin patient, and you're using that grading scale.

Those patients have 25% or less of articular involvement. These are not patients with

advanced arthritis of the joint. According to Coughlin, and really all literature that I see,

these are patients who have a cheilectomy with greater than 85% or 80% success rates. So I

don't think there's a simple answer to that, but I didn't understand that part.

That's a very important issue, though, because you also mentioned lots of studies by

Jim Brodsky. And I know Jim and other people have put in the literature that for Grade 2

Coughlins, only a simple debridement is needed. I don't do it. I do a cheilectomy, and I take

off 25%. But Dr. Glazebrook mentioned what he does, but there are papers that talk about

good success just simply taking off the dorsal spurs. So perhaps your Coughlin 2 patients

are not getting better because of the implant. Maybe they're just getting better the way

other Coughlin 2 patients get better, because you simply are taking off the spurs. I just

don't get it, and maybe you could help me out with that. And definitely I'd like to know the

results, which you can't do over lunch. If you exclude your Coughlin 2 patients, that would

be personally much more convincing to me, in patients we know are not a candidate just for

a simple debridement. Okay, so that's that.

The other issue is there are many other excellent options for hallux rigidus, for

arthritis of the big toe that are not mentioned in your protocol, and I wonder if they were

mentioned to your patients or if you do them. Interpositional arthroplasties. Greg Berlet,

who we all know, did a paper that cited -- many of you in 2015 at the AOFAS meeting -- the

Graftjacket equivalents. In this country, those are used with great success where you don't

have to fuse the joint, you don't have to put an implant of some type in, but you use the

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patient's own soft tissue or equivalent. Why are those not discussed? And I'm concerned,

in your informed consent, if those weren't mentioned to the patient, that it biases this

study in some way that precludes a patient of wanting to have that Cartiva implant. So why

were those not mentioned?

The other issue is, is one of the Panel members asked you how you measured -- and

it's my last broad question -- how you measured the angle. I think the exact question was,

how do you have 15 degrees of motion in a fusion patient? And you very nicely answered

that question for us, and you included pictures of how you measured the fusion patients.

And the picture that you showed on how you measured a fusion, I have never seen in any

orthopedic literature, and it worries me. Maybe you could explain it later, how you do that.

You showed an angle -- and again, you don't exactly define your 15 degrees. The

picture that you showed, showed a 15-degree angle of the fusion measured from the

metatarsal on a foot. It's not a bony angle, which is what we normally talk about, right, in

measuring fusions, and it's not an angle of the great toe off of the horizontal axis of the

foot. You showed a 15-degree angle of metatarsal proximal phalanx on a foot. Now, that

wouldn't be a good fusion.

So I'm concerned on how you did your fusions. I mean, you're all brilliant people

who were part of the study, but if you're doing fusions that are having clinically, on the

foot, a metatarsal toe angle of 15 degrees, that means you're not elevating your great toe

slightly off the weight-bearing axis or 15 degrees off of the horizontal plane, or 10 degrees,

which is how it should be done. So that confused me, and I was worried it might have

compromised the results of your already excellent fusion groups. That's just confusing to

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me. I'm sure there's an obvious answer to that.

Did you teach your fusion doctors how to do fusions? You went to all of the sites on

how to do this Cartiva implant, which is a pretty simple procedure, as you all say. But did

you go to your sites to try to standardize among your doctors, or did the fusion doctors

meet to try to standardize the technique of fusion? Because if the techniques are not

standardized, which they were not, we know, you add tremendous confounding variables to

this study, right? Some of the plates are bothering some of the people. Some of the toes

may have been fused in five degrees or not.

So those are my major questions that we can answer later, I think, or whenever

you'd like, sir.

DR. RAO: Thank you very much, Dr. Pfeffer.

Are there any other questions from the Panel?

Dr. Finnegan.

DR. FINNEGAN: So I have two questions, and they're sort of related to each other in

reverse. On page 58 and 59 of the materials that you sent us early, there are eight or --

seven or eight classifications for injury, poisoning, and procedural complications that could

be classified as pain. And I'm wondering, when you did your pain, were these all grouped

together, or did you separate them out?

And the reverse of that is that you said the 5% deficit in the mean ADLs was not

clinically relevant. I think you can't really tell that unless you separate out were all of the

deficits in the same activities of daily living, or was the 5% just spread out over all of the

activities? If any of that makes sense.

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DR. RAO: Does the Sponsor have a quick 30-second response to that, or should we

wait until the afternoon?

MS. MOORE: I'll have to get back to you regarding the seven or eight because I just

need to understand what slide we're referring to. But with respect to the 5% deficit, that,

on the mean scores, was the mean Activities of Daily Living Subscale. So again, that

subscale is the combined combination of those questions because that's how that score is

validated. It's not an individual question.

DR. FINNEGAN: Can you, over lunch, see if it separates out into certain areas that

were more affected than others?

MS. MOORE: We could take a look at that. But I think it's important to note that the

clinically meaningful difference in the literature is with respect to the specific scale and not

the individual questions.

DR. RAO: Could we have Dr. Blumenstein's slide up, please?

And while we're doing that, Dr. Trier.

DR. TRIER: I do have a short question. This is Dr. Trier. A follow-up to Dr. Golish's

question posed to the Sponsor. He raised the question about OUS data used for a PMA

submission. Is there guidance from FDA on their acceptance of OUS data and exclusively

OUS data? And to your knowledge, have there been other PMA products that have been

approved based solely on OUS data?

MS. MOORE: Yes, there is a guidance document that indicates that OUS data is

acceptable for a PMA submission, as long as you follow the appropriate guidelines, and

which we did. Thank you.

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DR. TRIER: And are you aware of any other products that have been approved, a

PMA product that has been approved by FDA that included only OUS data?

MS. MOORE: Yes, there are HA devices that have been approved only with --

hyaluronic acid device submissions that had been approved outside the -- have been

conducted outside the U.S. in support of their PMA approval.

DR. RAO: I'll go to Dr. Blumenstein. Dr. Blumenstein has an exploratory question on

the basic concepts of a non-inferiority study design. And before he asks the question, I just

want to confirm with the Sponsors that what I read somewhere is accurate, that the non-

inferiority margin was actually changed during the course of the study at some point. So

keep that in the back of your mind while Dr. Blumenstein asks his question.

DR. BLUMENSTEIN: So my question is motivated -- my question specifically to the

Sponsor, that I'm hoping to get some response to, is how did you adjust your non-inferiority

assessment to the fact that you had planned for a 60% response in the control arm but you

observed for your primary outcome something more like an 80% response? And so I want

to know how you adjusted the interpretation of the trial in regard to that.

Now, this is important because the FDA has asked us to judge whether the 15-point

difference or definition of inferiority, a non-inferiority margin, as it's called, was

appropriate. And so what I wanted to do is -- more or less, as a small tutorial for the Panel

members, is discuss the implications of this. The graph that you see there has a vertical line

at 0.6 or 60% for the assumption for the control arm outcome that was used to plan the

study. Now, as I understand it, the 15-point or 0.15 non-inferiority margin was determined

by consulting experts about their opinion of what constituted inferiority. So what I've

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shown on the graph here is the line of identity in light gray, and I've shown the red line

being the definition of inferiority in the experimental arm that is the consequence of the

0.15 margin that was used in the study, and as you can see, the red line is straight. Now

what this means is, when you get to something like a 0.8 outcome from the trial instead of

the 0.6 that was planned, that you get a margin that takes you down to -- what is it, 0.75,

where the red line crosses the vertical line at 0.8.

But when you asked the clinicians about what constitutes a non-inferiority margin,

their answer was most likely based on you having told them that your expectation was 60%

or 0.6. But this expectation is the -- the response you get from the clinician is conditional

on that expectation.

Now, we statisticians -- and I think probably the epidemiologists would agree with

me -- we love odds ratios. But odds ratios are not something that's easy to communicate to

clinicians and other people like that. Yeah, he agrees. I'm pointing to the epidemiologist,

Stephen Lyman. The reason that we like odds ratios is because of what I'm going to tell you

now. If we take that 0.15 margin that was identified by the clinicians that you asked and we

convert that to an odds ratio, that is, the ratio of the odds of success in the experimental

arm divided by the odds of success in the control arm, the result is 0.15 -- 0.55. You see

that in the second line of the title up there. All I did was take the control arm 0.6 that was

used to elicit the margin from the clinicians that you consulted with, and they came up with

a delta of -0.15 or -15%. Fifteen points, actually. So the odds ratio that corresponds to that

is 0.55.

Now, if we take -- and we can do a non-inferiority trial with either a fixed difference,

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defining, that is, the margin based on the difference of proportions or percent, or we can do

a non-inferiority trial based on a fixed odds ratio. Now, the preferable way to do this is with

a fixed odds ratio, if the expectation is that the outcome of the trial may not resemble what

was used to plan the trial.

Now, the blue line is the difference computed from a fixed odds ratio for different

values of the outcome in the control arm, and what you can see here is that the difference,

the vertical difference, between the gray line of identity and the blue line is less than the

difference between the gray line of identity and the red line at the vertical of 0.8, meaning

that for a fixed odds ratio, the actual difference that defines inferiority is smaller than the

0.15 that was used to plan the trial.

The extreme of this would be to go out to, say, 0.95 where you can see that the

difference now is really quite small for the fixed odds ratio method of doing the non-

inferiority trial, as opposed to the 0.15 that was used in this study, that is, a fixed difference

between defining inferiority.

Now, what you have to ask yourself is, if the outcome was high, say 0.9, 0.95, or

even 0.8, does it make sense to define inferiority as being 0.15 less than, say, 0.95 or 0.9

and so forth? I don't think it does. What does make sense is that fixed odds ratio that

corresponds to what you got out of the clinicians when you asked them to define inferiority

based on the assumption that the outcome would be 0.6. So the point here is that the

interpretation of the trial has to be conditional on the outcome that differs markedly from

what was used to plan the trial. And so I would like to have the Sponsor respond to that.

DR. RAO: If we could maybe have -- if you have a brief response, we'll take it now.

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But if not, let's just hold, and if one of you could explain Dr. Blumenstein's issue after the

break, that will be better.

MS. MOORE: Yes. Chairman Rao, can I just have a brief response --

DR. RAO: Sure.

MS. MOORE: -- and we'll address some of the points and then we'll have a follow-up

after lunch? Is that appropriate?

DR. RAO: Hold on just a second.

Dr. Lyman, is your question on the same issue or slightly different?

DR. LYMAN: It's slightly different.

DR. RAO: Go ahead, please respond.

MS. MOORE: Okay. Well, first I want to clarify. I think you made a statement that

our non-inferiority margin changed over the course of the study, and that is not true.

DR. RAO: Okay, thank you.

MS. MOORE: The non-inferiority margin was always specified as 15%. And when we

went to our physicians, the odds ratio, in describing that, is not something that's relevant.

We went to the literature to determine what is the appropriate estimated success rate, that

we could determine in the literature, that was appropriate and determine what that success

rate -- I think, as we reviewed earlier today, there's very limited literature to determine

what the success rate was going to be when you're looking at a composite and incorporated

VAS Pain, FAAM, and success and radiographs and all of those areas, in this area. So we had

to estimate what that success was. Then we had to ask our clinicians, what's that difference

that's clinically insignificant to you? And that was how that was determined. And I think

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what's important -- and we will address your comment after lunch, specifically, but we need

to look at what the observed success was over the course of the study. And so as you can

see, we observed nearly 80% success in almost every analysis with very little difference.

The two groups are spot on between the two, and those differences that were observed, as

Dr. Baumhauer stated, were clinically insignificant.

And I think the non-inferiority margin, it's important to note that that's a clinical

issue. It's important to look at the benefits associated with -- it's a clinical question. It

doesn't answer -- it's not one -- it's device specific, and we need to look at the risk-benefit

associated with it, and that was what we took into consideration looking at range of

motion, the shorter recovery time, the minimal bone loss, and the salvage. And the

clinicians felt that that margin of difference in success rates, 15%, was appropriate based on

that.

DR. RAO: Thank you, Ms. Moore.

Dr. Heckman.

DR. HECKMAN: Thank you, Dr. Rao.

I have great admiration for the group that conducted this clinical study. I think it is a

substantial advance over most of the clinical research that's been done in foot and ankle

surgery, and I compliment you on setting up a prospective, randomized study to try to

answer this important question.

I have one very substantial concern about the randomization and one issue about

the complications. If I heard you correctly, there were 65 patients who were randomized to

control, and of those, 13 dropped out once they heard that they were going to be in the

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fusion arm. If that's correct, that would be 20% of the patients dropped out. And then it

seems to me that if there were 20% of the patients who were randomized to the Cartiva

arm, they would be very happy that they received that because they probably had the same

bias going in. And so I would like for you to address my concern that the high dropout rate

was because there was not adequate equipoise established initially with regard to the two

options, for whatever reason, and perhaps there is some bias favoring the Cartiva group, as

those patients who wanted a Cartiva to begin with, got one.

And the second thing that bothers me a bit more is the complication or the

subsequent secondary surgical interventions. I asked a question earlier of the Sponsor, and

I'm still a bit confused about how many patients actually had a non-union that went on to

surgical treatment. That's the major complication as far as I'm concerned. Surgical removal

of hardware that is symptomatic is a lot less of a procedure than removal of a failed implant

and also a lot much smaller procedure than revision of a fusion. So I think that a couple of

these patients had asymptomatic or minimally symptomatic radiographic non-unions. And

then one or two patients may have had a non-union or a failure of the fusion device that

required repeat fusion. I need some clarification on those numbers.

MS. MOORE: Sure. So to address the question you have regarding the non-unions

and whether they were surgically required, we had a total of four non-unions. Two of those

resulted in a secondary surgical operation. All four of them, however, were clinically

symptomatic. And then further, the definition of non-union was reviewed, you know,

previously. Again, the intent of the treatment was not met, and that was why that was

considered a failure.

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With regards to the dropout that you had mentioned, there were a total of 15

subjects that dropped out in the fusion arm, and 10 of those were because they wanted to

have the Cartiva. They didn't want to have fusion. We handled that in a number of ways.

So the original analysis was the intent to treat, and so those subjects would have been

considered failures. However, that was why we felt it was appropriate to look only at the

modified intent-to-treat population moving forward, because it took out those failures.

But, in addition, we went back and did an analysis of the intent to treat, looking at

multiple imputation as well as a tipping point analysis to look at the various ways to see

what impact that would have. And in all situations, we were able to demonstrate non-

inferiority with respect to that.

DR. RAO: Thank you. Thank you, Ms. Moore.

Dr. Lyman.

DR. LYMAN: Thank you.

I'd like to follow up on Dr. Heckman's point about -- and I think a way that you could

look at that -- in trials that I've been involved with, especially when there's not a good

treatment option for some patients, there's this bolus of early patients that are desperately

looking for something, and that appears to be what may have happened since you had all of

these people drop out of the fusion randomization but not out of the Cartiva

randomization. So what you might look at is patients who were enrolled early in the trial

versus later, because you may have more satisfied patients early because they were just

looking for something other than a fusion. So I would be less worried about Dr. Heckman's

point if your late enrollees had similar outcomes to your early enrollees.

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Now, I don't know where that cut point would be and how long it would take to get

the patients enrolled that were easily satisfied because they were looking to avoid fusion,

but I think that that's worth exploring to address Dr. Heckman's concern.

And then my bigger comments and questions are around the use of your patient-

reported outcomes. When you dichotomize a patient-reported outcome, you have

enormous information loss. You've taken 22 questions in your ADL score, and that's

reduced to a single score, and then you dichotomized that continuous or ordinal variable

into a binary variable to determine whether or not you have success, and I have problems

with that.

Now, I understand you agreed with the FDA on this composite outcome measure and

you used these binary cut points, but a big part of your argument for the success of your

trial is that you've maintained range of motion in these patients and yet they have -- I

would actually argue that they have inferior ADL scores because there's an 8-point

difference between baseline and 2-year follow-up in their ADL scores, what you've listed as

the MCID for the ADL score. So you actually have worse function, worse ADL, in the Cartiva

patients than in the fusion patients, despite the fact that they've maintained their range of

motion.

So I think that Dr. Finnegan's point, that looking at the individual questions may be

useful because there may be items that are specifically related to this flexion, that you may

show a benefit in the individual items. But it's a foot and ankle survey, right? So there are

items that are related to the ankle and items that are related to the foot, and I think the

foot questions may be more relevant. So you might want to -- I would be interested in

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whether or not you have different responsiveness to individual items in the ADL score.

DR. RAO: Thank you, Dr. Lyman.

I'd like the Sponsor, as well as Dr. Lyman, to remember this question and issue and

respond to it after the break when we discuss it at more length.

Dr. Kelly had a quick question. Again, no responses, please.

DR. KELLY: No response.

DR. RAO: We'll just raise the issues now.

DR. KELLY: I just wanted to reiterate and to develop what Dr. Heckman said.

Dr. Baumhauer, in your own words, said the patients wanted the Cartiva. So I think there's

an inherent bias. I think that the results are largely skewed towards in favor of Cartiva, and

I don't think you can eliminate that just with the intention to treat because there were only

so many dropouts. So I think that's a huge inherent bias, that the patients came in -- I don't

know how you can control for that honestly, but they wanted motion sparing. And the one

thing I know after 26 years of surgery is belief is everything.

DR. RAO: Thank you, Dr. Kelly.

Dr. Carrino.

DR. BAUMHAUER: Could I just --

DR. RAO: Hold on just a second, please.

Dr. Carrino.

DR. CARRINO: Just some minor imaging clarification questions. It had been

mentioned that there were some deviations related to imaging, and my question was, did

any of the Cartiva subjects undergo advanced imaging, like CT or MRI, and do we have any

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insight into what the implant would look like? I also thought it was mentioned under the

radiographic assessment for synovitis and how synovitis would be ascertained on a

radiograph versus a soft tissue modality.

And the third clarification would be in the follow-up, for the future follow-up,

whether radiographic surveillance was going to be included in that yearly follow-up or

recommended, because as we know from other arthroplasties, even though they're not

symptomatic, it may be useful to have imaging follow-up for development of osteolysis and

other preclinical complications.

DR. RAO: Thank you, Dr. Carrino.

I'd like a response to that after the break also, please, in addition to Dr. Lyman's

question.

Dr. Gilbert, you had a quick question?

DR. GILBERT: I do, yeah. Thank you.

So one of the elements of this device is that it's made from polyvinyl alcohol and

saline, and I understand this is the first application of this material in orthopedics. And so

I'm just interested a little bit in the fact that you have essentially a hydrogel and an ability

to exchange the fluids that are in it with fluids that are in the tissue, and also that

significant changes in material properties can occur over time, as you say, have proteins

being taken up by the material. So I'm just wondering about that. Have you looked at

changes in the device properties over time? Were you able to look at retrievals when you

convert to a fusion, to look at the device itself and understand any sort of changes that

result from its long-term exposure in the body?

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And then a related question is the heterotopic bone formation. Is there any

evidence that you can provide that the polyvinyl alcohol material isn't inducing that?

DR. RAO: Thank you, Dr. Gilbert.

Dr. Sayeed, you had a quick question? We need to go to a break within about 45

seconds.

DR. SAYEED: I'd just like to say that I share Dr. Lyman's concerns.

DR. RAO: Thank you very much.

DR. SAYEED: And I actually have one more question. They used the FAAM score of

an 8 as being clinically -- the minimal clinical level. You know, in the literature that I've

read, a more meaningful number would be 17 as a better measure of functional outcomes.

I'd just like for the Sponsor to address that issue.

DR. RAO: Could we get a response to that after the break, please?

Dr. Subhawong.

DR. SUBHAWONG: Yes, thanks. Ty Subhawong.

I'm wanting some clarification on Table 840 regarding the heterotopic ossification.

There were 22 subjects in the fusion group that had Class IV, which was defined as

ankylosis. But I was just wanting clarification as to why wasn't that number higher if the

goal of the fusion was complete ankylosis of the joint?

DR. RAO: Thank you. We'll get that after the break.

Dr. Lyman, you had a quick follow-up?

DR. LYMAN: Yeah. Sorry, I wasn't finished with my prior comments. One is the

MCIDs. It's a great point. Actually, MCIDs are population distribution based, and you had a

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global assessment of change, a global assessment question, so you could calculate your

MCIDs to make the determination. And then also your SF-36 score, I was confused by that

because if these were population norm scores, then all your patients were at the average of

the U.S. population before surgery and improved to an exceedingly amazing state of

physical function afterward. So I'd like clarification, after the break, on whether those were

norm scores or some sort of raw score for the SF-36.

Thank you.


I have one final quick follow-up comment. Your indications, as well as Dr. Daniels',

spoke about hallux valgus as possibly being included in the indications for the procedure,

but somehow the word "hallux valgus" came up. But in your contraindications for the

procedure, hallux valgus of more than 20 degrees is listed as a contraindication. My

understanding of hallux valgus is it has to be about 15 degrees to even be called hallux

valgus and some people say 15 to 20 degrees.

So could you clarify the role of this device in patients with hallux valgus? And if you

are including hallux valgus, did you obtain radiographs, like Dr. Carrino mentioned, where

you measure the preoperative and postoperative hallux valgus angles to ensure that the

device is safe in that subset of patients?

Thank you very much. We'll await the responses to these questions after the break.

There's a 15-minute break now. We'll meet here at exactly 10:20. Thank you.

(Off the record at 10:03 a.m.)

(On the record at 10:20 a.m.)

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DR. RAO: It is now 10:20, and I would like to call this meeting back to order. The

FDA will now give their presentation.

I'd like remind public observers at this meeting that while the meeting is open for

public observation, public attendees may not participate except at the specific request of

the Panel Chair.

The FDA will also have 90 minutes to present. FDA, you may now begin your

presentation.

MR. DEDANIA: Good morning, distinguished panelists and members of the audience.

My name is Jemin Dedania, the lead reviewer of the Cartiva Synthetic Cartilage Implant

premarket approval application sponsored by Cartiva. We are seeking the input of the

Orthopaedic and Rehabilitation Devices Panel on this PMA application that is being

reviewed by the Agency.

I'd like to take a moment to recognize the FDA project team that is currently

reviewing the Cartiva PMA.

The Agency's presentation on the Cartiva PMA will follow the outline as shown.

Please note that the Panel questions will be presented in the afternoon.

I'll now introduce the purpose and rationale of this Panel meeting, briefly describe

the Cartiva investigational device and its proposed intended use, indications for use, and

briefly review the nonclinical studies provided in support of this PMA application.

The purpose of this meeting is to obtain input from the Panel on the safety and

effectiveness results of the Cartiva device for its proposed indications for use. In addition,

the Agency is seeking Panel input on questions related to the appropriateness of the chosen

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non-inferiority margin, primary and secondary endpoint analysis, risk of secondary surgical

interventions, assessment of function, and the radiographic outcomes. The Agency has

concerns about the impact on the interpretation of the study results for the purpose of

evaluating safety and effectiveness of the Cartiva device and is seeking feedback from the

Panel on these issues.

As previously mentioned by the Sponsor, the Cartiva device is a polymeric,

viscoelastic hydrogel that is press-fit into place.

The Sponsor described the investigational device as intended to replace focal areas

of damaged cartilage by providing pain reduction while maintaining range of motion of the

joint.

The Sponsor's proposed indications for use for the Cartiva device are shown here.

Proposed contraindications, warnings, and precautions for the Cartiva device are described

in your Panel pack.

The Cartiva device was studied outside of the U.S., in the United Kingdom and

Canada, and was not subject to IDE regulations. The Sponsor requested feedback for their

protocol through pre-IDEs and pre-submissions. The Sponsor's study was registered on

clinicaltrials.gov.

Cartiva provided the nonclinical studies, shown here, in their PMA application. After

review of the nonclinical data provided, the Agency does not have any remaining concerns

with the information provided and is not seeking Panel input on the nonclinical study

results related to the Cartiva device at this time.

I would now like to introduce Dr. Laurence Coyne, who will present the clinical

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background information as well as the FDA review of the study results.

DR. COYNE: Good morning. I'm Larry Coyne, and I'm Chief of the Restorative and

Repair Devices Branch in the Division of Orthopedic Devices. And on behalf of Dr. Nona

Colburn, who is performing the clinical review of this PMA, we'll be giving FDA's clinical

overview presentation. I would like to thank the Panel members for their time and input.

The Cartiva Synthetic Cartilage Implant is intended to treat osteoarthritis of the first

metatarsophalangeal joint. OA of the MTP joint has a number of etiologies, which are listed

here. These include trauma, repetitive microtrauma, hallux valgus, and recurrent hallux

deformity after surgery.

Hallux rigidus, arising from OA-induced osteophyte development, is a condition

associated with pain and limited range of motion. Patients with hallux rigidus may

experience pain in pushing off and may be unable to wear shoes.

Hallux valgus, arising from static subluxation of the first MTP joint, also can arise --

hallux valgus may result from wearing tight, narrow, or high-heeled shoes or may arise from

other factors such as family history or aging.

Current treatment options for OA of the first MTP joint are listed here. There are a

variety of conservative nonoperative treatments ranging from the use of orthotics and stiff-

soled shoes to anti-inflammatory medications and injections. Operative treatments range

from cheilectomies to fusion and resurfacing procedures. The choice of treatment can be

dependent upon the severity of the symptoms.

I will now present some details regarding the clinical trial conducted to study the

Cartiva device.

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The objective of the MOTION clinical trial was to compare the safety and

effectiveness of the Cartiva device to an arthrodesis control in treatment of first

metatarsophalangeal joint arthritis.

The Sponsor hypothesized that the study would demonstrate non-inferiority of the

Cartiva device to conventional fusion of the first MTP joint. Non-inferiority was to be

demonstrated in the primary composite endpoint, comprised of measures of pain and

function and whether or not subjects underwent a secondary surgery or experienced

undesirable radiographic outcomes.

Some details of the study design are shown in this slide. The pre-specified primary

study success criteria consisted of assessment of a single composite endpoint for pain,

function, and safety, with safety to be evaluated through 24 months and effectiveness at 12

months. Again, although the study was conducted outside the U.S. and therefore not

subject to IDE regulations, some feedback was provided to the Sponsor prior to the study.

Relating back to one of the FDA recommendations from this pre-study feedback, a

post hoc effectiveness assessment at 24 months was requested by FDA and was provided by

the Sponsor.

The target population for the study is shown in this slide and consisted of subjects

with either degenerative or post-traumatic arthritis in the first MTP joint and with an

availability of good bone stock. Specifically, the study was to include subjects with hallux

valgus or hallux limitus, hallux rigidus, and an unstable or painful metatarsophalangeal joint.

Key inclusion criteria, which were covered by the Sponsor in their presentation, are

shown on this slide.

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This slide and the next show the key exclusion criteria that were utilized for study

enrollment. And, again, these were presented earlier by the Sponsor.

The control cohort for the MOTION study was treated by arthrodesis or fusion of the

first MTP joint. Study investigators were instructed to use their own standard surgical

technique for these arthrodesis subjects. Typical steps utilized in the procedure are

outlined here. In addition, post hoc wound dressing and mobilization procedures and

subsequent rehab procedures are summarized on this slide.

Some notable aspects of the surgical procedures for implantation of the Cartiva

device in post hoc treatment are summarized here. As opposed to arthrodesis subjects,

patients treated with a Cartiva device could begin weight bearing immediately.

This table details the previous pre-op screening and baseline assessments as well as

the various assessments conducted according to the follow-up schedule.

Adverse event information was collected intraoperatively and at discharge as well as

throughout each of the scheduled follow-up visits. Full post hoc evaluations occurred at 2

and 6 weeks and at 3, 6, 12, and 24 months. Pain and function assessments at 12 months

were inputted into the pre-specified primary composite endpoint, and pain and function

assessments at 24 months went into the FDA-requested post hoc reanalysis of the

composite endpoint.

Details are shown here for the pre-specified single composite primary endpoint,

which again incorporates pain, function, and safety. An individual subject's outcome was

considered a success for pain if the VAS Pain assessment decreased by at least 30% at

1 year, and was considered a success for function if the Foot and Ankle Ability Measure or

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FAAM Sports Subscale measure was maintained within a maximum clinically insignificant

difference of 9 points at 1 year.

From the standpoint of safety, an individual subject's outcome was considered a

success if there was an absence of subsequent secondary surgical interventions through

2 years, as well as an absence of radiographic failures. Radiographic failures were defined

differently for the Cartiva and arthrodesis treatments and are shown here.

The FDA had provided feedback to the Sponsor on its clinical trial design prior to the

outside-of-the-U.S. study being conducted. Part of this feedback was FDA's belief that the

effectiveness assessment for the pain and function components of the composite endpoint

be analyzed at 24 months rather than 12 months. FDA's reasoning was that a 2-year

analysis was needed to adequately assess any effects from longer-term adverse events and

to more reliably determine fusion and other clinical outcomes.

In addition, the submitted PMA clinical dataset relied upon the FAAM Sports

Subscale for the functional component of the composite endpoint, rather than the FAAM

Activities of Daily Living, or ADL, measures that have been incorporated into the protocol

that had been reviewed by FDA.

FDA believes that the ADL measure would provide a more useful assessment of

function in the more general population studied in the MOTION trial, as opposed to a

population predominantly focused on the ability to return to sports activities post-

treatment, and the Sponsor agreed with this assessment as well.

On the basis of this feedback, FDA requested that the Sponsor provide a post hoc

analysis of the composite endpoint, incorporating the pain and function assessments at 24

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months and use of the FAAM ADL measure for assessing the function component. The

Sponsor, as I said, did provide this post hoc analysis, and as will be seen later, these changes

proved to be more favorable to the Cartiva device.

The changes introduced to the primary composite endpoint in FDA's requested post

hoc analysis are shown here in red font.

In addition, FDA also provided feedback prior to the study on the Sponsor's

incorporation of a 15% non-inferiority margin into the statistical analysis plan of the FDA-

reviewed study protocol. FDA provided feedback that the non-inferiority margin should be

chosen to correspond to a maximum clinically insignificant difference.

The Sponsor retained use of the 15% non-inferiority margin for its analysis of the

primary composite endpoint and provided justification in the PMA for the margin, in part as

quoted here.

Summarized input from the clinicians taking part in the study felt that the 15% delta

constituted a clinically insignificant difference and was appropriate based on the potential

benefits of the Cartiva device, including the ability to retain motion of the joint, quicker

rehabilitation, less restrictive postoperative requirements on the patient, a quicker return

to function and sports activities, and the general impact of these potential benefits on a

patient's quality of life.

While the inherent potential benefit of the Cartiva device to maintain motion of the

joint served as part of the Sponsor's justification for its chosen 15% non-inferiority margin,

the demonstrated superiority of the Cartiva device in range of motion did not necessarily

translate to any advantage over arthrodesis in functional capability, according to the results

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of the study. In actuality, the FAAM functional capability scores were found to be

substantially better for arthrodesis subjects than for Cartiva subjects at all of the later time

points of the study through Month 24, including the pre-specified primary functional

assessment, FAAM Sports Subscale scores at Month 12.

In addition, it should be noted that a lower non-inferiority margin of 10% for safety,

effectiveness, and composite endpoints is typically utilized in non-inferiority studies for

other orthopedic implants. Overall, FDA believes that whatever non-inferiority margin is

chosen, it should correspond to a maximum clinically insignificant difference appropriate

for the particular study at hand.

The FDA will be asking the Panel to comment on the 15% non-inferiority margin used

for the study and to either provide a rationale if the Panel agrees with this margin, or if not,

to provide a margin it believes would be appropriate and clinically meaningful.

I'll now continue with a summary of the results and observations of the study.

The Sponsor provided a subject accounting flowchart, as shown here. This was

discussed in detail in the Sponsor's presentation, so I won't cover that again.

The Sponsor provided this table summarizing protocol deviations by type within each

study arm in the study as a whole. A total of 416 protocol deviations occurred in the study,

with 331 occurring in the Cartiva treatment arm and 85 in the arthrodesis control arm. The

two columns on the right summarize major protocol deviations, as determined by the

Sponsor, for two per-protocol analyses of the composite primary endpoint.

The first such analysis, shown in this column, excluded for two subjects who had

outside-of-window follow-up visits at 24 months. The second analysis, shown in this

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column, excluded for major protocol deviations two other subjects who did not meet

inclusion/exclusion criteria.

The FDA's own assessment was that as many as 28 patients, 22 investigational and

6 controls, should potentially be excluded for major protocol deviations from a per-protocol

analysis. However, an FDA analysis with all of these 28 subjects removed from

consideration showed no significant impact upon the primary composite endpoint.

Patient demographic by gender in the mITT cohort are shown in this table provided

by the Sponsor. Noted here are that 80% of the Cartiva device treatment subjects and 76%

of the arthrodesis control were women. As pointed out by the Sponsor, this is consistent

with the literature that shows that MTP osteoarthritis is more prevalent in women.

This table provided by the Sponsor shows the baseline demographics and

assessments for the ITT population and confirms that all of these were well balanced

between the Cartiva and arthrodesis treatment groups. The same conclusion holds true for

the mITT cohort.

In addition, the Sponsor also provided analyses of baseline demographics and

assessments which demonstrate that the baseline characteristics were not different for

randomized subjects who chose to withdraw prior to treatment compared with those who

were treated and remained in the study.

This table provided by the Sponsor shows the demographics by gender, of age,

height, weight, and BMI, and baseline assessment measures for the mITT population. The

p-values noted here confirm that all of these were well balanced between the Cartiva and

arthrodesis treatment groups.

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And according to all available surgery information, the mean procedure time was

about 23 minutes less for a Cartiva device placement compared to an arthrodesis

procedure. And the corresponding mean time for anesthesia was, on average, 28 minutes

less for Cartiva subjects.

I will now present on the safety assessments of the Cartiva device.

Adverse event information collected for the study was categorized by system organ

class and preferred term. Events were further subcategorized into treatment and non-

treatment emergent events and assessed as either device- or operative-related events.

A total of 318 total adverse events were reported. These were further subdivided by

severity, seriousness, resolution status, and unanticipated events.

This table provided by the Sponsor summarizes information on the 317 total adverse

events reported for the study. As noted here in the table, over the duration of the 24-

month study, about 69% of the Cartiva patients had at least one adverse event, a rate

comparable but slightly lower than the 72% rate for arthrodesis patients. As also shown in

this table, adverse events were further subdivided by severity, resolution status, and

categorization as anticipated or unanticipated events.

This table, also provided by the Sponsor, summarized those serious adverse events

assessed by the Sponsor as being device related. Overall, Cartiva had a somewhat higher

incidence rate of serious device-related adverse events than arthrodesis subjects (7.2% to

4%). All of the serious device-related adverse events for Cartiva subjects were pain events,

and the two for arthrodesis subjects consisted of a device complication event and a device

pain event.

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This slide serves as a reminder of the safety components making up the primary

composite endpoint, which includes the absence of subsequent secondary surgical

interventions as well as an absence of radiographic failures, which were defined differently

for the Cartiva and arthrodesis treatments and are shown down here.

For Cartiva device, displacements or fragmentation or the development of avascular

necrosis constituted a radiographic failure, while mal-unions or non-unions from 3 to 24

months or hardware failures were deemed as radiographic failures for arthrodesis subjects.

The results in this table provided by the Sponsor show that the rate of all SSSIs for

randomized and treated Cartiva subjects, which were 10%, as well as only those treated

subjects (11.2%) was slightly lower than the rate of all secondary surgical interventions in

arthrodesis subjects, which was a rate of 12%; 9.2% of Cartiva subjects and 8% of

arthrodesis subjects had the implant and/or hardware removed during the course of the

study.

Turning now to a discussion of the safety evaluations from radiographic data,

assessments were made through 24 months by an independent review of plain radiographs

which looked for abnormal bone formation at the fusion site in arthrodesis subjects and the

loss of implant integrity in Cartiva subjects.

Qualitative evaluations included assessments for heterotopic ossification,

radiolucency, bony fractures, avascular necrosis, adverse bony reactions, device

displacement, fusion status, device integrity, and additional observations.

Results of the assessments are shown in this table provided by the Sponsor, which

reflect the different radiographic assessment criteria used for the primary composite

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endpoint. For Cartiva, no findings of avascular necrosis or device displacement or

fragmentation were reported among all treated subjects. For arthrodesis, four findings of

non-union and one finding of fractured hardware were reported among all treated subjects.

On the basis of these five radiographic findings, 10% of the overall arthrodesis cohort was

deemed as radiographic failures for the primary composite endpoint. In contrast, no

Cartiva subjects were deemed radiographic failures.

Other assessed radiographic findings not incorporated into the primary composite

endpoint included radiolucency, bony fracture, bony reaction, and heterotopic ossification.

And the numbers and rates for these are presented, as well, in this table.

Looking at some of these other radiographic findings in more detail, as this table

provided by the Sponsor shows, the Cartiva group had a higher rate of bony reactions (49%

for Cartiva as opposed to 6% for arthrodesis). However, this difference in the respective

ambient rates is not likely to be of concern. However, rather it is the most extreme bony

reactions, namely osteolysis, that would be the predominant clinical concern.

For the study, the two Cartiva subjects who experienced osteolysis were nonetheless

deemed to be successes by the Sponsor. For arthrodesis, one subject was deemed to be a

success, while the other two arthrodesis subjects were deemed as failures due to other

criteria.

Results of the assessments are shown in this table provided by the Sponsor, which

reflects the different radiographic assessment criteria used for the primary endpoint. For

Cartiva, no findings of avascular necrosis or device displacement or fragmentation were

reported among all treated subjects. For arthrodesis, four findings of non-union and one

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finding of fractured hardware were reported among all treated subjects. On the basis of

these five radiographic findings -- oh, sorry. Okay. Numbers and rates of heterotopic

ossification are shown -- sorry. Numbers and rates of heterotopic ossification are shown in

this table provided by the Sponsor. As was the case with bony reactions, not all incidents of

heterotopic ossification are necessarily of significant clinical concern. But Class III

heterotopic ossification, which corresponds to the presence of bone spurs contiguous with

the first metatarsal proximal phalanx of the great toe or sesamoid bones and which may

contact with or nearly contact adjacent bones or bone spurs, can present a significant

clinical concern.

As shown here, Class III heterotopic ossification was observed in 11 randomized and

treated Cartiva subjects. Nonetheless, all of these 11 subjects were considered by the

Sponsor as successes.

The ramifications of these radiographic assessments on the analysis of the primary

composite endpoint, and perhaps again as a question to be addressed in a potential post-

approval study, will be discussed later in FDA's statistical analysis presentation.

No Cartiva subjects experienced Class IV heterotopic ossification, but this would also

have been concerning as well, if it had occurred. Class IV heterotopic ossification is an

anticipated result for fusion subjects.

In summary, about 69% of the Cartiva subjects had at least one adverse event within

24 months as opposed to 72% of the arthrodesis subjects.

Cartiva subjects had a somewhat higher incidence rate of serious device-related

adverse events than arthrodesis subjects (7.2% to 4%). The serious device-related adverse

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events for Cartiva subjects were all pain events.

The rates of all subsequent secondary surgical interventions for Cartiva (10% for

randomized and treated subjects and 11.2% for only treated subjects) were slightly lower

than the 12% rate of all SSSIs in all arthrodesis subjects.

Continuing on, utilizing the different pre-specified criteria for radiographic

assessments of Cartiva and arthrodesis treatment groups, five of the arthrodesis subjects,

or 10% of the total cohort, were deemed as radiographic failures for the primary composite

endpoint as opposed to none for the Cartiva subjects.

Among the radiographic findings not incorporated as a radiographic assessment for

the purpose of the primary composite endpoint, osteolysis, the most clinically concerning

bony reaction, was observed in two Cartiva subjects and three arthrodesis subjects. And

Class III heterotopic ossification, also not incorporated as a radiographic assessment for the

composite endpoint, was observed in 13 treated Cartiva subjects.

The Agency will be asking the Panel a voting question on whether a reasonable

assurance of safety has been demonstrated for the PMA device for its proposed intended

use.

I will now present on the effectiveness assessments of the Cartiva device.

This slide serves as a reminder of the effectiveness components of the composite

endpoint. It entails an individual subject being termed a success for a decrease from

baseline in VAS Pain scores of 30% or more at 12 months, and a maintenance of function

from baseline no worse than 9 points in the FAAM Sports Subscale score at 12 months. As

discussed earlier, the Sponsor also provided an FDA-requested post hoc analysis in which

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pain and function were now assessed at 24 months and the FAAM ADL measure was

utilized.

Turning to the pain component, this table provided by the Sponsor shows mean VAS

Pain scores spanning from baseline assessment through 2 years. Both the Cartiva and

fusion treatment groups demonstrated substantial clinically important reductions in mean

VAS Pain scores over the course of the study. However, the mean pain scores for

arthrodesis were substantially less at each time point starting at the Week 6 assessment all

the way through to the final 24-month assessment. In addition, the arthrodesis cohort

experienced a greater mean reduction in pain for all of the same later assessments.

For the 12-month assessment used for the Sponsor's pre-specified pain component

of the composite endpoint, the mean VAS Pain score for Cartiva patients was 17.8 mm as

compared to 5.7 mm for arthrodesis patients.

This table provided by the Sponsor -- at the earlier assessment time points in the

study, these mean FAAM Sports scores were greater for the Cartiva cohort, substantially

greater at the Week 6 and Week 12 assessments in particular. However, at the later

assessment time points in the study, the mean FAAM Sports scores were now greater for

the arthrodesis cohort, substantially greater at 6- and 12-month assessments and slightly

greater at the 24-month assessment.

Of note is that any inherent advantage in functional improvement for the Cartiva

device emanating from its ability to retain range of motion in a patient isn't necessarily

apparent in any of the long-term 12- and 24-month assessments both for FAAM Sports

Subscale score assessments shown here, and for the Activities of Daily Living score

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assessments shown on the next slide.

This table shows those ADL functional assessment scores spanning through 24

months. And again, as for the Sports scores, both the Cartiva and fusion treatment groups

demonstrated clinically important improvements in these scores, the ADL scores, over the

duration of the study. Similar to the pattern for the mean FAAM Sports scores, the mean

FAAM ADL scores were initially greater for the Cartiva cohort at Weeks 2 and 6 but greater

for the arthrodesis cohort for the later time assessment points of 3 through the end of the

study at 24 months, although the magnitudes of the mean differences in the FAAM ADL

scores were generally less than those for the FAAM Sports scores at corresponding time

points.

In summary, both the Cartiva and fusion treatment groups demonstrated substantial

and clinically meaningful reductions in mean VAS Pain scores over the course of the study.

However, the mean pain scores for the arthrodesis control cohort were substantially less at

each time point starting at the Week 6 assessment and all the way through to the final 24-

month assessment.

And for function, both treatment groups demonstrated clinically meaningful

improvements in mean FAAM Sports and ADL functional assessments over the duration of

the study. Both sets of scores favored the Cartiva device at earlier time points through

Week 6 but favored the arthrodesis treatment at all of the later time points of 6 through 24

months.

Of note is that any inherent advantage in functional improvement for the Cartiva

device emanating from its ability to retain range of motion was not apparent in any of the

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longer-term functional assessments both for FAAM Sports and ADL scores.

The Agency will be asking the Panel a voting question on whether a reasonable

assurance of the effectiveness has been demonstrated for the PMA device for its proposed

intended use.

I would now like to introduce Alvin Van Orden, who will be presenting the statistical

review of this PMA.

MR. VAN ORDEN: Hi, my name is Alvin Van Orden, and I am a mathematical

statistician, and I will be presenting our review of the clinical study data from a statistical

perspective.

The hypothesis for the primary endpoint is shown here, where P is the proportion of

subjects that meet the composite endpoint. The Sponsor pre-specified a 15% non-

inferiority margin, and using the 15% non-inferiority margin means we can say, with 95%

confidence, that the true success rate for Cartiva is not lower than arthrodesis by more than

15%. By choosing a 10% non-inferiority margin as opposed to a 15% margin, the FDA is

saying we want to be confident that Cartiva is no more than 10% worse than arthrodesis.

The Panel will be asked to comment on an appropriate non-inferiority margin.

Here are the three main analysis populations and one unofficial dataset. The ITT

population includes all randomized subjects. The mITT population includes all randomized

and treated subjects. The completed cases population includes all subjects that were

randomized, treated, and completed at 24 months.

The final dataset is presented as a point of clarity. About 10% of subjects in both

groups had their device removed at some point within the first 2 years. Many of the Cartiva

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subjects were given arthrodesis, and most of the arthrodesis subjects simply had part or all

of the device removed. For the primary composite endpoint, these subjects are always

treated as failures. For endpoints such pain and function, there are multiple ways to

account for these subjects that no longer have the device that they were treated with.

Over the next three slides I will discuss the different reasons -- the different reasons

subjects are missing and different options for accounting for this missing data. The FDA

does not want the story to be about missing data. We feel like the differences between the

populations shown here are minor. The Sponsor did an excellent job of following up with

subjects that were treated, and they should be congratulated. Our goal in presenting the

differences between the datasets is only to clarify the patient accounting.

Two subjects that were randomized to Cartiva and 15 subjects that were randomized

to arthrodesis withdrew before being treated, many of whom stated that their reason for

withdrawal was that they wanted the alternative device. This is 23% of the arthrodesis

subjects and less than 2% of Cartiva subjects.

Keep in mind that subjects volunteered for a study that they knew was randomized

2:1 Cartiva to arthrodesis. So if they agreed to be in the study, they may have thought that

they were most likely going to be part of the Cartiva group.

If last observation carried forward (LOCF) imputation is used, then 23% of the

arthrodesis subjects would be failures before the study even begins. LOCF is not a

meaningful imputation for untreated subjects. It is important to check to see if the subjects

that decided not to participate in the study are different in some measurable way from the

subjects that decided to participate in the study. However, no differences were found for

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these missing subjects. We would estimate that -- for these missing subjects that weren't

treated, we'd estimate the same success rate as those that were treated.

There were only five subjects out of 180 that were treated and then lost to follow-up

before 24 months. One of these subjects had a secondary surgery before leaving the study.

So for this subject, we do not have to guess his result for the primary endpoint. We know

he would have been a failure if he had completed the study.

This table shows what is known about the other four subjects that were lost to

follow-up. Subject 1 only had X-rays post-baseline. No pain or function measurements

were ever taken. Subject 2 did have a function measurement at 6 weeks but did not have a

baseline measurement. Subjects 2, 3, and 4 all had large improvements in pain and

function at their last visit.

There were 13 Cartiva subjects and 6 arthrodesis subjects that had secondary

surgery events. Ten of the Cartiva subjects had the investigational device removed and

were converted to arthrodesis. It is clear that these subjects should be counted as failures

for the primary endpoint, but it's less clear how to analyze the data from these subjects in

terms of secondary endpoints.

One approach is to drop the subjects from the analysis at the time they have their

device removed. The reasoning is that if a subject had the Cartiva device removed and then

was treated with arthrodesis, one might reasonably think that Cartiva should not get credit

for a low pain score after they have been fused. For other endpoints such as satisfaction, it

is difficult to understand why subjects that had secondary surgery should be excluded.

Throughout the Sponsor's presentation and in the previous clinical presentation, the

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numbers presented often don't include the subjects that have had a secondary surgery or

SSSI event.

A second approach is to impute secondary endpoints at later time points using the

last value recorded before the surgery. For example, if a subject had a pain score of 50

immediately preceding the surgery and at 6 months, then that subject would continue to be

counted as having a pain score of 50 for the rest of the surgery, even if pain improved after

the secondary surgery. This method avoids throwing out any subjects and shows what

might happen if subjects had continued with the treatment to which they originally were

assigned. This method has not been presented and will not be presented in any analyses

today.

A third approach is to continue to include subjects that have had SSSI events without

deleting or imputing data. The reasoning is that upon receiving their initial treatment,

subjects begin down a path. That path may include a secondary surgery, but you're still

interested in where they will finish based on the original path they started on. This follows

an intent-to-treat principle. All of the analyses in the statistical section are based on the

completed cases dataset and include the secondary surgery subjects unless specifically

noted otherwise.

When the results for the primary endpoint are calculated using the pre-specified

primary endpoint analysis, the lower bound of the 95% confidence interval is 11.6%. This is

within the 15% margin pre-specified by the Sponsor. Please note that we have questions

for the Panel related to the chosen non-inferiority margin. As has been noted previously,

the FDA requested an additional analysis of the primary endpoint, looking at the 24-month

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time point and using FAAM ADL instead of FAAM Sports. As can be seen in this analysis, the

lower bound of the confidence interval is closer to the 10% non-inferiority margin often

used in orthopedic device studies.

Here we have the completed subjects on the top row followed by two imputations.

The first imputation considers all four of the treated but missing subjects as successes, and

the second considers the four subjects as failures.

Now, a composite endpoint combines distinct endpoints into one number, and it

gives each part equal weight, which may or may not be an appropriate assumption. The

results for two groups may vary drastically on each part of the composite endpoint yet

combined have similar overall results. Thus, similar composite results may not be evidence

of similar risks and benefits.

There were four parts to this composite endpoint: pain, function, secondary surgery,

and radiographs. Each was simplified to be either a success or a failure. Over the next few

slides, I will discuss each part of the composite endpoint.

This table shows the responder rate for VAS, where a responder is defined as a 30%

reduction in pain. By 3 months, the arthrodesis group has a responder rate of 94%, which it

maintains through 2 years. The Cartiva group nears a 90% responder rate at 1 and 2 years.

On the right is the confidence interval for the difference between the two groups, where a

negative difference means the arthrodesis group was better than the Cartiva group. If the

confidence interval does not include zero, this represents a significant difference. At the

pre-specified time point of 1 year, there is a significant difference. Also please note that

some subjects may continue to experience pain in spite of being responders in this analysis.

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For example, one responder at 24 months had a VAS of 60, and there were 6 Cartiva

subjects and 0 arthrodesis subjects that were VAS responders and overall successes that

had 24-month VAS rates over 30.

These box plots show the pain scores over time. This box plot shows six numbers.

The minimum and the maximum are the two ends. The middle line is the median, and the

diamond represents the mean. The top and bottom represent the 25th and 75th

percentiles.

So, for example, we can see that roughly 25% of subjects at 1 year -- Cartiva VAS

scores at 1 year are higher than the minimum Cartiva VAS at baseline. We can see from this

graph that both groups have large declines in pain from baseline. We also see that the

Cartiva VAS scores are higher and have a wider variability than the arthrodesis VAS scores.

The Panel will be asked to discuss their interpretation of the Cartiva and arthrodesis

pain score results.

Here we show the two functional endpoints, FAAM Sports and FAAM ADL. I will

discuss more about the questions that make up these questionnaires in a few slides.

To be a responder for these endpoints, the only requirement was to not get worse

by either 8 or 9 points, depending on which scale is used. The reason for this bar was that

some subjects began the study with quite high functional scores. Given these definitions of

a responder, the responder rates were near 100% for both groups at both 1 and 2 years.

The confidence intervals at the primary time point of 1 year do not include zero, but the

differences in the responder rates are small and are similar for both measures of function.

Here we see the box plots for FAAM ADL over time. Higher functional scores are

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better with a max of 100. You can see the wide range of functional scores at baseline with

several near 100. The functional scores in both groups dip lower at Week 2, and at Week 6

the Cartiva group is better. This perhaps shows the effect of how many arthrodesis subjects

were required to wear a boot through about Week 6. The functional benefit of Cartiva

versus arthrodesis is limited to these first 2 months. By Month 3, the two groups are even,

and at Month 6 and Year 1, the arthrodesis group is better.

If a subject marks slight difficulty on every item of the FAAM ADL questionnaire, then

the subject will score a 75. At 1 year, 81% of Cartiva subjects are above 75 as compared to

96% of arthrodesis subjects.

Here we see the box plots for FAAM Sports over time. Again, higher functional

scores are better with a max of 100. For this endpoint, subjects ranged from 0 to 100. We

see a very similar pattern as in FAAM ADL. The function gets worse in both groups, with

Cartiva doing better early. Then both groups improve, with arthrodesis doing better at the

later time points.

The FAAM ADL questionnaire is made up of 21 questions, and this is a sampling of

those questions, many of which are only slightly different from the ones seen here. For

example, here we show walk for 15 minutes. Other questions included walking for 10

minutes, walking uphill, and such like that. So of the 21 activities in the survey, only for up

on toes, listed here, was there a higher percentage of subjects that had no difficulty in the

Cartiva group than in the arthrodesis group. The FAAM Sports questionnaire is made up of

eight questions, though only five are shown on this slide. In none of these activities was

there a higher percentage of subjects that had no difficulty in the Cartiva group than in the

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arthrodesis group. The gap between the Cartiva group and arthrodesis group is larger here

than in the previous slide and is as high as 26% for the low-impact activities. The main

reason is because this table shows results at 1 year for FAAM Sports, and the previous table

showed results at 2 years to keep the time points consistent with the pre-specified primary

endpoint and the FDA-requested endpoint.

The Panel will be asked to discuss their interpretation of the Cartiva and arthrodesis

functional results.

The rates of SSSI, or subsequent secondary surgery intervention, were 10% for the

Cartiva group and 12% for the arthrodesis group. The rate of Cartiva events does not

include the roll-in subjects and does not include an additional four SSSI events that

occurred after 24 months. We don't know if any arthrodesis subjects had an SSSI event

after 24 months, as this data was not collected. The median time to SSSI was about

6 months for the arthrodesis group and about 1 year for the Cartiva group.

This table shows the pain and function of the 13 Cartiva subjects and the

6 arthrodesis subjects that had an SSSI event. Recall that the median time for an SSSI event

in the arthrodesis group was 6 months, and both before and after that time point the mean

pain was very low. The Cartiva subjects, on the other hand, averaged pain scores of about

40 until Year 1 when they were revised at fusion. So while the rates of SSSI events are

similar, the experiences of these subjects may be different. This may also be a partial

explanation for why there is a larger difference between the two groups in pain and

function at 1 year as opposed to 2 years.

Three of the arthrodesis subjects, all at the same site, had the device removed

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where the reason for removal was listed as elective. One had a VAS score of 1 and a FAAM

ADL of 100 before the SSSI event. He needed treatment on the other foot and, because of

some mild erythema, decided to get the screw removed. One has a VAS of 2 and a FAAM of

99 before the SSSI event and said the screw was bothering him. The third was the subject

that had two events and did experience pain that led to a removal.

Literature submitted by the Sponsor suggests that the expected SSSI rate for

arthrodesis subjects is 8.5%, which would be lower than the 12% seen in the study.

Higher rates of SSSI among roll-in subjects and continued SSSI events after 2 years

suggests the SSSI rate for Cartiva may be above 10%, as estimated in the primary analysis.

Additional follow-up may be necessary either in a pre- or postmarket study to understand

the long-term risks of secondary surgery for Cartiva subjects.

As has been noted previously today, the Cartiva -- the criteria for determining that

the subject was a radiographic success or not were different for the two groups. These pre-

specified criteria led to defining 10% of arthrodesis subjects as failures as compared to 0%

of Cartiva subjects.

In the clinical review, we saw that there were other radiographic findings. We did

not find any clear link between these radiographic findings and pain and function. If there

was a direct link between these findings and pain and function, then we wouldn't need

radiographic endpoints to be part of the composite endpoint. We could simply look at the

pain and function. Additional studies that go beyond 2 years may be necessary to tell if

these radiographic findings are important.

This table shows the three subjects that were radiographic failures that were not

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failures due to SSSI. Subjects 1 and 3 did experience inflamed skin, which is not accounted

for in this table. For Subject 2, a fracture was noticed in the device on the X-rays, but there

were no other symptoms. The subjects had no pain and perfect function and did not

require any surgical intervention. Certainly device fracture is an undesired event. However,

it may be difficult to understand how to weigh these events and other radiographic events

in relation to pain, function, and secondary surgery.

While both Cartiva and arthrodesis were effective in terms of reducing pain and

increasing function, the arthrodesis group was more effective. To declare non-inferiority in

terms of the composite endpoint at 15% depends on the Cartiva group doing better on the

safety endpoints.

The radiographic criteria were not the same between the two groups. If we change

the radiographic criteria to add Class III heterotopic ossification or if we remove the

radiographic criteria altogether, then the primary endpoint would not be met at the 15%

level.

The Sponsor pre-specified a list of secondary endpoints that they plan to test in

order. Testing secondary endpoints in order potentially allows testing of multiple

secondary endpoints without inflating the Type I error rate. The first secondary endpoint

was tested, and if it was significant, then one would proceed down the list until coming to a

secondary endpoint that was not significant. As the first secondary endpoint on this list was

not significant in favor of Cartiva, official testing of the secondary endpoints was stopped

and none of the secondary endpoints would be considered significant.

I will present the data from all of these secondary endpoints. As I present the data, I

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will show confidence intervals for the difference between the two groups. If the confidence

interval does not include zero, this would typically correspond to statistical significance.

However, please be aware that there are lots of secondary endpoints evaluated at multiple

time points, and these intervals have not been adjusted for multiplicity. So we urge caution

in declaring statistical significance for endpoints or time points beyond the first endpoint

listed here.

This table shows the change from baseline in pain VAS. As mentioned in the

previous slide, Cartiva failed to show statistical significance at the pre-specified time point

of 1 year. Instead, the improvement from baseline in the arthrodesis group was

significantly greater than the improvement in the Cartiva group. Both groups experienced

large improvements in pain from baseline. The improvement from baseline was higher in

the arthrodesis group at every time point.

This table shows the change from baseline for FAAM ADL. And again, both groups

saw large improvements from baseline. Cartiva was better than arthrodesis through 6

weeks, and arthrodesis was better than Cartiva at 3 months to 2 years.

This table shows the change from baseline for FAAM Sports, and Cartiva was better

than arthrodesis at 2 and 6 weeks, and arthrodesis was better than Cartiva at later time

points, including the pre-specified time point of 1 year.

The study recorded the subjects' peak dorsiflexion throughout the study, and both

groups had baseline peak dorsiflexion of about 23 degrees. This table shows the peak

dorsiflexion change from baseline for all subjects. And since in this case it seems more

reasonable to exclude those subjects that were converted to arthrodesis in the analysis, the

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bullet points show the numbers that excluded converted subjects.

The Cartiva group increased their range of motion from baseline from 23 degrees to

about 29 degrees, while arthrodesis subjects' range of motion decreased on average.

Arthrodesis is designed to limit the range of motion, so it was expected that there would be

differences in peak dorsiflexion. That being said, not all Cartiva subjects saw an increase in

motion, and not all arthrodesis subjects saw a decrease in motion. Twenty-six percent of

subjects that had the Cartiva device in the entire -- the Cartiva device the entire 2 years saw

a decrease in range of motion.

The Panel will be asked for their assessment of range of motion and function results

and if any specific information would need to be provided to patients to ensure that they

are properly informed.

The subject global assessment asked the subject to rate his or her overall well-being

since the beginning of the study and whether it has improved. Possible responses included

strongly agree, agree, neither agree nor disagree, disagree, and strongly disagree.

This table includes or looks at the percent of subjects that either agreed or strongly

agreed. The satisfaction level was higher in the arthrodesis group at every time point from

6 weeks on. And the difference between the two groups was largest if looking at those that

strongly agreed.

The Sponsor presented this additional endpoint earlier today. It is not a designated

secondary endpoint, but it is helpful to discuss here in comparison to the designated

secondary endpoint just shown, which also measures subject satisfaction.

In the Sponsor's analysis, they left out the subjects that had a secondary surgery,

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which makes the results look more favorable towards Cartiva. And it is also helpful to view

all of the time points for this endpoint. For both groups, the willingness to repeat the

procedure peaked at Week 2 when their pain and function were at their worse. So this may

not be an appropriate reflection of the effectiveness of the device. Also the subjects were

not blinded to the treatment received, so the interpretation of this question is not as

straightforward as the question on the previous slide.

The investigators were also asked to rate the subjects' overall well-being since the

beginning of the study and whether it has improved. They felt that more arthrodesis

subjects had improved at 3 months, 6 months, and 1 year, but the investigators felt that

there was little difference in the two groups at the early time points or at 2 years.

The 10-item physical functioning scale captures the presence and extent of physical

limitations. Cartiva subjects performed much better at Week 6. The later time points

favored arthrodesis.

The FFI-R short form includes a 34-item global assessment of foot functioning. It has

sections asking about pain, stiffness, difficulty, activity limitation, and social issues. There

was a substantial difference in favor in arthrodesis from Week 2 to Month 24.

In conclusion, the lower bound of the confidence interval for the composite primary

endpoint is between 10% and 12% for the completed cases, per protocol, and reasonable

mITT and ITT.

Cartiva subjects experienced large improvements in pain and function from baseline

but showed substantially less improvement in pain and function than arthrodesis subjects

at the pre-specified primary time points.

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The radiographic criteria were not the same for both groups, and it is difficult to

estimate the long-term SSSI rate for Cartiva.

The secondary endpoints all favor arthrodesis, except for mobility of the toe, where

arthrodesis is designed to limit mobility.

I'll now turn the time back over to Dr. Coyne.

DR. COYNE: I will now present FDA's benefit-risk assessment for the Cartiva device.

When making a determination of the benefit-risk profile of a device, the Agency considers

benefits, including the type and magnitude of benefits, the probability of a patient

experiencing benefit, and the duration of the effect.

Risks are also assessed, including the types, numbers, and rates of harmful events

associated with the use of the device as well as the probability and duration of these

harmful events. Additional factors in the benefit-risk assessment are also included in this

slide at the bottom.

Some of the benefits of the Cartiva device observed in the clinical trial are shown in

this slide and the following slides.

There was clinically important improvement in VAS Pain scores for most Cartiva

subjects. Cartiva showed an 88% and 89% responder rate at 12 and 24 months, where a

responder was defined as having at least a 30% decrease in VAS Pain score. Corresponding

responder rates in the arthrodesis group were 100% and 98% at 12 and 24 months,

respectively. In addition, there was clinically important improvement in function for most

Cartiva subjects as assessed either by FAAM Sports or FAAM Activities of Daily Living scores.

Cartiva showed an improvement from baseline of 38.9 points on a 100-point scale at 12

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months and 42.6 points at 24 months for mean FAAM Sports function scores.

Corresponding improvements from baseline for arthrodesis were 48.5 points at 12 months

and 47.1 points at 24 months.

The Cartiva group was substantially better than the arthrodesis group -- pardon me

-- was substantially better in the arthrodesis group at the earliest assessments at Weeks 2

and 6.

Continuing on, other benefits for Cartiva included improvement in quality of life, as

measured by the SF-36 assessment, for most Cartiva patients with 89% and 94% responder

rates at 12 and 24 months respectively. Here a responder was defined as having improved

from baseline by 10 points. The corresponding responder rates in the arthrodesis control

group were 93% at both 12 and 24 months. The Cartiva group was substantially better than

the arthrodesis group at Week 6 for this particular assessment.

Improvement in function, as measured by FFI-R assessment, was for most Cartiva --

occurred for most Cartiva patients with 94% and 95% responder rates at 12 and 24 months.

Here a responder was defined as having improved by 5 points from baseline or more. The

corresponding responder rates in the arthrodesis control group were 100% and 95% at 12

and 24 months, respectively.

Additional benefits observed for the Cartiva device from the clinical trial are shown

on this slide. There was general agreement on the part of Cartiva subjects at 12 and 24

months post-treatment with the patient satisfaction question, "My overall well-being has

improved since the beginning of the study?" Specifically at 12 months, 75% of Cartiva

subjects agreed or strongly agreed, and 74% at 24 months. The corresponding percentages

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for arthrodesis subjects were 79% and 85% at 12 and 24 months, respectively.

The Cartiva device demonstrated a clear advantage over arthrodesis in maintenance

of range of motion as measured by active MTP dorsiflexion, with the Cartiva group showing

substantially greater range of motion at all time points. However, it should be pointed out

that this greater range of motion for Cartiva subjects did not appear to ultimately correlate

with function assessments, which were substantially better for arthrodesis subjects at

longer time points.

And in those cases where data was available for patients, there were shorter surgery

times for Cartiva subjects, with the average procedure time 23 minutes less than for the

arthrodesis group.

Turning to the risks for the Cartiva device as observed in the clinical trial, the overall

rate of any device-related adverse event at 24 months was numerically higher in Cartiva as

opposed to the Cartiva control (15.1% for Cartiva as opposed to 8% for arthrodesis).

The overall rate of any serious device-related adverse event at 24 months was

numerically higher in Cartiva as compared to the arthrodesis control (here, 7.2% for Cartiva

as opposed to 4% for arthrodesis).

The rate of osteolysis, the most severe bony reaction, was 2% for the Cartiva safety

analysis cohort but was less than the 6% observed for the arthrodesis cohort. Class III

heterotopic ossification occurred in 8.6% of the Cartiva safety analysis cohort versus none

in the corresponding arthrodesis cohort. Reductions from baseline VAS Pain scores were

substantially less for the Cartiva group as compared to arthrodesis at every time point from

Week 6 to Month 24. The FAAM Sports function scores as a change from baseline were

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worse or substantially worse in the Cartiva group as compared to the arthrodesis control at

all of the later assessment time points from Month 6 through Month 24.

A similar behavior was observed for the FAAM ADL function scores, which were

worse or substantially worse in the Cartiva group compared to arthrodesis at all of the later

assessment time points from Month 6 through Month 24.

The Foot Function Index-Revised (FFI-R) function scores as a change from baseline

were substantially worse in the Cartiva group as compared to arthrodesis at every time

point from Week 6 to Month 24.

The patient global assessment where subjects responded to the question, "My

overall well-being has improved since the beginning of the study?" showed lower rates of

patients answering "strongly agree" at Month 12 (33% for Cartiva versus 53% for

arthrodesis) and at Month 24 (39% for Cartiva versus 55% for arthrodesis).

The Cartiva device demonstrated non-inferiority to the arthrodesis control

treatment in the primary composite endpoint with a 15% non-inferiority margin, both by

the Sponsor's pre-specified analysis and by an FDA-requested post hoc analysis.

Large clinically important reductions in pain and increases in functional assessments

were demonstrated for the Cartiva device, and study results confirmed that the device

successfully retained range of motion as intended. However, FDA does have questions

regarding the chosen non-inferiority margin and the robustness of the study results.

Continuing on with the benefit-risk assessment, the examination of the individual

components of the primary composite endpoint revealed that the Cartiva device, in general,

performed worse or substantially worse than arthrodesis in pain reduction and functional

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assessments at longer study time points

Safety analyses for subsequent secondary surgical interventions and radiographic

assessments utilized criteria that may not have necessarily been consistent for the

respective treatment groups.

And the impact of some potentially more clinically significant adverse events such as

heterotopic ossification may not have been adequately incorporated into the safety

assessment.

Consequently, in consideration of all of these points, a determination of the relative

weight of the benefits and risks of the Cartiva device remains unclear.

The Agency will also be asking the Panel a voting question on whether a favorable

benefit-risk has been demonstrated for the PMA device for its proposed intended use.

Thank you very much for your attention. And that concludes our presentation.

DR. RAO: Thank you, Dr. Coyne. There's a couple of extra slides on the handout that

you gave us. Do you want to talk to us about those, or are they just for our reading

material?

DR. COYNE: Oh, those --

DR. RAO: Those are backup slides that says -- I believe it says -- and it talks about

how Cartiva patients were converted to fusion. Would you like to tell us anything, or was

that just for our information?

MR. DEDANIA: Yeah, those were backup slides for this afternoon, in case there are

any additional questions on any of those.

DR. RAO: Okay, thank you very much. Very good. Thank you for your presentation,

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Dr. Coyne, Mr. Orden, and Mr. Dedania.

I would now like to open this meeting again for any brief clarifying questions that

any members of the Panel have for the FDA. Let me start with Dr. Lyman.

DR. LYMAN: Thank you very much for the additional information. Something struck

me. I went back through the survey that was used, this ADL survey, and virtually all of those

activities require two feet, and yet we haven't had any information about contralateral

disease. My bias is that if you have more severe OA in the treated foot, in the treated toe,

you're more likely to have contralateral disease. I may or may not be right about that, but

in the other joints that I study, that tends to be true with osteoarthritis. So we haven't seen

anything about whether or not there were symptomatic OA in the contralateral foot and

whether or not that may be affecting your scores, because in my experience patients don't

differentiate which foot is hurting when they're trying to do those activities. They just have

limitations in doing those activities.

So it would be really helpful to me to make any sense of what's been presented as to

whether or not we have any problems here, because it looks like you have more severe OA

in the Cartiva group than in the fusion group, on average, because you have all those OA

Grade 2's. Thirty-six percent of your fusions were in Grade 2's, I believe. So that's one

point.

The other thing that may be happening is -- sorry, let me look at my notes. It looks

like you have probably pretty substantial ceiling effects, right? You have very, very high

scores at 12 months and 24 months, and I'm wondering if that's not -- I think what's

interesting really here is at the margins of these surveys, right? The means don't mean that

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much necessarily. So how many patients hit the ceiling in each group?

And then also it looked like, in the Cartiva group in particular, you had at least one

patient who had really, really low scores. I don't know if they were revised or not, but they

had scores below the average pre-op scores, and that seems to maybe explain some of why

you have a little bit lower mean effect in that group. But that was striking to me because

you don't have -- the lowest score in the fusion group was much higher at 12 and 24

months.

Also I noted that in your baseline pain slide, you had patients with baseline pain

below 40, but that was your inclusion criteria. So I'd like clarification. That was in the

fusion group. I'd like to know why patients were enrolled in the study with baseline pains

below 40. That's just what was presented. That just might have been a mistake in the slide,

but I just would like clarification with that.

And then do you have any measure of preoperative activity, like some activity level?

Because it looks like you didn't have very sporting people in your Cartiva group, and that

might have just been randomization, but they just didn't seem to be participating in sports

or interested in sports or the sporting activities. And so I'm wondering if you have any

baseline measure of expected activity or what their activity was before surgery and if that

differed between the groups.

DR. RAO: Thank you, Dr. Lyman. Now, would those questions be directed at the

FDA? Many of them seem to be directed at the Sponsor.

DR. LYMAN: Anybody who can answer them.

DR. RAO: Anyone who can answer them.

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DR. LYMAN: Yeah, thank you.

DR. RAO: Would the FDA have a response to that? Or what's your response to

Dr. Lyman's questions?

MR. VAN ORDEN: I can try and answer some of them. So tell me -- I don't have

them all written down. So it was not a mistake that there were patients admitted into the

study with a baseline pain below 40, and it was -- there were about four or five subjects

there in the Cartiva group, and as low as 28 was the lowest. So that inclusion criteria was

not always -- most of them were like 39, 38, but there was one that was as low as 28.

DR. LYMAN: Okay. So I guess maybe we can talk about it later, but what do we think

about the fact that there were patients without much pain enrolled?

DR. RAO: So when you use the word "most," that may be misinterpreted. Could you

give us some specifics of how many were in the 38s, 39s, 28s, so it's not over-interpreted?

MR. VAN ORDEN: There was one 28 and all the rest were --

DR. RAO: You don't have to do it right now. You can give it to us after lunch.

MR. VAN ORDEN: -- 39s and 38s.

DR. RAO: Yeah.

MR. VAN ORDEN: When we did our own per-protocol analysis, we eliminated these

subjects that didn't make it. And as far as the -- we don't feel like it affects the overall

composite endpoint.

As far as OA on the contralateral foot, I have not seen that information. I don't

believe that we have that. We did look at models that adjusted for OA in the original -- in

the treated foot and did not find any significant significance.

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DR. RAO: There was a third component.

MR. VAN ORDEN: There was another part.

DR. RAO: Yeah, it was contralateral foot and baseline pain levels.

DR. LYMAN: The question was about the ceiling effects.

MR. VAN ORDEN: There's definitely a ceiling effect that affects how we could define

a responder. We couldn't define a responder as a certain amount of improvement. We

could look at different cutoffs to say, you know, subjects that were above, say, 75, we could

consider those a responder. Or if anyone has a suggestion of what -- but I think even using

different cutoffs for -- there looked to be, you know, a 10, 15% difference for --

DR. LYMAN: I guess what I'd like to see is what proportion of the patients in each

cohort hit the ceiling at, say, 12 and 24 months.

MR. VAN ORDEN: Which got to 100 or 95?

DR. LYMAN: No, it's at a ceiling that they maxed out their scores. Their function

may have actually been higher than that, but the survey wasn't able to --

MR. VAN ORDEN: You can't get beyond no difficulty, that's true.

DR. LYMAN: Right.

MR. VAN ORDEN: We can find out the number, if they got 100 --

DR. LYMAN: Yeah, there's literature out there suggesting that there is a ceiling

effect to the instrument. So I'm just curious what that ended up being.

MR. VAN ORDEN: Okay, we can look at the percentage.

DR. LYMAN: Thank you.


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Ms. McCall, do you have your hand up or no?


DR. RAO: All right. Dr. Yusef Sayeed.

DR. SAYEED: I'd just like to follow that up. In terms of functional outcomes, was

there any consideration, instead of a subjective tool, to use real functional outcomes like

true disability or return to work or return to play?

MR. VAN ORDEN: I have not seen anything that has not been presented here.

DR. RAO: Dr. Heckman.

DR. HECKMAN: Yes, just for the FDA. Can you define for me the terms "worse" and

"substantially worse" and how that relates to the statistically significant difference?

MR. VAN ORDEN: Do you have a specific endpoint in mind?

DR. HECKMAN: Yes. Well, it's on several of your slides and the summary results. For

instance, on that last summary result slide it says, "FAAM ADL function scores, measured as

change in baseline, were worse or substantially worse in the Cartiva group as compared to

the arthrodesis control." And then other times you just say they were worse. So I need to

know what the difference is between those two terms.

MR. VAN ORDEN: I would just invite you to look at the numbers that we've

presented and you can decide -- I mean, if you're looking for a statistical significance --

DR. HECKMAN: Yes.

MR. VAN ORDEN: -- or not --

DR. HECKMAN: Yeah, that would be the most important thing, because worse

obviously means one-hundredth of one point less.

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MR. VAN ORDEN: Right.

DR. HECKMAN: And that's not critical.

MR. VAN ORDEN: I mean, I presented confidence intervals.

DR. HECKMAN: Uh-huh.

MR. VAN ORDEN: And if you go back to those tables, you can see which confidence

intervals don't include zero. We are hesitant --

DR. HECKMAN: Okay.

MR. VAN ORDEN: -- to use the word "statistically significant" when looking at so

many different endpoints at so many different time points.

DR. HECKMAN: So why do you use the term "substantially worse" than? That

obfuscates, I think.

MR. VAN ORDEN: Okay. Well, I apologize for that.

DR. RAO: Dr. Bailey had a quick question and then we go to Dr. --

DR. BAILEY: Thank you, Mr. Chairman.

Regarding the osteolysis, we were told there was a 2% incidence. It was not

characterized as to where or the nature of that. I assumed that was in the remaining

implants. And this is an FDA question, by the way.

And then we were told, in the nonclinical studies, basically that we were accepting

the goat implant study, which I assume was the only in vivo study and in vitro study of the

cycles. But we were not given any retrieval data on the material.

So with a history of implant osteolysis in the human body -- and I did not find any

similar implant, similar place in the body this had been implanted -- did the FDA consider

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exploring that possibility any further? Other than the statistician suggesting that we get

long-term studies. I did hear that.

DR. RAO: Does the FDA have a response for that?

MR. DEDANIA: We may defer that to the afternoon, but for the nonclinical studies,

we can go back and review some of the osteolysis information. We can also defer to the

Sponsor to answer any questions about their goat study.

DR. RAO: Thank you.

Dr. Gilbert and then Dr. Pfeffer.

DR. GILBERT: So I'm sort of thinking about maybe the flip side of Dr. Heckman's

comment. In these instruments, I guess what I'd like to know is could somebody pinch me

at a VAS score of 6 and then a VAS score at 15 so I can understand the difference? In other

words, you can show statistically significant differences, but they may not be -- I think the

phrase was clinically significant or clinically meaningful.

And so when we get down to those sorts of numbers, I want to rely on my statistical

colleagues to understand it, but I also understand that at some point it's not a meaningful

difference. And so can somebody tell me about these instruments? And, you know, we

make scores from 0 to 100, but is it really sort of between 0 and 20 is one group and 20 and

40 is another? How refined can you really make a VAS scoring system to look at those kinds

of numbers?

MR. VAN ORDEN: We defer to your clinical expertise. It looks like these are, on

average -- you know, even looking at the median, you are -- I mean, if every subject had

only a 6-point difference, it's different than the difference as a group. But we are looking

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for the Panel's clinical input on what is a meaningful difference on these.

DR. RAO: Thank you.

Dr. Pfeffer.

DR. PFEFFER: I have questions that perhaps you'd like to think on and answer after

lunch. I've noticed that the FDA is involved with the definition of "natural" when it comes

to food groups. They're now, this year, open to public commentary about that because of

certain people feeling the term "natural" in food groups has confused the public when it's

used.

So I'd ask you the same thing about the term "synthetic." Do you feel that calling

something synthetic cartilage only leads to confusing a patient? Because synthetic, when

gemstones -- we know how that's defined. They need to be chemically identical. This has

many properties that are similar to cartilage, but is it truly a synthetic cartilage, and should

a doctor be allowed to tell that to a layperson? So I'd like you to -- you can answer that at

some point. Do you have a definition for how synthetic is used by the FDA? I spent time

looking it up online and I couldn't find anything. So that's one question.

And the other one is the STAR study. The FDA protocol has been brought up. I don't

know who else was there, but I was on that Panel that approved the STAR Total Ankle in

2007, so I'm personally well aware of what went on there and what I think are the

differences between this study and that study. But I'm wondering if the FDA, after lunch, or

someone could look that up and tell us why you didn't ask us to discuss 15% non-inferiority

in 2007 and now you do. And perhaps if you can delve into it, what similarities you feel

there were between the STAR and why you allowed a 15% inferiority and here it makes you

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potentially nervous.

DR. RAO: Just to add on to that, at what point did you decide that 15% should be

transitioned to the 10% you're recommending now?

Dr. Kelly.

DR. KELLY: Yes, two quick questions. Did the FDA consider why something -- the

polyvinyl alcohol, which is used in contact lenses, has such an appreciable high rate of

osteolysis and reactivity? Number one.

Number two, there was no mention again about another inherent bias in the study

design. I'm looking at these exclusion criteria, and there's defects greater than 10 mm,

1 cm osteochondral cyst. Was that done upon opening the joint? I didn't quite get that

because to me you're kind of calling out the worst of the worst, and it's favoring the Cartiva,

because most of the Grade 4's that I've seen in my -- not as much as Dr. Pfeffer -- do have

these things. So I think it's a very, very significant limitation and a bias towards Cartiva

when you're excluding those two cohorts.

But again, to the first question, any thoughts on the reactivity and the synovitis in

something, again, that's used in contact lenses?

MR. DEDANIA: We can go back during lunch and look at the reports from their

nonclinical studies and report back on that.

DR. KELLY: Thank you.

DR. RAO: Thank you. Dr. Kelly, any more, or was that osteolysis and synovitis

issues? Right?

DR. KELLY: Also, I still think there's a significant bias in selection of the patients.

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We're looking at the best of the best for fusion, and I'm still getting my Irish up over why

36% got fusions of Grade 2, which to me is just aggressive.

DR. RAO: Thank you.

Dr. Lyman.

DR. LYMAN: Yes, I have two additional questions. I guess I'm just seeking

clarification. It seems to me -- I'm not a radiologist, but it looks like the Cartiva implant is

radiopaque. So how could you have a radiologic outcome with an opaque instrument or

implant? So I wanted some clarification on that.

And the other thing is whether or not hardware removal for a fusion is really a

revision or a failure as opposed to sort of an elective decision based on some nuisance to

the patient. I mean, you had a patient with a pain score of like 1 -- and you know,

extremely good, you know, 98 points on the functional scale or something like that. I don't

remember the exact numbers -- who had a revision just because they had hardware

removed, which sounds like an elective decision.


And Dr. Subhawong had a question.

DR. SUBHAWONG: Ty Subhawong.

Just to clarify, Dr. Lyman, I had the exact same question about the implant and how

fractures through it are detected radiographically. It's radiolucent. So I'm just unsure as to

how the Sponsors would have detected a fracture through the hardware.

My other question has to do with the patient experience, and I noted that in the

Sponsor's presentation, 86% of Cartiva subjects would have recommended the procedure or

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would have had the procedure again versus 78% of the fusion group. But in the FDA's

presentation we saw that the patients' global assessment, you know, for strongly agree in

terms of their patient well-being, arthrodesis -- the arthrodesis group actually

outperformed the Cartiva group. And I was wondering if the FDA had any more statistical

analyses of that assessment of the patients' global assessment, like a Wilcoxon type of

analysis for this ordinal data, ordinal response data, as to whether they agree or strongly

agree with the statement that they were better off after the surgery.

DR. RAO: Do you have a slide number for that?

DR. SUBHAWONG: Sorry. For the Sponsor's presentation it was --

DR. RAO: Not the slide, but the FDA --

MR. VAN ORDEN: I would like to refer to two slides.

DR. SUBHAWONG: Eighty-nine.

MR. VAN ORDEN: So they are two slightly different questions, and they are Slides 89

and 90. Slide 90 is the one that the Sponsor referred to, willingness to have the procedure

again, and our numbers are different than their numbers because they did not include any

subjects that had a secondary surgery. They excluded those subjects from their analysis.

DR. PFEFFER: So the 18 -- the 23 rollover patients who went on --

(Off microphone comment.)

DR. PFEFFER: Sorry. Of the rollover patients, those who went on to fail in the fusion

were not included, you're saying, but were included in your data?

MR. VAN ORDEN: Not the roll-in subjects, but subjects that had their Cartiva device

removed and then needed arthrodesis --

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DR. PFEFFER: Right.

MR. VAN ORDEN: -- were excluded from their analysis but are included in our

analyses. And they do -- 89 and 90, they do -- they are slightly different questions.

DR. RAO: So 89 refers to the Sponsor's data?

MR. VAN ORDEN: No, 90 is the one the Sponsor was --

DR. RAO: Okay, so 89 is yours? Eighty-nine is the FDA?

MR. VAN ORDEN: So 89 is the official secondary endpoint; 90 was just an additional

endpoint that the Sponsor had highlighted.


DR. PFEFFER: I'm sorry. Forgive me, I've got to get this. So when you're talking in

your slide of willingness to have the procedure again, all right, as opposed to a real disparity

that the Sponsor showed, you show a 3% difference. Are you talking about patients who

failed the Cartiva's willingness to have a fusion or patients who had the Cartiva's willingness

to have had the Cartiva had they known what they know now?

MR. VAN ORDEN: Right. So that's why the Sponsor decided to exclude that, is there

may have been some confusion about whether it was fusion or arthrodesis. We feel like

ignoring the subjects is not the right answer. So we included them as they answered it, I

think, on -- you could've just imputed -- if you wanted to say these are all failures, that

would be one other option. I mean, we don't know how to answer this to begin with. I

mean, at Week 2 we see some weird stuff. So we were just reporting it as it is, but we do

feel it's inappropriate to just exclude those subjects.

DR. RAO: Thank you.

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Just a brief comment by Mr. Melkerson.

MR. MELKERSON: I would pose the same question to the Sponsor in terms of their

interpretation of their analysis.

DR. RAO: So just reiterate, this is the Sponsor's presentation slide where they show

a 3% difference in favor of the Cartiva using the criteria they used, correct?

MR. VAN ORDEN: In their slides they would show -- I believe it's a 9% -- a bigger

difference.

DR. RAO: So this is with the group that had revision surgeries excluded, correct?

This data that we see on the slide right now.

MR. VAN ORDEN: The one you're seeing on the slide includes all of the subjects.

DR. RAO: Includes all of the subjects. So this shows a 3% difference in favor of

Cartiva?

MR. VAN ORDEN: That's correct.

DR. RAO: Now, let's go to Slide 89. The slide before, please. And what does this

slide show?

MR. VAN ORDEN: This again shows all of the subjects, but they're just asked, has

your overall well-being improved? So it's a different question.


Dr. Gilbert had a question.

DR. GILBERT: Yes, this sort of goes to maybe a little bit of mechanism of action and

questions I have about the material. So as Dr. Kelly said, this material, the polyvinyl alcohol

is a hydrogel. It's like a contact lens. So in some sense it's kind of a squishy material. I

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haven't taken it out of its water container here to feel it, but it's squishy. However,

hydrogels are also known to be sort of constant-volume materials. In other words, if you

squish it in one direction, it spreads in the other in a constant-volume circumstance.

And so my question has to do with the placement of the material and any available

space that that material can spread upon compression. So if it's well placed and it looked

like this hole is a little undersized so you can kind of fit it in, then as you squeeze on the

outside, there's no place for the material to go, and that provides you that gap to keep the

two surfaces away. If there is some space because the surgeon hasn't quite done the

preparation of the bone properly or perhaps the bone has a cyst or some other openings,

now that material can exude into those spaces and collapse.

And so my question is, is the increased pain associated with this device a result of a

bottoming out of this material because of that ability to compress and allow the two sides

of the joint to come together in a bone-on-bone-like contact?


Dr. Heckman had a question.

DR. HECKMAN: There seems to be a substantial interest in teasing out patients with

Coughlin 3 and 4 disease. Did you do any subgroup analyses of those, particularly with

regard to the primary endpoint or some of the important secondary endpoints?

MR. VAN ORDEN: We did not see any difference. We can try and find those

numbers --

DR. HECKMAN: Okay.

MR. VAN ORDEN: -- for you for after lunch.

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DR. HECKMAN: I think that would be very important.

DR. RAO: Thank you.

Dr. Page had a question.

DR. PAGE: Two quick points. The first is whether or not there was any teasing out or

separation of patients whose indication was hallux valgus as opposed to hallux limitus or

hallux rigidus, as it relates to labeling down the road.

And my second question is for the FDA. Was there any concern expressed about the

results on Tables 839 and 840 that demonstrate substantial boning reaction and

heterotopic ossification as potential harbingers for further radiographic change and

potentially clinically significant changes in this patient population down the road?

DR. RAO: Thank you, we'll get the response for that after lunch.

Dr. Trier had a question.

DR. TRIER: Dr. Trier.

That's a nice lead-in to my question. I was curious and actually need some

clarification about the discussion about osteolysis and heterotopic ossification. It didn't

seem that those were part of the original radiographic criteria at the time or before the

data analysis. It looks like now you're looking at the X-rays and doing that. We were told

also before the Panel that there is data OUS that would provide that longer-term data on

radiographic findings, and I was curious whether or not the Agency had asked for any of

that information to look at those long-term radiographic effects from those two findings,

radiographic findings, osteolysis, and also heterotopic ossification.


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Dr. Pfeffer.

DR. PFEFFER: Very quickly, but I think it will be important to us. If you could look at

page 54 of your -- of the FDA's presentation. I don't know what slide it's on. Maybe you

didn't -- but we discussed this. Let me read it just slowly, and then we can discuss it at any

point because I don't get it. It has to do with certain subjects that didn't seem to meet the

appropriate criteria for being in the study, and if they're eliminated, there's no statistical

significance even in terms of a 15% non-inferiority.

But just to read it to have it in the record, here's 54 FDA: "The inclusion criteria

required that subjects have a baseline VAS of at least 40, although four subjects were

enrolled in the study with baseline scores below 49 [sic], including one subject with a

baseline score as low as 28. There were six Cartiva subjects that were considered successes

in terms of pain that had a 24-month VAS score over 30 (3 above 40). If these 6 subjects

with high 24-month VAS scores were considered failures, then Cartiva would not be able to

demonstrate non-inferiority at the 15% level." Certainly our Panel has to understand that

better either from the Sponsor or FDA.

DR. RAO: Thank you.

There was someone else here. Dr. Golish, yes.

DR. GOLISH: A quick clarifying question for FDA. You frequently calculate post hoc

and sensitivity analyses, as you presented here. Did you or did you ask the Sponsor to

calculate a sensitivity analysis with the non-inferiority margin cutoff, since you're asking us

about that, on the X-axis and then positivity/negativity, meaning null hypothesis, alternative

hypothesis on the Y-axis, in the context of the effect size for the primary composite

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endpoint and then the four subordinate endpoints?

And the reason that's important is that, you know, every numerically literate person

in the room knows that that number exists and we continue to look at it through the lens of

should it be 15 or 10. You might as well just tell us what it is because the Sponsor only gets

to present once, but FDA and the panelists are considering this question of non-inferiority

two-arm trials and the non-inferiority margin as it affects that all the time. So that

sensitivity analysis, I think, will reassure us and just kind of lay that bare. So that's probably

an ask for the Sponsor.

DR. RAO: Thank you, Dr. Golish.

I think we'll stop the FDA questions at that point, and I'd like the FDA to respond to

these themes after the break. Just to reiterate for both the Sponsor as well as the FDA,

these are some of the general themes that have come up during the two presentations, and

I will be keeping tabs, and I'd like you to give us some feedback on this after the lunch.

One theme is the general concept of imaging of these patients and imaging not just

to determine the affected side but also the contralateral side, imaging and other studies.

So was there any other data available to tell us how the patient's gait was, how the

contralateral foot did, X-rays, gait studies of the contralateral? That will give us some more

insight into how the patient was walking, overall, and how the contralateral side did.

Was there any imaging on the degree of hallux valgus? That, Dr. Page raised. And

was there any effort to tease out patients with "hallux valgus," which is listed in your

indications for the procedure but is excluded from the patients -- is listed also and the

patients excluded?

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There are questions about the role of heterotopic ossification. There was one

mention of an osteoclasis of a patient, a patient who underwent an osteoclasis.

And then there are general questions about the use of the 15% non-inferiority

margin and the transition from the 15 to the 10% that we'll be asking the FDA for feedback

on.

There was a question raised on the FAAM scores or whether the MCID should be 8 or

whether it should be 17, as listed on prior studies by Dr. Sayeed.

And then there is finally a question on whether hardware removal, if it's just a single

screw or something limited, should be considered a failure.

So we look forward to hearing back from you after the break on these issues. It is

now 12:04, and we will meet here at exactly 1:00. Let me just see if there's anything else

Commander Anderson would like me to say before we break.

Panel members, please do not discuss the meeting topic during lunch amongst

yourselves or with any member of the audience. We will reconvene in this room at 1:00. I

will ask that all Panel members please return on time. Please take any personal belongings

with you at this time. This room will be secured by the FDA staff during the lunch break.

You will not be able allowed back into the room until we reconvene.

Thank you. And enjoy your lunch.

(Whereupon, at 12:03 p.m., a lunch recess was taken.)

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A F T E R N O O N S E S S I O N

(1:01 p.m.)

DR. RAO: I think we're going to go ahead and get started. It is now 1:01 p.m., and

I'd like to resume this meeting. We will now proceed with the Open Public Hearing portion

of the meeting. Public attendees are given an opportunity to address the Panel to present

data, information, or views relevant to the meeting agenda.

Commander Anderson will now read the Open Public Hearing disclosure process

statement.


Both the Food and Drug Administration and the public believe in a transparent

process for information gathering and decision making. To ensure such transparency at the

Open Public Hearing session of the Advisory Committee meeting, FDA believes that it is

important to understand the context of an individual's presentation. For this reason, FDA

encourages you, the Open Public Hearing speaker, at the beginning of your written or oral

statement, to advise the Committee of any financial relationship that you may have with

any company or group that may be affected by the topic of the meeting. For example, this

financial information may include a company's or a group's payment of your travel, lodging,

or other expenses in connection with your attendance at the meeting. Likewise, FDA

encourages you, at the beginning of your statement, to advise the Committee if you do not

have any such financial relationships. If you choose not to address this issue of financial

relationships at the beginning of your statement, it will not preclude you from speaking.

DR. RAO: Thank you, Commander Anderson.

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For the record, we have received five requests to speak for today's meeting. Each

scheduled speaker will be given 5 to 10 minutes to address the Panel. We ask that you

speak clearly to allow the transcriptionist to provide an accurate transcription of the

proceedings of the meeting. The Panel appreciates that each speaker remains cognizant of

their speaking time.

The first speaker is Paul Voorhorst, Vice President of Clinical Research, DePuy

Synthes Joint Reconstruction, Mitek and Power Tools, on behalf of the Orthopedic Surgical

Manufacturers Association.

Dr. Voorhorst, you have 10 minutes.

DR. VOORHORST: Thank you very much. Good afternoon, I'm Paul Voorhorst. I'm

speaking here to you today representing the Orthopedic Surgical Manufacturers

Association, more commonly known as OSMA. OSMA is a trade association with about 30

members. It welcomes this opportunity to provide comment, general comments today

during this Panel meeting. OSMA's comments should not be taken as an endorsement of

the products that are being discussed today. We ask instead that our comments be

considered during today's Panel deliberations. These comments represent the careful

compilation of the member companies' views overall.

OSMA was formed over 50 years ago and works cooperatively with the FDA, the

American Academy of Orthopaedic Surgeons, the American Society for Testing and

Materials, and other professional member societies and standards development bodies.

This collaboration has helped to ensure that orthopedic medical products are safe, of

uniform quality, high quality, and supplied in quantities sufficient to meet national needs.

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Association membership currently produces over 85% of all orthopedic implants intended

for clinical use in the United States. Like the American public, OSMA has a strong and

vested interest in ensuring ongoing availability of safe and effective orthopedic devices.

The deliberations of the Panel today and the Panel's recommendations to the FDA

will have a direct bearing on the availability of new products designed to improve the

quality of life of patients treated in the United States. We urge the Panel to focus its

deliberations on today's safety and effectiveness based on the data provided.

Reasonable assurance of safety and effectiveness. The FDA is responsible for

protecting the American public from drugs, devices, food, and cosmetics that are either

adulterated or unsafe or ineffective. However, the FDA has another role to foster, and

that's innovation.

The Orthopedic Devices Branch is fortunate to have available a staff of qualified

reviewers, including a board-certified orthopedic surgeon, to evaluate the types of

applications brought before this Panel. The role of the Panel is very important to the

analysis of the data on the manufacturer's application and to determine the availability of

new and innovative products to treat patients in the United States. Those of you on the

Panel have been selected on your expertise and based on your training. You also bring the

view of practicing clinicians who treat patients with commercially available products.

Our objective here today is to emphasize two points that will have a bearing on

today's deliberations: (1) Reasonable assurance of safety and effectiveness, and (2) valid

scientific evidence.

Point 1: Reasonable assurance of safety and effectiveness. There is reasonable

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assurance that a device is safe when it can be determined that the probable benefits to

health outweigh the probable risks. Some important considerations associated with this

standard include valid scientific evidence and the proper labeling and that safety data can

be generated in the laboratory, in animals, or in humans.

There is a reasonable assurance that a device is effective when it can be determined,

based on scientific evidence, that a device provides clinically significant results in a

significant portion of the patient population. Labeling in the form of adequate directions

for use and warnings against unsafe use play an important role in this determination.

Point 2: Valid scientific evidence. Valid scientific evidence consists not only of well-

controlled investigations but also partially controlled studies, studies in objective trials

without matched controls, well-documented case histories, and reports of significant

human experience with a marketed device. While a well-controlled investigation may be

the highest order of evidence used to determine safety and effectiveness, OSMA

respectfully reminds the Panel that other types of valid scientific evidence may provide a

reasonable assurance of safety and effectiveness.

In addition, while the scientific community recognizes that among the essentials of

well-controlled investigations are the methods of selecting subjects, of observing and

recording the results as well as comparison of results of treatment with control, including a

historical control, OSMA also urges the Panel to recognize that a clinical study with some,

but not all, of these essentials may have a higher order of valid scientific evidence than

other types of evidence that can be provided to a reasonable assurance of safety and

effectiveness. The Panel has an incredibly important job today. You must listen to the data

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presented by the Sponsor, evaluate the FDA presentations, and express an opinion about

the safety and effectiveness of the Sponsor's product. We speak for many applicants when

we ask for your careful consideration. Please keep in mind that the standard is a

reasonable assurance balancing the benefits with the risks. A greater degree of certainty is

not required.

When considering making recommendations for further studies, remember, the FDA

takes these recommendations seriously, often as a consensus of the Panel as a whole, and

recommendations for additional studies may delay the introduction of useful products or

result in burdensome and expensive additional data collection. Therefore, you play an

important role in reducing the burden to bringing the new products to market, which you

and your colleagues use in treating patients.

Please be thoughtful in weighing the evidence. Remember that the standard is

reasonable assurance of safety and effectiveness and that there's a broad range of valid

scientific evidence to support that determination.

OSMA thanks the FDA and the Panel for the opportunity to speak today. Our

association trusts that its comments are taken in the spirit offered, to help the FDA decide

whether to make a new product available for use in the U.S. marketplace. OSMA members

are available in the audience today and are available to answer questions at any time during

the deliberations.


DR. RAO: Thank you, Dr. Voorhorst.

Our second speaker who has asked to speak today during the public hearing open

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session is Gail Butt.

Please go ahead. You have 5 minutes, Ms. Butt.

MS. BUTT: Mr. Chair, honorable members of the Panel and the audience, good

afternoon and thank you for affording me the opportunity to share my experiences of living

with a Cartiva implant for the past 6 years.

As you mentioned, my name is Gail Butt. I live in Vancouver, British Columbia.

Cartiva sponsored my travel here and attendance at this meeting, but I don't own any stock.

First, I will tell you a little bit about me. I'm an almost 70 years young wife, mother,

and grandmother with over 50 years experience in healthcare as a nurse, an educator, and a

scientist. But none of that experience could stop the joint in my left great toe from

deteriorating, but it did give me the knowledge that I needed to manage the pain through

supportive footwear. I also knew that the only surgical -- the only option available to me

surgically was a joint fusion, and this I resisted because I didn't wish to lose any function

that would result from the loss of joint movement.

But finally, after over 10 years, I was forced to seek a surgical opinion because of the

pain and the loss of function. For example, even though I had a high pain tolerance, if I had

to stop suddenly or if for some reason I inadvertently put pressure on the joint, the pain

response would bring tears to my eyes, and my legs would buckle, and I would fall. Well, I

was nearing retirement at that time, as well, and realized I had to do something, other than

being stubborn, or I would be completely sedentary for the rest of my life. So I made an

appointment to see an orthopedic specialist who specialized in foot problems, even though,

as I mentioned, I really didn't want a fusion. The surgeon told me, happily, that they were

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just considering becoming part of a randomized controlled trial that was getting underway

at the hospital, and the study involved a new device that was an alternative to fusion. He

was a little bit skeptical about whether the device would actually work, but he told me that

if it did, it would preserve the limited function or the limited movement that I had, but it

would not improve it. The device was expected to last at least 5 years, and if it failed, I

could still be offered a fusion.

So this was unlike other procedures that had previously been tried. From what I had

been given to understand, they'd been offered, but that made the joint unfit for a fusion if

they failed. So the long and short of it was that from my perspective, I had an opportunity

to preserve the joint function for at least 5 years, and the only downside was that I may

need to have a second surgical procedure, namely, that fusion.

So I went home and looked the device up on the Internet, and I discovered that it

had been successfully used in Europe and was now in research trials in North America,

namely, Canada. So I decided to enter the study. Then I had to wait to find out if I was

randomized or not to the Cartiva group, and I was quite definitely relieved when they called

me to say I was selected and that I would be receiving the Cartiva device.

And I must tell you, quite honestly, I had wondered whether I would go through with

it if I were randomized into the other part of the trial, to the fusion, because in my mind, of

course, being a scientist, I kind of figured that eventually it would be on the market if I

could hold out. But quite frankly, with the pain, I couldn't hold out. So anyway, I had the

surgery, and I received the implant, and I did all the recommended physical therapy, and

within 6 months I could do virtually anything I chose to do. And I was able to resume all of

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the activities from before I had any symptoms, which was a good 10 years back before the

pain started in that joint. And since my surgery, my husband and I now take an annual trip

to the south of France to escape Vancouver's rainy winter. And we go on long walks. We

can walk all day long. We have no restrictions. We can hike on all kinds of uneven ground,

and I'm truly glad not to be left behind. And back home I'm golfing, I'm hiking, I'm playing

tennis again. I'm doing yoga. I have had no restrictions that I can quite honestly share with

you.

When I go back to my doctor for checkups, and when he says, well, would you have

the surgery again, and of course I say, absolutely, in a minute. I have had no restrictions.

I'm pain free. Why wouldn't I? But I will share with you that I do have two regrets. I regret

that the device is only available once the joint is severely impaired, and I regret that if my

implant fails, I won't be offered it again.

So, in summary, I wish the Cartiva device had been available sooner in Canada. I'm

so glad I held out for the non-fusion option to treat the pain.

And thank you for your kind attention.

DR. RAO: Thank you, Ms. Butt.

Ms. Nancy Schmelter. Ms. Schmelter, you have 5 minutes.

MS. SCHMELTER: Thank you. Good afternoon. My name is Nancy Schmelter, and I

live in Vienna, Virginia. I was not reimbursed or paid for my travel expenses today.

I had arthritis in my great toe. I didn't even know I had a great toe until I entered

this process. I thought it was a big toe, but now I know that it is the great toe. After 5 years

of pain and an unsuccessful cheilectomy, I started looking at my treatment options. After

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doing research, I learned about the Cartiva product, and I wanted it for two reasons: (1) It

would preserve the natural motion in my toe, and also I knew that if for some reason the

Cartiva procedure didn't work, I would always have fusion as a fallback option. Both of

these considerations were very important to me.

I knew the product was not yet available in the United States, so I explored having

the surgery done in Canada. I learned that this was not an option, even if I offered to pay

for it myself, due to Canadian insurance restrictions. In the U.S., my only option was fusion.

So in November of 2014, I had the first metatarsal joint of my great toe fused. For

the most part, I'm satisfied with my fusion, and it mostly took care of my pain. But to me,

fusion means the following: I need to walk and run in an entirely new way. Because of

that, I now have pain in the joint next to the first metatarsal joint. I can't really tiptoe

anymore. So this means, whenever I reach for something on a high shelf, whenever I stoop

down to pick up something off the floor or even just walking up and down the stairs, I am

reminded that my right toe is fused. You don't realize how often you use that joint until

that natural motion is no longer there.

My big toe is fused slightly angled up, and this was intentional. But because my toe

doesn't now fully touch the ground when I'm standing, my balance is a little different, and

I've adjusted for that. And it's not really a huge problem now, but I worry about when I get

older, that it will become a problem. My ability to keep active, and fit has also been

negatively impacted. Tennis is my sport of choice. I love tennis. It's how I get my exercise.

Prior to my surgeries, I played competitive singles tennis about three or four times a week.

Since then, I don't play the same level anymore. I can't run as well, and I can't cover the

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court as well. I do play doubles, and it's fun and it's social, but it's just not the same, and

I'm not getting the same level of exercise.

I did need to have another surgery this past December because one of the screws

started to come out. This is my third surgery in 3 years.

Finally, it's extremely difficult purchasing attractive shoes that fit well. And I know

this may seem very trivial to some of you. We all have friends and family members with

battling cancer and other chronic diseases, but I cannot wear high heels anymore. A stylish

pair of boots in the winter, wearing a nice pair of pumps with a work dress, these are just

not options for me. I'm not very tall, and wearing flats to a cocktail party or a special

occasion is not really flattering. It limits my clothing choices as well. This is something that

matters to me on an everyday basis.

Before the fusion surgery, my doctor warned me about the potential adverse effects

that the fusion surgery had: gait abnormalities, arthritis pain in adjacent joints, and shoe-fit

problems. I have experienced all three of those. Even though the fusion is not -- is the

most common procedure in the United States, I really wish that I had an option and you all

would consider allowing the Cartiva product to be available.

Thank you for considering my experience.

DR. RAO: Thank you, Ms. Schmelter.

John O'Meara. Mr. O'Meara, you have 5 minutes.

MR. O'MEARA: Thank you. Thank you to the members of the FDA Panel. My name

is John O'Meara, and I'm from Vancouver, British Columbia, and Cartiva has paid for the

travel expenses for me to attend this meeting. I was in the Cartiva MOTION study, and I am

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one of the MTP osteoarthritis patients you have been discussing today. Let me tell you a

little bit about myself and experience with this condition.

Before I got arthritis in my big toe, I was quite active. I ran marathons, and I've run

the Boston Marathon a couple times, and things changed significantly after I got arthritis.

And I did get the arthritis from all my running. I'd run thousands of kilometers every year

and eventually got arthritis in the big toe. And also the pain got so bad that I did have to

eventually stop running. And then it got to the point where even walking hurt. So quite a

significant impact on my life.

When the pain got that bad, I went to see a podiatrist. My GP recommended a

podiatrist. He said, you'll really like this guy. He can help you. He can -- so anyways, he

proposed a treatment to help the pain in my big toe, and it involved grinding the bone

down with a big grinder, and he thought that would work. But of course it didn't. And then

unfortunately, when that didn't work, when I went walking and running, it still hurt, and I

was very limited in my movement.

Of course, my next step was to see the orthopedic surgeon in British Columbia, at

St. Paul's. He explained that my cartilage was worn out, and he told me about the Cartiva

MOTION study, which really intrigued me. So, of course, like everybody else, I went home

and looked up the device on the Internet, and I decided yes, I would be part of the study. I

signed up, first of all, because I thought I was going to get the Cartiva device. I was sold on

that. And then I found out I had been randomized into the fusion arm of the surgery, and

then I had the surgery, and that was 3 years ago.

After the surgery, after the fusion surgery, rather, I needed to wear a ski boot for 10

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weeks straight, 24 hours a day. Because the surgery was on my right foot, of course, that

meant I couldn't drive. And I'm a generic pharmaceutical sales rep in Vancouver, so

obviously a huge inconvenience because I drove every day. And my wife, who traveled with

me this week, she was my chauffer for 10 weeks straight. And that was tough. Tough on

her actually. And at the end of 10 weeks, it's kind of funny, I had a 2,200 km road trip,

which she drove every step of the way, and at the end of the 10 weeks, she said she was

quitting, and I said, that's okay, I didn't need her anymore. So that worked out fine.

I thought that having my toe fused was going to relieve all my pain, but I still had

some pain. And there are other issues too. For example, the toe is rock solid. And I know

that was the point of the surgery, but it just doesn't feel a hundred percent right to have a

toe that's a hundred percent fused.

According to the questionnaire I filled out after my surgery, I had great function. At

my 2-year follow-up visit, my score was 99 out of 100, but the questionnaire is quite

general. Yes, I can walk without any trouble, and I can go up and down stairs easily.

However, if I do pushups in the gym, my left foot bends normally but the right foot, the toe

doesn't give at all. And there are four screws in my toe still, and I can feel those every day.

Another problem is the position of my fused toe. He fused it too close to the second

toe, so I have to wear a spacer between the two toes because otherwise it rubs, and it

wears all the skin off both toes, and it's quite painful. I don't know if he was serious, but my

doctor said he could re-break my toe and set it in a different position, but I didn't really

want to go through the ski boot thing again for 10 weeks.

After all of this, I'm still unable to return to running. When I tried to run, I needed to

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stop because my toe hurt even after 1 km. Also my toe -- my foot slaps down in a weird

motion, and at this point I have to avoid running. And interestingly, since I've had this toe

fusion, I have a sore hip because my gait has changed greatly for walking and any kind of

gym activity I do. So it's kind of affected my hip at this point as well. I still try to be active.

I can go hiking, but I need to use a certain brand of shoe that's got a rounded bottom to

make it easier to walk. Fusion, yes, has gotten rid of most of the pain in the big toe, but it

doesn't feel a hundred percent right, and I miss the motion that I used to have with my big

toe. And during your discussions this afternoon, I thought it was important to let you know

of the drawbacks of having a fused toe.

So thank you for letting me share my perspective.

DR. RAO: Thank you very much, Mr. O'Meara.

Ms. Janet Geisberger. Ms. Geisberger, you have 5 minutes.

MS. GEISBERGER: Thank you. Good afternoon, and thank you for allowing me to

present. I'm Janet Geisberger. I'm from Toronto, Ontario, Canada. I am the director of

corporate services for the Information and Privacy Commission of Ontario. We agree with

full disclosure, so yes, Cartiva has paid for my trip down.

I'd like to tell you my story. Before I got arthritis in my big toes, I was never an

athlete, but I was active, and that's important to know. In the winter, I would be a downhill

skier, going west for a week's holiday every year. And in the summer, I'm active with my

yacht club. This includes racing 30-foot boats twice a week, running races one night a week,

and most weekends I would be running races. My position in the past has been the

foredecker, and if you know anything about sailing or not, it's at the pointy end of the boat,

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putting up the pretty colored sails. So you're bouncing, the boat's heeled, and you're

working like mad to put up sails in a race. So that's what I was doing.

Then I started having trouble with my toes, and certain shoes became

uncomfortable. I couldn't get into my ski boots, and long walks became painful. I live in

downtown Toronto, and I do not have a car. So all of those errands that you do with your

cars, I do with my feet. So I have to continue to walk every day. The pain kept getting

worse, and walking became more difficult. So I saw my GP to make sure my name was on a

list to see a specialist, to see what could be done. When I got to the specialist, he asked me

about my symptoms and my activities, and I explained to him about the sailing, and he said

we have a relatively new Cartiva device, and I think it would be a good option for you. If it

doesn't work, we can always try fusion. And I said, okay, what the heck.

So I had the surgery in 2009 and had Cartiva devices implanted in both big toes on

the same day. In a very short recovery period, about 2 weeks, I was back to walking around

town, but without pain. I don't avoid doing anything because of my feet. I really don't

think about the implants at all. I'm still skiing. And, in fact, it's the first time in a long time I

haven't gone west. I don't know why.

Race management is a big part of my retirement, and I should be able to apply for

my Canadian race officer's certificate this fall, and I'll be 1 of 16 people in Canada to have

that. Why I'm telling you this, because the implants make this possible for me to work all

day on a committee boat. What does that look like? Well, you take out a 36-foot fishing

boat, you anchor it. Hopefully there's wind and 4- or 5-foot swells. So the boat's going like

this all day long, and then it hits the anchor, and it yanks back. So it's constantly moving.

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I'm out there for 8 hours a day, and on a weekend, it would be both Saturday and Sunday.

So as the race officer, my job is to start the race, set the course, watch the weather, et

cetera, and hopefully get three races in, in a day. Part of that, though, has me running the

full length of the boat, back and forth, checking wind directions, running back to the stern

to do starts and finish lines and hopefully get the three races in so the sailors are happy.

I'm moving, the boat's moving. I'm pain free at the end of the day. Hopefully the sailors are

happy, but we'll find out.

Many times throughout the day, my hands are full of the tools of the trade. So I'm

standing on that boat while it's moving, not holding on. What did your mother say? Always

hold on to the boat. Well, it's sort of balancing on a balancing ball because your feet are

constantly telling you where the boat is and you're constantly balancing. So that's what I

do, because if you don't balance, you end up in the water, and the sailors get angry because

you're not running races. And that doesn't look good.

So I'm here, 7 years in, and I'm very happy with the results. I'd like to thank Cartiva

for the implants and making my retirement plans a possibility. And thank you for your time

today. Thank you very much.

DR. RAO: Thank you very much, Ms. Geisberger.

Does anyone in the audience wish to address the Panel at this time? If so, please

come forward to the podium and state your name, affiliation, and indicate your financial

interests. You will be given 3 minutes to address the Panel.

(No response.)

DR. RAO: Seeing none, are there any questions from the Panel members for the

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open public speakers?

DR. PFEFFER: Yes, sir.


DR. PFEFFER: Where's that nice person from Vancouver?

DR. RAO: They're all from Vancouver.

(Laughter.)

DR. PFEFFER: Who was that? Everybody. No, I think it was -- no, I think it was you

in the nice blue scarf. I have a question for you about something you said. You said that

you didn't want a fusion, so you were very happy that there was an option in the Cartiva

device. Were there any other options that you knew of, other than a fusion or a Cartiva

device or live with the pain?

MS. BUTT: So if I understand the question, when I went in, I knew I didn't want a

fusion. Did I know of any other options?

DR. PFEFFER: Right.

MS. BUTT: I had looked on the Internet and understood that there were other

devices that could be, to me, in my layman's terms, like artificial joints.

DR. PFEFFER: Uh-huh.

MS. BUTT: So I did go with those questions to the surgeon, and when I posed them,

that's when he informed me that (1) he didn't do those procedures, much like I heard from

some of the folks this morning, because of the fail rate, because if they go bad, it's very bad,

and I wouldn't be able to have a fusion after that.

DR. PFEFFER: Um-hum.

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MS. BUTT: I would lose a lot of options. So I was quite upset when I heard that, and

I didn't know about the Cartiva, but it seemed to me that I was only going to have one

option, and which was the fusion. And I was at the point in time where it was -- I had to do

something. I had no choice.

DR. PFEFFER: No, thank you so much for giving us your input. So as I take home

from this, then, you weren't presented with options that preserve motion and don't put an

implant in the joint. You won't know these terms, but --

MS. BUTT: No.

DR. PFEFFER: -- I would explain it to you if you were my patient, and I would say you

don't have to have an implant, and if you want to keep motion, we can tuck some of the

soft tissue from your joint into it and you'll do very well without burning bridges. That type

of discussion, from what I took down of your notes, didn't take place with you because it

sounds like your doctor didn't do those things.

MS. BUTT: Well, about 5 years before I went to see the surgeon, I did go to another

-- I guess it would be like a podiatrist, who suggested they could debride that --

DR. PFEFFER: Um-hum.

MS. BUTT: -- but also said that really what I would need to have at that point, even 5

years previous, was a fusion.

DR. PFEFFER: I think I understand it.

MS. BUTT: Okay.

DR. PFEFFER: Thank you.

MS. BUTT: Thank you.

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DR. RAO: Are there any other questions for the public speakers at this time?

(No response.)

DR. RAO: Seeing none, I now pronounce the Open Public Hearing to be officially

closed. We will now continue the Panel deliberations. As a reminder, although this portion

is open to public observers, public attendees may not participate except at the specific

request of the Panel Chair. Additionally, we request that all persons who are asked to

speak identify themselves each time. This helps the transcriptionist to identify the

speakers.

Is the Sponsor prepared to respond to the Panel's questions posed this morning?

MS. MOORE: Yes, Chairman Rao.

DR. RAO: Let's go ahead and get started, then.

MS. MOORE: Okay. I would like to propose, if this is possible, that we've grouped

the questions into the appropriate categories based on some of the baseline characteristics,

radiography, function, those kinds of things, and we'll address them in that order, if that

makes sense to you.

DR. RAO: That sounds good. And then as you -- after you're done with each theme,

if you just pause a second, then we'll see if there's any specific questions on that theme,

and we move to the next theme.

MS. MOORE: Okay, it makes sense. And actually, Debbie Moore, for the record as

well. So one of the questions that was raised earlier in the morning was related to the non-

inferiority margin and looking at the non-inferiority rates. And so I would like Greg Maislin,

who is our statistician, to address that question.

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MR. MAISLIN: I'm Greg Maislin, principal biostatistician of Biomedical Statistical

Consulting, which receives compensation for biostatistical services rendered to support the

study. This is my only financial relationship with the Sponsor.

First, I want to thank Dr. Blumenstein for his great graphical demonstration of the

implications of designing a non-inferiority study using either a fixed margin approach or a

fixed odds ratio approach relative to the expected observed success rates. In fact, the

Cartiva study was indeed designed with a fixed margin of 15%.

How do I get that slide up? Thank you. But as Dr. Blumenstein's graphical

representation demonstrated in the title, had the fixed odds ratio approach been used, the

target threshold would've been 11%. As the slide shows, the study would have achieved its

study success criterion using this alternative approach. It is also important to note that the

composite success rates on the slide are nearly identical between the Cartiva and fusion

groups in all analysis sets.

Thank you.

DR. RAO: Are there any questions in response to this specific response?

Dr. Blumenstein.

DR. BLUMENSTEIN: Thank you for that. So I'm wondering if you can pull up page 37

of your Exec Summary briefing book. Is that possible?

MS. MOORE: One second, please. As clarification, that's not a table, correct? That's

just text?

DR. BLUMENSTEIN: Yes, it has to do with how you computed your trial size.

MS. MOORE: Right. I don't believe we have the text of that in slide formation.

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DR. BLUMENSTEIN: I think I can wing it. So when you computed your trial size, you

used a specification of 60% response in the control arm, and you also specified 64% in the

experimental arm. And so what I'm wondering is how this was used in the analysis, in the

analyses that you did.

MS. MOORE: Okay, I'll let Mr. Maislin respond to that.

MR. MAISLIN: Those were indeed the a priori assumptions. The expectation was

60% success rate for the control and 64% success rate for the experimental device based on

the clinician's expert opinion about the advantages. That's the only place where those

numbers were used, just in the design. They were not used in the analysis.

DR. BLUMENSTEIN: Okay. So that's kind of an unusual specification, that is, what

you're doing is really spotting the experimental arm and the four-point advantage over the

control arm prior to computing the trial size required.

MR. MAISLIN: Yes.

DR. BLUMENSTEIN: What's the justification for that?

MR. MAISLIN: I think there's text that you were referring to, that the justification

was the preservation of motion and an expectation of greater success rate.

DR. BLUMENSTEIN: Okay, so you did that. And I have my own method of computing

these things. I computed your trial size requirement at 183 using that method. You

computed it at 177. That difference is not worth considering. But then I went back and

computed it based on making the control arm response proportion equal to the

experimental arm response proportion. Instead of getting a total of 183 patients required, I

get that 297 patients were required if you do not make that assumption. Can you comment

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on that?

MS. MOORE: The observed success rate wasn't known until the end of the study, so

it would be difficult to evaluate that. We did an interim analysis on 70 patients to justify

our sample size calculations, and that assessment indicated that the sample size was

appropriate at that time. And again, I guess I think it's also important to note that the

observed success rate that we saw in both groups was nearly 80%, almost identical between

the groups. And if there was a difference, it was not clinically significant. And I think that

there is a lot of discussion between the 10 and 15, but I think what's important is that's a

clinically observed difference that's insignificant to the clinicians.

DR. BLUMENSTEIN: Well, my question isn't really about the margin here so much,

although it had something to do with it. The question is that you made an assumption that

you were somewhat superior, four points superior, in the experimental arm than you would

be in the control arm.

MS. MOORE: It was a very small advantage. And again, because the literature was

lacking these results, we really didn't have a way to truly estimate either group's success

rate. And I think if your -- if we, in fact, had a larger sample size in the study, what the

effect of that would've been is we would've shown actually even below the non-inferiority

margin that we showed of 10%. If we had more patients, we would've shown even a tighter

window of the lower bound. And so hopefully that answers your question.

DR. BLUMENSTEIN: Well, other than pointing out that the margin is dependent on

what the control arm outcome is if you're using the fixed odds ratio method. I'm not really

commenting on the margin. I'll leave that to other people, since this is really an intuitive

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determination. But this assumption that you were somewhat superior could lead to -- well,

it does. If you had not made that assumption, you would've required a much larger trial. I

mean, I computed 183 using my formula. You computed 177. Taking that advantage away,

I computed 297 required without correction for dropouts.

MS. MOORE: Right, I don't have that analysis --

DR. BLUMENSTEIN: That's a much larger trial. I mean, that's not trivial and --

MS. MOORE: No, I understand that, but I think my point being that if we had a larger

trial with the same success rates that we saw in the study, we would actually have a lower

bound that's even lower. And so I think that's what's important, that we would continue to

show the same level of success rate that we had.

DR. RAO: Dr. Golish.

DR. GOLISH: This is a direct follow-up on Dr. Blumenstein's important points and the

lady's response. You know, take succor that you're not the first sponsor in recent memory

who has misestimated the effect sizes of their control and experimental arms in designing

their trial a priori, checked to those at an interim of final analysis, realize that your

observed effect sizes are different and in fact smaller, and then gone back and calculated

what would've been your computed end from that and gotten an unwelcomed response.

Okay, this has happened in recent memory. And so the critique that you've pointed out,

that, well, if we had done it differently, our n would've been larger and that would've

actually helped us is an important one because there's some truth to that.

And so having a study that is essentially underpowered, as Dr. Blumenstein is

pointing out, and a small n, only really hurts the sponsor. But it does leave open the

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question where the data from the trial are kind of finely balanced on its input parameters,

and you all have been very candid that the input parameter of the 15% non-inferiority

margin is really just a clinical thumb sketch. You've been clear that it's based on very few

data. But it's also apparent to you that there's really only two rigorous ways to design a

non-inferiority margin: (1) with a three-arm trial, and (2) with a previous trial, the nearly

identical structure of the superiority trial over the active controls, neither of which you

have.

So in the absence of that, that doesn't mean you can't do anything, but it does mean

that your non-inferiority margins, they're a very rough, as you have put it clearly and

appropriately, clinical thumbnail sketch. And so the under-power does come back to haunt

you in that particular way and that it leaves -- it sort of endlessly leaves open this non-

inferiority question. If you had had that larger trial and got better numbers and showed

that your margin could've been all the way down to 7%, then everybody would be

persuaded that this 15/10 issue is irrelevant.

MS. MOORE: Well, I guess I want to clarify. I don't believe our study is

underpowered. And further, we did an interim analysis that looked at sample size, and at

that time the sample size was determined to be appropriate. We did not need to make any

adjustments accordingly.

DR. GOLISH: Okay, that's a very important point. But your interim analysis, it looked

like your original analysis was spot on, and then now, at your final analysis, it turns out

that's not true. So that belies your statement that if you continued the trial, you'd get the

same numbers as your current analysis; that could change yet still.

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MS. MOORE: Let me clarify. The outcome results were not necessarily 60 and 64 at

the interim analysis, but the difference between the two groups was comparable, and that

was what we evaluated, whether or not the sample size was appropriate.

DR. GOLISH: Thank you.

MS. MOORE: Thank you.

DR. BLUMENSTEIN: And just one more little follow-up on this.

DR. RAO: Dr. Blumenstein, just one second. I'd like the FDA to also respond to

Dr. Blumenstein's comments, so if you get that prepared while he's making his comments

currently.

DR. BLUMENSTEIN: When you asked people to come up with that 15-point non-

inferiority margin, were they informed that you were going to give a 4-point spot to the

experimental arm when you planned the trial?

MS. MOORE: Absolutely. Dr. Baumhauer was instrumental in helping us develop

that. We were very upfront about all of our assumptions, and those were developed in

concert with Dr. Baumhauer. Actually, Dr. Daniels as well. And so they were in agreement

with that and also in agreement with our approach as we moved forward.

DR. RAO: Mr. Van Orden, do you have comments on Dr. Blumenstein's question?

MR. VAN ORDEN: Yeah. This is Alvin Van Orden.

We're certainly used to companies not guessing exactly right, and there is -- I mean,

what they missed in the 4%, I think as they get to the 80%, that works. You don't need to

show the same difference as you get closer to the tails, right? There's less variability. So I

think it kind of balanced out. I mean, I think they're correct in saying that it's not

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underpowered, if that answers the question.


DR. HECKMAN: Did you run this by the FDA at the time of the planning, as well as

Dr. Baumhauer and the study group? When did the FDA get involved in this? Did they have

knowledge about this discrepancy at the time they gave you advice about setting up the

study?

MS. MOORE: Yes, they did. So we developed it with the clinicians. Thank you. And

FDA.

DR. RAO: Dr. Gilbert.

DR. GILBERT: My question was very similar to Dr. Heckman's, and maybe I'll say it a

little differently. Somewhere in the planning of this study, 15% was discussed and you

proceeded with that. I'm sure FDA was aware of that and you had discussions. I'm not

entirely clear whether they said that's okay at the time, and now it's changed to 10%. And

then we have Dr. Blumenstein who's come and has done an independent analysis using the

odds ratio, and I'm out of my depth at this point, but the bottom line was this 11%

difference. And now the statistician from the Sponsor comes back, and says well, even with

that number, we're still below and showing a benefit. And so I'm just -- I want to make sure

I -- is that correct? Is my understanding of this, right now, kind of a correct understanding?

DR. BLUMENSTEIN: Well, I mean, I can tell you that what the statistician said about

passing criterion with a 15% pre-specified fixed margin; yes, they seem to pass criterion. If

you use the fixed hazard -- not hazard ratio, odds ratio method, yes, it would have been 11

points with an 80% proportion for withdrawal. But I would point out that if you change

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down from 15 to something else, say 10, as the FDA has suggested, that the margin would

have then been 7 points, not 11.

DR. GILBERT: Just to follow up. That 15%, as I understand it, came from the clinician

discussion in establishing the study, right? So the initial input was not really a statistical-

based input; it was just sort of the expertise of the clinicians in trying to set that number.

DR. BLUMENSTEIN: You know, in designing non-inferiority trials, sometimes that's

all you can do. Whether or not you agree with 15 points is part of the question. Whether

you agree with 15 points being specified with a 4-point advantage given to the experimental

arm in addition to that has to do with the power of the study and how it's interpreted and

so on. So it's not a simple matter, and it never is with non-inferiority trials.

MS. MOORE: Chairman Rao, may I please respond to that, as well? I think it was a

combination of clinical input of what was clinically -- the insignificant difference was one

piece of it, but there was regulatory precedence. As I reviewed in my presentation, the

STAR Ankle that was just -- had been -- gone to Panel, approved right after we were done, it

was available at the time when we were designing our study, and they had a 15% non-

inferiority margin that was for overall safety and -- overall success and safety. And so those

two components were what we evaluated.

And to answer your question regarding FDA, FDA did indicate early on that they

would prefer a margin that was different. They asked to do -- provide clinical justification,

and I'll defer to FDA to speak specifically to their comments on that.

DR. RAO: Thank you.

Dr. Pfeffer.

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DR. BLUMENSTEIN: But on the precedent -- let me ask a question. You cited a

precedent, and you said a 15-point margin was used in that precedent, but you didn't say

what the control arm proportion of response would have been or was for that precedent.

MS. MOORE: That is correct. And off the top of my head, I don't recall what that is.

DR. RAO: Dr. Pfeffer and then Dr. Trier after that.

DR. PFEFFER: I wish I understood every bit of this, but I don't, and I think a lot of the

Panel members don't understand every bit of this. And I think my vote for these things

won't sway, honestly, however fascinating I find it, on the outer bounds of my statistical --

far outer bounds and my statistical knowledge. So I'd like to review something that I take

away from this and I'd have anybody in the room comment on it.

The Sponsor's commentary I'm reading verbatim. The 15% delta from the study

group was considered appropriate by you guys, not because of any of the statistical issues.

At least I don't find that in the writing. And you talk about less restrictive postoperative

instructions. None of the clinicians who I know here are going to convince me that that

makes a difference, really. Return to better quality of life. You know, you haven't shown

that. So what you do say is that the 15% was because of a quicker rehabilitation,

meaningless to me. But the ability to maintain motion of a joint, right, that's why

Dr. Baumhauer's not -- that's why the Sponsor came up with the 15%. Now, we can discuss

that. Okay. Then, as I understand it, FDA from the beginning commented on this, and I'd

like FDA's comment on that. And FDA recommended an MCID in a way that I've never

heard discussed, the maximal, not minimal, but the minimal clinically important difference.

Now, I'd like to know when FDA recommended that. That would certainly make a

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difference if millions of dollars were spent with FDA approval only to have them turn in the

middle of the study. That would affect me, but that's how I get this 15%, right?

So as a panel, we need to decide whether this increase of motion was worth that

extra 5% that they got, as opposed to other orthopedic implants that are 10%. Is that a fair,

real, distilled, simple summary from FDA and the Sponsor's point of view? And if not, help

me out.

DR. RAO: Well, let me just expand on that a little bit --

DR. PFEFFER: Please.

DR. RAO: -- also, Dr. Pfeffer. From the little reading I did on the whole concept of

non-inferiority studies -- I'll get back to you, Dr. Trier, in a second -- the basic idea is that, in

not doing a superiority study, because you're assuming that the trial arm is going to be a

little inferior to the control arm, and you're assuming that the trial arm will be inferior, but

you're still willing to go ahead because of some presumed advantages of the trial product --

the trial product in this case -- the advantage, like Dr. Pfeffer points out, is the preserved

range of motion. But it's not just preserved range of motion from 23 to 29 degrees, but it's

also the consequences of the preserved range of motion.

Now, the only objective data we have to assess whether this range of motion

actually helped is the FAAM ADL and the FAAM Sports. Now, if we are told that if we

exclude that 9-point negative that was included as being acceptable, if we look at the raw

scores, both the FAAM ADL and the FAAM Sports, if both of those scores are less than the

fusion group, which is my understanding -- the raw scores -- then the consequences of this

preserved range of motion are negated. Now, if the consequences of the preserved range

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of motion are negated, is that non-inferiority margin still acceptable? That's the question

I'd like the Sponsors to answer, to respond to.

And I'd like also the FDA to respond to that. How do you assess the validity of any

non-inferiority margin? Forget about 15%. Let's say 7%, 9%, but there's a presumption that

the negatives are acceptable because of the presumed advantages. Now, if the presumed

advantages are not shown, what happens to that non-inferiority margin? I'd like maybe the

FDA to respond to that first, and then I'll go back to the Sponsors, to give the Sponsors a

little more time. And then Dr. Trier after that.

DR. COYNE: This is Dr. Larry Coyne of the FDA.

That actually is precisely one of the issues that we are bringing to the Panel, and

which we'd like their feedback. We've made that very point. I did want to clarify that it's

been stated a number of times that the FDA is recommending a 10% delta. That's actually

not the case. We're actually looking for the Panel's input on that.

DR. RAO: Thank you.

DR. COYNE: We do cite that a 10% non-inferiority margin has typically been utilized

in other orthopedic implant non-inferiority studies. That's correct. The Sponsor also

brought up the question of the -- brought up and cited as a precedent the STAR Ankle PMA.

There was a question associated with that, on whether there was any discussion of that

with the Sponsor. I can only talk about what is actually available within the public domain.

You have the summary of safety and effectiveness data, or the SSED, for the approved PMA

in the Panel transcript, and the Sponsor is correct that there is -- was no discussion of that.

DR. PFEFFER: I'm sorry, but when did this start? In other words, the FDA -- I can't

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find it out of the thousand pages of paperwork, but I think my almost exact memory is, is

FDA is asking our Panel about the 15%, and FDA feels that the maximal clinically important

difference would be a better reference mark than a 15% non-inferiority. I could find your

own writing for that, but I don't get that. When did you tell these people, when did you tell

Cartiva that, and why is the MCID maximal clinically -- which I've never even heard of --

better in your mind than the 15% non-inferiority? We need to know that, right? I don't

mean to glom on it, but I can't vote without understanding that.

DR. RAO: Thank you.

Dr. Coyne, let me let you off the hook now for a second. I want to give the Sponsors

just a couple more minutes to prepare their response to my specific question. But in the

meantime, let me get Dr. Blumenstein's opinion on what happens to the inferiority margin,

non-inferiority margin, if the presumed advantages are negated or there's no evidence for

the presumed. What's the theoretical implications on that non-inferiority margin?

DR. BLUMENSTEIN: Well, I'm going to be -- I'm going to repeat something I said

before. Non-inferiority trials are anything but simple, and what you have here is a

composite binary endpoint that includes an element that assesses the putative benefit of

the device. Normally, when a non-inferiority trial is done, the outcome, the binary outcome

does not include the benefit because it's usually focused on adverse events being the

benefit. In other words, you have a new treatment that you think is, for all intents and

purposes, equivalent to a precedent, and what you're trying to show is that you at least get

that. And there might be other advantages like a lower frequency of AEs or a certain type

of AEs or whatever. In this case it's complicated by the fact that the composite binary

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outcome has both the disadvantages and the advantages in it, and then they put an

increment on the experimental arm, and then they determined that it would be 15 points

that was appropriate. I can't comment on the 15 points. That's strictly a judgmental thing.

But I would say this, that whenever the margin is discussed or the precedent for a

margin, as in this case the precedent being also a margin that was just made up out of

intuition or whatever, that you must talk about what the control arm proportion of

response is. Because if the proportion of response in the control arm is 90% and you're

saying that a margin is 15, that is a completely different meaning than if you say that the

control arm proportion is expected to be 50% and you have a 15-point margin. You see?

So that's why I was asking about what was the precedent that was decided -- cited as

being 15 points? Why that's confusing to me is because I don't know what the control arm

expectation was, or the reality of it or whatever, for that precedent. So I would argue that

whenever one talks about non-inferiority margins in this kind of a context, that you must

always identify either the expected or the actual control arm proportion.

MS. MOORE: Sure. Can I --

DR. RAO: Is the Sponsor prepared to respond on two specific issues: number one,

the reliability of any margin level when the presumed advantages are not demonstrable,

and number two, Dr. Pfeffer's maximal insistence on the maximal CID?

MS. MOORE: Yeah. Well, I guess there are a couple questions, and I think there's

also a question regarding what the timing was when FDA told us specifically the 10%. So in

the early discussions with FDA in 2009 -- and I mentioned we had five total discussions

throughout that course -- they only indicated that they would recommend a lower margin

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without giving us a specific number. We provided clinical justification, we felt, that was

appropriate. Then after the PMA was submitted, that's when we learned that 10% was

what the number was that they thought was appropriate. And again, I think it's important.

We are talking about 15%, but that's the assumption going into the trial. I think

everybody on the Panel needs to think about what the non-inferiority margin was observed

in the study, which was nearly 10%. So irregardless of what was estimated in the beginning

of the study, as you'll see on the slide, we saw nearly a 10% non-inferiority margin. It

becomes somewhat of a moot point, the 10 versus 15%.

With respect to why the FAAM Sports didn't show that particular benefit of range of

motion, I think I'd like Dr. Baumhauer to speak to that and address that.

DR. RAO: There's a statistical issue in there, too. The question is if the FAAM score

doesn't show an impact of that range of motion preservation, then what effect does that

lack of demonstration have on the validity of the non-inferiority margin?

MS. MOORE: Well, because the non-inferiority margin wasn't based on the

assumption that the FAAM score itself was going to have that significant a benefit. Cartiva

showed 81% or 79 -- excuse me -- 79% versus 78%. We did, in fact, show that we were

slightly better in our success rates over time. That's what we assumed. Again, it was a

larger number, but the difference wasn't as small. Our clinical rationale was based on the

advantages of something that's not reflected in our primary endpoint, so range of motion is

not incorporated in our primary endpoint. Unlike STAR, which actually had range of motion

as part of that assessment tool, we weren't allowed to incorporate that into our primary

endpoint because there's no validated measure that incorporates that. That's a very

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important feature of a motion-preserving device, is having range of motion. We couldn't

incorporate that in a valid way. If we did, every fusion subject would have been a failure.

DR. BLUMENSTEIN: Well, but the consequences of range of motion are related to

that third element of your composite endpoint, correct?

DR. BAUMHAUER: So the FAAM score, which has some generalized questions, as we

saw earlier from the FDA popping those up, we know that it doesn't actually measure how

well someone moves their great toe. What it does is it asks a little complicated, complex

activity. And we just heard from our patients that told us how they had to adjust to be able

to do some of those activities with a fused toe. It speaks to the item that yes, they may be

able to do it, but they don't do it in a functional way. And does that impair their ability to

do it? Yes, it does. We heard it from the horse's mouth, if you will.

Secondly, the FAAM -- I don't know anything about this maximum clinically

important difference. I've never heard of it. I do have my master's in public health. It

doesn't mean I'm a statistical wizard, I guarantee that. But I do know the minimally

clinically important difference, and there was a question about that, about should we use a

different value than the published value from the original paper in 2005? The 8 points is a

validated score, and I did not find any other literature that indicated any other scores were

validated for a more generalized patient population. I saw a different value for diabetics,

but that wasn't our patient population here. I did also take the liberty to e-mail the author

of that paper for the validation study, and he is not aware of any either. So I apologize if

I'm unable to answer that question, but I'm not aware of anything, and I could not come up

with any information in regards to that.

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Now, we do recognize that the FAAM scores, the median FAAM scores were identical

at 12 and 24 months. The median FAAM scores were identical for these two groups. That

tells us that the patients are functioning at a very high level, and this is some of the

information that I presented previously.

Does that answer your question, Chairman?

DR. RAO: Actually, it's a little off, but I think it's good. Thank you.

DR. BAUMHAUER: Thank you.

DR. RAO Dr. Sayeed had a question. And actually, before that -- Dr. Sayeed, I

apologize. Dr. Trier had a question earlier, and I've neglected her.

DR. TRIER: Thank you.

Yes, this is Dr. Trier, and this is a question to FDA. At least based on my knowledge,

when you look at studies of this type and you do a non-inferiority study, that there's no

magic number of what the non-inferiority margin needs to be and that there are -- correct

me if I'm wrong, but there are studies that have an eight-point non-inferiority margin. FDA

is saying that they looked at 10% or 10 points. The Sponsor made a case for 15 points.

What's the decision making, the criteria, I guess, that you would use in determining

what is an appropriate non-inferiority margin, and is it in fact based on literature and

clinical input and guidance?

MR. MELKERSON: This is Mark Melkerson. I'm going to jump in, in terms of timing

and other things. The Orthopedic Division actually had a workshop on what's a clinically

important -- let me get this right -- minimally important clinical difference in orthopedic

devices. It was a 2-day workshop, and we picked on different prostheses. So citing a

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previous PMA, my understanding is the PMA was about the same time as this workshop.

But the issue of coming up with a justification is just that, what's a clinically relevant

difference for determination? So typically -- and I'll use the Harris Hip Score because I'm

familiar with it -- there's a 10-point difference and you go 90 to 100 is excellent, 80 to 90 is

good, so a 10-point difference is clinically meaningful. In the issue of having a composite

endpoint, it's going to be the combination of what's a clinically meaningful difference for

each of those individual scores and can you justify it from literature?

So the short answer is, there is probably no right or wrong answer in terms of, from

a clinician's point of view and a patient's point of view, how do you define what can be

distinguished between a good outcome and a bad outcome? Knee Society Score, the same

type of thing. But those are scores that have been used in literature. With a device for the

great toe, there aren't many studies out there that have validated scales, other than the

ones that they've been citing today. And then it gets back down to the literature, as to

which, Dr. Sayeed mentioned earlier, is what does the literature report is an important

difference?

DR. RAO: Thank you, Mr. Melkerson.

DR. TRIER: If I could just add one comment. You know, that was really my point,

Mark, that you know there isn't a golden number, that it is the justification. And it's a

composite of what you put together as the rationale for the determination of that non-

inferiority margin.

DR. RAO: Dr. Sayeed.

DR. SAYEED: So I have two questions actually. The first one is for Dr. Coyne, Slide

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74. You had mentioned, in your FAAM ADLs over 2 years, the only -- up on toes was the

only category where Cartiva performed better; is that correct?

MR. VAN ORDEN: Yes. If you look at each question individually, if you look at the no

difficulty, that was the one question. Yeah.

DR. SAYEED: My second question is, you know, when we're talking about functional

implications, the FAAM is a subjective scoring system, and so it's a Likert scale, and you

grade it on points. So basically you're telling me if a patient just chose, you know, one less

or one more, then you would get to eight out of however many questions it is. I think it's

15 or 18 questions. And then you're telling me that's clinically significant in terms of this

particular study. I'm having a hard time putting that together in terms of real clinical

functionality. Instead, why doesn't the FDA look at real functional outcomes like, you know,

whether or not a patient went back to work or whether or not a patient returned to sports?

It just seems like we're getting into nuances that maybe we shouldn't be getting into.

DR. RAO: Thank you, Dr. Sayeed.

Dr. Finnegan.

DR. FINNEGAN: So not only am I not a statistician, but in fact, the statistics are going

to come from the information that you put in, and there's a famous saying that says, you

know, what goes in comes out. So I have a couple of questions. First of all, there are

evidently 10 Cartivas that went to fusions. Can somebody give us some idea if these were

all the same problem, if they were, you know, people jumping off of roofs, out of trees, or

what exactly was the cause? The second part of that question is the Class III heterotopic

ossifications. Was their range of motion and function the same as everybody else's?

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DR. BAUMHAUER: So first, the first question is the Cartiva removals. There were 14

Cartiva removals and 12 of them were pain related. One was due to fibrosis or stiffness,

and one was due to progressive arthritis that involved the sesamoids. Those were the

indications for the removals.

And the second question? I'm sorry.

DR. FINNEGAN: So actually do you know why they had -- why did these patients

have pain?

DR. BAUMHAUER: They had ongoing pain within their joints. Now, we did look at

each one of those patients for any demographic indicators, any specific factors that would

have indicated to us that they might have been a poor choice to go have an implant placed

in. We could not define anything that became consistent, so it's unclear, but it was pain in

the joint.

DR. FINNEGAN: Did you do implant retrieval, and what did you find on implant

retrieval?

DR. BAUMHAUER: Yes, we did. We did implant retrieval, and I'm going to turn this

over to Debbie Moore to answer that question.

MS. MOORE: Yeah. So we analyzed all the explants that were returned to us, which

was the majority, more than the majority, and we evaluated them to determine if they were

still meeting the product specification, if they were appropriate. And we'll show you what

the implants look like. These are the exact implants that were removed. We looked at the

diameter, the height, determined if there was any wear on the implant, and we found no

abnormalities. There were no reports of infection or inflammatory reaction or mechanical

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failures at the time.

DR. FINNEGAN: Okay. And my last question to the clinicians is the heterotopic

ossification Class III. What was their range of motion and function?

MS. MOORE: We did an analysis actually looking at radiographic findings with range

of motion and found no clinical impact with respect to that.

Chairman Rao, I have about probably 20 different questions from lunch.

DR. RAO: I know. Yes.

MS. MOORE: I want to make sure that we get through those, and I want to make

sure that we're answering all the previous questions as well.

DR. RAO: Dr. Gilbert has a related quick question.

DR. GILBERT: Jeremy Gilbert.

Just a really quick follow-up to that. So any assessment of, like, impingement where

the device was no longer providing the functional separation in the joint?

MS. MOORE: That was evaluated at the time to determine if it was sort of a

mechanical failure, if you will, if the implant wasn't providing the appropriate intended

function, and that was not the case. It was just a patient's report of increased pain that

wasn't adequate to the patient. And many of those patients actually still had a significant

improvement in pain. It just wasn't enough for what they wanted.

DR. PFEFFER: Dr. Rao, we still haven't answered Dr. Heckman's question or mine. I

can read one sentence, which will answer it for everyone, unless the FDA or the Sponsor

disagree. This is from page 71 from FDA's summary. This is what it says here: "In feedback

provided to the Sponsor prior to the OUS study" -- prior, prior -- "the Agency recommended

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the use of a non-inferiority margin corresponding to a maximal clinically insignificant

difference in lieu of the 15% non-inferiority margin." I thought maximal was a typo. I've

looked it up, and it appears many times in FDA's report, Dr. Baumhauer.

And then it goes on: "A non-inferiority margin of 10% has typically been utilized in

non-inferiority studies for other orthopedic implants." This sentence is very persuasive

because when I read this, I say ha, FDA came to the Sponsor and said we recommend 10%.

The Sponsor came back and said no, we want to do 15%. And then FDA said well, we think

it should be the maximal clinically insignificant difference. But I see no data from FDA on

what that result would have been had FDA run those numbers, so I'm completely confused,

and I think everybody here has to be confused also.

MS. MOORE: In 2009 FDA did not request that we do 10%.

DR. BLUMENSTEIN: Let me clarify something here. When you say maximum

clinically important difference, that's a language that would be used in the non-inferiority

trial as opposed to the superiority trial, where --

DR. PFEFFER: Maximal. The Agency recommended a margin corresponding to a

maximum clinically insignificant difference.

DR. BLUMENSTEIN: Clinically insignificant difference. Yes, I'm sorry. Clinically

insignificant difference. That's language that is appropriate for a non-inferiority trial

because what you're trying to do is set up what defines inferiority, so you're trying to find

out what's insignificant about the deficit that you're going to get when you compare the

two interventions, whereas if you were doing a superiority trial, you want to achieve a

certain amount that you get the minimum.

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MS. MOORE: At the time --

DR. RAO: Okay.

MS. MOORE: Yeah.

DR. RAO: Let's move forward a little bit.

MS. MOORE: Right. Yes.

DR. RAO: And let's go to the next theme. What's the next theme?

MS. MOORE: The next theme I had was a couple of questions regarding patient

selection, possible bias, looking at specifically the OA Grade 2 subjects removed.

DR. RAO: Okay.

MS. MOORE: I'd like to have Dr. Daniels refer to that.

DR. RAO: Okay.

DR. DANIELS: Thank you. Tim Daniels. I've introduced myself.

So, first of all, I'd like to put up this slide. We did look at the Grade 3 and Grade 4

excluding the Grade 2, and the outcomes were similar, if not slightly better, when only the

Grade 3 and 4s were included.

I'd like to talk about selection bias because there's been an inference that patients

that were candidates for cheilectomy may have gotten the Cartiva, and also a question as to

why cheilectomy wasn't involved. First of all, this study was not advertised. It is patients

come in to the clinicians with a diagnosis of hallux rigidus. The clinician undergoes a

discussion with the patient about motion-preserving and motion-sacrificing procedures, and

one of these options for motion preserving was Cartiva. Now, you might ask, why didn't we

look at cheilectomy? Well, first of all, cheilectomies, although in the hands -- in your hands,

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Dr. Kelly, in a surgeon's hands, it does work. There's no literature to support that to any

great strength. In fact, the surgical recommendation for cheilectomy is a Grade C, whereas

fusion, which we all talk about the standard of care, has a Grade B recommendation in the

literature. So I assume it didn't make sense to compare a not-so-validated or a

recommended procedure to one that is new, and fusion was the obvious comparison, and I

think that also set the bar higher.

So patients were given the option of Cartiva and fusion. Every patient that came in

was a candidate for fusion. They all had pain at their joint. They all had joint space

narrowing, as the Coughlin grade indicates.

With regards to the hallux valgus portion, we did not -- the hallux valgus angle had to

be less than 20 degrees to decrease confounding factors, and there was no attempt at the

time of surgery to do any deformity correction. So this is purely to manage the arthritis.

The -- I'm just trying to get my thoughts together here. With regards to the actual

fusion procedure, these were all experienced surgeons that had done fusions for many

years. This is a standardized orthopedic procedure that's taught in residency, and we

anticipated that the surgeons would perform that procedure as per a standardized level of

acceptance. Whether screws or plates were used was again a surgeon preference.

And that's about what I have to say with regards to patient selection and some of

the points raised.

MS. MOORE: And then there is one additional -- I'm sorry, go ahead.

DR. RAO: If you could come back, Dr. Daniels. Dr. Kelly has a question for you.

DR. KELLY: I would actually call on my colleague, Dr. Pfeffer, I think -- to say, you

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know, we have to be aware of our academy. A lot of the academies' recommendation is C

recommendation, but I do think that there's a good element of literature supporting the use

of cheilectomy in Grade 2 and 3. And again, I still have an ethical issue of doing a fusion. In

my 26 years of surgical experience -- this is Level 27 evidence, Panel, but I've had many,

many, many happy patients with a cheilectomy.

So, Dr. Pfeffer, I would call on you, that the results of cheilectomy, I think, are

established in Model A.

DR. PFEFFER: I'd refer you to an AOFAS paper or something. Dr. Baumhauer, I've

been involved in this from 2015. Greg Berlet ran this at maybe our summer meeting or

something. Its conclusions support what Dr. Daniels said, that the -- here's the conclusion,

cheilectomy is predictable for Grades 1 and 2 hallux rigidus, although, as Dr. Daniels said,

it's only a Grade C recommendation.

But I know of no study in the literature, Dr. Daniels, that talks about fusion for Grade

2. Certainly Dr. Coughlin didn't talk about it. Dr. Brodsky doesn't talk about it. I personally

have never done it. So it's okay as long as you're consistent here, right? But my concern is

what I said earlier; it adds a confounding variable that perhaps the Grade 2 patients were

really mostly better because you took off the spurs. Do you know if they would've

benefited from -- so that's the issue. You understand. Dr. Glazebrook knows this.

DR. RAO: Yeah. Dr. Daniels, respond to that, please.

DR. GLAZEBROOK: This is my work, and if it's okay with the Panel, I'll respond to this.

DR. RAO: Sure, because he's the one that brought it up, but either of you can

respond to that.

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DR. GLAZEBROOK: Thank you. So when we're designing the trial, we have to get two

criteria. We have to get a procedure to compare to if we're going to do a randomized

controlled trial that works. And the other design, the procedure should be it treats the

same condition that our experimental device is going to treat. If we look at Cartiva, it treats

arthritis of the toe joint, Coughlin Grade 2 to Grade 4. Cheilectomy does not do that. We

couldn't use a cheilectomy in this procedure.

Furthermore, when you look at the device -- and I'll bring this slide up. If you could

just leave it up, please. When you look at this, this is my review of all the procedures that

are available for hallux rigidus. There's only one that gets a Grade B support. I mean, you

can say that I know someone who does cheilectomies and they like them, but this is the

fact. These are the literatures. This is based on review of the literature, and cheilectomies

only receive a Grade C support. In fact, all other procedures only receive a Grade C support.

So we had to use a fusion, and we had to use a device that compares to what the Cartiva is

going to do. Otherwise it's a poorly built design trial, and we've got all kinds of other

sources of bias.

DR. PFEFFER: Unless you just waited another couple of years, which is hard to do,

and got adequate 3 and 4 patients, you wouldn't have had adequate power, probably, or

statistical significance. But what you've done is thrown in Grade 2 patients, which

according to the AOFAS's review here, it says indication for Grade 2 is cheilectomy. And you

didn't discuss with patients or give them other options such as interposition arthroplasty.

Why did all your failures of the Cartiva have a fusion, for example? Why would all of these

women who want to maintain motion, when they fail Cartiva, not get offered a Graftjacket

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or an interposition arthroplasty? There's some intrinsic bias in this study, which may not

disqualify it in my mind, toward taking patients and fusing them if they're not given a

Cartiva device, and I'd like to be get my hands around it, but I can't.

DR. GLAZEBROOK: Sure. No, my bias is, is I rely on science. That is my bias. And I

don't rely on a review article or even if my good mentor, Dr. Daniels, says it works. I look at

the literature, and the literature clearly states that the Graftjacket that you bring up,

interpositional arthroplasty, Grade C, these are not proven entities.

DR. RAO: Just a quick follow-up question for Dr. Daniels. Again, I'm just reading

from your Executive Summary here. Section 3 is indications for use and it says "is indicated

for the following clinical conditions: hallux valgus or hallux limitus, hallux rigidus, and an

unstable or painful metatarsophalangeal joint."

So along the lines of Dr. Page's earlier comments, would you consider modifying

that, or would those indications for use still be in play? I'm just kind of curious. How did all

those -- that bucket get into this indications for use, when we don't have clear data to

suggest that it should be used in any other condition besides hallux rigidus and we're

debating even within hallux rigidus which grade it should be for?

DR. DANIELS: So, first of all, hallux valgus is defined as an angle greater than 15

degrees. We included up to 20. So there are patients in there with, by definition, hallux

valgus. But the primary goal of the study was to look at this effect on arthritis, not

deformity. So I can't comment on the indications, only to say that the primary purpose of

the study was to look at the effects of the Cartiva implant --

DR. RAO: I agree. The concern I have is that if this kind of transmits down

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subsequently to some other product literature, then we don't know where it's going to

spiral out of control. So if you think that there's no clear data on hallux valgus, I'd like to

know.

DR. DANIELS: From the study?

DR. RAO: Yeah, for use of the Cartiva device specifically for patients with hallux

valgus.

DR. DANIELS: We have the measurements, the postoperative measurements, but

the maximum angle accepted was 20 degrees, which is a very mild hallux valgus.

DR. RAO: Which postoperative measurements do you have?

DR. DANIELS: On the hallux valgus. I'm not sure if we have it to report, though.

DR. RAO: Because that wasn't presented to us, to my knowledge.

MS. MOORE: From the radiographic outcomes, we didn't look at hallux valgus

degrees before, I mean, post-treatment. That wasn't important. What we were making

sure is that the patients were appropriately enrolled. We weren't looking to see if that

changed over time. That wasn't important in terms of the way we're evaluating the

radiographs. Radiographs are specifically for radiographic findings that were either the

failures as well as the observations. I do think it's important -- we will obviously be more

than happy to work with FDA on the labeling, but I think there is confusion that the Grade 2,

3, and 4 subjects did not do well. They all did well between the groups, and there was no

statistical difference. And I think, again, as we started the session, if you take out the

Grade 2, those subjects did very well. We also showed the results with them included, and

they also did very well, with no statistical difference between the groups. So I think I want

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to make sure that it's clear that there is no difference between the groups, depending on

the grade.

DR. RAO: Thank you.

Dr. Kelly had a comment.

DR. KELLY: And, again, to sort of reiterate what Dr. Pfeffer said, it doesn't really

affect the study results. I'm a minimally invasive guy. I like the fact there's an alternative

out there that we consider here, but I have an ethical problem that in my heart of hearts,

that many people were subjected to fusions when I don't think it was indicated. There are

other alternatives. It's just a big, big issue with me that you either put them in A or B when

there other options involved. And I think that we all know of adjacent joint disease and

wear and tear. I've got a problem with saying you've got to get a fusion for this.

DR. DANIELS: So the grading system is based on clinical and radiographic analysis,

and there is some subjectivity there. I can only speak for myself and the patients that were

enrolled in the study. But personally, in my mind, a patient had to be a candidate for

fusion. I understand that some Grade 2 patients are candidates for a cheilectomy, but you

will also see patients that are categorized as Grade 2 that you just know are not candidates

for a cheilectomy. Eccentric wear. They've got some cartilage on the medial side, so

technically they're a Grade 2, but they've got the eccentric wear, and that is a class that in

my hands doesn't do well with cheilectomy.

So I can only speak for myself, but it's very important to understand. Every patient

that was entered into the study, the clinician determined that they were candidates for a

fusion. I can't speak to the specifics of that, but that was a very important criteria for entry.

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And I would have the same ethical problem as you have if I were put in the situation like

you're suggesting. I didn't feel like I was in that situation, and I don't think any other

surgeons did.

DR. RAO: Thank you.

Let's move on to the next theme. What is the next theme?

MS. MOORE: The next theme was related to should the SSSIs be considered study

failures, and specifically related to fractures and non-unions.

DR. RAO: Sure. And I mean, while you're talking about SSSIs, you'd want to talk

about hardware removal also.

MS. MOORE: It was the hardware removals, yes. So I think there was a question

about specifically, should the hardware removals be considered a failure? And I think it's

important that, as Dr. Baumhauer stated, and I'll have her elaborate on that -- I mean, that

was hardware failure does connote a clinical significant event that could lead to down-the-

road problems, and we felt that that was appropriate and that was pre-specified in the

protocol.

Regarding the non-unions and the SSSIs, the SSSIs, we were requested by FDA, in the

beginning of the study, to follow FDA's orthopedic guidance for defining removals and

revisions. And in that guidance document, it gets very explicit that if any hardware is

removed, whether it's an individual screw or the complete hardware, it needs to be

captured as a revision or removal. That's the guidance we were told to follow. That's how

we followed it. We followed it consistently for both groups. And we were only told after

the PMA was submitted that perhaps maybe we should consider some of these events as

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not being something that should be a failure. However, I think, as we also noted, they were

all clinically symptomatic. But I would like Dr. Baumhauer to elaborate a little bit further on

the specific hardware failure.

DR. RAO: I believe this was your question, Dr. Heckman. Great.

DR. BAUMHAUER: Yes. So the hardware removals were symptomatic. All the non-

unions were also symptomatic, and there was fractured hardware which was also

considered a failure. The fractured hardware, we know as clinicians, if you have motion,

which were usually associated with motion across a joint surface, that you'll have fractured

plates and screws because those screws will fatigue over time. I always say it's the

paperclip theory. You can bend it, bend, it, bend it, and eventually it will break. And that's

why those hardware removals were identified as -- or hardware fractures were identified as

a failure per the -- pre-specified per the documentation.

Thank you.


DR. HECKMAN: Hi. This goes back to the point I was making originally. I would

much prefer to take out a painful screw than have to go in and take out a painful implant

and do a fusion, because I think the latter would be much more complex, much more

challenging, and at a much higher risk for the patient. So they're not equal, I don't think.

DR. BAUMHAUER: I think if we return to the operating room, if you look at a

common denominator of return to the operating room, I believe that there are still

operative risks that make them equivalent. Granted, the surgical procedure may in fact be

simpler to take out hardware, although I've had my challenges with that on occasion.

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There's no question, particularly if they're broken, trying to get that stuff out of there.

However, revision to an arthrodesis or getting a primary arthrodesis for their surgery, I

think the Cartiva -- the implants were the option.


DR. PFEFFER: Quickly. Dr. Baumhauer, did you use bone graft to fill that hole in the

metatarsal head when you did the fusion on the failures?

DR. BAUMHAUER: I'm going to actually refer you to Mark Glazebrook because he did

one. And remember, it's not cleared in the United States, so I've never put one in.

DR. PFEFFER: Oh, yeah, that's right. Good point.

(Laughter.)

DR. GLAZEBROOK: Yeah, it was probably the easiest revision fusion I've ever done

with an implant in place; a K-wire to pop the Cartiva implant out, demineralized bone

matrix, artificial bone matrix approved, placed in the cavity, two screws across the joint.

The same as my index procedure.

DR. PFEFFER: So there are intangibles like cost and patient pain and the suffering as

they went up to the procedure, but I think you did an excellent job in trying to sort this out.

I commend you for that. A very difficult problem.

DR. RAO: Thank you.

Let's go to the next theme.

MS. MOORE: The next theme was asked about how we actually did the

measurements with respect to range of motion, so I'd like Dr. Baumhauer to speak to that.

DR. BAUMHAUER: So the range of motion was assessed as active -- weight-bearing

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active range of motion of the great toe. And I'm sort of proud to say that in 1999 we

actually validated the ability to measure great toe motion with a goniometer in our lab,

correlating it to a flock of birds, walking them along in a gait lab. So I felt very comfortable

that this was an appropriate method to use.

And Dr. Pfeffer also asked about the fusions and how the fusions were. This was an

active range of motion, not a fusion patient. This wasn't an intraoperative fusion patient.

So the comments that you made about how do we assess how the fusion position was and

those sorts of things, clinically, we did the exact same thing after they came out of the

operating room and followed them along, but they obviously had no motion and were stuck

in a certain position.

DR. PFEFFER: If I may, what position were you shooting for fusion? In other words,

we speak the same language.

DR. BAUMHAUER: Um-hum.

DR. PFEFFER: We talk about bony fusion or the angle of fusion off the weight-

bearing axis. This is the picture -- can I just show Dr. Baumhauer this? This is a picture that

you sent one of us to answer how you measure the fusion, and you're showing that. I've

never seen that type of measurement before. If that's 15 degrees, that means that toe was

fused flat on the ground, which would not be the right way to do it.

DR. BAUMHAUER: So that essentially is, you know, placing a flat plate against the

bottom of the foot. That's really what that's trying to do, simulate that -- Mark? Sure.

(Off microphone comment.)

DR. GLAZEBROOK: Yeah. So I did 11 fusions. Or, sorry, 10 fusions. I did 30 Cartivas

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and 10 fusions. So we teach residents and we examine residents on position of fusion

degrees. It's not degrees; it's related to your pes planus and pes cavus.

DR. PFEFFER: Right.

DR. GLAZEBROOK: If you have a high metatarsal angle, you're going to have to put it

in a larger angle, so your degree of fusion is going to be higher so your toe will touch the

ground as you walk. Unless you prefer to walk on the heel, you might leave it up higher. So

there's no correct answer on what to do and how to do it, but a good clinician will make a

fusion suitable for walking, doing weight-bearing activities. So you'll do what you needed in

the paper. You'll push a plate against the foot, and you'll make sure the foot just touches

the plate. That way, the angle will correspond to the degree of pes planus or pes cavus. So

that was the method we used at my center for that.

DR. PFEFFER: So you didn't ask your fusion surgeons to fuse the great toe 10

degrees off the weight-bearing axis, which is what you -- that's the board answer for how to

do a fusion of the great toe.

DR. GLAZEBROOK: That answer is incorrect. If you have someone --

DR. PFEFFER: Okay. No, I'm just going on science.

DR. GLAZEBROOK: Sure. If you have someone in a high cavus and you do 10

degrees, they're going to say, Doctor --

DR. PFEFFER: No, no.

DR. GLAZEBROOK: -- my toe pushes against the ground. Why is that?

DR. PFEFFER: No. But sir, we're not -- let's not waste time.

MS. MOORE: And just one clarifying point. I think the image that you're referring to

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is actually a subject that had a Cartiva patient -- I mean, had a Cartiva implant, and it was

not an arthrodesis patient.

Is it appropriate to move to the next question?

DR. RAO: Yeah, let's go to the next theme.

MS. MOORE: Yes.

DR. RAO: Actually, Dr. Finnegan has a quick question.

DR. FINNEGAN: I still haven't gotten a feel for the range of motion with the Class III

heterotopics.

MS. MOORE: Oh, I indicated that we looked at range of motion across all

radiographic outcomes and saw no difference specific -- you know, saw no difference in

outcomes associated with that.

DR. FINNEGAN: So the III, heterotopic III's moved the same as no heterotopic

ossification?

MS. MOORE: I interpreted the result to be, was the clinical outcome different

between the different radiographic findings? And that was not -- specifically, what was the

range of motion of heterotopic III? Is that what you're asking?

DR. FINNEGAN: Yes.

MS. MOORE: Okay, we'll need to get you that specifically. I misunderstood the

question.

DR. RAO: Okay, what's the next theme?

MS. MOORE: The next theme is related to pain adverse events. This was another

question Dr. Finnegan had asked. She had a clarification question regarding our treatment-

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emergent adverse events and the pain that was reported there. So I'll put that back up

again for clarification.

So as you'll see, implant site pain -- or pain was reported verbatim at the sites

according to what the clinician felt was the appropriate description of the pain, and then

that was categorized according to a MedDRA coding system to put them in those various

categories. So it really depended on how the clinician reported that pain event. And so it

could be included as implant site pain, procedural pain, or medical device pain, were the

three different kinds of pain categories that were reported in the course of the study.

DR. FINNEGAN: You also had arthritis and pain in the extremity. So all of those got

classified together as pain?

MS. MOORE: No. In terms of the way the table goes, so injury, poisoning,

procedural complications, that's the system organ class in which all of the foot function,

medical device complication, all of those events are in that overall category.

DR. FINNEGAN: Okay, so this graph is not the same as the one you have in here. So

in here, under injury, poisoning, and procedural complications, you have foot fracture,

device pain, joint pain, limb injury, procedural pain.

MS. MOORE: Right. The table that we're showing here, just because it's a very small

table, it only includes the events that had an incidence of greater than 2%. So yes, there

are probably some smaller numbers or incidence events that were in the complete

summary of the Executive Summary provided, but the overall heading category is where it

was categorized in terms of system organ class.

DR. FINNEGAN: Okay.

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DR. RAO: Okay.

MS. MOORE: The next group of events or questions were related to the radiographic

observations, and one question was regarding the deviations related to the imaging. I think

I want to clarify, too, that none of those -- it was related -- those imaging deviations, almost

all occurred at unscheduled visits. So the subject came in for an event that may not even be

related to the Cartiva procedure, and they had to have imaging associated with that

procedure. They didn't necessarily do the X-ray per our protocol. It wasn't clinically

warranted or clinically appropriate.

There was a question of do we have any CT or MRI data? I don't have that available

here because, again, the majority of those, if it was done outside of the X-ray, it was for

another event that was not related to the device.

You also asked a question in regards to future follow-up with radiographic

surveillance, would that be included as part of our post-approval study? And absolutely. I

think our intent would be to use the same composite endpoint, capture the same events,

VAS Pain and the radiographic outcomes, so we would clearly want to continue to look at

those events.

The other question related to radiographs clinically was, was synovitis assessed on

the radiograph? How was that assessed? And that wasn't a radiographic assessment; it was

a clinical determination of whether or not synovitis was present.

There were also some questions specifically regarding why did the fusion patients

experience Grade IV HO, and also the radiolucency of the implant. And I would like

Dr. Evangelista, a radiologist, to address those comments to the Panel now.

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DR. EVANGELISTA: Well, Peter Evangelista, a musculoskeletal radiologist from Brown

University. I am being reimbursed for my time and travel, but I have no equity interest and

no financial interest in the outcome of this meeting.

So to begin with, I'll start off with, first of all, the radiopaqueness of the implant. To

begin with, it's similar in some ways to that of elastic implants. It is hard to see, but you can

get a sense for it. When you look at a radiograph, the implant looks like a priori. I was

involved in the initial part of this. This was all done by an independent radiology lab. I was

asked to come in and look at the data afterwards. And I applaud Cartiva for actually looking

through and actually documenting all of these findings because I think it, in the future, can

only help.

So the device integrity was looked at. Fragmentation was defined as bone formation

within the space formerly occupied by the device, in a pattern suggestive that the device

has fragmented or widened the first MTP joint. So we would expect, if it did fragment, a

piece would go into the joint and cause widening of the joint, just like we see in meniscal

tears in the knee, et cetera; also migration, change in the position of the device, which may

be associated with remodeling of adjacent bone or widening of joint space. Again, if the

implant completely explanted into the joint, you would expect to see widening. So that's

how that was evaluated based on the radiographs.

The second thing that I'd like to talk about was somebody asked how do we know if

the PVA is causing heterotopic ossification, which I think is a good question. You can never

completely know for sure, unless you actually are going to go in there and look at it. But if

you look at the literature, it occurs at all sites where surgery is done. It's usually related to

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surgery. It's either trauma or based on where the surgery is located. This is most

extensively studied looking at the hip, and if you look at patients who've had a hip surgery,

total hip arthroscopies -- sorry, total hip arthroplasties, it can occur in up to 82% of those

patients. If you look at patients who had just arthroscopy, just little scopes, it can occur in

up to 40% of those patients. It's also been looked at in patients who've had total ankle

arthroplasties, and again, that could be up to 40, 50%. So I think we're in keeping with

those numbers. The last thing, it occurred in both groups. It also occurred in the patients

who underwent arthrodesis. They also developed heterotopic ossification; close to about

50% were.

So on that basis alone, I don't see anything from the implant itself that would be

causing it. In all cases, heterotopic ossification was more capsular and likely related to, you

know, where they did surgery and took out the osteophytes.

The last thing I'd like to talk about, too, has to do with you asked about the

heterotopic ossification related to arthrodesis patients. So the arthrodesis patients are

mainly fusing by means of direct bone healing where the two bones are contacting, and

some of those patients who went into surgery, they also developed a capsular heterotopic

ossification, but it didn't occur in everyone. We see that all the times when bones are

fusing or any joints are fusing. And so that's where the difference was there.

Thank you. Any questions about those?

DR. RAO: Dr. Kelly.

DR. KELLY: Yes. And this may not be to you, Dr. Evangelista. I would concur that HO

is not a big deal in my mind, and I do hip arthroscopy, and it sees like very little clinical

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consequences. What concerns me more are the osteolysis, the reactions or the cystic

changes. Any bone reaction in 49% -- I guess I would put this back to the other Panel -- to

the other Sponsors. I mentioned earlier something as inert as this substance, how do you

explain this reactivity?

And was there any -- and to Maureen's question about the retrieval studies, was

there anything indicative of any form of giant cell reaction? Was there pathology done on

some of the explants, the capsule, et cetera? It just, to me, makes no sense that you'd have

such a high number of reactive changes in something that's purportedly so inert.

DR. EVANGELISTA: We're going to get to -- I'm going to show you a case just to kind

of show you that. So there were a couple cases of osteolysis, and I'll show this first case. So

here we have a preoperative image on the screen, on the left. In the middle is the 2-week.

And at the 6-week mark, you can actually see two things: the little bit of lucency

surrounding the implant, and you can actually see where the implant is by that cortical

margin. The blue arrow to the right and to the left on the right image at 6 weeks is what we

called or what was called osteolysis in the study.

If you continue to follow this 1 year and 2 years, there's been no progression of that

osteolysis. In patients who had, you know, reaction, foreign body reaction, you would

expect that this would keep growing and getting worse. We did not see this. There were

only two patients. The second patient who had a similar finding to this, again, he was --

that patient was explanted, and at the time there was no evidence of loosening, no

evidence of foreign body reaction. And those are the only two that we have. So it was a

very small minority, again two patients.

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DR. KELLY: So would failure be classified as just lack of sufficient cushioning? I

mean, I'm trying to get my mind on why these things fail. There's no giant cell reaction, no

florid synovitis. Was it just not enough of a spacer?

DR. BAUMHAUER: The indication for the patient to go back to the operating room

was pain. So the implant was painful. It was not loose when they went in to take the

implant out. It was not dislodged. It was not fragmented. And we showed you all the

retrieval studies. It was painful in the joint.

DR. RAO: Best guess. Why?

DR. BAUMHAUER: I don't really know. Because we looked at all -- everyone had

different characteristics, so there wasn't anything consistent, honestly.

DR. CARRINO: Just to follow up on that point, it looked, in that case with the

osteolysis, that the implant was not proud anymore, at least --

DR. EVANGELISTA: Yes.

DR. CARRINO: -- on the AP view without the lateral, and when they were retrieved,

to go back and look at, you know, did they maintain their proud status?

DR. EVANGELISTA: So I'd like to show this. This is the lateral. On top is the 2-week.

It's that same patient. This is the 2-year, and if you look, there's no difference in the joint

space. It was purely projectional on that AP, that it looked that way.

DR. CARRINO: Thank you for validating the radiology axiom that one view is no view.

(Laughter.)

DR. RAO: Okay. Dr. Golish.

DR. GOLISH: A direct follow-up to Dr. Kelly's point. The gentleman said that on that

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one explanted patient, there was no evidence of giant cell reaction, foreign body reaction.

So a pathology was run, and you have some results from that admittedly one patient that

was specifically referenced.

DR. BAUMHAUER: There was nothing to actually run. The reason he commented

giant cell, I don't know. But synovitis or wear fragmentation or implant fragmentation,

there was no tissue that was pathologic in that joint. The investigator reported that the

joint did not appear significantly osteolysed. Although you see it here to some degree, they

were able to convert it to a fusion, and they had successful outcomes.

DR. GOLISH: I'm sure the Sponsor is sensitive to the awareness of the biologic

effects of particulate wear and debris have never been more topical, and I would even

speculate that one of the reasons we're here today is because of the novelty of your

implant as an orthopedic biomaterial. And furthermore, you're aware that though you

distinguished your implant's biomaterial properties, the track record of elastomers, silicone,

urethanes, and other non-hard bearings in small joint arthroplasty is rather checkered.

MS. MOORE: Absolutely, we're very aware of that, and I think that kind of leads into

the next question, which is we did an extensive particulate study looking at the wear debris,

the analysis of the tissues over time. In fact, we did two different studies and showed no

inflammatory reaction. And then clinically, during -- upon an explant, we asked the

clinicians to evaluate if they felt it was appropriate to take a histologic sample, and that was

not warranted. And as I mentioned, in the animal studies, not only did we do a wear study

but we also -- there were some questions about our large 1-year animal implant study, and

there was no osteolysis observed with that. Again, yes, there have been those observations

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with silicone-type implants, but again we have not seen it in any of the studies that we've

done, whether it be the large animal study, in our subjects that we've treated in our wear

particulate -- both our wear particulate studies.

DR. RAO: Okay, should we go on to the next theme?

MS. MOORE: Yes. I think the only remaining question I had was somewhat related

to that, which is have you looked at the device properties over time, and have you looked at

the explants? I believe we already discussed that we did look at the explants that were

removed, and we saw no wear characteristics associated with that.

We also did extensive -- sorry. We also did extensive wear -- sorry, biomechanical

tests, that we looked at the product aged and un-aged. So we looked at it over a fatigue

sample so that we made sure that it was clinically appropriate for the life of the product

and that the device did not change over time and its biomechanical properties did not

change over time.

I think the other important aspect is we've treated or we've distributed over 4,000

implants, of this product, to date, and we only have a report of 1% of complaints. So while

the clinical study is limited in nature, we know that we're not having these type of implant

material reactions in the broader distribution of our product.

DR. RAO: Thank you.

Dr. Heckman.

DR. HECKMAN: Well, with regard to those 4,000 subjects, since you brought it up,

you have not done a prospective follow-up on these patients, right? You say you only had

one report, and there are no studies in the literature that report on the long-term durability

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of this; is that correct?

MS. MOORE: Sure. No, in the 4,000 subjects, my comment was we had -- in the

complaints that are reported in to the company, because it's a commercial product, any

failure of the device is required to be reported to us. So that complaint rate is 1%. There's

literature reports the product's been used in the knee, in the CMC. There's been long-term

reports that had been reported in the literature. Again, the removals are very small

reported in that. I could also defer to Dr. Daniels, who has followed up a subset of the

MOTION study patients.

DR. HECKMAN: That would be great. I'd like to hear about that.

DR. DANIELS: I don't believe this data has been submitted, but we were asked to

look at our five-plus-zero outcomes. The three Canadian centers that enrolled the most

patients, so Vancouver, Toronto, and Halifax, were involved, and we only looked at the

Cartiva group. There are 29 patients. Two were lost to follow-up. That left 27. One of

those patients had the implant removed within the 2-year window and fused. The rest of

the implants were in place, and all of the scores that we've looked at to date have not

changed, including range of motion. The VAS Pain score at 5.3 years in those 25 individuals

was 5.5. So they were doing very well.

DR. RAO: Thank you.

Dr. Pfeffer.

DR. PFEFFER: Thank you again for all your hard work, for everybody. I just have a

few summary issues that relate to what you talked about.

Number one, the 4,000 were mostly knees, right? Those aren't 4,000 implants in the

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-- they're 4,000 implants in the great toe? No, they're knees that were -- I'm sorry, go

ahead and answer.

MS. MOORE: Four thousand product was distributed. The majority of implants that

are happening around the world are related to the MTP joint. I don't have the specific

number of MTP implants, but the majority currently --

DR. PFEFFER: Good.

MS. MOORE: -- is related to the MTP.

DR. PFEFFER: Okay, good. And if I take a second or we take just a second to forget

about all of the view from 100 feet here, could you comment on this? If we take a view

from 30,000 feet, we have a study of an implant that has a proud 10% failure rate at 2

years. Is that what we've got?


DR. PFEFFER: Well, no, this study is only related to 2 years. You know, we're just

doing science here. Sorry, Mark. We're just doing science, but based on this study, which is

how we vote -- this has come up before with FDA and whether we vote on world literature

and that stuff. But based on this, that's what we've got in front of us. Yes? Somebody?

They're shaking their heads. Okay.

And the last question I have, if this is approved by FDA, will you market this in the

United States, and other hydrogel products that will then come in easily to be approved, as

a synthetic cartilage? Is that the terminology you're going to use? I asked that earlier of

FDA, but I'm worried we're going to run out of time.

MS. MOORE: I'll let FDA address the synthetic.

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DR. PFEFFER: But will your company -- that's your terminology and FDA's

terminology. Will you want to market this in the United States as synthetic cartilage?

Perhaps the president could answer that question.

Sir, synthetic, is that what we have here?

MR. PATRICK: Yes. Tim Patrick.

It's a very good question, and we actually called it synthetic years ago because there

was a lot of confusion when we talked about a polymer or a hydrogel. And you looked at a

lot of the interest in cartilage repair and research at the time. There would be some

confusion that we were trying to re-grow cartilage. And so there was so much confusion

about that, that we actually used the word "synthetic" so that we would differentiate that

from someone who's trying to re-grow cartilage. That was the intent at the time.

So I will tell you that that phrase happens to be patented, or it was trademarked, I

should say. And if that ends up being an issue both -- or for the Panel or for the FDA, I don't

think it's imperative what the product is named. The intent was actually to keep users from

being confused that it was intended to re-grow cartilage, and the word "synthetic" was

intended to say it's not doing that.

DR. PFEFFER: Okay, so up to the FDA. Thanks very much for all of your answers.

DR. RAO: Dr. Bailey and then Dr. Lyman after that.

DR. BAILEY: As an implant surgeon with an interest in revisions and from my time at

the University of Pittsburgh, I can tell you that your chance to see if you really had a

problem was electron microscopy of the membrane in that cyst and a macrophage count of

that cyst. So if you have that opportunity again, I would suggest that you do that. That's

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all.

DR. RAO: Thank you.

Dr. Lyman.

DR. LYMAN: Yes. Had you finished all of your responses? Because several things

that I had brought up haven't been addressed.

MS. MOORE: No, we have not finished our responses.

DR. LYMAN: Okay.

MS. MOORE: So I guess one that I just have quickly off the top of my head related to

the peak dorsiflexion related to the HO class. So if you look at all subjects, the degree was

29 degrees. In that subset of just subjects with Class III HO, it was 30.6, so very similar.

Your question specifically was related to the SF-36, was this a normalized or raw

score? And that was a raw score that was provided.

You also asked for the results of the subjects in the first half of the study versus the

second half of the study, and they were comparable between the two groups.

DR. RAO: Go ahead, Dr. Lyman.

DR. LYMAN: And I also asked about bilateral disease --

MS. MOORE: Oh.

DR. LYMAN: -- because patients don't -- they use both feet, right, with a lot of

activities on the surveys?

MS. MOORE: They do in some instances, but the study excluded subjects that had

active bilateral disease. So patients that would require active treatment of their other foot

would not be included in the study, so those subjects aren't included in the study.

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DR. LYMAN: Sorry. For clarification, was it simultaneous treatment or simultaneous

surgery? What was the --

MS. MOORE: We did not want to have a subject have two Cartivas during the course

of the study. So it was not only -- it was over the course of the study.

DR. RAO: Dr. Finnegan.

DR. FINNEGAN: You had one of your witnesses who had bilaterals.

MS. MOORE: She was not part of the study. She was treated -- she was one of our

first patients. We thought if we did include that, it would be confounding of the results

after the study to have a subject with two implants.

DR. RAO: Dr. Lyman.

DR. LYMAN: Yeah, I'm sorry. So I understand that was an exclusion criteria, but am I

correct in assuming that nobody in your study had bilateral disease? I'm asking about even

if you're not actively treating it and however you define that. And that's now unclear to me

because I thought that it would be some sort of surgical intervention. But are there

differences between those with unilateral versus bilateral disease, as far as their outcomes,

because the survey is not side dependent?

DR. BAUMHAUER: Yeah. So the exclusion criteria was that the patient did not have

concurrent contralateral foot problems that would require any type of treatment. They

didn't need any help with anything. If they had any problem, it was minimal to any degree.

So all I can comment on is that there was no significant problem in the contralateral limb.

DR. RAO: There was one question raised about whether any of these patients had

gait analyses.

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MS. MOORE: None of the subjects had gait analyses, to my knowledge. I think

another question that was raised also by you was whether or not a number of subjects had

hit the FAAM ADL ceiling.

So, Dr. Baumhauer, would you be able to address that?

DR. BAUMHAUER: So the patients did do very well in this study and about 25% had a

ceiling effect in each group, specifically 27 in the Cartiva group and 26 -- essentially

equivalent in both groups.

DR. RAO: Thank you.

MR. VAN ORDEN: That's at 2 years. There's a much larger difference at 1 year for

the ceiling effect, because I looked at that. But there's about 35% in the arthrodesis at

1 year that hit the ceiling, as compared to about 20% in the Cartiva group.

And if I can also answer a question Dr. Pfeffer phrased earlier. It was about a post

hoc analysis that was brought up in the Executive Summary. When we looked at some of

these responders, we saw some of them still had high pain rates. And so, for example, one

subject started as a 90 and reduced to a 60, which we're not -- do not intend to argue that

that wasn't improvement, but it is a clinically meaningful improvement from 90 to 60. Sixty

is still a lot of pain. And so we looked at what would happen if we excluded all of the

subjects that were above the minimum at baseline, or if we didn't exclude them, if we

treated them as failures, if they were still at a high pain that's been higher than 30. So that

was a post hoc analysis that we included it in. And if you would put everyone that had a 30

or higher, 30 VAS or higher at 24 months, if you made them all failures, then that would

have made the composite endpoint go above that 15% level.

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DR. PFEFFER: Why did you allow the Sponsor -- why did the Sponsor include patients

that didn't meet criteria for inclusion in the study? Thirty-nine is not 40, right? Twenty-

eight -- why did that happen? Just slipped through the cracks?

MS. MOORE: If I could, can I address that? So there were four subjects that were

VAS eligibility criteria exclusion. Three of those, if you'll see, were 38, 39, 39.3. The criteria

was 40. The way the VAS measures, it's a 0 to 100 scale where a subject puts a mark on the

scale. So that 39 point, that's a measurement error for those three subjects. The 27.8, I

can't address why that was -- why that happened. We identified that as a significant

deviation and considered that a failure and reflected that in our per-protocol analysis. But

again, I think, as we saw earlier, if you do exclude that subject, we still meet our non-

inferiority.

DR. RAO: Thank you.

Any further questions? Any further questions for either the FDA or the Sponsor?

MR. MELKERSON: I believe there were three questions you had posed to the FDA; is

that correct?

DR. RAO: I think we've kind of covered them. I've been checking them off here as I

went through the list. There was a synthetic cartilage issue that Dr. Pfeffer asked. I think

we've covered them, Mark.

Any further questions?

Dr. Finnegan.

DR. FINNEGAN: So for the Sponsors. You talked about one of the problems of fusion

being transfer of metatarsal. Did you see any transfer of metatarsals in your Cartiva group?

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MS. MOORE: No, we did not. However, as Dr. Baumhauer mentioned, that was

observed in the fusion group.

DR. RAO: Dr. Page.

DR. PAGE: In those patients that were followed out 5 years or longer, was there any

increased evidence of boning reaction or heterotopic ossification?

DR. DANIELS: There were eight patients, I believe, that had HO, but I can't comment

on whether they had it from the beginning, like at the 2-year versus the 5. And there was

no patient that had any osteolysis in the metatarsal head.

DR. RAO: Dr. Pfeffer, you had a comment?

DR. DANIELS: Sorry. And none of the implants -- no additional removals.

DR. RAO: Dr. Pfeffer and then Dr. Gilbert.

DR. PFEFFER: Did any of the clinicians happen to see the article that came out

2 weeks ago in Foot and Ankle on this topic from HSS? Anybody? Just me? Two weeks,

Foot and Ankle, from HSS, looking at arthrodesis and functional outcome, by De Santis.

DR. RAO: I was just about to read it, but I just passed on it.

DR. PFEFFER: Yeah, I know. I hardly get to this foot stuff because I have to do all of

my spine and hip reading first. But what their conclusion was -- I'm just looking to read it

for you, but I was wondering if you agree with it. Basically, it said that -- I'll have to

paraphrase it. But basically, they said that patients come to a fusion with a negative

outlook; it's not going to be a good thing. And their study, in their minds, showed that

there was no functional deficit from a fusion -- I'll find the exact sentence if you want --

except for people who want to wear high heels. So would it be fair to say, in this paper, to

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extrapolate what Dr. Baumhauer showed, is that although the fusion shows in your paper

equivalent -- let's say equivalent function in all parameters, but there is a clear role for a

Cartiva in patients who may want to wear heels or go salsa dancing or scuba dive or wear

cowboy boots, which is -- I mean, how do you put the HSS conclusion -- and I'm sorry, I

don't have the sentence here -- in perspective for your study?

DR. BAUMHAUER: Sure. I would say that patients that want to have motion at their

toe would want to have an implant in their toe because they will be able to raise up their

foot to wear high heels or to do activities that require things that require that same motion,

that it puts you in that position for your shoes.

Again, I'm so appreciative to the patients that came here. They have given us the

information that they had to adjust their gait because of their toe fusion, and we shouldn't

just put that away out of our minds. That's very important information, and we hear it as

clinicians in our offices. I'm sure that those around the table have heard it from their

patients that they've fused. A fusion is a great operation for pain relief, there is no question

about it, but it comes at the expense of motion.

DR. PFEFFER: Judy -- sorry, Dr. Baumhauer. Are there patients -- are there studies

you could cite on that? I've reviewed everything in the literature on this. Jim Brodsky

shows good papers that gait is not that significantly affected for everyday activities. It's

certainly affected for salsa and certain activities, but for everyday activities, I don't think

anyone has shown that it's not. As a matter of fact, in your Sponsor report you talk about

limitations in the literature, and twice when you say that the only citation you give is for an

online journal, there's nothing else you come up with from 2011 that talks about gait and

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ankle push-off. So I don't see a lot of literature as I try to understand this. It talks about

the limitations for ADL.

Dr. Daniels?

DR. RAO: And before you respond, may I just add to that? It also seems that if you

ask the patients who had the fusion versus the patients who had the Cartiva, on their

satisfaction, if you took out the groups, if you took out the right groups and presented it the

way -- or took out some groups and presented it the way the FDA did, the satisfaction

scores were actually equivalent or even better in the groups that had the fusions done. So I

just give you that additional piece of data to respond to Dr. Pfeffer's question.

DR. DANIELS: So I mean, this is an area of study for me. I have a Ph.D. student

working on this because we all ask ourselves this question: How important is motion for

any joint? Any patient that undergoes an orthopedic device to preserve motion, that

patient and the physician understands that one salvage is fusion. It's not necessarily

desirable. How do you quantitate the positive effects of motion, like in the great toe? We

don't have a good way of doing that.

I know this is getting a little bit philosophical, but it's a theoretical philosophical

question. Our outcome scores, in my mind, are not sensitive enough to tease these things

out. But what you have to understand as clinicians, we're always talking to the patient, and

we hear this, and patients, I feel, are our best advocate in terms of what we do and where

we need to go. I have one patient with a fusion on one side and a joint-preserving option

on the other side, and he tells me, whenever -- he's a golfer. Whenever he puts his foot

into the sand trap, it's his motion side first. How do you quantitate that in an outcome

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score? Stairs is a common concern I have. I talk to my fusion patients. They all mention

stairs. I don't hear that same thing from patients that have had a joint-preserving option

like Cartiva. I believe that this is more of a reflection of our limitation as opposed to the

limitations of the benefits of this joint-preserving option.

DR. RAO: Thank you, Dr. Daniels.

Dr. Pfeffer, any follow-up on that?

DR. PFEFFER: No. Thanks, a good answer.

MS. MOORE: And Chairman Rao, I'd like to also address your comment regarding the

censored data versus uncensored data. And I think the reason why we presented that data

that way, which it was important to us, is that when we asked the question, would you have

the procedure again, if they've been revised, had their Cartiva removed, and then we've

following them up at 24 months, when they're answering that question, we don't know if

they're answering it related to the index procedure, that they got Cartiva, or now the fusion

procedure they had. So those results would not tease that out because that's specifically

how it was asked.

But if you look at the uncensored data, and I'll show that to you now, you also saw

that Cartiva patients preferred having the Cartiva versus the fusion device. But we felt it

was much more appropriate to present the data the way we originally did in the

presentation this morning, for those reasons.

DR. RAO: Thank you.

Dr. Gilbert.

DR. GILBERT: So from dancing to the device, I want to go back to the nature of the

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device for just a second. It's a hydrogel. So there's some amount of that material that's

water, and if there's water that starts in the hydrogel when you put it in, that water can

exchange with body fluids. And so I'm just wondering about how those body fluids get

taken up by the material, what sorts of things might be there, soluble factors, other

elements in this hydrogel that may be impacting some of the observations like osteolysis or

heterotopic bone formation.

You know, polyvinyl alcohol is used as a carrier for drug delivery systems, and so you

know, there's this ability to exchange with the environment. You know, saline coming out is

not a concern, but how it takes up things and what changes happen to that interface and

how that impacts on the biological interaction are things that I think are very important to

understand.


MS. MOORE: Well, I think one of the things we did, obviously, is we looked at the

device, both in a confined compression and an unconfined compression, trying to look at

how it absorbed fluids and how its biomechanical properties were in both a confined

fashion and unconfined fashion to see its behavior characteristics. If it's appropriate, I

could ask Dawn Lissy, who's an engineer with ETC who's done a lot of our biomechanics

testing, who could maybe speak to your specific question.

DR. RAO: If we could make that a brief quick answer, please.

MS. LISSY: Absolutely, sir.

Hello, my name is Dawn Lissy. I'm president and founder of Empirical Testing Corp.,

and we provided a lot of the mechanical testing that was done for the preclinical testing.

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And what I can tell you is that the test specimens that were utilized with the extensive

evaluation of the preclinical testing that was outlined in FDA Slide 10, we used a

combination of sterile, non-sterile, fresh, aged, and fatigued specimens, and we looked at

the evaluation of all of those things. What I can tell you is that the preclinical data shows --

I'm sorry, the clinical data shows that the preclinical testing values were valid. And the FDA

also had no further questions with our preclinical test results.

DR. GILBERT: I'm interested in the retrievals and what sorts of things might be in

there. For example, if you have an inflammatory reaction adjacent to the implant and there

are significant soluble species released due to that inflammation, can the device take those

inflammatory species up and perhaps have a prolonging effect on the local tissue?

MS. MOORE: We did a complete analysis of the explants from our animal studies

that were 1 year, just to try to see what kind of impact they had. Were there any biologic

components associated with it? Biologically, we didn't evaluate any of the Cartiva devices

removed from the patients. But again, we didn't really observe anything of significance,

both in the cavity or even on the implant itself.

DR. GILBERT: One more follow-up. So the animal study, is that a validated osteolysis

model?

MS. MOORE: It's the best model that we had at the time.

DR. RAO: Any further questions for either the Sponsors or the FDA?

(No response.)

DR. RAO: If not, let's take a 10-minute break. Let's get back in the room and ready

to start at 3:25, so we try and keep this moving.

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(Off the record at 3:12 p.m.)

(On the record at 3:25 p.m.)

DR. RAO: Is the FDA ready with their questions?

(Pause.)

DR. RAO: At this time let us focus on the FDA questions. Panel members, copies of

the questions are in your folders. I would ask that each Panel member identify him or

herself each time he or she speaks to facilitate transcription. I will go around the Panel, and

I will ask each member individually what his or her response to the question will be, and

then I'll try and summarize the response for the FDA.

Mr. Dedania, please show the first question.

MR. DEDANIA: Sure. First question: Please comment on a 15% non-inferiority

margin used for the Cartiva clinical study in terms of effectiveness, safety, and overall

success. If a 15% margin for overall success is an appropriate margin for this study, please

explain your rationale. If the Panel does not believe this margin to be appropriate or

clinically meaningful, please recommend a non-inferiority margin that you believe to be

appropriate and clinically meaningful for this study.

DR. RAO: Is there a slide on the question by any chance? Thank you.

Dr. Trier, what do you think?

DR. TRIER: This is Dr. Trier.

Based on the fact that the determination of the margin for non-inferiority needs to

be justified both clinically and statistically, it seems to me that -- by the Sponsor, have made

a case for 15% as a non-inferiority margin. The additional comment that I think is important

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for us to recognize and has been discussed already is the fact that FDA has different margins

or has allowed different margins in other PMA-approved products, and in particular,

another one, the STAR Ankle, which did have a 15% margin. The margin was not a topic of

discussion at that point. So from my perspective, I believe that they have justified a 15%

margin.

DR. RAO: Thank you.

Dr. Pfeffer.

DR. PFEFFER: Yeah, I'd like to clarify one thing, and that's to my understanding if the

Panel -- the Panel can still vote in favor of a product even if it's not statistically significant.

Is that true, FDA? I think if this product does not meet whatever margin we decide on, the

Panel can still vote in favor of the product going forward. This came up at a previous FDA

meeting I was at.

MR. MELKERSON: If you believe it's clinically -- I mean, this question kind of goes to

that point. In other words, is it clinically meaningful and what would that meaningful

difference be.

DR. PFEFFER: Yeah, difficult. Okay. Well, briefly, I was on the STAR panel. I think

this is very different. For the STAR patients, the 15%, had we discussed it, I might have

accepted because there's really no good option with a patient who has diffuse hindfoot

arthritis. Someone who has subtalar arthritis, they don't have a good choice. Here, even

though it wasn't discussed with these patients clearly, there are other good choices, and I

would support a 10% non-inferiority margin for that reason.


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DR. SAYEED: In terms of the 15% margin, I agree with Dr. Pfeffer that a 10% margin

would be considered clinically relevant.

DR. RAO: Thank you.

Dr. Bailey.

DR. BAILEY: I would go with a 15% margin based on the clinical impression of the

investigators and the historical record.

DR. RAO: Do you have a rationale -- oh, I'm sorry. So you said the clinical

impression?

DR. BAILEY: The clinical impression of the investigators and the historical 15%.

DR. RAO: Okay.

DR. BAILEY: On the STAR study.

DR. RAO: Ms. McCall.

MS. McCALL: Based on other adcoms that I have served on, I'd go with the 15%, as

well.

DR. RAO: Dr. Subhawong.


I believe 15% is a clinically meaningful upper -- the lower bound on the non-

inferiority margin because of the difficulty in capturing some of that data and capturing

patient improvement with improved function with the Cartiva.

DR. RAO: Dr. Page.

DR. PAGE: Given the information available on the Sponsor's -- at the time of

designing the study, I think they're justified in selecting a 15% non-inferiority margin. And I

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support that margin, especially in view of the outcomes, which in my mind make this

argument of 10 versus 15% moot.


DR. GOLISH: You know, I have the opportunity to be candid, that there's only a

couple of ways to really rigorously and systematically choose a non-inferiority margin,

neither of which applies here, and FDA's suggestion, which is reasonable, of the maximum

clinically insignificant differences is subordinate to what I called Way Number 2, meaning to

have an underpinning superiority trial of the control device to some usual care or a sham.

Now, we can start dating the time at 2010, when FDA chose their panel voting

questions to be a little bit different. Since 2010 I knew of only one two-armed non-

inferiority trial that came before this Panel in which the sponsor actually had the data to

choose that non-inferiority margin and calculate it. They actually chose not to do that and

went with 10%. So to me, if you're not able to calculate that, and that is clearly the

situation here, it really is a clinical judgment, a thumbnail sketch, which is one of the

multiple arbitrary essentially or judgment parameters that go into the design of any clinical

trial.

Even the p-value cutoff of 0.05 is essentially an arbitrary judgment in which we say

I'm going to use as a convention to choose a 1-in-20 false-positive rate. So given that, I

don't think that the 15% value is very rigorous, but it doesn't make a 10% value any more

substantially rigorous; it just makes it more frequent. So I think that the number is

adequate because ultimately every sponsor should be calculating a sensitivity analysis

relative to this regardless of what is chosen a priori and doing that post hoc, and when you

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look at those numbers, it seems like the outcome was acceptable.


Dr. Carrino.

DR. CARRINO: Yes, for this application and what I've heard in discussion, I believe

that 15% is appropriate.


Dr. Blumenstein.

DR. BLUMENSTEIN: Well, since I'm a mere statistician and don't treat these patients,

I have a hard time balancing these things because I don't really know much about this. I'm

not going to weigh in on whether 15 or 10 or whatever is better, but I would say that it

should -- the assessment should be made based on a fixed odds ratio rather than a fixed

difference, and therefore, as was pointed out, if you stick with 15 points as being the non-

inferiority criterion, they squeaked by on the main endpoint.

DR. RAO: Thank you, Dr. Blumenstein.

Dr. Heckman.

DR. HECKMAN: I support a 15% figure, as well, primarily because of the subjective

nature of the judgments on which this number was arrived at, and in large part because of

the patients -- the real issue on the patients who have substantial but very difficult-to-

measure needs that we haven't been able to quantitate.

DR. RAO: Thank you, Dr. Heckman.

Dr. Lyman.

DR. LYMAN: So I'd just like to reiterate my earlier comment that there's such

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tremendous information loss in these outcome scores when I dichotomize these in this way,

and then putting them into a composite measure, I have a real issue with that as far as

using this for assessing safety or effectiveness of these novel devices, and I also think that

we need to be holding ourselves to a very high standard of evidence in assessing these new

technologies, and we're talking about this is a first in orthopedic use of this material, so I

think I'd be more comfortable with a higher level of rigor. But I think if I were to choose,

based on this discussion, I actually would agree with Dr. Blumenstein. I'd rather see an

odds-ratio-based approach to this.

DR. RAO: Thank you.

Dr. Finnegan.

DR. FINNEGAN: Maureen Finnegan.

I'm really glad to see I'm not the only dissenter. I'm very concerned because this is

the first-time orthopedic use -- first-time use of this material in orthopedics, and both the

biological environment and the mechanical environment are totally different from anything

that this material has been exposed to before, and we have a long history of what happens

to materials over a much longer time than 2 years. So I actually think that this should not

have been a non-inferiority study.

DR. RAO: Thank you, Dr. Finnegan.

Dr. Kelly.

DR. KELLY: I have no issues with 15%. From what I heard, I'm in the Dr. Golish camp.

I don't think it's going to materially affect the way I view the study.


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Dr. Gilbert.

DR. GILBERT: I, too, would support a 15% non-inferiority. Dr. Bailey and Dr. Page

and Dr. Golish summarized it very well.


Mr. Melkerson, with regard to Question 1, and without making comment on the

effects of the use of a set percentage for non-inferiority, I think the Panel generally

believes, based on relying on the clinical judgment of the Sponsors, physician/clinician

investigators, as well as historical records, that a 15% margin appears to be appropriate for

this study. Is that adequate?

MR. MELKERSON: Yes, thank you.

DR. RAO: Let's go to Question No. 2.

MR. DEDANIA: Thank you. Question 2: Both groups experienced pain reduction.

However, the reduction from baseline pain scores was substantially lower for Cartiva

subjects compared to Arthrodesis subjects at the pre-specified primary time point of 1 year.

Similar results for comparisons of pain reduction occurred at every time point from 6 weeks

to 2 years. Please discuss the clinical interpretation of these findings for the Cartiva device

group and the Arthrodesis control group.

DR. RAO: Thank you.

So this is a question now that relates to the effect of the pain scores. Is that correct?


DR. RAO: Let's -- Dr. Lyman.

DR. LYMAN: So I think, for me, reflecting on this, this is the tradeoff of retaining

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joint motion and having the option of going to a fusion later. If the patient wants to have a

high level of activity after treatment, then it seems like they may be willing to accept this

pain, increased pain after surgery, decreased from what they had preoperatively, but

residual pain, and that just has to be part of the discussion with the patient. The patient

should be aware of this, that -- I'm not a clinician. I don't know how those conversations

would go.


DR. FINNEGAN: Well, I'm not sure. I don't actually think it's significant comparing --

I don't think the difference is significant enough for it to be an issue.

DR. RAO: The difference in?

DR. FINNEGAN: Pain.

DR. RAO: Between the two groups?

DR. FINNEGAN: Between the two groups.

DR. RAO: Okay.

DR. FINNEGAN: Yes.

DR. RAO: Thank you.

Dr. Gilbert.

DR. GILBERT: I would agree with Dr. Finnegan. Both of them show substantial

improvement in the VAS score, and I think you're up at this boundary issue, and in terms of

median VAS Pain, at 2 years the difference between 2 and 5, I still need somebody to pinch

me to tell me -- show me how much of a difference that is.


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Dr. Kelly.

DR. KELLY: I think I would echo the comments of Dr. Lyman. I think it's part of the

tradeoff inherent in these choices.

DR. RAO: Dr. Blumenstein.

DR. BLUMENSTEIN: I have nothing to add over what Dr. Lyman said.


DR. GOLISH: Yeah, I think this gets exactly to your point, Dr. Rao, about what is sort

of the existential function of a non-inferiority trial in this setting and if -- we have

substantial evidence that the pain reduction is less for the experimental device; maybe not

significantly less, but less to some degree. But if it is non-inferior in that measure, it's some

non-inferiority level. Then what are we left with? The possibility of some other benefit,

increased range of motion, which is not fully captured in the primary endpoint but yet

clearly has some appeal to patients and surgeons alike. So I think that the differences are

probably not important.


Dr. Subhawong.

DR. SUBHAWONG: Ty Subhawong again.

Just echoing what Dr. Lyman had pointed out. When you dichotomize these VAS

scores, you lose a lot of information and so looking at, you know, a reduction greater than

30% and showing kind of a slight inferiority for the treatment group, if you look at the raw

numbers, the p-values and the t-tests are pretty robust in terms of showing a very strong

statistical difference, but that -- the magnitude of that difference may not be clinically

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significant, especially when you're weighing the ability to preserve joint motion, so you

know, I think it's -- I think there's clear statistical inferiority for the Cartiva group, but I don't

know if it's clinically important.

DR. RAO: Thank you.

Dr. Bailey.

DR. BAILEY: I agree. I think there's a small improvement in the fusion group;

however, it may be overridden by concerns of the retention of motion in certain patients.

DR. RAO: Thank you.

Dr. Pfeffer.

DR. PFEFFER: I have nothing else to add.

DR. RAO: Thank you.

Dr. Trier.

DR. TRIER: Yes, this is Dr. Trier.

The results on the pain measurements, whether it's median or mean, don't really

represent anything that's clinically meaningful.

DR. RAO: Thank you.

Dr. Sayeed.

DR. SAYEED: I think the VAS scores are actually clinically meaningful, and the reason

for that is twofold. Number one, you get better function when you're in less pain and your

rehabilitation is much better improved. You can participate in PT, you can participate in

other modalities including sport and return to work. So in this case, if the fusion group

performs better in terms of pain, then to me that's a better treatment.

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DR. RAO: Thank you.

Ms. McCall.

MS. McCALL: Well, I'm not going to pinch Dr. Gilbert.

(Laughter.)

DR. GILBERT: Thank you.

MS. McCALL: I mean, this is an interesting question. To me, what's more meaningful

is "would you have the procedure again," because that's the end result: Did this help you,

did it not? And I think that's the better number.

DR. RAO: Thank you.

Dr. Page.

DR. PAGE: I think it's -- we should not lose sight of the fact that the patients that

receive the Cartiva implant did improve substantially with their pain, albeit not as much as

those who received a fusion. Yeah, it's difficult to conceive of a situation where you'd

perform a surgical procedure that retains motion where 100% of the pain is abolished, so I

don't think the differences are clinically significant.

DR. RAO: Thank you.

Dr. Carrino.

DR. CARRINO: No additional comments.


DR. HECKMAN: I think the differences are clinically significant, and first of all, I must

see and quibble with the FDA on their use of the term "substantially less pain" in their

summary statement. I think that needs to drop out of future comments. And I think

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probably the most important reason is that Dr. Baumhauer said that the patients who

underwent surgery with a failed implant did so because of pain, and that's somewhere

between 10 and 20% of the patients had pain as the primary indication for a second surgical

procedure, so I think it is important.

DR. RAO: Thank you.

Mr. Melkerson, with regards to Question 2, there is some concern about the way the

question itself is phrased, and the question specifically asks us to look at the clinical

interpretation of these findings and not the effects of any change in pain scores on the

eventual outcome of the composite end result. With that being said, the Panel generally

feels that the clinical results in both groups were roughly the same. Is that adequate?

MR. MELKERSON: That's adequate.

DR. RAO: Thank you.

MR. DEDANIA: Thank you. Question 3: Arthrodesis was substantially better for the

pre-specified primary functional assessment, FAAM Sports at Month 12. In examining

change from baseline FAAM ADL (FDA requested post-hoc) scores, Arthrodesis subjects

performed better than Cartiva subjects at every time point from Month 3 to Month 24. A

responder analysis showed non-inferiority, but to be a responder, the only requirement is

to not worsen by 8 or 9 points in terms of function. In consideration of these assessment

criteria, please discuss the clinical interpretation of these findings for the Cartiva device

group, in which the device is intended to maintain motion over time, and the Arthrodesis

control group.

DR. RAO: Okay, let's start with Question 3 now.

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Dr. Finnegan.

DR. FINNEGAN: So I think this is a little more important than the pain, but I think it's

important in educating patients as to making -- decision making, and I think it's important

enough that perhaps it needs to be in the labeling if there is labeling involved.

DR. RAO: Thank you.

Dr. Heckman.

DR. HECKMAN: This is an important issue, but again, both groups improved

substantially from baseline and the long-term difference, in my mind, is not substantial

between the two groups.

DR. RAO: Do either of you have any thoughts on the not worse -- to not worsen by 8

or 9 points in terms of function?

DR. FINNEGAN: I do, but I think the next question actually is where I can answer

that.


Dr. Gilbert.

DR. GILBERT: This is primarily a clinical interpretation. I'm not a clinician, so I think I

will defer to my clinical colleagues except to say that the time course of the improvement of

scores seem to be similar between the two groups.

DR. RAO: Thank you.

Dr. Kelly.

DR. KELLY: I have nothing to add.

DR. RAO: Thank you.

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Dr. Lyman.

DR. LYMAN: So I have a little bit different reading on this. I do think that there's a

meaningful difference here if we accept the 8 or 9 points. I'm a little bit -- so to the

question, itself, it's bizarre to me that we're talking about a cut-point which you're not

making the patient worse after surgery when the whole point is to try to make them better

functionally, right? You're going to reduce their pain and improve their function,

presumably get them back to where they were before they had the condition, trying to

resolve the issue, and yet we're considering them a success if they didn't get worse. So that

is strange to me.

But a secondary point for me is that there actually is, depending on rounding the 8

or 9 point difference to -- change the score between the two treatment groups, between

Cartiva and the arthrodesis groups in favor of arthrodesis. So it suggests that, from a

minimally clinically important different standpoint, the novel treatment is comparatively

inferior, functionally. Now, I have concerns about the survey because it's a foot and ankle

survey, not directed just to the foot, but if we're going to use that as a criteria, I think we

need to look at it that way, so --

DR. RAO: Thank you.

Dr. Blumenstein.

DR. BLUMENSTEIN: I think I might be saying the same thing that Dr. Lyman said, but

perhaps in different words. I'm interested in the 4-point spot that they gave the

experimental arm because they thought that this range of motion benefit would be

important to take into account when they calculated the trial size, and the FAAM

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supposedly is going to reflect this range of motion or the absence of the deficit in range of

motion and therefore give an improved FAAM score. And so this is going counter to the

whole theory of how the study was designed and so forth, and therefore, I can't -- I'm

having a real hard problem understanding what this means and how it relates to the whole

program.

DR. RAO: Thank you, Dr. Blumenstein.

Dr. Carrino.

DR. CARRINO: The only thing I would add is to resonate that maybe the instrument

used was not getting at exactly the painful area that they wanted and they had to use the

only validated instrument that was available, and there wasn't one specific for the first

MTP.

DR. RAO: Thank you.

Dr. Page.

DR. PAGE: The use of this instrument would seem to indicate inferiority of the

implant over fusion, but I agree that it cannot sufficiently discriminate the breadth of

athletic undertakings that an individual might wish to participate in or be specific enough to

the function of the first metatarsophalangeal joint.

DR. RAO: Thank you.

Ms. McCall.

MS. McCALL: I have nothing to add.


DR. SAYEED: Obviously, I think this is a poor tool. I don't think it really gives us any

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objective data; it's more subjective data. I don't think, you know, changing one answer one

point over 15 to 18 answer is significant functionally. Instead, the FDA should be looking at

tools that give us objective measures of functionality post-surgical treatment. That should

be the goal of the FDA, and I'm very surprised that we're analyzing a device this way.

DR. RAO: Dr. Trier.

DR. TRIER: Yes, Dr. Trier.

I have nothing to add.

DR. RAO: Thank you.

Dr. Golish.

DR. GOLISH: Yeah, I think that, as it's been pointed out, the functional outcome

measures are relatively coarse-grained tools. You know, in other areas outside of

orthopedic surgery, actually gold standards include surrogate outcomes; that those

surrogates are at least more objective. There's some irony in the fact that in orthopedic

surgery, we're accustomed to using functional outcome measures, and we're thought to be

in the vanguard in regulatory science in this regard, but we must admit that they can't

capture all the outcomes; it's a summary measure. They can't capture, for example, the full

effect of increased range of motion, which I think we agree upon, so I don't think this

difference is probably terribly important.



I don't have anything to add.

DR. RAO: Dr. Bailey.

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DR. BAILEY: I have nothing to add. I would echo Dr. Page's comments, though.


DR. PFEFFER: Yeah. You know, I agree with what Dr. Daniels said before, I think. I

mean, the FAAM is not just sensitive enough, and therefore this question doesn't have that

much meaning for me. But I would respond to what a few people said, that I think FDA, if

not the Panel, has to keep in mind. This is not really a long-term study; this is a 2-year study

on an implant, and I don't know of any implant in orthopedics that doesn't have increased

failure over time.

And I know that fusions have been around for a century, and if they're done well,

you don't get IP arthritis and you don't get much transfer metatarsophalangeal. So in terms

of patient safety or education, we certainly have to not lose that point, that one is a done

deal, and if you take out a screw, then you take out the screw and it's over. The other, I

think, has to deteriorate over the next 20 or 30 years; well, there's no scientific data to

prove that.

DR. RAO: Thank you, Dr. Pfeffer.

Mr. Melkerson, with regards to Question No. 3, I believe the Panel generally believes

that function is a more important parameter to assess than pain is, but the measurement

tool we have currently is not sensitive enough to accurately identify any gain or loss in

function after this or other procedures. There's also concerns over the 8- or 9-point loss as

still being considered equivalent or okay, particularly when we're introducing a novel or a

new product to the American public. Is that adequate?

MR. MELKERSON: It's adequate, yes.

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DR. RAO: Thank you.

MR. DEDANIA: Thank you. Question 4: The rate of Subsequent Secondary Surgical

Intervention events among randomized Cartiva subjects through 24 months was 10%. This

does not include the 18% of roll-in subjects and does not include 4 SSSI events that

occurred after 24 months. There is an element of subjectivity for determining the threshold

for surgical intervention in either the Cartiva or Arthrodesis groups. Please comment on

whether or not SSSI patients in the Cartiva and the reported procedures for device removal

following successful Arthrodesis should be successes or failures. Please discuss the long-

term clinical interpretation of these findings for the Cartiva device group and the

Arthrodesis control group.

DR. RAO: So let's start with Dr. Trier, give you the easy ones.

(Laughter.)

DR. TRIER: This is Dr. Trier.

You did that the last time, too. Give me the difficult ones first.

Well, first of all, I guess the initial comment, as I read this question, is that

responding to the portion of the question about the removal of, for example, a screw for

arthrodesis, based on my understanding of the guidance document, based on what I know

to be true about other device studies like this, a removal of a component of an implant is

always considered to be a removal and a failure. So I would say definitely that a screw

removal for arthrodesis is definitely a failure. With regards to SSSI procedures, I believe

that there was agreement with FDA initially with regards to the definitions of those

removals as presented by the Sponsor, and so I believe that the definitions that were used

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in the study are appropriate and that those things that were identified as removals,

revisions, and failures in that sense, for SSSI, should be seen as failures.

DR. RAO: Thank you.

Dr. Pfeffer.

DR. PFEFFER: If I read this question right, is -- I would answer that a failure of an

arthrodesis just has to be, for this study or otherwise, a failure of an arthrodesis, not a

proud screw. So I think there are two patients in this study who had true non-unions that

needed to be operated on; that's our failure rate. In terms of the Cartiva, any removal of

the device regardless of what happens afterward is a failure of the procedure. Just very

simple without getting complicated. Does that answer that question, do you think? Yeah,

does that address the --

DR. RAO: Sure.

DR. PFEFFER: Yeah, okay.

DR. RAO: How about the long-term clinical interpretation of these findings?

DR. PFEFFER: Well, as I just said, I've been in practice for 27 years, 26 years. I don't

recall any toe fusions I've done that come back 4 or 5 or 6 or 7 or 8 years later and say gee,

I'm getting arthritis or now I'm limping around. If they fail, perhaps I didn't get in the best

position right away, and I certainly remember patients like that, there are a few of them.

But the Cartiva, I think, because I don't know of any other implant in orthopedics that

doesn't fail over time, will have increased failure. Does that answer that?

DR. RAO: It does, thank you.

DR. PFEFFER: Unless there's something that the Sponsor knows about it that I don't

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understand.

DR. RAO: Thank you.

Dr. Bailey.

DR. BAILEY: If I understand the question correctly, my personal feeling about fusion

and arthrodesis would be if the arthrodesis failed. I would not worry about screw breakage

unless it was in that context. I would certainly not characterize a simple proud screw

removal as a failure. I think the failure of the Cartiva implant is characterized correctly in

the study. The long-term clinical interpretation of these findings, I mean, would be as to

whether it failed or not. I don't think I'd have anything further to add on that.

DR. RAO: Thank you.

Dr. Subhawong.


I think to be -- to apply a consistent standard would be important, so for me any

return to the OR should be considered a failure, even if it's just to remove a proud screw. If

that screw is causing pain and the intent of the fusion was to relieve pain, that has to -- that

would, in my mind, constitute a failure. In terms of long-term clinical impact, to me, a

failure in implant group is not as bad as a failure in the arthrodesis group because you have

arthrodesis as a salvage procedure, so you haven't burnt any bridges.

DR. RAO: Thank you.

Dr. Golish.

DR. GOLISH: I think it's typical, in surgical clinical trials, to consider any unplanned

reoperation to be a failure.

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DR. BLUMENSTEIN: To me, this is the hardest question. I'm going to interpret it as

immediate versus delayed fusion, and so the hard part, for me, is to figure out whether

there's been a sufficient benefit of Cartiva before it fails. And so since it is possible to still

get fusion, and that's regarded as a feature, a positive feature, of Cartiva, that's why I have

a hard time answering this question. And so the problem that I have is that I haven't been

convinced that there is a benefit of Cartiva before it fails, and that would be going even

beyond the 2-year data that we have here. And so when I regard the study as immediate

versus delayed fusion, with Cartiva being that which causes -- which implements the delay, I

don't feel like I have enough data to be able to answer this.


DR. SAYEED: I pretty much echo what the Panel has said so far. One thing that we

should consider when we are evaluating this device is, is it okay for us to have a secondary

surgery, maybe unnecessarily, to complete the actual outcome? I don't know the answer to

that.


MS. McCALL: I think any time you have to go back into surgery, something failed.

It's hard on the patient to go through it a second time, no matter what you're doing. As for

the long-term clinical interpretation between a new device and something that's been

around for a hundred years, you're asking me the same question between warfarin and a

NOAC. They're two different things.

DR. RAO: Dr. Page.

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DR. PAGE: I agree with Dr. Subhawong in that anytime something has to be removed

and it was occasioned by pain, that that would be considered a failure. And while it has

been the natural history of implants to deteriorate over time, we don't have that data yet,

and I think the failure rate in the Cartiva group of 10% is an acceptable rate at this stage of

the game.

DR. RAO: Dr. Carrino.

DR. CARRINO: I think for the arthrodesis group, the definition of failure could've

been a little bit tighter. I think we've heard a broad range of opinions of what would be

considered a failure rate for that, and that's up to the orthopedic surgeons, but I think it

could have been -- the definition could've been tighter, whether it's removal for pain versus

simply just removal for fixation. And I don't have anything else to add.


DR. HECKMAN: Yeah, I think we're challenged because we're creating two

dichotomous groups here, and I think there's a middle range. I'd restate, taking out a

painful screw is not like trying to do, redo a fusion or to recover from a failed Cartiva

implant. So I think those are very, very different things, and while they are indeed

complications and surgical failures in the literal sense, they are not equal, and they should

not be considered equal.


DR. FINNEGAN: So this area actually was the area I was most disappointed in

because I think that there wasn't as much discussion on the Cartiva failures as there

probably should have been. And I would also define failure as an unexpected event, and I

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think most of us who put plates and screws in, particularly when they're close to the skin,

tell the patients up front that they're probably going to have some of the screws taken out,

so the patients know that going in. So I would not actually consider screw removal to be a

failure, but I do agree with Dr. Heckman that you cannot compare screw removal to

removal of an implant and a fusion.

DR. RAO: Thank you.

Dr. Gilbert.

DR. GILBERT: So, you know, in orthopedics there are joint registries that focus on

revision rates and defining failure as they need to revise, and what I understand in here, the

comments about simple fractured screw perhaps not rising to the level of a full revision, so

you know, I think I fall to the side of if you have to revise, you have to call it a failure. In

terms of the long-term effects -- so, again, I'd go to the joint registry analog and say that we

are going to see, if this device goes forward, failure modes that will begin to show clearer

frequency and type of failure, and so it will be important to do long-term clinical follow-up

of these kinds of failures going forward. Ten percent for introduction of a new technology, I

would agree, is an acceptable level, but as it moves forward, I think that rate will not be

acceptable long term.


Dr. Kelly.

DR. KELLY: I concur with Dr. Heckman. I've take out many ACL screws, but I've not

had to revise the graft. It's an unfair comparison; it's an apples-and-oranges issue. It's an

adverse event; it does not constitute a failure.

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DR. RAO: Dr. Lyman.

DR. LYMAN: So I know the study was performed outside of the United States, but

there's some evidence that the biggest risk factor for hardware removal is adequate

insurance, so keeping that in mind, I think that hardware removal, which seems like it may

be somewhat elective with these screws -- and I agree, it sounds very different, I'm not a

clinician, but -- but I think if the Cartiva removals were primarily for pain and the screw

removals were primarily for pain, then we have to, at least for research purposes, we have

to consider them equivalent because the Cartiva patients' pain levels may have been

reduced but not enough to meet their expectation, just as the screws may be more

irritating and not meeting the patient expectation.

So I think it's fine as they defined it. I agree that a 10% failure rate at 24 months, for

a new technology, probably is fine. If it's 20% at 48 months, we might have to think more

about it. Early failure is understandable, consistent. Long-term failure might be a bigger

issue. But I think that the definitions were appropriate for this research.

DR. RAO: Mr. Melkerson, with regards to Question No. 4, the Panel generally

believes that an SSSI incidence of approximately 10% for new technology would generally

be acceptable provided it doesn't get much higher over subsequent year follow-up. There is

some concern about the definition of SSSIs for the arthrodesis group where minor

procedures that are not unanticipated should not be considered failures and should be

considered more of an adverse event that happens occasionally. The long-term clinical

interpretation of these SSSIs depend on the specific SSSI and for the follow-up on these

implants. Is that adequate?

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MR. MELKERSON: I believe so. Thank you.

MR. DEDANIA: Thank you. Question 5: The two devices have different criteria for

determining radiographic success or failure. Please discuss the clinical interpretation of

these findings for the Cartiva device group, in which the device is intended to maintain

motion over time, and the Arthrodesis control group which is intended to eliminate motion.

DR. RAO: Thank you.

Dr. Kelly. If you wink at me, that's what happens.

(Laughter.)

DR. KELLY: I'm going to catch my train. Again, unfair comparison. I mean, these are

really two different spheres of success. One would be loss of alignment catastrophic

synovitis and breakage, which then would be arthrodesis soma fusion, so it's really a moot

question to me, and I really don't know how to answer it, so -- so final answer is that the

interpretation of these findings is irrelevant.

DR. RAO: So just to kind of go over it for the Panel members, could you just go over

the radiographic criteria again? For Cartiva it was implant displacement, migration, and

there was a third?


DR. RAO: Fragmentation of the device. And then for the arthrodesis, it was

mal-union, non-union, and hardware displacement or migration. Is that correct? Anything

I'm missing?

MR. DEDANIA: And hardware fracture.

DR. RAO: Hardware fracture. So those are the things. So with the arthrodesis, it

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was mostly issues related to the fusion; with Cartiva, it was mostly issues related to the

implant itself.

Dr. Kelly, anything to add to that answer?

DR. KELLY: Not really. The one is very concrete, solid fusion. The other is, I would

say, any perturbation in bone alignment or integrity, so just take it what it is.

DR. RAO: Dr. Lyman.

DR. LYMAN: I'd defer to Dr. Carrino on this. I don't read X-rays.

DR. RAO: Okay.

Dr. Finnegan.

DR. FINNEGAN: So I actually agree with Dr. Kelly. I think they are two totally

different things, and I think that the criteria that they put up are suitable.


DR. GILBERT: I agree.


DR. HECKMAN: I agree with Dr. Finnegan with the exception that seeing that one

radiograph of the implant, I can't tell whether it's fractured or not because you can't see it.

So I think that's a very weak radiographic criterion. Those could be broken or fractured, and

you wouldn't know it, looking at the plain radiographs.


DR. CARRINO: So I agree with the rest of the group. There are two different devices;

there would be two different sets of imaging criteria, and I think for arthrodesis, that's very

well established. For this new implant, the limitations are -- that it's not radiopaque. I

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think what was described by the radiologist was some indirect signs of fragmentation,

which is what you would have to use, so I think I agree that what they used was appropriate

or suitable for their study, from an intellectual interest, because it's a motion-preserving

device, some kind of kinematic or cinematic imaging would have been intellectually

interesting, but I don't think necessary.

DR. RAO: Thank you.

Dr. Page.

DR. PAGE: I really have nothing to add. They did a fine job. I can't think of any

other criteria I would've substituted or added. This had to be the way it was.

DR. RAO: Thank you.

Ms. McCall.

MS. McCALL: Nothing to add.


DR. SAYEED: Abstain.

DR. RAO: Dr. Trier.

DR. TRIER: Nothing to add.


DR. BLUMENSTEIN: I have no comment.

DR. RAO: Thank you.

Dr. Golish.

DR. GOLISH: I had to laugh when Dr. Carrino said the radiographic criteria for

arthrodesis are relatively well established. We spend hours in this room on various days

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discussing them for the hindfoot, the spine, and other joints, so maybe we need to do it

here every time.

(Laughter.)

DR. CARRINO: I said -- did I say relatively?

DR. GOLISH: Yeah, I think so. But though radiographic non-union is an outcome

criteria, you need to -- in arthrodesis, a degree of heterotopic ossification sufficiently severe

to limit the motion is unique to an arthroplasty, is similar to a cervical arthroplasty, so I

think that if the HO is bad enough to create a functional arthrodesis, if you had a true bony

union or a stable fibrous non-union that diminishes motion, that ought to be considered

radiographic failure. With the kinematic analysis Dr. Carrino's suggesting, unfortunately, I

don't know that we have the information to make that judgment.


DR. SUBHAWONG: Yeah, I just -- this kind of brings in one of my concerns, was the

fact that in the composite endpoint, the radiographic failures for the fusion group kind of

contributed to the two groups eventually becoming equivalent on the final composite

endpoint. It was worse in the pain scores. I don't know of a better way to evaluate it

though in terms of a radiographic assessment for the fusion group and Cartiva group, but I

was reassured, I guess, by the post hoc analysis and then presented by the FDA showing

that if you just remove your radiographic analysis from the composite endpoint, the lower

bound on the difference was still 15%, which we already decided was probably, you know, a

clinically acceptable lower bound.


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DR. BAILEY: Agree with the previous discussions about the fusion group. I would

feel that the Cartiva criteria need to be more robust. I see nothing in there about

progressive radiolucent lines, I see nothing in there about cyst formation, which we had an

example of. And I would think, on that basis, they should -- those criteria should be more

robust. What they captured in this is catastrophic failure. Much more likely the device will

fail insidiously and not catastrophically.


DR. PFEFFER: Nothing to add.

DR. RAO: Thank you.

With regards to Question 5, Mr. Melkerson, the Panel generally feels that the two

arms of the study, the control and the trial arm, are relatively different devices, and the

radiographic criteria that we use to evaluate these two devices are generally acceptable.

However, there are some areas of subtlety that are not well picked up with the current

criteria, and the criteria should probably include something for radiolucency, radiolucent

lines, osteolysis, subtle implant migrations, and implant fractures, to be more precise, for

the implant group. Is that adequate?

MR. MELKERSON: I thought I heard heterotopic bone --

DR. RAO: And heterotopic ossification, thank you. Is that adequate?


DR. RAO: Hang on, there's a question here.

DR. CARRINO: Well, I didn't have nothing -- radiography is a very easy modality and

is readily available. We use more and more CT imaging in our practice, and I was going to

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ask the Panel if they thought CT was going to enhance any of the imaging parameters. It

just came to me as we were discussing it.

DR. RAO: And there is some thought of possibly having either CT or cinematic

studies to better assess the gait in these patients. Is that adequate?

DR. CARRINO: At least for radiolucent devices that are fractured, you have a better

opportunity with CT for seeing them. We can see linear fractures and other implant failures

with that modality.


DR. HECKMAN: Well, I think in the big picture, the radiographic elements here are

not very important frankly. Sorry. I think the clinical outcome is much, much more

important, and what you want to find, for sure, is catastrophic failure, and then the

insidious deterioration over time, I think, are the more important things. And to start

talking about very expensive -- I think MR might even be better than CT for some of these

things, so I -- rather than get into all that discussion, I think we should focus more on the

clinical outcomes than the radiographic.

DR. RAO: Mr. Melkerson, I have nothing further to add to my previous comments. Is

that adequate?


DR. RAO: Thank you.

MR. DEDANIA: Thank you. Question 6: Prospective subjects will likely have the

impression that increased mobility will allow for greater function in Cartiva as compared to

Arthrodesis. However, the level of function for Cartiva appears to be the same or worse

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than Arthrodesis from 3 months to 2 years. Does the Panel have any suggestions regarding

the education of prospective subjects so they are able to make informed decisions with

regards to realistic expectations and goals regarding function following Cartiva or

Arthrodesis procedures? Can the Panel provide a discussion on how best to objectively

capture patient preferences with regards to either procedure?

DR. RAO: This is along the lines of your comments, Dr. Lyman. Do you have any

comments on this?

DR. LYMAN: So I think, you know, this gets into a much broader area of shared

decision making between surgeons and patients and that sort of thing, but I won't go off in

that direction. I think the patient should be aware that they will maintain or gain range of

motion, but that doesn't necessarily mean that they're going to have complete resolution of

pain or an improvement in their activities of daily living or their ability to do sports and

recreation. We heard anecdotally that that's maybe not the case, but the evidence isn't

showing us that.

So I think what would be nice to have, and this is something I brought up earlier, is

some measure of baseline activity and then hopefully some measure of expected activity

because that's going to help inform the decision, and it's going to help the patient make the

decision with the guidance of the surgeon about which approach would be most

appropriate. And I think that's where you might get at the patient preferences. If

somebody wants to run marathons, I don't think that the fusion is the right option, right?

So I think there needs to be some discussion around both preoperative activity, expected

post-operative activity, or other measures of expectation for the patient as part of the

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discussion.

DR. RAO: Dr. Kelly.

DR. KELLY: Nothing kills like the truth. I think that there was sort of an implicit -- my

read, of course, biased, a little salesmanship to patients; well, if you want your motion, and

as the happy patients testify, they have their motion. But the literature is clear. The most

reliable way -- is fusion. And to your point, Dr. Lyman, there are many, many people out

there running 10K's with arthrodeses. Glenn will testify to that. So I think that it has to be

disclosed to the patient, yeah, you'll get motion, but your most reliable procedure will be an

arthrodesis, the truth.

DR. RAO: Thank you.

Dr. Gilbert.

DR. GILBERT: I guess the way I look at that data of recovery after either of the two

treatments, it's a difference in the course of the rehab, right? One of them, it's -- you're in

a boot and it's painful for the first 6, 8, 10 weeks, and then you're pretty much better. And

in the other, you have a longer period where pain remains, and you're limited in some of

your function, and then after a year or so, you're pretty much at the same place. So it

seems to me it's really counseling about the nature of the rehabilitation process and what

the expectation should be of the patient during that rehab process, that long term, it seems

to me they both kind of end about the same place.


DR. FINNEGAN: So I think the best way to educate the patients is to make sure that

any marketing material actually outlines the fact that it may or may not give you increased

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mobility, and it may or may not, long term, be different from an arthrodesis. And, in fact, I

think some of them become pseudo-arthrodesis. I'm not sure how you capture the

patients' preferences, because I think if you went around this table or this room and asked

everybody would you like motion or no motion, they're going to say we'd like motion, so --

and that's probably the incentive for starting this research in the first place. So that, I'm not

sure how to answer.


DR. HECKMAN: Yeah. I think (a) they have not demonstrated increased mobility.

There's 7 degrees more motion at follow-up between the two, before and after. So that

may not be a clinically significant improvement. You do retain motion, as opposed to the

fusion group, which is going to lose motion and that's -- but that needs to be said. I don't

think increased mobility is not something that should be promoted or encouraged in

patients. I think the expectations narrow down to a very, very small number of elements.

High-heeled shoes is one, cowboy boots is another. And there may be a couple of other

reasons why people would want to get up on their tiptoes. But beyond that, there's not a

lot of difference in -- that we've seen in the two groups.


Dr. Blumenstein.

DR. BLUMENSTEIN: You know, this question is much too touchy-feely for a

statistician.

(Laughter.)

DR. RAO: Okay.

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Dr. Golish.

DR. GOLISH: We have some precedence in this with spinal arthroplasty in which the

primary outcome measures were non-inferiority on a composite measure, but there's

always this underlying concept of gee, wouldn't retaining the motion be nice, and mustn't

that achieve something? I think here this absolutely needs to be disclosed, were the device

to be approved, with very clear labeling language in which the concept of overall function is

distinguished from that of motion and that the latter does not mean it's equivalent to the

former.

And I'd like to make a closely related point about potential marketing language, were

it to be approved. I think that the phrase "synthetic cartilage" or any mention of cartilage is

aspirational marketing language that ought to be expunged. I think it might reinforce this

concept of magic of motion, which, as we've seen today, is more complex than it seems.

DR. RAO: Thank you. I think Dr. Pfeffer is excited about your comments.

Dr. Subhawong.

DR. PFEFFER: No, I'm always excited. Actually -- did you call me?

DR. RAO: Go ahead, go ahead.

DR. PFEFFER: No, please.

DR. RAO: Dr. Subhawong, please.

DR. PFEFFER: Sorry, go ahead.

DR. SUBHAWONG: So using the opportunity to address one part of the proposed

language in the SSED, which, you know, speaking to patient education, you know, there's a

paragraph, and I'm quoting, "Based on the treatment options currently available, the minor

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risks of implantation of the Cartiva device are tremendously outweighed by the benefits of

improved function and decreased pain that the device provides."

So I just think that kind of language should be -- because I think the data shows that

it's equivalent or slightly worse than fusion, but you do have to educate patients that --

fracture patients will, maybe, be able to preserve some of the activities that they have a

very high interest in continuing to engage in, and they just have to have that discussion with

their surgeon as to whether the risks of the surgery are, you know, whether the tradeoff is

worth that risk.

DR. RAO: Thank you.

Dr. Bailey.

DR. BAILEY: I think Dr. Lyman's on the right track when he says it's got to be shared

decision making, and that in the end, it falls back on the ethics of the individual surgeon. I

think as far as what the FDA might put in any -- should this be approved, in any language,

would certainly have to incorporate the patients I see in the indigent downtown clinic

versus the patients from a very affluent-type neighborhood, so I think whatever language

was included would need to incorporate that divergent population.


DR. PFEFFER: You know, we do such a good job here -- we try -- but the problem is

that the system's a little flawed because no matter what the FDA puts on the little device

panel or what's in -- it's what the physicians say in their office. After the STAR Ankle was

approved, surgeons all over the country received promotional material from the company,

and I have it on my computer, that says make sure to tell your patients about all the

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problems with fusions, because that's why total ankles are so good. So what will happen

regardless of what we do here, and I'm voting -- well, I won't say I'm voting, but I'm -- can I

-- I'm in favor of this -- you'll find out soon. I will vote in favor of this.

But all over the world, all over the United States, doctors will say to their patients

look, there's no scientific data, but why lose any motion? You're 55 years old; you want to

be 55 going on 45, not 55 going on 75. So our system is greatly -- we do the best we can,

but we can't get to that private informed consent, and if the FDA can, it would be great. In

answer to the specific question, there's no question that the evidence -- there's no evidence

that Cartiva increases function, and I agree with Dr. Daniels why that is.

It certainly would increase function on many, many activities of daily living, and I

know that from, you know, being a doctor -- in other words, a foot and ankle person, but --

how important those daily activities are, I don't know. I tell my patients you can't get up on

your toes on that side to reach the top shelf, and they go okay. So the other -- and so the

issue here is that patients somehow, if we can do it, have to be told that there are other

joint-preserving options available: cheilectomy, interposition arthroplasty.

I understand Dr. Daniels and the Canadian point of view, but it ain't the Los Angeles

point of view, and my partner invented one of these interposition arthroplasty procedures

with soft tissue, and they do well. So the real problem or the real issue with this study is

not how the Cartiva -- in my mind -- how the Cartiva does against fusion; it's how the

Cartiva would do against joint-sparing procedures, right, which have probably the same

failure rate as the Cartiva does. So anyway. It's not a synthetic cartilage, and I don't think it

should be allowed in the Coughlin Level 2. I don't know how you would stop that because

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this is all -- could be all off-label use, but there's no evidence other than the Canadian

feeling that the Coughlin 2 is appropriate. And Dr. Glazebrook said there's Level C evidence,

and I agree with that, but Mark, it's the best we got, right? Level C is the best we got. It's

not Level D or F or I, so the best we got says that the procedure of choice is cheilectomy for

a Level 2. Long answer, but I don't think I'll have a chance to summarize my feelings later

on.

DR. RAO: Thank you.

Dr. Carrino.

DR. CARRINO: I have nothing else to add.

DR. RAO: Thank you.

Dr. Page.

DR. PAGE: I think we should take care with the use of the word "mobility" and not

confuse it with the word "motion." I think what was intended here, it was the impression

that they increased motion in the joint, will offer greater function. The study didn't actually

assess mobility, which is a different issue. That said, though, I, a surgeon, will ascertain his

patients' expectations and then align them realistically with the capabilities of the

procedure proposed. And if they are not aligned, both the patient and the surgeon will be

unhappy at the end.

DR. RAO: Thank you, Dr. Page.

Ms. McCall.

MS. McCALL: Well, I'm going to dovetail on Dr. Bailey, Dr. Subhawong, and

Dr. Lyman in that this should be an informed decision between surgeon and patient with

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three pretty basic questions: What were your favorite things to do before you had the OA,

what are the activities you truly enjoyed? Where you are today, what activities are

important to you? And where do you want to be in a year? No matter what decision we

make, where do you want to be in a year? What activities are really important to you?

Once you answer those questions, I think both the patient and the surgeon can make a

good decision based on the facts the patient can provide.

DR. RAO: Thank you.

Dr. Sayeed.

DR. SAYEED: I would just urge caution in terms of telling patients that they will

recover function, because the evidence in this study does not indicate that and, you know,

in comparison to arthrodesis. And, you know, subsequently they may need a secondary

surgery that will move to an arthrodesis, so that also has surgical complications including

infection risk, et cetera.

DR. RAO: Thank you.

Dr. Trier.

DR. TRIER: Dr. Trier.

I appreciate the comments that have been made around the table about the shared

decision making between the patient and the surgeon. The one comment that I do need to

add at this point is the fact that, you know, whatever -- if this device were to be approved

for use in the U.S., the approved labeling will include the results of the clinical study, and

that includes all of the labeling which includes a patient brochure that lays out all of the

risks and benefits and findings from the study; it includes the SSED that you commented on,

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as well as in the package insert and, you know, the actual outer box label. So I think it's

important for us all to understand that the results of this study, findings, comparison for

pain, activity, so forth, will all be included in that approved labeling.

DR. RAO: Thank you.

Mr. Melkerson, with regards to Question No. 6, the Panel is generally concerned that

the allure of preserving motion is fairly high for patients but that the expectations from this

device need to be clearly identified. The expectations of the patient from any surgical

procedure need to be clearly identified. The patient needs to be informed that while range

of motion will be preserved with this device, the function that they expect from this

preserved range of motion may not be substantially different from the function obtained

with the fusion procedure. Is that adequate?


DR. RAO: Question No. 7, please.

MR. DEDANIA: Thank you. Question No. 7 deals with a discussion of the PAS. I'll

read out the reminder regarding the discussion of the PAS: The discussion of a PAS prior to

FDA determination of product approvability should not be interpreted to mean that FDA is

suggesting that the product is safe and effective. The plan to conduct a PAS does not

decrease the threshold of evidence required by FDA for product approval. The premarket

data submitted to the Agency and discussed today must stand on its own in demonstrating

a reasonable assurance of safety and effectiveness and an appropriate risk/benefit balance.

Question 7: Please comment on the need for a post-approval study and what

questions should be addressed by such study should FDA determine that this PMA

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application is approvable.

DR. RAO: Thank you.

This is another tough question. Dr. Trier, I'm going to start with you.

(Laughter.)

DR. TRIER: Thank you. Dr. Trier.

There have been several comments and the recognition that this is really a first-of-a-

kind for this material being used in the orthopedic space. So I think a post-approval study

would be appropriate and necessary, and the questions that have been raised about the

long-term radiographic results, the long-term clinical benefit over time, are appropriate

types of data that should be gained in that post-approval study.


DR. SAYEED: As the consumer advocate, I'm tasked with protecting the consumer,

which is the American public. So, overall, I'm very concerned with this device. I don't feel

like they've demonstrated safety or efficacy. From the study design, there are many

concerns -- Dr. Lyman and Dr. Blumenstein addressed those -- to the adverse events. To

approve a device that has negligible positive benefits for a population just to increase the

diversity of treatments is not a good standard that the FDA should undertake.

We should be evaluating treatments that are superior to the current standards.

Additionally, the superiority of the treatments should result in a better quality of life

demonstrated by real-life functional outcomes. This device demonstrated none of that. In

addition, to consider a backup plan of more surgery invites higher risk to the patient,

including possibility of failure, infections, or additional adverse outcomes. In my mind, as

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an advocate for the people, we should be considering high-quality evidence-based

treatments with large randomized control trials.

DR. RAO: Thank you, Dr. Sayeed.

Ms. McCall.

MS. McCALL: Dr. Sayeed makes very good points about looking out for the American

public and their safety. I gently disagree with patients should have options, and I agree

with what Dr. Trier said.

DR. RAO: Thank you.

Dr. Page.

DR. PAGE: I also disagree with Dr. Sayeed at this point. I think this was an excellent

study. As far as these studies have been designed previously, this is as good as we've got.

There does need to be follow-up on the issues that were already raised by Dr. Trier.

Thank you.


DR. CARRINO: So I think with regards to post-approval studies, I think this is one

area where imaging could give some insight into some insidious, potentially insidious,

complications like other arthroplasties that are being surveilled with imaging that could

demonstrate preclinical changes or failures. And then what I would consider is, should

those post-approval studies include advanced imaging or continue with radiography, so is

there a value of using CT and/or MRI? I think CT gives you more information about the

bone stock, can give you more information about implants that are relatively radiolucent,

and also about bony bridging, as is done with other -- you know, some other arthrodesis,

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other implants.

DR. RAO: Thank you.

Dr. Heckman.

DR. HECKMAN: I think we need to give this device a chance, but I think it should be

deployed in a limited sort of way with a very careful registry follow-up of the patients, at

least, so that we can see about their longer-term outcome with a commitment from the

Sponsor to make sure that they are followed up appropriately. And I think we need further

to limit the indications for use, and the proposed indications for use presently is listed on

slide 8 from the FDA, include hallux valgus and an unstable or painful joint, and I think it

should be very clearly restricted to hallux limitus or hallux rigidus and a painful first

metatarsophalangeal joint.


Dr. Finnegan.

DR. FINNEGAN: So I absolutely agree there should be post-approval studies, I agree

with the radiology. I think also that the question of persistent pain, and while pain may be

decreased, it stays above the acceptable level in the Cartiva as well as the percentage of

Cartivas that get changed to fusions.


DR. GILBERT: I agree with Dr. Heckman about the need for a post-approval study,

looking at survivorship, some sort of registry. I would also strongly encourage retrieval

analyses that would include capture of tissue adjacent to any implants if there's evidence of

some local action, either heterotopic bone formation or perhaps osteolytic lesion or cyst, in

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which you can get a better handle on what the local biological reactions are and so that will

better inform you as to long-term survivorship.

DR. RAO: Thank you.

Dr. Kelly.

DR. KELLY: Yeah, I'm going on the record is I think this thing deserves a shot. It is

minimally invasive. It is -- in my considerable experience, having the blessing to serve on

this Panel -- reasonably safe. I think it's somewhat efficacious, but Dr. Heckman would say,

I think, that the indications have to be extremely explicit, and I would like to see the study

involving, as Dr. Pfeffer alluded to, a head-to-head comparison with non-arthrodesis

options.

DR. RAO: Dr. Lyman.

DR. LYMAN: Yes, I think it's clear we need long-term follow-up studies of this device,

should it be approved. I'd think that it's really about safety and implant survival. I don't

know that you're going to get much more gain in pain and function over more time, but I do

think making sure that the implant is safe and long-term implantation is safe and that the

survival rate of the implant, that your revision rate isn't -- doesn't, you know, go through

the floor.

DR. RAO: Thank you.

Dr. Blumenstein.

DR. BLUMENSTEIN: Well, I generally prefer randomized studies, and I feel like there

should be a real benefit from more randomized study of the alternative, against alternative

interventions. I realize that that's very difficult. The one burning question that I have at the

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end of the day here is why is it that the pain persists, apparently? Maybe it's mild, but

nonetheless, it's there. In the experimental arm. And so it seems like, to me, that some

studies focused or some study focused on trying to find out what the mechanism is for that

pain to persist would be a huge benefit.


DR. GOLISH: I agree with others that a PAS would be mandatory, at least a

longitudinal observational study experimental device out to 5 to 7 years, and that should

include, in any revised device, both retrieval analysis and comprehensive histological

analysis to assess the biology, in particular, where to --


DR. SUBHAWONG: I agree, I think there should be continued study after -- for a

longer term, and just echo what Dr. Carrino said, I think incorporating cross-sectional

imaging could shed light onto the reason some of these patients have been having pain,

first thing off the top of my head. But if you had, you know, specific patterns of bone

marrow edema that were associated with patients that had more pain or stress reaction in

the bone that you could potentially pick up on in MRI, that might be important.


DR. BAILEY: I would agree with the last two comments. I think the PAS studies

would be critical. I think they should include histologic and mechanical analysis of the

failures. I'm not sure -- echoing previous comments -- I'm not sure MRI scan is really, is

going to be financially doable. I think probably plain radiograph lucencies and things like

that, hopefully that would correlate to the failures in the future.

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DR. RAO: Thank you.

Dr. Pfeffer.

DR. PFEFFER: These guys summed it up nicely. I would just hone down a little bit

more on Dr. Heckman's, you know -- Golish. I agree with Dr. Golish's comments here, and

Dr. Bailey. But I would hone down a little bit more on Jim Heckman's comments. I would --

a 10% failure rate, we're minimizing. I mean, a new knee comes out, and we say that's only

a 10% failure rate, we'll get it better. But that would never occur. Where, in orthopedics,

do we accept a 10% failure rate, whether it's a new device or an old device? Well, I'm

willing to accept it because all the motion-preserving surgeries I would do would also have a

10% failure rate.

But we need to follow this really closely; as we've all said, what's going to happen at

3 years and 4 years and 5 years? Look at the STAR, which we've talked about. The failure

rates have gone up much higher than our Panel ever considered initially. I would personally

only allow this for Coughlin 3 and 4 where the scientific data is irrefutable, where a

cheilectomy can't be used. And at 5 years, I would probably revisit it and then perhaps start

approving it for Coughlin 2's.

DR. RAO: Thank you.

Dr. Heckman.

DR. HECKMAN: If I may make a comment, since I'm probably the oldest one in the

room at 72 and remember when cement was released to a limited number of institutions

with a number and trials were conducted for very restricted fashion to individuals who had

experienced hip surgeons, I think something like that, rather than just releasing it to the

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general public with every orthopedic surgeon being able to do these procedures is

premature at this time. If we could restrict it that way.

DR. RAO: Thank you.

With regards to Question No. 7, Mr. Melkerson, I think there are some concerns the

Panel has on the safety and efficacy of the device, and there's also some concerns and lack

of clarity on why some of these people have persistent pain, had the follow-up periods in

the study. Overall, the Panel generally felt that these concerns were mitigated by the

presence of -- by the motion that the device offered, but felt that there needed to be close

follow-up of this device for possibly a period of 5 years to determine the survival rate and

determine if any other safety issues would arise. There should be strict limitations on the

indications for use of this device, with specifically being careful to exclude patients with

hallux valgus or "unstable joint."

And that any devices that were followed and went down to explantation should be

carefully monitored for histological and biomechanical changes in the device and the

surrounding soft tissues. There is a role for a continued imaging follow-up of these

patients, most likely with just plain X-rays. There may be a limited role for advanced

imaging of some of these patients to determine subtle lucencies or other radiographic

findings that may show up that have not been visualized to this date. Is that adequate?

MR. MELKERSON: Just a clarification. Some of the questions that you're raising

sound like it's continuing to follow those patients already enrolled, i.e. longer follow-up. I

thought I also heard questions that may require a new enrollment. Can you clarify if that's

a correct understanding?

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DR. RAO: I'm not so sure, maybe just a show of hands. Did anyone feel -- let's just

start with the first question. Do people feel that the same cohort of patients with the

implants could be followed a longer period of time? Just raise your hand, so we just kind

of --

(Show of hands.)

DR. RAO: I think that seems to be the majority. Does anyone feel that a new cohort

of patients with more defined criteria for inclusion should be also carried out?

(Show of hands.)

DR. RAO: And that -- I think there's a role for both types of studies. I think the same

cohort should be followed, and I think maybe Dr. Heckman's point is just that we've got to

restrict our criteria for inclusion in this new cohort. I suspect that those who wanted this

new cohort with more defined criteria are mostly talking to exclude some of the criteria, or

did you want to include something else? Or could you just elaborate, those who had the

hands up for the new cohort, if you could just explain.

DR. HECKMAN: Yeah, it would be a more restrictive criteria in terms of definition of

inclusion criteria. And then I think in order to get -- the failure rate is maybe 10%, but that's

still pretty small, but that's why you need a thousand patients to really see what the long-

term outcome of this device is going to be before -- particularly before it's released for

similar lesions in the elbow and who knows where else, okay?

DR. RAO: Anyone else who felt a new cohort should be necessary, what the criteria

for inclusion in that new group -- Dr. Blumenstein.

DR. BLUMENSTEIN: Well, I'm very disappointed that I do not know more about the

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putative benefits of this kind of an implant. In other words, there's a lot of talk about it, but

we don't have measures that clearly indicate that they're there. I don't know what kind of

new measures can be devised, but I would guess that this would be -- go a long ways

towards convincing that this, in fact, is a good thing to do. Maybe, I don't know, they use

6-minute walk or -- you know, timed 6-minutes walks or -- that's just off the top of my head.

I don't know anything about that. But if there is a claim that there is benefit to having

flexibility, then they should be able to figure out a way to measure that.

DR. RAO: Anyone else who has thoughts on what should be -- how the new cohort

should differ from the original cohort?

Dr. Page. That's the issue here.

DR. PAGE: That was not why I raised my hand. I will say that this implant cannot

correct angular deviation, so hallux valgus should be off the list. Or can it improve stability

of an unstable joint? So that seems that it should be off the list of potential inclusion

criteria. I was merely going to argue against Dr. Heckman's recommendation that the use of

this implant be restricted to a handpicked group of surgeons. What you really want to

know is how well it fares in general use because the best outcomes would be expected by

handpicked use of surgeons. Maybe for an additional cohort for a short period of time, but

I wouldn't restrict its release to just a few.

DR. RAO: Dr. Kelly.

DR. KELLY: The one question I still find peculiar is that -- and Glenn, it's Cog-lin in

Ireland, not Coff-lin, okay? Just correction. The Coughlin 2's, 3's, and 4's did about the

same, which to me, I find very peculiar with this device. It makes no sense because

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everything we treat in the joint, whether its osteotomies or even having replacements, that

the more severe the arthrosis, the less predictable, so I'd like to look at the -- looking at that

question, why are the Coughlin 2's, 3's, 4's doing about the same? And maybe those results

will parse out in time.

DR. RAO: And it's not even an Irish last name, is it?

Dr. Pfeffer.

DR. PFEFFER: Well, Mike Coughlin, who wrote the article, indicates a cheilectomy for

Grade 2. Dr. Heckman or Dr. Page, Dr. Kelly, those who do foot and ankle a lot, right?

Dr. Heckman just knows everything, so it's okay to include him. Is it reasonable, initially, to

indicate this specifically for what the literature would indicate it for? It's Coughlin 3 and 4.

If this were approved by the FDA for 3 and 4 only, not patients who could have a simple

cheilectomy with less than 25% of the joint preserved, it gives me a little check and balance

because it gives pause to the doctor, in his private examining room, saying why don't you

get the implant, knowing that's only a mild arthritis of the joint and that he'd be susceptible

to a malpractice suit if it goes -- if it's black -- if it's off label and contraindicated by the FDA.

So would anyone think that that's reasonable, to say for the next 5 years it's indicated -- or

whatever time -- for 3 and 4 only when there are fewer options as there are more options

with Grade 2?

DR. RAO: Any other comments on a new cohort?

(No response.)

DR. RAO: Mr. Melkerson, in addition to follow-up of the old cohort that I talked

about just moments ago, I think there is some role for a new cohort with more restrictive

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criteria that exclude hallux valgus, unstable joints, and also possibly restricting inclusion

criteria to Coughlin 3 and 4 osteoarthritis at the MTP3 joint. Is that adequate?

MR. MELKERSON: One more clarification, but not on this point. I heard continued

studies, and I thought I heard 7 and 5. Is that 5 in addition to the existing 2-year data, or is

that 7 years after the 2-year data? Just point of clarification.


DR. FINNEGAN: I think if you look in the literature, if things are going to fail, they fail

by 5 years, so I would think that if it makes it to 5 years with no problems, that they're

good.

DR. RAO: Dr. Lyman.

DR. LYMAN: Yeah, I'd actually be in favor of longer-term follow-up. I think, for

example, osteolysis and those sorts of things are later outcomes than 5 years and

arthroplasty. So it may make sense to have longer follow-up beyond that. Sorry, I don't

know what the right number is, though.

DR. RAO: Any other comments on -- I think we kind of have a tie-breaker, so I'll go

with the 5 years. I think a 5-year follow-up study of these patients will generally be

recommended.

MR. MELKERSON: It's 5 years in addition to the --

DR. RAO: No, 5-year total follow-up. So for the old cohort, a total of 5 years and for

the new cohort, an additional -- a new 5-year group.

MR. MELKERSON: Thank you.

MR. DEDANIA: Thank you.

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DR. RAO: At this time, the Panel will hear summations and comments and

clarifications from the FDA. Mr. Dedania. You have 10 minutes.

MR. DEDANIA: We have no further comment.


At this time, the Panel will hear summations, comments, or clarifications from the

Sponsor. You have 10 minutes.

MS. MOORE: So thank you to the Panel today for a great discussion and to FDA and

other speakers today. To summarize, we know that this advisory panel has been primarily

focused on the risk and benefits of the Cartiva implant compared to the standard of care,

fusion. All study subjects had to be candidates for arthrodesis on the basis of their clinical

symptoms, and we believe that there's no better study of the MTP joint treatment available

and that the study appropriately supports this product as proposed for the intended use.

Whoops, this isn't the presentation. Apologize.

Fusion does a good job of reducing pain, as you would expect for a procedure that

prevents joint motion, but does so at the irreversible sacrifice of the motion of the joint.

People can and do find ways to work around the loss of motion, but with discomfort,

difficulty, and at the risk of future issues arising from other joints from accommodations, as

noted by the patients.

DR. RAO: Would you like to get your right presentation up? We can wait. That's all

right.

MS. MOORE: Sure. Actually, I think we're -- I think we're good.

DR. RAO: Okay.

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MS. MOORE: But thank you, I appreciate that.

There are dozens of FDA-cleared Class II products available to surgeons for treating

MTP OA, and yet there have been reported safety problems in the literature, and there are

no well-studied alternatives, including graft products, diffusions, standard of care for

advanced moderate to severe arthritis of the great toe including the toe graft. There's been

a rigorous evaluation of the Cartiva implant, as we've discussed today.

The Cartiva implant has been tested to assess the safety and effectiveness in the

largest MTP study conducted. The clinical study was designed with FDA guidance, dialogue,

and input. It was executed with the same fashion as an IDE. The randomized controlled

study that utilized a composite endpoint to assess safety and effectiveness risk-benefit was

executed with over 97% follow-up at 2 years.

The motion study was robust, thoroughly investigated all components of the Cartiva

implant in comparison to the current standard of care, which is not an appealing option to

many patients as fusion sacrificed joint motion. This was an excellent study. The 8-year

results that Dr. Daniels presented today show that there was no additional explants in his

cohort.

And the long history of products, since the approval in 2002, have demonstrated

there have been no safety or material issues with the product. Each prong of the composite

endpoint demonstrated incredible success over baseline, demonstrating safety and

effectiveness with composite success of near 80% and greater than 80% in all components

of the endpoint.

This level of success in a composite endpoint combining safety, effectiveness, and

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radiographic measurements is higher than the vast majority of orthopedic PMAs reviewed

and presented in front of this Panel. You've also seen post hoc analyses requested by FDA

that further confirm how effective and safe the device is. Significant pain relief and

functional improvement was observed for the Cartiva subjects.

And no matter which prong of the endpoint you look at, whether you look at percent

improvement in pain and function, whether you relied on the means or the medians,

utilized various cutoffs, or rely on validated or unvalidated post hoc analyses, the Cartiva

group showed dramatic pain relief even though it was slightly less than the pain reduction

seen in the fusion group; however, it was at the expense of the loss of the joint. There was

also improvement or maintenance of function compared to that of fusion. The difference

observed at 2 years in the Activities of Daily Living Scale was zero when you looked at the

median values and 5 when you looked at the mean, which was well below the MCID

reported in the literature.

The majority of the subjects experienced significant pain relief and significant

improvement in function, both of which continue to improve over 2 years. The safety and

effectiveness was proven in the study by the a priori study design. Looking at the risk-

benefit, the number one goal of motion-preserving surgery was achieved. Patients' range

of motion improved following treatment with Cartiva, and we believe that the ability to

retain or improve motion of the great toe MTP joint was a huge factor in patients opting to

have this procedure over fusion. From a risk-benefit perspective, as with any implanted

device, especially for those that could be the first option for the surgeons, you want to

assure that you don't lose the availability of other options a surgeon can turn to in the

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future, if needed. Cartiva provides exactly that option for the few patients who might not

achieve significant pain or functional improvement, an option that allows them to be easily

revised to a fusion with fusion results on par with the primary procedure. And the rates of

the revision reported for Cartiva were similar to fusion and also consistent with literature

reported -- the rates reported in the literature.

The Cartiva SCI is an excellent option for surgeons and patients who want to

maintain their motion. It's the only option that has been shown with Level 1 evidence of

safety and effectiveness. It is the only option that has demonstrated the benefits of

motions, avoids the risk of other Class 2 motion-preserving devices, and does not

irreversibly eliminate joint motion as fusion. The device offers a good alternative for the

treatment of arthritis of the MTP joint.

Thank you. And at this point, Dr. Baumhauer has asked for a minute of my

summation, and I will turn it over to her at this time.

DR. BAUMHAUER: Thank you.

First, I'd like to thank all the Panel members for your thoughtful consideration of this

presentation and the patients that gave their time to come down here and share their

perspective. I've been working on this Cartiva project since the study design phase in 2009.

As the PI, I reviewed every outcome for every patient in the study. The Cartiva patients

experienced clinically significant improvement of both pain and function at all time points;

in addition, showed an excellent safety profile. Its safety profile even looks better when

you compare it to the literature report of the adverse events of many of these 510(k)

hemiarthroplasty and total toe replacements, which are still on the market and people are

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still putting in. My Canadian colleagues and my UK colleagues and their patients have

access to this Cartiva implant for years and years now. I'd like to have the opportunity to

offer this motion-preserving option to my patients, too.


DR. RAO: Thank you very much to Dr. Baumhauer and all the Sponsors and the FDA

presenters.

Before we proceed to the Panel vote, I would like to ask our non-voting members,

Dr. Trier, Dr. Sayeed, and Ms. McCall, if they have any additional comments.

Dr. Trier.

DR. TRIER: Yes. As had been presented by the representative from OSMA, the

questions that the Panel look at, at this point, is to determine whether or not there's a

reasonable assurance of safety, effectiveness, and also to take a look at the risk-benefit

profile. And, of course, the definition of clinical or of the evidence that it needs to be

scientifically valid evidence. So I would ask that as the Panel makes their final decisions or

determinations with regards to the voting questions for this device, that those two items,

reasonable assurance and scientifically valid evidence, are taken into account.


Dr. Sayeed.

DR. SAYEED: I have nothing further to add.


MS. McCALL: I have nothing to add.


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We are now ready to vote on the Panel's recommendation to the FDA for the Cartiva

Synthetic Cartilage Implant.

Mr. Melkerson.

MR. MELKERSON: Just one point of clarification. In the previous discussions, people

were talking about modification of the indication for use, and before you get to the vote, in

the description, the indication for use is as stated in the panel package, not as modified or

suggested modifications. So I just wanted to make sure you're voting on that indication for

use, which will be read into the record.

DR. RAO: So just to clarify, if we voted yes for the device, then we're voting for the

indications as proposed by the Sponsor today?

(No audible response.)

DR. RAO: Thank you.

MR. MELKERSON: That's correct.

DR. RAO: The Panel is expected to respond to three questions relating to safety,

effectiveness, and benefit versus risk. Commander Anderson will now read three

definitions to assist in the voting process. Commander Anderson will also read the

proposed indications for use statement for this device.

CDR ANDERSON: Okay. The Medical Device Amendments to the Federal Food, Drug

and Cosmetic Act, as amended by the Safe Medical Devices Act of 1990, allow the Food and

Drug Administration to obtain a recommendation from an expert Advisory Panel on

designated medical device premarket applications, PMAs, that are filed with the Agency.

The PMA must stand on its own merits, and your recommendation must be supported by

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safety and effectiveness data in the application or by applicable publicly available

information.

The definitions of safety, effectiveness, and valid scientific evidence are as follows:

Safety as defined in 21 C.F.R. Section 860.7(d)(1) - There is reasonable assurance that

a device is safe when it can be determined, based upon valid scientific evidence, that the

probable benefits to health from use of the device for its intended uses and conditions of

use, when accompanied by adequate directions and warnings against unsafe use, outweigh

any probable risk.

Effectiveness as defined in 21 C.F.R. Section 860.7(e)(1) - There is reasonable

assurance that a device is effective when it can be determined, based upon valid scientific

evidence, that in a significant portion of the target population, the use of the device for its

intended uses and conditions of use, when accompanied by adequate directions for use and

warnings against unsafe use, will provide clinically significant results.

Valid Scientific Evidence as defined in 21 C.F.R. Section 860.7(c)(2) - Valid scientific

evidence is evidence from well-controlled investigations, partially controlled studies,

studies and objective trials without matched controls, well-documented case histories

conducted by qualified experts, and reports of significant human experience with a

marketed device from which it can fairly and responsibly be concluded by qualified experts

that there is reasonable assurance of the safety and effectiveness of a device under its

conditions of use. Isolated case reports, random experience, reports lacking significant

details to permit scientific evaluation, and unsubstantiated opinions are not regarded as

valid scientific evidence to show safety or effectiveness. The valid scientific evidence used

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to determine the effectiveness of a device shall consist principally of well-controlled

investigations, as defined in paragraph (f) of this section, unless the Commissioner

authorizes reliance upon other valid scientific evidence which the Commissioner has

determined is sufficient evidence from which to determine the effectiveness of a device,

even in the absence of well-controlled investigations.

The Sponsor has proposed the following indications for use: The device is indicated

for treatment of degenerative and post-traumatic arthritis in the first metatarsophalangeal

joint, MTP, in the presence of good bone stock along with the following clinical conditions:

hallux valgus or hallux limitus, hallux rigidus, and unstable or painful metatarsophalangeal

MTP joint.

Panel members, please use the buttons on your microphone to place your vote of

yes, no, or abstain to the following three questions. I will now read the voting questions.

Voting Question 1 reads as follows.

Voting Question No. 1: Is there a reasonable assurance that the Cartiva Synthetic

Cartilage Implant is safe for use in patients who meet the criteria specified in the proposed

indications for use described above?

(Panel vote.)

DR. PAGE: Is there any way for us to know a better vote was counted or we push the

button properly?

(Pause.)


Voting Question No. 2: Is there a reasonable assurance that the Cartiva Synthetic

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Cartilage Implant is effective for use in patients who meet the criteria specified in the

proposed indications for use described above? Please vote.

(Panel vote.)


Voting Question No. 3: Do the benefits of the Cartiva Synthetic Cartilage Implant

outweigh the risks when used in patients who meet the criteria specified in the proposed

indications for use described above? Please vote.

(Panel vote.)

CDR ANDERSON: Okay. Thank you, everybody. The votes have been captured, and I

will now read the votes into the record.

On Question 1, the Panel voted 10 yes, 2 no, that the data shows reasonable

assurance that the Cartiva Synthetic Implant is safe for use in patients who meet the criteria

specified in the proposed indications.

On Question 2, the Panel voted 9 yes, 3 no, that there is reasonable assurance that

the Cartiva Synthetic Cartilage Implant is effective for use in patients who meet the criteria


On Question 3, the Panel voted 8 yes, 2 no, 2 abstain, that the benefits of the Cartiva

Synthetic Cartilage Implant outweigh the risks for use in patients who meet the criteria


The three voting questions are now complete.

DR. RAO: Thank you, all. I will now ask the Panel members to discuss their votes. I'd

like to go around the table and have each Panel member state how they voted on each

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question so it can be entered into the public record. Please also discuss the reasoning for

your vote. If you answered no to any question, please state whether any changes to

labeling, restrictions on use, or other controls would have made a difference to your

answer. Let's start with you, Dr. Pfeffer.

DR. PFEFFER: Okay. Glenn Pfeffer.

I voted yes on all three topics. I have my concerns, which I voiced, and I'm sure

those will be considered by FDA. But I think the benefits far outweigh any of the

drawbacks.

DR. RAO: Thank you.

Dr. Bailey.

DR. BAILEY: James Bailey.

I voted yes on all three, as well, although I will say that 10% failure rate at 2 years

was at the limit of my tolerance. However, I was reassured by the time course. It did not

look like the failures were ramping up. And I'm also reassured by the postmarketing

surveillance that the committee has recommended.

DR. RAO: Thank you.

Dr. Subhawong.

DR. SUBHAWONG: Yes. I voted yes on all three questions. I believe the concerns

that I had were -- many of the concerns I had were shared by the Panel members, and those

were addressed, and I think based on the data that was presented and our discussion, that

the benefits outweigh the risk, and this implant seems reasonably safe.

DR. RAO: Thank you.

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Dr. Golish.

DR. GOLISH: I voted yes, yes, abstain with regard to safety. It's extraordinary that

we've had very little opportunity to talk today about the extensive preclinical data FDA

asked of the Sponsor, and those data ought to be scrutinized closely, especially since

they're the entire rationale for taking the OUS approach. I think, also, that the post-

approval studies are mandatory to assess for increasing failure rate over time and

possibility of particulate wear degree. With respect to efficacy, I think that despite the

manifold problems with the non-inferiority margin, some of the design parameters, even

looked at as a single arm observational study, the device appears effective with some

possible advantages over available alternatives. With respect to risk-benefit, I feel that risk-

benefit is not the same thing as safety and efficacy, for which the trials are designed, and

occasionally that question appears a little ill-defined to me today as it does.


DR. BLUMENSTEIN: Yes. I voted yes, no, no. My major concern is the flaws in the

clinical trial, particularly the non-inferiority margin, the interpretation of non-inferiority

margin, whether the non-inferiority margin was adequate to prove that -- provide evidence

that the -- that we have something here that is going to benefit patients. Also, I'm

concerned that the study was vastly underpowered and the fact that they squeaked by,

even with the correct margin based on a fixed odds ratio, is -- was more accidental than it

was convincing.

But the main thing that gave me pause on efficacy was the fact that there was just

simply too many measures that just didn't line up with what the original theory of the

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benefit of the product was represented. And also, I had a hard time understanding why it

was that there wasn't a greater pain equivalency between the two interventions. And so I

just could not get everything to line up that would give me a reason to vote yes on efficacy.

And then, of course, the third question, I couldn't answer yes on that.

DR. RAO: Thank you, Dr. Blumenstein. And thank you also for the explanations and

the focus on the non-inferiority studies and trials. That was useful to the whole Panel.

Dr. Lyman.

DR. LYMAN: So I voted yes on all three questions, somewhat against my better

judgment, but I do trust my esteemed colleague, Dr. Kelly, in his statement that this implant

deserves a chance. I do think that's true. I do think that the postmarketing studies will be

vital, and I'm also placing great faith in the FDA that since -- we saw no evidence today of

safety or effectiveness for hallux valgus greater than 20 degrees or joint instability, so I

don't think that those should be approved uses, although I didn't vote against.

DR. RAO: Dr. Kelly.

DR. KELLY: I voted yes on all three, and I've expressed my concerns, and some of

them profound, over the study design, and I'm having a hard time letting go of all those

people who had fusions which weren't indicated, in my considered opinion. However, I

think this has potential promise. I'm a big fan of minimally invasive treatment, and this may

serve as a useful adjunct to treatment of MTP arthritis.


Dr. Gilbert.

DR. GILBERT: I also voted yes for all three questions. I do think the study was well

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designed and well executed given the circumstances of the day and really the inadequacy or

flaws in the tools that were being used to try to assess the outcomes. I think they didn't

line up well, as we saw. But I do -- you know, if you take a step back and look, the device

did improve patients' pain, did improve their outcome. I do think it demonstrated

effectiveness. Maybe it wasn't better than or maybe it was almost inferior to the fusion,

but I think there was efficacy, I think there was safety demonstrated in this scientifically

valid study, and that's why I voted yes on those first two questions. And the risk and

benefit, I think, to the extent that we know the risks, I think they've been reasonably

mitigated, and I think there may be risks that we don't know yet and we can't mitigate

them. But overall, from what I saw, the benefits outweigh the risk, and I voted yes.


Dr. Finnegan.

DR. FINNEGAN: So I'm a Dr. Blumenstein fan. I voted yes, no, no. I think there is

good, reasonable safety assurance. I actually don't think we can say if it's effective or not,

partly because we're comparing apples and oranges, and it would've been nice to see a

motion-retaining control group instead of a fixed-motion control group, and as well, the

pain was not one of their outlined objectives, originally. But I think they really do need to

look into pain and see why those patients are having pain. And I agree that risk-benefits -- I

voted no on risk-benefits because I think we don't know, and I think we need a much longer

follow-up to make sure.

DR. RAO: Thank you very much, Dr. Finnegan.

Dr. Heckman.

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DR. HECKMAN: I voted no on the first two questions because I did a very literal

interpretation in the reading of the question and cannot accept this device to be used for

hallux valgus or unstable joints. If that indication were revised, I would vote differently. So

I differed a little bit from Dr. Lyman in my vote, but our thinking is exactly the same, I think.

And I abstained with regard to the issue of risk-benefit because I don't think we have

enough information yet.

DR. RAO: Thank you very much, Dr. Heckman.

Dr. Carrino.

DR. CARRINO: Yes, I had exactly the same concerns as Dr. Heckman with the way

this is written, since our discussion from the orthopedic colleagues revolved around hallux

valgus, and the investigator stated that up to 20 degrees they would include patients, but

beyond that -- and that's not really captured in the statement here. And also, we didn't

really focus on instability. But that notwithstanding, I, like Dr. Lyman, gave better judgment

in voting yes for two questions and no for one question.


Dr. Page.

DR. PAGE: I voted yes on all three of the questions largely because I feel that this

may be an improvement over the existing motion-retaining alternatives that we currently

have in our armamentarium despite the fact that it was comparison to a fusion study. I

think it deserves a shot.

DR. RAO: Well, thank you all for a very thoughtful, honest discussion of all of the

issues today. I'd like to thank all of our panel members. I'd also like to thank the FDA

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presenters and the FDA support staff who helped put a great product together. I'd also like

to thank the Sponsors for staying on time, for an excellent study, a well-presented study,

and a thoughtful assessment of the issue here.

Mr. Melkerson, do you have any final remarks?

MR. MELKERSON: I would just like to echo the same thanks, but I would also --

thanks to the Panel members for putting up with a typically difficult scenario that we ask

them to go to is, a study was performed, and how does that constitute valid scientific

evidence, and how do you interpret that? So thank you very much.

DR. RAO: Thank you.

I now pronounce the April 20th, 2016 meeting of the Orthopaedic and Rehabilitation

Panel Devices closed. Thank you.

(Whereupon, at 5:21 p.m., the meeting was adjourned.)

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C E R T I F I C A T E

This is to certify that the attached proceedings in the matter of:

ORTHOPAEDIC AND REHABILITATION DEVICES PANEL

April 20, 2016

Gaithersburg, Maryland

were held as herein appears, and that this is the original transcription thereof for the files

of the Food and Drug Administration, Center for Devices and Radiological Health, Medical

Devices Advisory Committee.

____________________________

ED SCHWEITZER

Official Reporter

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