Device World:The Basics SR and NSR DeterminationsExpanded AccessSusie HoffmanUniversity of Virginia

Margaret Foster Riley, J.D.University of Virginia, School of Law, School of Medicine, Batten School of Leadership and Public Policy

2

Definition of Device §201(h)•“an instrument, apparatus, implement,

machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part or accessory, which is▫…(2)intended for use in the diagnosis of

disease or other conditions, or in the cure, mitigation, treatment or prevention of disease

3

Definition of Device §201(h)•“(3)intended to affect the structure or

function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animlas and which is not dependent upon being metabolized to achieve its primary intended purposes”

4

Medical Devices•Vast number

▫Tongue depressor, stethoscope, stents that hold blood vessels open

•Vary in complexity and risk as well as benefit•Characterized by “on the spot” innovation

•FDA interprets the statute broadly and claims authority over many articles that may not seem to be devices: e.g. reagents for assays, genetic tests and software (even maybe medical records)

5

Line between device and drug not clear•Saline•Contrast imaging agents

▫Can be either but must treat them consistently

•Combination products▫E.g. Clot busting stents▫Office of combination products at FDA

Devices are Different

•Not just in “substance” but in regulation•Different pathways (different statutory

roots)

•Devices can be confusing because there are a number of different types of “risk assessment”—need to be clear on what question is being asked

Three Classifications based on Risk

▫I bedpans, crutches, ▫II blood pressure cuffs, catheters,

wheelchairs, heating pads, and x-ray film processing machines

▫III defibrillators, heart valves, and implanted cerebral stimulators

Marketing Pathways for New Devices

• New and novel automatically class III; go through PMA (device analog to drug NDA) process unless they are reclassified

• New and not novel—enters the market as “substantially equivalent”—inherits the classification status of the device that it emulates-- “the 510k process”

510(k) process: The new and not novel

•This is a notification process, not an approval process

•A positive response to a 510k application is a “clearance”—FDA makes no representation that the device is “safe and effective for its intended use(s).”

•98% of all post-1976 devices have entered the market through this mechanism

Substantial Equivalence

•Must have same intended use as a predicate device.

• “Piggy backing” now codified—substantially equivalent to a device that was substantially equivalent to a pre-1976 device

Investigational Devices

•IDE similar to IND for drugs, except not all IDEs require FDA approval

•If pose no significant risk, just require IRB approval—IRB makes that determination

Device World Significant Risk/Non-Significant Risk Determinations

What is Significant Risk?

• Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;

• Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject;

• Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or

• Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. (21 CFR 812.3(m))

Likely Significant Risk (SR) devices•Many devices that are obviously SR will be

submitted to FDA for IDE approval▫Most of those devices are submitted to IRB

review after FDA has made that determination▫An SR device must meet all FDA IDE regulations

and must have FDA approval before enrolling• IRBs do not have to make the SR or NSR

determination if FDA has already made the risk determination. ▫IRB role is then to confirm the issuance of the

IDE

Likely Non-Significant Risk (NSR) Devices•Here the sponsor does not need to submit

to FDA and FDA leaves the determination to the IRB▫In most of these cases, FDA will have no

role in the risk determination—and will not even be aware of the study

IDE Exempt

•If using an investigational device in research must first determine if the device is exempt from IDE regulations.

IDE Exempt Devices• Consumer preference testing• Testing of a device modification• Testing of two or more devices in commercial

distribution if the testing does not collect safety or effectiveness data, or put subjects at risk.

• Studies of an already cleared medical device in which the device is used or investigated in accordance with the indications in the cleared labeling ▫ If the study is looking at a new use, it is not exempt

IDE Exempt Devices

•A diagnostic device if the testing: Is noninvasive Does not require an invasive sampling

procedure that presents significant risk Does not by design or intention introduce

energy into a subject AND Is not used as a diagnostic procedure

without confirmation by another medically established diagnostic product or procedure.

Not Exempt?

•If a device is determined to NOT be exempt from an IDE, the full IRB must determine if the device meets the criteria of Significant Risk

•Exempt from IDE requirements does not mean that the device study is exempt from other IRB/FDA requirements for clinical research study

IRB Considerations of NSR Determination

• The sponsor’s description of why the study is not SR • Whether the proposed NSR research study meets

the definition of “significant risk” ▫The proposed use of the device as well as any

protocol related procedures and tests, not just the device (test article) alone. (This process is different and separate from the typical IRB review of risk)

▫Whether the subject will undergo additional procedures

• Additional information from the sponsor, if needed. •

Significant Risk Criteria (Review)

▫A device that presents a potential for serious risk to the health, safety, or welfare of a subject AND: Is intended as an implant or Is used in supporting or sustaining human life or Is for use of substantial importance in diagnosing,

curing, mitigating or treating disease, or otherwise prevents impairment of human health: or

Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

 

Sometimes Examples provide the Most Insight NSR:

• http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126418.pdf

▫ Conventional Gastroenterology and Urology Endoscopes and/or Accessories

▫ Conventional General Hospital Catheters (long-term percutaneous, implanted, subcutaneous and intravascular)

▫ Conventional Implantable Vascular Access Devices (Ports) ▫ Digital Mammography ▫ Externally Worn Monitors for Insulin Reactions ▫ Urethral Occlusion Device for less than 14 days

Sometimes Examples provide the Most Insight--SR

• http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126418.pdf

▫ Catheters for General Hospital Use - except for conventional long-term percutaneous, implanted, subcutaneous and intravascular

▫ Collagen Implant Material for use in ear, nose and throat, orthopedics, plastic surgery, urological and dental applications

▫ Aortic and Mitral Valvuloplasty Catheters ▫ Organ Storage/Transport Units ▫ Cochlear Implants ▫ Biliary Stents ▫ Electrical Stimulation Devices for sperm collection ▫ Antepartum Home Monitors for Non-Stress Tests▫ Cervical Caps ▫ Condoms (for men) made from new materials (e.g., polyurethane) ▫ Contraceptive In Vitro Diagnostics (IVDs) ▫ Computer Guided Robotic Surgery

Effect of Decision

•NSR▫If the device does not meet the criteria of

Significant Risk, then is by default a Non-Significant Risk Device

▫Do not need IDE from FDA to enroll subjects

•SR▫Must have IDE from FDA prior to enrolling

subjects

Device World

Expanded Access

From FDA website: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm051345.htm#treatmentuse

 

Ways to Access an Investigational Device for Clinical Care

•Compassionate Use•Emergency Use•Treatment Use•Continued Access•* Humanitarian Use

Device Summary Table- see handout  Clinical Care:

Compassionate Use

Clinical Care:Emergency Use

Clinical Care:Humanitarian Use

Clinical Care:Emergency or Off Label Use of an HUD

Clinical Care:Treatment Use

Clinical Care:Continued Access

Research

Background Use for patient or small group who do not meet protocol inclusion criteria. Treating physician feels device will help patient(s).Allowed before or during a clinical trial

Subject does not meet inclusion criteria, clinical trial is not open at the institution, life threatening situation and no time to get IRB approvalAllowed before or after start of clinical trial

Device that would be used in less than 4000 patients /year in the US. ( Orphan Device)

If use meets criteria for emergency use see Emergency Use column.  Off label use: Follow same criteria as Humanitarian Use.

Provides access to investigational devices early in development process. Allowed during a clinical trial

Allows patients access to device after clinical trials are completed- awaiting FDA approval.

Use of an investigational device for research purposes

Other Issues Must first identify patient, then sponsor submits IDE application to FDA, then submit application to IRB.

May only use as emergency use one time at each institution- then must have a compassionate use protocol.Within 5 days of use submit notification to IRB. Sponsor cannot submit data as part of an FDA application.

Called:Humanitarian Use Device (HUD)OR Humanitarian Device Exemption (HDE) Sponsor must have HDE designation from FDA.

For Off Label Use FDA recommends patient sign a consent form and that the PI has a plan to protect the patient. PI should submit summary report to IRB following the use. Must report AE's to IRB.

For patients with serious or life threatening condition- may receive outside of a clinical trial.Sponsor must obtain a Treatment use IDE from FDA.

May use outside IRB.

IRB must determine if device is exempt from IDE regulations. If not exempt, must determine if device is significant risk.

Considered Research?

No- however FDA requires an IDE# and IRB Concurrence

No- but use must be reviewed by full board AFTER USE.

No, however IRB review required. 

No, however IRB review required. 

Yes Yes Yes

Protocol Yes-submit sponsors protocol only

No No, but need tosubmit Investigators Brochure

No, but for off- label use, need some type of plan of methods to protect patient.

Yes- submit sponsors protocol only

Yes-submit sponsors protocol only

Yes- may submit per local protocol template or sponsors protocol

Consent Yes-submit and use sponsors consent

Yes-use sponsors consent if patient able to consent.

No- may provide patient with product information

Yes, may use sponsors template.

YES- use local research template to develop consent

Yes-may use local research template or one approved by outside IRB.

Yes-use local research template to develop consent unless waiver approved

Training No No No No Yes Yes YesReview Type IRB Chair only Full Board- AFTER

use Initial – Full BoardContinuations- Expedited

Initial – Full BoardContinuations- Expedited

Full Board Full Board Full Board

Response Letter of Concurrence from IRB Chair

Letter of Concurrence from IRB

IRB Assurance Form

IRB Assurance Form

IRB Assurance Form

IRB Assurance Form

IRB Assurance Form

Clinical Care: Compassionate UseBackground

Other issues

Research? Protocol Consent Training Review Type

Response

Use for patient or small group who do not meet protocol inclusion criteria. Treating physician feels device will help patient(s).Allowed before or during a clinical trial.

Must first identify patient, then sponsor submits IDE application to FDA, then submit application to IRB.

No- however FDA requires an IDE# and IRB Concurrence

Yes-submit sponsors protocol only

Yes-submit and use sponsors consent

No IRB Chair only

Letter of Concurrence from IRB Chair

Clinical Care: Emergency UseBackGround

Other Issues Research? Protocol Consent

Training Review Type

Response

Subject does not meet inclusion criteria, clinical trial is not open at the institution, life threatening situation and no time to get IRB approvalAllowed before or after start of clinical trial

May only use as emergency use one time at each institution- then must have a compassionate use protocol.Within 5 days of use submit notification to IRB. Sponsor cannot submit data as part of an FDA application.

No- but use must be reviewed by full board AFTER USE.

No Yes-use sponsors consent if patient able to consent

No Full Board- AFTER use

Letter of Concurrence from IRB

Clinical Care: Treatment Use Background

Other Issues Research? Protocol Consent Training Review Type

Response

Provides access to investigational devices early in development process. Allowed during a clinical trial

For patients with serious or life threatening condition- may receive outside of a clinical trial.Sponsor must obtain a Treatment use IDE from FDA.Different from Compassionate Use: do not need to identify patient before IRB approval.

Yes Yes- submit sponsors protocol only

YES- use local research template to develop consent

Yes Full Board

IRB Assurance Form

Clinical Care: Continued AccessBackground

Other Issues

Research? Protocol Consent Training Review Type

Response

Allows patients access to device after clinical trials are completed- awaiting FDA approval.

May use outside IRB.

Difference between Treatment Use : does not have to be life threatening or serious disease.

Yes Yes-submit sponsors protocol only

Yes-may use local research template or one approved by outside IRB.

Yes Full Board

IRB Assurance Form

Clinical Care: Humanitarian UseBackground

Other Issues

Research? Protocol Consent Training Review Type

Response

Device that would be used in less than 4000 patients /year in the US. ( Orphan Device)

Called:Humanitarian Use Device (HUD)OR Humanitarian Device Exemption (HDE) Sponsor must have HDE designation from FDA.

No, however IRB review required.

No, but need tosubmit Investigators Brochure

No- may provide patient with product information

No Initial – Full BoardContinuations- Expedited

IRB Assurance Form

Clinical Care: Emergency Use or Off Label Use of an HUDBackground

Other Issues

Research?

Protocol Consent Training

Review Type

Response

If use meets criteria for emergency use- see Emergency Use column.  Off label use: Follow same criteria as Humanitarian Use.

For Off Label Use FDA recommends patient sign a consent form and that the PI has a plan to protect the patient. PI should submit summary report to IRB following the use. Must report AE's to IRB.

No, however IRB review required.

No, but for off- label use, need some type of plan of methods to protect patient.

Yes, may use sponsors template.

No Initial – Full BoardContinuations- Expedited

IRB Assurance Form

ResearchBackground

Other Issues

Research?

Protocol Consent Training Review Type

Response

Use of an investigational device for research purposes

IRB must determine if device is exempt from IDE regulations. If not exempt, must determine if device is significant risk.

Yes Yes- may submit per local protocol template or sponsors protocol

Yes-use local research template to develop consent unless waiver approved

Yes Full Board

IRB Assurance Form

Device Review Decision TreeDoes this study involve the clinical investigation to

determine the safety and effectiveness of a device? ( e.g. – Are you evaluating the device for safety and

efficacy? )

Is the device a Research Use Only Device (RUO)?

Does the device being used have FDA approval for any

indication?

To Full Board for Review. As expedited criteria # 4 not applicable. DO NOT use Expedited Criteria # 1 as the device is not being evaluated therefore FDA regulations do not apply.

NOTE: FB does NOT determine SR/NSR status but may determine if protocol is minimal risk, therefore allowing future continuations to be expedited via category # 9.

Category # 9: Continuing review of research, not conducted under an

investigational new drug application or investigational device exemption where categories (2) through (8) do

not apply but the IRB has determined and documented at a convened full

IRB meeting that the research involves no greater than minimal risk

and no additional risks have been identified.

NO

NO

Will results be used to

diagnose or treat

subjects?

Yes

NO

Do all other procedures fit under

an expedited criteria?

YES

Is study minimal risk?

YesTo Full

Board for Review

NOTE: FB does NOT determine SR/NSR status

NO

Expedite under

category # 4 and any

other applicable

categories. (RUO

devices not considered a

medical device.)

Yes

NO

Is study exempt from IDE Regulations ?

Answer NO if an In-vitro diagnostic device.

Expedite under

category # 1

Yes: FDA Regs apply

Will other procedures require study to be

reviewed by full board?

(e.g all procedures do not fit under expedited criteria or study is not

minimal risk )

Yes

Send full protocol to

IRB for review.

No

Do all other procedures fit under an expedited

criteria

Is study minimal risk?

Send protocol to full board

for review and SR/NSR

Determination

Send study to full board to

make SR/NSR Determination.

YesNo

No

Yes

NoYes

Full Board determines study is SR: Full Board

to review protocol .

DO NOT expedite review of protocol.

Full Board determines study is NSR- Expedite review of protocol

under cat# 1.

NSR SR

No: FDA Regs DO NOT apply

Is the device an in-vitro diagnostic device?

No

Yes

Yes

Study Involves Device: Overall SummaryUse only/No evaluation of device: FDA regulations do NOT apply: expedited via category # 4

Evaluation of Device- FDA regulations DO apply- If device exempt from IDE regulations or NSR and protocol may otherwise be reviewed by expedited review procedures expedite via category # 1.