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Cross Labeling Combination Products and User Fees

Bradley Merrill Thompson, MBA, JD, RACEpstein Becker & Green PC

Pharma MedDevice 2007 ConferenceNew York, NYApril 25, 2007

1. Combination Products Coalition2. Background on Cross Labeling Issue3. An Approach to Address Cross Labeling4. User Fee Issues

Topics

Combination Products Coalition

1. History

2. Existing Policy Positions

3. Future Strategies

CPC: PurposeTo get promising combinations to marketTo clarify and streamline the regulatory

paradigm for combination products through enhancements to the existing process

While protecting the public health

Up to 20 drug, device and biologics companies have engaged in CPC activities. Some members include:

► Pfizer► Baxter► Roche Diagnostics► Abbott► Becton Dickinson

Most active participants are regulatory affairs professionals for member companies.

Diversity of industry representation is encouraged.

Membership

Started in 2003 with developing consensus policy positions

Advocating policy positions and working with FDA►Providing comments to FDA on proposed

rules and guidances Partnered with RAPS to host January, 2005

Summit that drew about 150 people. Topics included--►Cross labeling, kit labeling and the labeling of

integral products, ►That policy summit resulted in a consensus

white paper that was submitted to FDA.

Activities

Cross LabelingModification of approved combination

productsAdverse incident reportingQuality systems/GMPsClarification of OCP role

CPC Key Priorities

Companies interested in CPC should visit: www.combinationproducts.com

►Membership structure►Policy Positions

Background on Cross-labeling Issues

(many slides courtesy of FDA)

What is a Combination Product?

Statute -- 503(g)(1)►Products that constitute a combination of a drug, device, or biologic

Combination products are diverse:►Drug-device

►Device-biologic

►Drug-biologic

►Drug-device-biologic

21 CFR 3.2(e)►Single-entity: a product comprised of two or more

regulated components that are physically, chemically or otherwise combined or mixed as a single entity

►Kits: two or more separate products packaged together (e.g., drug and device products)

►Cross-labeled: provided separately but intended for use together where both are required to achieve the intended use and where cross labeling is needed

Three Types of Combination Products

Drug requiring specific device for administration

Diagnostic device required for use with a specific drug or biological product

Photodynamic therapy drug and laser/light source

Examples of Cross-Labeled Combination Products

Most concomitant use of drugs, devices and biologics

Drug-drug, device-device, or biologic-biologic combinations; e.g.,►Products with two biologics, even if shared

CDER and CBER roleGeneral devices intended for use with a class or

otherwise unspecified drug/biologic products►Unfilled syringe or diagnostic test without

specifying a particular drug

Not Combination Products

What is Cross Labeling?

(3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g. to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose….

21 CFR 3.2(e)(3)

What’s so hard about that?Hypothetical

Company A is the sponsor of approved drug product A.

Company B wants to obtain premarket approval for device B which will administer product A in a new dosage form, strength, route of administration, or intended use.

Company A does not want to cooperate with Company B in this venture.

Can FDA approve device B?

What does individually specified mean?

What if product B has other approved intended uses?

When does label of Product A “need to be changed?”

If labeling of Product A does need to be changed, but Company A does not want to submit a supplement to its marketing application, does that mean that Product B cannot be approved?

Some of the questions…

Public Workshop

May 10, 2005Transcript and presentations accessible

on OCP website: http://www.fda.gov/oc/combination/

Comments available on docket

Why is a cross labeling policy important?

Confusion about whether Company A must participate may deter product development

Greater clarity may be more efficient

A note on terminology

Cross labeling

Mutually conforming labeling

Is there any difference?

Situations where cross labeling issues arise

Product B enhances safety or effectiveness of Product A

Product B uses Product A in a new route of administration

More cross labeling situations….

Product B uses Product A for new indication, new patient population

Product B is a new component of an already approved combination product► originally approved under two applications► originally approved under one application

And still more…

Labeling of Product B and Product A will be inconsistent in some way

Labeling of Product B and Product A will be contradictory

Categories of Issues

Labeling issues – possible end user confusion

No ongoing relationship between manufacturers issues – what if product A is reformulated or redesigned

Will reviewing application covering Product B necessarily rely on proprietary information in application covering Product A?

Pathway issues

Why is this so challenging?

Company A’s proprietary interests

FDA’s core beliefs about labeling

Company B’s commitment to Product B

Protect and Promote the Public Health

FDA prefers cooperation

In the absence of cooperation, FDA’s goal is to identify a regulatory pathway for Product B while ensuring adequate regulatory oversight.

What should be FDA’s default position?

Consider whether labeling of Product A “needs to be changed”►Is Product A intended to be used for a new intended

use, dosage form, strength, or route of administration, ►Is end user confusion likely?►What would happen if Product A is reformulated or

redesigned without notice to Company B?►Would Company B rely on proprietary information in

application covering Product A?

Points to Consider

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CPC’s Proposed Approach

The Answer Requires Greater Precision in the Definition of a

Combo ProductMost of the questions disappear when

products are properly categorized into:►Combination Products►Nearly combination products, but not►Clearly not combination products

We will show an algorithm for properly classifying products

Four Principles FDA should not play matchmaker between

companies. The economic incentives that are most likely to

lead to important public health breakthroughs are outside of FDA’s control.

FDA must approve or disapprove the products as companies propose them, based on the evidence.

But FDA, importantly, does have flexibility under the law to weigh the risks.

Why Companies Don’t Always Want to Collaborate

Potential impact on their product’s safety-effectiveness profile

Intellectual property and confidentiality concerns

Conflicting business strategies Resource priorities Costs Product liability issues Interest in competing products

(drugs or delivery systems, for example)

Existing partnerships

Why Companies Don’t Want to Collaborate

Control Risk of having someone else’s “issues” control your resources

Potential limits on flexibility Changes have greater impact

Manufacturing and quality concerns Desire to develop and retain internal expertise Familiarity or lack of familiarity with a potential “partner” or product Differing perceptions on market size and what constitutes

“success” Ex: A sizeable market to a small device company may not

appear as large to a major pharmaceutical company Additional regulatory exposure

FDA’s Authority FDA derives its authority from the Food, Drug and Cosmetic Act (“Act”).

The Act gives FDA broad authority. For example, FDA can: Promulgate regulations for

enforcement of the Act Some limitations

Approve drugs and devices, license biological products

Regulate use of drugs, biologics and devices, including those used for investigational purposes

Require manufacturers to include “adequate directions for use” in labeling

FDA’s Authority Limits

FDA’s authority is not all-encompassing. For instance, FDA does not have the authority to:

Require that companies work together Mandate that a manufacturer seek approval for new uses of its

product Association of American Physicians and Surgeons, Inc. v. FDA

Force manufacturers to “mutually conform” their labeling to include new uses

Open or reference proprietary information in a drug sponsor’s file for another sponsor seeking approval of a combination product

Except: 505(b)(2)

Tools for Encouraging Collaboration

FDA cannot require companies to work together, but FDA can encourage companies to collaborate in a way that leads to innovation.

Existing tools include:User fee waiversExpedited review and

approval timesPower of persuasion – “just

ask”—but don’t lean

Return to the Categorization Question

A proper determination of whether a product is truly a combination product answers many of FDA’s questions

A risk assessment is a key determinant of whether the product must be treated as a combination product

FDA has more flexibility when a product is not a combination product

Lo o k a t p ro p o s e d d e v ic e la b e lin g :d o e s it , o r d o e s it n e e d to

in o rd e r to b e u s e d s a fe ly a n de ffe c t iv e ly , in d iv id u a lly s p e c ify a

b ra n d o f d ru g (n o t ju s t a g e n e ric ty p e )e xp re s s ly o r b y c le a r imp lic a t io n ?

D o es th e d ev ic e lab e lin g ex p r es s lys ta te th a t th e d r u g is to b e u s ed f o r ad if f e r en t in ten d ed u s e , d o s ag e f o r m ,s tr en g th , r o u te o f ad m in is tr a t io n o r

d o s e th an s ta ted in th e d r u g lab e lin g ?

D o es th e d ev ic e I F U im p ly s u c h ad if f e r en c e?

Yes

N o

N o

Yes

Yes

F lo w C h a rt fo r D e te rm in in g W h e th e r D ru g a n d D e v ic eR e p re s e n t C ro s s L a b e le d C o m b in a tio n P ro d u c ts L a b e le d a s S u c h

D o es th e n a tu r e o f th e d ev ic e ,r eg ar d les s o f its I F U, r eq u ir e

s u c h a d if f e r en c e?

Ar e th o s e d if f e r en c es o r r eas o n s s ig n if ic an ten o u g h , as s h o w n th r o u g h a r is k

as s es s m en t, th a t th e d r u g lab e lin g s h o u ld b ec h an g ed to as s u r e s af e an d e f f ec tiv e u s e o f

th e d r u g ?

N o

C r o s s L ab eledC o m b in a tio n P r o d u c t

r eq u ir in g C r o s s - L ab elin go f d r u g an d d ev ic e

N o t a C o m b in a tio n P r o d u c tan d N o S p ec if ic C r o s s

R ef er en c e

Ar e th er e an y o th er r eas o n s w h yap p r o v al/c lear an c e o f th e d ev ic e

w o u ld r eq u ir ea c h an g e to th e d r u g lab e lin g

N o

N o

Yes

Yes

N o

Yes

N o t a C o m b in a tio n P r o d u c tb u t I n c lu d es a R ef er en c e to

"u s e o n ly w ith " a s p ec if icb r an d d r u g

Kit C o m b in a tio nP r o d u c t w ith n o c h an g e

to d r u g lab e lin g

C an th e s a f e an d ef f ec tiv eu s e o f th e c o m b in a tio n b e

ad d r es s ed th r o u g h th ed ev ic e o r k it lab e lin g an d

c o - p ac k ag in g w ith o u tr eq u ir in g a c h an g e in th e

d r u g lab e lin g ?

N o Yes

Not a Combo Product and No Specific

Cross Reference

Not a Combo Product But Includes Specific Reference

Cross Labeled Combo Product

Is an agreement

between the parties

assuring coordination required to approve the

device?

No Maybe, depending on a risk assessment.This risk assessment would consider:(1)The likelihood that product A will be changed in the future.(2)The consequences of possible changes to product A. (3)The effectiveness of company B’s ability to monitor product A for such changes.(4)The ability of company B to effectively label the combined use without the need to relabel product A.(5)Any other issues that bear on the ability of company B to assure the safety and effectiveness of the combined product without the cooperation of company B.

Yes, an agreement

between the two companies is

required

Summary

Can product B be used safely and effectively with already-approved product A if the labeling for product B only includes a generic reference to the category of products that contains product A? ►If the answer is yes, the two products together are not

combination products, there does not need to be any cooperation between the two manufacturers, and product B may be approved despite any lack of cooperation.

►If the answer is no because a specific cross-reference to product A by brand is necessary to assure safety and effectiveness, we must ask a second question:

Summary

Do the two companies need to cooperate to ensure that the products can be used together safely and effectively? For example, does company A need to agree to change its labeling to permit the combined use of the products?►If the answer is yes, the product is a combination product, and

by definition cooperation between the two companies is required for the agency to approve product B.

►If the answer is no, the two products are not combination products, and there does not need to be cooperation between the two manufacturers, and product B may be approved despite any lack of cooperation.

Next Steps

Later this year, FDA plans to publish a straw man proposal

FDA will then hold a public meeting again to get further input

OCP is in transition

How are User Fees Applied to Combination Products?

User Fee Guidance

Draft User Fee Guidance: ►Single marketing application: fee associated

with that type of application►Multiple marketing applications: fee for each

application:Sponsor may choose to submit two marketing

applications (limited waivers/reductions possible)FDA may require multiple applications: fees for

each application (waivers/reductions possible)

User Fee Guidance

Draft User Fee Guidance (cont.)►Waivers:

Innovative combination products (only if FDA requires multiple applications)

MDUFMA and PDUFA waivers available

CPC Comments

CPC Comments on Draft User Fee Guidance►FDA needs to address issue of what assignment means►Specific enhancements recommended:

Clarify when multiple filings requiredProvide automatic waiver of partial fee when FDA requires

multiple applicationsExpand eligibility for Innovative Combination Product waiver to:

– Sponsors choosing to file multiple applications

– Products approved and labeled for another use

– Products that offer significant benefits other than “clinical”

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Questions?