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I do not object to people looking at their watches when I'm speaking. But I strongly

object when they start shaking them to make sure they are still going.

William Norman Birkett

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Update on Regulatory Requirements

for Combination ProductsBradley Merrill Thompson, MBA, JD,

RACEpstein Becker & Green PC

June 2, 2009Cambridge Healthtech Institute

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1. Overviewa. What are combination products?b. What is the Combination Product Coalition?

2. Where are Combination Products Going?3. Where is Combination Product

Regulation Going?4. Where are the Challenges and

Opportunities?

Topics

I feel like Zsa Zsa Gabor’s fifth husband. I know what I'm supposed to

do but I don't know if I can make it interesting.

Al Gore

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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

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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

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Most concomitant use of drugs, devices and biologics

Drug-drug, device-device, or biologic-biologic combinations►Example: Products with two biologics,

even if shared CDER and CBER roleGeneral devices intended for use with a

class of or otherwise unspecified drug/biologic products►Example: Unfilled syringe or diagnostic

test without specifying a particular drug

Not Combination Products

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How are they Regulated? Different Frameworks

Different Types Different Reviews

NDA, BLA,NDA, BLA,

PMA, 510(k),PMA, 510(k),

IND, IDEIND, IDE

DeviceDevice

DrugDrug

BiologicBiologic

CDRHCDRH

CDERCDER

CBERCBER

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CPC: Purpose

To clarify and streamline the regulatory paradigm for combination products

While protecting the public health

I have always wanted to be somebody. I guess I should have been more specific.

-Lily Tomlin

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

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

Most active participants are regulatory affairs professionals for member companies.

Diversity of industry representation is encouraged.

Membership

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Started in 2003 with developing consensus policy positions

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

and guidances Partnered with RAPS to host January 2005

policy summit attended by about 150 people. ►Topics included cross labeling, kit

labeling and the labeling of single entity products.

►The summit resulted in a consensus white paper that was submitted to FDA.

Activities

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Will partner with RAPS to host policy summit on GMPs when proposed rule is published, during comment period.

Working on comments re injector guidance (more later)

Shepherding a clinical trials proposed guidance

Legislative work

Activities

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2007 SurveyGoals

►Evaluate current industry concerns and priorities

►Communicate these to FDA

►Inform CPC policy agenda

Why?►In 2007, the OCP underwent several leadership and

personnel changes; new permanent director effective Jan. 7, 2008

►Also wanted to take a step back and reflect on CPC activities

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Survey Scope & MethodologyFocused questions on:

►Demographics►Satisfaction with existing

guidance (FDA and non-FDA)►Topics on which more or better

FDA guidance is neededDisseminated widely among industryAsked companies to complete only

one survey, but to collaborate with their colleagues

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Level of satisfaction with existing guidance (FDA and non-FDA)

0 2 4 6 8 10 12 14

Very satisfied

Somewhatsatisfied

Not satisfied

Very dissatisfied

No opinion

Over 56% indicated some level of dissatisfaction with existing guidance

No one said they were “very satisfied”

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Overall Weighted Rankings

(13) Recall requirements(13) Recall requirements

(12) User Fees(12) User Fees

(11) Advertising/promotion & RFD/prod jurisdiction (tie)(11) Advertising/promotion & RFD/prod jurisdiction (tie)

(10) PMOA(10) PMOA(9) Labeling(9) Labeling

(8) Preclinical Research(8) Preclinical Research(7) Pre-approval inspections(7) Pre-approval inspections

(6) Combo prod def’n & Post-approval modifications (tie)(6) Combo prod def’n & Post-approval modifications (tie)(5) Adverse event reporting(5) Adverse event reporting

(4) Cross-labeled combination products(4) Cross-labeled combination products(3) Premarket approval submissions(3) Premarket approval submissions

(2) GMPs(2) GMPs(1) Clinical Studies(1) Clinical Studies

(15) Resolving disputes

(14) Post-approval inspections

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Draft guidance on injectorsQuality systems/GMPs Combo product clinical trialsModification of approved combination productsAdverse incident reportingClarification of OCP role

Priorities are organic and change as new developments occur and progress is made.

Current CPC Key Priorities

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Ways to Get InvolvedCompanies interested in CPC should

visit: www.combinationproducts.com►Membership structure►Policy Positions

Active LinkedIn group (you don’t need to be a member to join)

Free wiki experiment for drafting injector comment, link www.combinationproduct.com

I've often wondered how some people in positions of this kind . . . manage without

having had any acting experience.

Ronald Reagan

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1. Overview2. Where are Combination Products Going?

a. FDA experienceb. Trends in submissions

3. Where is Combination Product Regulation Going?

4. Where are the Challenges and Opportunities?

Topics

Politics gives guys so much power that they tend to behave badly around women. And I hope I never get into

that.

Bill Clinton

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Number and Types of Combination Products FY 2007

COMBINATION PRODUCT KEY:     1 =   convenience kit or co-package

   2 =   prefilled drug delivery device/system    

   3 =   prefilled biologic delivery device/system

   4 =   device coated, impregnated, or otherwise combined with drug   

5 =   device coated or otherwise combined with biologic

   6 =   drug/biologic combination

   7 =   separate products requiring mutually conforming labeling

   8 =   possible combination based on mutually conforming labeling of separate products

   9 =   other type of combination product

Application Type

Combination Product Category

1 2 3 4 5 6 7 8 9 TOTALS

Original NDAs

4 8 -- -- -- -- -- 2 -- 14

Original BLAs

-- -- 3 -- -- -- -- -- -- 3

Original PMAs

-- -- -- 4 -- -- -- -- -- 4

Original 510(k)s

5 2 272

6 1 3 5 13 109

Original INDs

263

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7 710

10

45 4 166

Original IDEs

2 -- 112

10

-- 7 2 2 36

Original HDEs

-- -- -- -- 1 -- -- -- -- 1

TOTALS 1373

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95

24

11

20

54 19 333

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Primary Assigne

d Center

Consulting Center

Number of Consults

CBERCDE

RCDRH

CBER -- 9 33 42

CDER 2 -- 87 89

CDRH 2 257 -- 259

 Totals 4 266 120 390

Consultations 2007

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Combination Product Application Trend

0

50

100

150

200

250

300

350

FY04 FY05 FY06 FY07

CDRH

CDER

CBER

Nu

mb

er

of

Su

bm

iss

ion

s

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1. Overview2. Where are Combination Products Going?3. Where is Combination Product Regulation

Going?a. Congressb. FDA c. Internationally

4. Where are the Challenges and Opportunities?

Topics

One way to make sure crime doesn't pay would be to let the government run it.

Ronald Reagan

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CongressWhere has Congress been

recently?Where is Congress going?

The voters have spoken—the bastards.

Richard M. Nixon

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Historical Development

Safe Medical Devices Act (1990)►Added § 503(g)►Required determination

of “primary mode of action” (i.e., drug, device, or biologic)

►Gave primary jurisdiction to the center with premarket review authority for that type of product

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Food and Drug Administration Modernization Act of 1997 (“FDAMA”)►Added § 563, Request For Designation

►Allowed sponsor to request designation as drug, biologic, device, or combination product, and/or reviewing center

Historical Development

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Medical Device User Fee and Modernization Act of 2002 (“MDUFMA”)► Established Office of Combination

Products in order to assure: Prompt designations and review

assignments Timely and effective premarket review Consistent and appropriate

postmarket regulation

Historical Development

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Where is Congress Going?FDA Commissioner confirmation hearings

and budget discussions►The need for combination product policy

development specifically discussed

Future issues►Some talk of unified regulation for combination

products, but not serious yet►Other talk of unified adverse reporting system

Congress trails technology, instead of leading►That’s not a bad thing, unless they fall too far

behind

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Where is FDA Going?1. Office of Combination

Products2. Clinical Trials3. Injector Draft Guidance4. GMPs5. Adverse Events6. Cross Labeling7. Submissions Actual Trial Question

How far apart were the vehicles at the time of collision?

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Office of Combination Products Relatively new leadership

► Thinh Nguyen replaced Dr. Joanne Less who replaced Mark Kramer

Formerly Director Premarket Approval Section at ODE/CDRH

► Patricia Y. Love, MD, MBA - Associate Director► Barr Weiner, from Chief Counsel’s Office► Leigh Hayes, JD - Product Assignment Officer

Statutory Duties► Assignment of combination products► Ensure timely and effective premarket review► Consistent and appropriate postmarket regulation► Dispute resolution (timeliness vs. substance)► Review/update guidance, agreement, practices► Reports to Congress► Resource to sponsors and review staff

» P.L. 107-250 – enacted 10-26-02

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CPC Draft Clinical Trial Guidance

Feb. 27, 2009, the CPC filed draft guidance, FAQs on Pre-Clinical and Clinical Research on Combination Products

Developed in response to industry’s desire for guidance in this area

Topics addressed include:►Pre-clinical safety studies►IND and IDE submissions►Clinical study design►Labeling, GMP, and safety reporting issues►Issues pertaining to specific technologies

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Draft Injector GuidanceFDA released draft injector guidance on

April 27, 2009 - Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products

Comments due July 27, 2009CPC soliciting open/public comments via

WikiVery broad scope

►Injector – “jet injectors, pen injectors, piston syringes, needle-free injectors, mechanically operated injectors, and injectors with computerized or electronic elements”

►Combination products with injector part and stand-alone, general use injectors

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Draft Injector GuidanceMajor concerns

►Could significantly increase burden for certain injectors (maybe 3X), for example stand-alone device injectors and simpler types of injectors

►Potential inconsistencies with existing device guidance (e.g., piston syringe guidance)

►Laundry list of data requirements, rather than focused, least burdensome guidance

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Draft Injector GuidanceMajor concerns (con’t)

►Omits discussion of fundamental policy issues, for example:How the type/composition of injector

influences regulatory requirementsTypes of submissions, e.g., when an

injector requires a separate clearance or approval

Post-market modifications to injectorsAny specific expectations for GMP or

adverse event reporting

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Draft Injector Guidance

More specific concerns►Definitions

Scope of “injector” – currently the definition seems all encompassing

Other terms (e.g., “product class”, “product line”)

►Clinical studiesImplies that there should be a clinical study for

all types of injectorsNeeds to clarify when FDA believes clinical data

are needed

►Very prescriptive data requirements

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GMPs Proposed Rule expected anytime Likely themes

► Combination product manufacturers must meet the requirements of both sets of applicable GMP regulations. Manufacturers may choose an “umbrella” system under which to operate, but this system must meet the requirements of both sets of applicable GMP regulations.

► Manufacturers must implement certain specific provisions in order to achieve compliance with both sets of regulations (e.g., design controls, purchasing controls, and CAPA for devices).

► May be a regulatory obligation to comply with certain GMP requirements even before constituent parts are physically combined, merged, or joined.

► Manufacturers cannot delegate ultimate responsibility for GMP compliance.

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GMP Comment Meeting with FDA and RAPS

Will be organized quickly during comment period

Will focus on pre-written case studies

Will be in person and virtual

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Adverse EventsProposed Rule expected anytime.Likely content might propose:

►mechanisms by which the postmarket safety reporting requirements ordinarily associated with the marketing application used to approve or clear a combination product may be supplemented, as appropriate, to take into account the combination nature of the product, or

►a reporting scheme in which the same types of postmarket safety reports would be submitted for a combination product, regardless of the type of marketing application used for its approval or clearance

Look at September 2005 Concept Paper

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Cross Labeling

May 10, 2005 Public Meeting►Transcript and presentations

accessible on OCP websiteNew straw man proposal likely

►New public meeting planned to discuss proposal

My mother never saw the irony in

calling me a son-of-a-bitch.

Jack Nicholson

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What is Cross Labeling?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)

Winter related injuries occur more often in the winter.

-newswoman for WHIZ-TV, Zanesville, Ohio

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SubmissionsQuestions:

►Initial submissions—number of them►Supplements for product

modificationsGuidance

►September 2005 Concept Paper for initial submissions

►Close to guidance on product modifications, unless goes to rulemaking

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Initial SubmissionsAgency goal seems to be to prescribe

the number and type to be filedCPC has argued for greater freedom

to determine the approval pathway, within the confines of the law.►We explain that a lot of factors,

many of which the agency won’t know, affect the optimal approval route

Not clear where the agency is going

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Submissions for Product Modifications

Agency has a draft guidance in hand►However, still grappling with

fundamental questions such as guidance or rulemaking

►Addresses pathway/type of submission issue, rather than type of evidence or data required

CPC has drafted its own guidance►Will shift to developing questions

and case studies

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International Trends Other jurisdictions are lagging behind FDA in the

development of new guidance and approaches►In Europe, specific regs not yet in place

Europe's approach is similarly based on primary mode of action, although it is determined differently

Medical Device Directive lays out pathway for combination products that operate as devices►If the drug and device are a single integral product

that is intended exclusively for use in a given combination, gets regulated as a drug.

►On the other hand, if a device incorporates a drug as an integral part and the drug acts on the body in an ancillary manner, the product is regulated as a device.

►In the case of a tie, it’s a drug There is a consultation procedure (MEDDEV 2.1/3 rev.

2 (2001)) Little energy is being directed at harmonization (2008

Initiative)

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1. Overview2. Where are Combination Products

Going?3. Where is Combination Product

Regulation Going?4. Where are the Challenges and

Opportunities?

Topics

What orators lack in depth, they make up for in length.

Charles-Louis De Secondat Montesquieu

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Combination products:► Increasingly state-of-the-art, innovative technologies

that challenge existing regulatory and scientific knowledge

►Require regulators to apply very different regulatory paradigms to one – often unique – product

►Force FDA’s nearly autonomous centers to work togetherThe OCP is still somewhat new, with limited

resourcesDifferent industries have different

perspectives and priorities – leaving OCP to weigh the options and make choices

Most existing trade association structures mirror FDA’s product-based centers

Practical Challenges

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The OCP will actively seek input on its initiatives. For example:►Injectors►GMP►Adverse Events

Because the OCP is so thinly staffed, industry has an opportunity to help fill the gaps with: ►Regulatory, scientific and practical knowledge►Research►Idea generation►Feedback

Practical Opportunities

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Questions?

Arguing with a lawyer is like mud wrestling with a pig: after a while you realize that the pig actually enjoys

it.