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The Future of Combination Products

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

RAPSSan Francisco, CA

April 27, 2007

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1. Overview2. Where are Combination Products Going?3. Where is Combination Product Regulation Going?4. Where is the Combination Product Regulatory Profession

Going?5. Where are the Challenges and Opportunities?

Topics

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Overview

1. What are combination products?

2. What is the Combination Product Coalition?

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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

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

► Abbott► Baxter► Becton Dickinson► 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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Cross labelingModification of approved combination

productsAdverse incident reportingQuality systems/GMPsClarification of OCP role

Current CPC Key Priorities

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

►Membership structure►Policy Positions

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1. Drivers2. Examples3. Quantitative

a. Reviews b. Projections

Where Are Combination Products Going?

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Combination Product DriversClinical

►Need/want enhanced outcomes in both safety and effectiveness

►Systemic effects and toxicities eliminate too many candidates, which in turn drives localized delivery, targeting and individualized therapy

Economic►Slow down in pharma industry productivity

Cost and times for new drug development are high►Patent life limitations

Growing tendency to collaborate

Harvard Business School, Lakhani, et al Oct. 2006

Collaboration Leads to Combinations

Study publicized 166 intractable scientific problems owned by high tech companies

Almost 1/3 quickly solved by mostly off-the-shelf technologies

Majority of solutions came from people versed in other fields►Indeed, the further from the field of the

problem, the more likely they were to solve it

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The “Ice Tray” Model of Convergence Dynamics

Silos: Knowledge, methods and discoveries made in isolated technology sectors.

Connection: One well connects to another. Knowledge can be applied quickly to adjacent areas.

Convergence: Greater innovation in the connected region than in the individual wells.

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Converging Technologies

Adapted from:Biology, Bioconvergence, InformationAnd Enterprise: Taking the Broad of ViewMay 20, 2004 Alan Barrell.

INFOTECHHardware Software

Communications

BIOTECHPharmaceuticals

DiagnosticsResearch/Info

Tools Industrial

INFOTECHHardwareSoftware

Communications

NANOTECHElectricalStructural

BiomedicalEnergy & Environment

NanodevicesNanosensors

Nanoelectgronics

GenomicsBioinformatics

Proteomics

BioelectronicsMicrofluidics

NanabiotechnologyDrug Delivery

Biosensors

Biochips

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Platforms to Watch

Tissue EngineeringMicro-electrical mechanical systemsBiomaterialsGene and protein deliveryTargeted medicineNew routes for delivering drugs

Nature Biotechnology (March 2006)

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Number and Types of Combination Products FY 2005

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 1 8 -- 1 -- 1 1 -- -- 12

Original BLAs 1 -- 1 -- -- -- -- -- -- 2

Original PMAs -- -- -- 2 -- -- -- -- -- 2

Original 510(k)s

5 -- -- 55 9 -- 6 -- 3 78

Original INDs 1 42 14 7 4 12 17 54 1 152

Original IDEs 1 -- -- 19 7 -- 1 1 -- 29

Original HDEs -- -- -- -- -- -- -- -- -- 0

TOTALS 9 50 15 84 20 13 25 55 4 275

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Combination Product Applications 2005

0

20

40

60

80

100

120

140

CBER

CDER

CDRH

CBER CDER CDRH

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Primary Assigned

Center

Consulting CenterNumber of Consults

CBER CDER CDRH

CBER -- 9 36 45

CDER -- -- 36 36

CDRH 9 185 -- 194

 Totals 9 194 72 275

Consultations 2005

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Combination Product Application Trend

0

50

100

150

200

250

300

FY03 FY04 FY05

CBER

CDER

CDRH

Nu

mb

er

of

Su

bm

iss

ion

s

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Quantitative ProjectionsThe combination products market is estimated at $5.98B

in 2004, and will continue to grow at a compound annual rate of 10% through 2009. By 2009, the market is expected to reach approximately $9.5B worldwide. ►Source: Navigant Consulting, Inc.

The global market for drug-device combinations is expected to increase at an average annual growth rate of 13.6% and reach $11.5B in 2010, compared with $5.4B in 2004. ►Source: Business Communications Co., Inc.

The US drug delivery market is expected to reach nearly $91B by 2009. ►Source: Fuji-Keizai, 2006

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Nanotechnology Projections

The 2005 market size for nanotechnology drug delivery systems alone was estimated at $980 million and expected to gross 54% annually over the next five years. ►Source: The Nanotech Report 4th Edition, Lux Research, 2006.

The demand for nanotechnology medical products will grow by more than 17% annually to reach $53 billion in 2011. ►Source: The Fredonia Group, Nanotechnology in Health Care to

2011 Report, February, 2007.

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Nanotechnology Projections With at least 12 nanomedicines already approved and progressively

more in active development, the next five years should see a steady succession of new nanotech-based drugs, imaging agents, and diagnostic products entering the marketplace. ► Source: Advance Tech Monitor, 2006.

As of mid-2006, 130 nanotech-based drugs and delivery systems and 125 devices or diagnostic tests were in preclinical, clinical or commercial development.► Source: The Nanotech Report 4th Edition, Lux Research, 2006.

The combined market for nano-enabled medicine (drug delivery, therapeutics and diagnostics) will jump from just over $1B in 2005 to almost $10B in 2010. The US National Science Foundation predicts that nanotechnology will produce half of the pharmaceutical industry product line for 2015. ► Source: The Nanotech Report 4th Edition, Lux Research, 2006.

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Where Is Combination Product Regulation Going?

1. Congress2. FDA 3. Internationally

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Congress

Where has Congress been recently?Where is Congress going?

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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?

New user fee bill►No specific talk about combination products

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 Products

2. GMPs

3. Adverse Events

4. Cross Labeling

5. Submissions

6. User Fees

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Office of Combination ProductsIn a state of flux, with new leadership

►Dr. Joanne Less replaces Mark Kramer►Formerly Associate Director for Clinical Research at CDRH

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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GMPs Proposed Rule due any week/month 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).

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GMPs More Likely Themes

► May be a regulatory obligation to comply with certain GMP requirements even before constituent parts are physically combined, merged, or joined. For example, design controls may come into play before actual

physical combination of a combination product’s constituent parts.► Manufacturers cannot delegate ultimate responsibility for GMP

compliance. While it might be acceptable to accept supplier design controls, a

manufacturer is ultimately responsible for ensuring adequate compliance with all GMP requirements, including those where a contractor helps.

Manufacturers should be cognizant of separate design control issues at the overall combination product level – i.e., after the manufacturer doing the final assembly receives the component/constituent part from the supplier.

Design controls apply to all constituent parts and the finished combination product--not just the device constituent part.

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Adverse EventsProposed Rule expected any week/month.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

►Might propose 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 website

New straw man proposal due out any week/month►New public meeting planned to discuss

proposal

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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)

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What’s So Hard About That?Hypothetical

Company A is the sponsor of approved Drug A.

Company B wants to obtain premarket approval for Device B that will administer Drug 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?

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What does individually specified mean?

What if Device B has other approved intended uses?

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

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

Some of the Questions…

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Protect and Promote the Public Health

FDA prefers cooperation. In the absence of cooperation, FDA’s goal is to identify a

regulatory pathway for Device B while ensuring adequate regulatory oversight.

Consider whether labeling of Drug A “needs to be changed”:►Is Drug 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 Drug A is reformulated or redesigned

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

covering Drug A?

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Submissions

Questions:►Initial submissions—number of them►Supplements for product modifications

Guidance►September 2005 Concept Paper for initial

submissions►Close to guidance on product modifications,

unless goes to rulemaking

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Initial Submissions

Agency goal seems to be to prescribe the number and type to be filed

CPC 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 requiredCPC has a draft guidance in hand

►Will shift to developing questions and case studies

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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 still required for each application (waivers/reductions possible)

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Draft User Fee Guidance

Draft User Fee Guidance (cont.)

►Waivers: Innovative combination products (only if

FDA requires multiple applications)MDUFMA and PDUFA waivers available

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Draft User Fee Guidance CPC Comments

►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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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

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Where is the Regulatory Profession Going?

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Growth

RAPS research shows steady growth in the number of regulatory professionals involved in combination products – from an estimated 12% in 1999 to nearly 30% today. ►Source: Sherry Keramidas, PhD, RAPS Executive

Director, September 2006.

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Alliances Will Govern

Normally core capabilities done in houseConvergence requires broad expertise

and experience only available through alliances

Numerous special issues and challenges►Regulatory differences►Cultural differences►Economic interest differences

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Differences

Devices Drugs

Engineering, materials Biology, chemistry

Local effects Systemic effects

Technology development Research

Systematic & rapid product development

Slow, trial & error product development

Engineers Scientists

Product lifetime usually short

Product lifetime usually long

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What Are the Practical Challenges and Opportunities?

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Combination products:►Are increasingly state-of-the-art, innovative

technologies that challenge existing regulatory and scientific knowledge

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

►Force FDA’s nearly autonomous centers to work together

The OCP is new, with limited resources

Practical Challenges

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Different industries have different perspectives and priorities – leaving OCP to weigh the options and make choices

Existing trade association structures mirror FDA’s product-based centers

Practical Challenges

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The leadership of the OCP is interested in hearing from, and working with, industry – opportunities exist for close collaboration.

The OCP is actively seeking input on its initiatives. For example:►GMP►Adverse Events►Cross Labeling

Practical Opportunities

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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?