The Future of Combination Products

1
The Future of Combination Products

• Bradley Merrill Thompson, MBA, JD, RAC
• Epstein Becker Green PC
• RAPS
• San Francisco, CA
• April 27, 2007

2
Topics

• Overview
• Where are Combination Products Going?
• Where is Combination Product Regulation Going?
• Where is the Combination Product Regulatory
  Profession Going?
• Where are the Challenges and Opportunities?

3
Overview

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

4
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

5
Three Types of Combination Products

• 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

6
Not Combination Products

• 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 role
• General 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

7
How are they Regulated?
8

• CPC Purpose
• To clarify and streamline the regulatory paradigm
  for combination products
• While protecting the public health

9
Membership

• 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.

10
Activities

• 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.

11
Current CPC Key Priorities

• Cross labeling
• Modification of approved combination products
• Adverse incident reporting
• Quality systems/GMPs
• Clarification of OCP role

12

• Companies interested in CPC should visit
  www.combinationproducts.com
• Membership structure
• Policy Positions

13
Where Are Combination Products Going?

• Drivers
• Examples
• Quantitative
• Reviews
• Projections

14
Combination Product Drivers

• Clinical
• 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

15
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

16
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.

17
Converging Technologies
Genomics Bioinformatics Proteomics
INFOTECH Hardware Software Communications
BIOTECH Pharmaceuticals Diagnostics Research/Info
Tools Industrial
INFOTECH Hardware Software Communications
Biosensors Biochips
Bioelectronics Microfluidics Nanabiotechnology Dru
g Delivery
Nanodevices Nanosensors Nanoelectgronics
NANOTECH Electrical Structural Biomedical Energy
Environment
Adapted from Biology, Bioconvergence,
Information And Enterprise Taking the Broad of
View May 20, 2004 Alan Barrell.
18
Platforms to Watch

• Tissue Engineering
• Micro-electrical mechanical systems
• Biomaterials
• Gene and protein delivery
• Targeted medicine
• New routes for delivering drugs
• Nature Biotechnology (March 2006)

19
Number and Types of Combination Products FY 2005
Application Type Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category
Application Type 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
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
20
Combination Product Applications 2005
CBER
CDER
CDRH
21
Consultations 2005
Primary Assigned Center Consulting Center Consulting Center Consulting Center Number of Consults
Primary Assigned Center CBER CDER CDRH Number of Consults
CBER -- 9 36 45
CDER -- -- 36 36
CDRH 9 185 -- 194
 Totals 9 194 72 275
22
Combination Product Application Trend
Number of Submissions
23
Quantitative Projections

• The 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

24
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.

25
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.

26
Where Is Combination Product Regulation Going?

• Congress
• FDA
• Internationally

27
Congress

• Where has Congress been recently?
• Where is Congress going?

28
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

29
Historical Development

• 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

30
Historical Development

• 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

31
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
• Thats not a bad thing, unless they fall too far
  behind

32
Where is FDA Going?

1. Office of Combination Products
2. GMPs
3. Adverse Events
4. Cross Labeling
5. Submissions
6. User Fees

33
Office of Combination Products

• In 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

34
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).

35
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 products 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.

36
Adverse Events

• Proposed 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

37
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

38
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)

39
Whats 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?

40
Some of the Questions

• 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?

41
Protect and Promote the Public Health

• FDA prefers cooperation.
• In the absence of cooperation, FDAs 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?

42
Submissions

• Questions
• Initial submissionsnumber of them
• Supplements for product modifications
• Guidance
• September 2005 Concept Paper for initial
  submissions
• Close to guidance on product modifications,
  unless goes to rulemaking

43
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 wont know, affect the optimal
  approval route
• Not clear where the agency is going

44
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 a draft guidance in hand
• Will shift to developing questions and case
  studies

45
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)

46
Draft User Fee Guidance

• Draft User Fee Guidance (cont.)
• Waivers
• Innovative combination products (only if FDA
  requires multiple applications)
• MDUFMA and PDUFA waivers available

47
Draft User Fee Guidance

• CPC Comments
• FDA needs to address issue of what assignment
  means
• Specific enhancements recommended
• Clarify when multiple filings required
• Provide automatic waiver of partial fee when FDA
  requires multiple applications
• Expand 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

48
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, its a drug
• There is a consultation procedure (MEDDEV 2.1/3
  rev. 2 (2001))
• Little energy is being directed at harmonization

49
Where is the Regulatory Profession Going?
50
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.

51
Alliances Will Govern

• Normally core capabilities done in house
• Convergence requires broad expertise and
  experience only available through alliances
• Numerous special issues and challenges
• Regulatory differences
• Cultural differences
• Economic interest differences

52
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
53
What Are the Practical Challenges and
Opportunities?
54
Practical Challenges

• 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 FDAs nearly autonomous centers to work
  together
• The OCP is new, with limited resources

55
Practical Challenges

• Different industries have different perspectives
  and priorities leaving OCP to weigh the options
  and make choices
• Existing trade association structures mirror
  FDAs product-based centers

56
Practical Opportunities

• 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

57
Practical Opportunities

• 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

58
Questions?