1. 1 The Future of Combination Products Bradley Merrill Thompson, MBA, JD, RAC Epstein Becker & Green PC RAPS San Francisco, CA April 27, 2007

2. 2 1.Overview 2.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

3. 3 Overview 1.What are combination products? 2.What is the Combination Product Coalition?

4. 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. 5  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

6. 6  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 Not Combination Products

7. 7 How are they Regulated? Different Frameworks Different Types Different Reviews NDA, BLA, NDA, BLA, PMA, 510(k), PMA, 510(k), IND, IDE IND, IDE DeviceDrugBiologic CDRHCDERCBER

8. 8 CPC: Purpose  To clarify and streamline the regulatory paradigm for combination products  While protecting the public health

9. 9  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

10. 10  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

11. 11  Cross labeling  Modification of approved combination products  Adverse incident reporting  Quality systems/GMPs  Clarification of OCP role Current CPC Key Priorities

12. 12  Companies interested in CPC should visit: www.combinationproducts.comwww.combinationproducts.com ►Membership structure ►Policy Positions

13. 13 1.Drivers 2.Examples 3.Quantitative a.Reviews b.Projections Where Are Combination Products Going?

14. 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. 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

16. 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. 17 Converging Technologies Adapted from: Biology, Bioconvergence, Information And Enterprise: Taking the Broad of View May 20, 2004 Alan Barrell. INFOTECH Hardware Software Communications BIOTECH Pharmaceuticals Diagnostics Research/Info Tools Industrial INFOTECH Hardware Software Communications NANOTECH Electrical Structural Biomedical Energy & Environment Nanodevices Nanosensors Nanoelectgronics Genomics Bioinformatics Proteomics Bioelectronics Microfluidics Nanabiotechnology Drug Delivery Biosensors Biochips

18. 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. 19 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 123456789TOTALS Original NDAs18--1 11 12 Original BLAs1--1 2 Original PMAs-- 2 2 Original 510(k)s 5-- 559--6 378 Original INDs14214741217541152 Original IDEs1-- 197--11 29 Original HDEs-- 0 TOTALS9501584201325554275

20. 20 Combination Product Applications 2005 CBERCDERCDRH

21. 21 Primary Assigned Center Consulting Center Number of Consults CBERCDERCDRH CBER--93645 CDER-- 36 CDRH9185--194 Totals919472275 Consultations 2005

22. 22 Combination Product Application Trend Number of Submissions

23. 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. 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 4 th 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. 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 4 th 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 4 th Edition, Lux Research, 2006.

26. 26 Where Is Combination Product Regulation Going? 1.Congress 2.FDA 3.Internationally

27. 27 Congress  Where has Congress been recently?  Where is Congress going?

28. 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. 29  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

30. 30  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

31. 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 ►That’s not a bad thing, unless they fall too far behind

32. 32 Where is FDA Going? 1.Office of Combination Products 2.GMPs 3.Adverse Events 4.Cross Labeling 5.Submissions 6.User Fees

33. 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. 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. 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 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.

36. 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. 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. 38 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)

39. 39 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?

40. 40 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…

41. 41 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?

42. 42 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

43. 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 won’t know, affect the optimal approval route  Not clear where the agency is going

44. 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. 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. 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. 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. 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, it’s a drug  There is a consultation procedure (MEDDEV 2.1/3 rev. 2 (2001))  Little energy is being directed at harmonization

49. 49 Where is the Regulatory Profession Going?

50. 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. 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. 52 Differences DevicesDrugs Engineering, materialsBiology, chemistry Local effectsSystemic effects Technology developmentResearch Systematic & rapid product development Slow, trial & error product development EngineersScientists Product lifetime usually short Product lifetime usually long

53. 53 What Are the Practical Challenges and Opportunities?

54. 54  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

55. 55  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

56. 56  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

57. 57  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

58. 58 Questions?