Food and Drug Law November 15, 2010

1. Food and Drug LawNovember 15, 2010 Ralph F. Hall

2. Overview • Current events • Medical devices • 510(k) process • PMA process • 510(k_ “reform” • Combination products • QSR and post market matters

3. Medical Devices

4. Device Classification and Approval

5. Device classification and approval 510(k) PMA Low risk High Risk Class I Class II Class III

6. 510(k) Submission for Some Class I and Most Class II Devices • Substantial Equivalence (SE) • The goal of a 510(k) submission is to demonstrate substantial equivalence to a device that is already legally marketed. (see section 510(k) of the FDCA (21 U.S.C. § 360 (k)). • The 510(k) process involves a comparison of one device to another. • The device used for comparison purposes is the “predicate” device.

7. Comparison to Marketed Device NSE No Same Intended Use? New Technological Characteristics and New Questions of Safety and Effectiveness Yes No Data Demonstrates Equivalence Yes SE 510(k) Decision-Making Process

8. Device Modifications • A new 510(k) notice must be filed for a legally marketed device if it is significantly modified in design, components, method of manufacture, or intended use • Significant modifications include: • Changes that could significantly affect safety or effectiveness, e.g., a significant change in design, material, chemical composition, energy source, or manufacturing process • Major changes in the intended use of the device

9. Determining Whether a 510(k) Must Be Submitted for a Device Modification • Is the proposed modification “significant”? • Is it a major change in the intended use? • New therapy • New patient population • “Could” it significantly affect safety or effectiveness? • Does it perform in a different manner

10. 510(k) Special Categories • Certain special categories exist: • Special 510(k)s • Device modification • Design controls/QSR • Declaration of Conformity • Abbreviated 510(k)s • Use of guidance documents/special controls • Declaration of Conformity • Allow faster handling of certain lower risk 510(k) applications

12. PMA Process • Purpose of PMA is to establish “reasonable assurance” that device is safe and effective • Cannot market or ship without an approved PMA • PMA required for Class III and some Class II devices • PMA filingincludes: • Animal studies • Clinical studies • Indications for use • Contradictions, warnings and adverse events • Manufacturing information • Proposed labeling

13. NDA/PMA Comparison • Standard for approval • NDA – safe and effective (355 (d) • PMA – “reasonable assurance of safety and efficacy (360e(d)) • Explicit consideration of risk/benefit • Clinical trials not mandatory for PMA

14. SPMA Process • PMA supplement is required for any change which could affect safety or effectiveness • Includes more changes than 510(k) standard • Examples include: • New indications • Sterilization changes • Labeling changes • Manufacturing changes • All other changes are to be included in an annual report

15. PMA Process • Special PMA – changes been effected • Certain narrow changes such as enhanced warnings can be made upon submission to FDA • Manufacturing Changes • Certain narrow manufacturing changes can be made upon 30 days notice • 21 CFR 814 and guidance documents set forth processes and requirements

16. PMA Process • Advisory Panel • FDA can assemble an “expert” panel from outside FDA for input on scientific or clinical questions • Panel conclusions are advisory • Panel meetings are public • Panels used for new or controversial therapies • Panel meetings add significant time to approval process • Regulated by FACA • Conflict of interest issues • Improper delegation of authority issues

17. PMA Process • 180 day approval clock • Standards for approval • Approve application if no grounds for denying approval exist (360e(d)(1)(A) (i)) • Based on proposed labeling • Reasonable assurance of safety and efficacy • Labeling not false or misleading

18. PMA Process • Reasons for denial • lack of showing of “reasonable assurance” of safety • lack of showing of “reasonable assurance” of efficacy • Quality system issues • False or misleading labeling • Failure to meet a performance standard

19. PMA Process • Fast track devices • breakthrough technology • No approved alternative therapies • Significant advantage over existing therapies • “best interest of patients”

20. Special Categories • Humanitarian devices (360j(m)) • Small population (4,000) • Designation • Exempt from effectiveness review • Safety still required • Custom devices (360j(b)) • Individual specifications • Dentures • Emergency use • Life threatening • No option • Notification

21. Revising the 510(k) system

22. Declining 510(k) clearances and PMAs over last 10 years *Original PMAs FDA PMA data  http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm FDA 510(k) data  http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm

23. FIVE AVENUES OF ATTACK CONGRESS INSTITUE OF MEDICINE (IOM) FDA MEDICAL COMMUNITY 510(k) Program and Industry PUBLIC ADVOCACY GROUPS

24. Key Issues PUSHING 510(k) Changes The “old” predicate (“genealogy” problem) and “bad” predicate issue Split predicates I can build a Frankenstein Mistaken clearance – must it live forever Technology changes Past industry control over CDRH ReGen Using a product in humans without testing it in humans Past recalls, enforcement and safety issues Lack of understanding of the 510(k) system

25. Four Key Avenues for Change • FDA proposed changes (round 1) • Stated to be “non-controversial” changes • Utilize three mechanisms • Administrative/process changes • New guidance • New regulations • IOM report • No limitations on scope • FDA (round 2) • Address IOM proposals • Congressional action • Statutory changes

26. Reality Check 510(k) under great pressure Congress, FDA, public advocacy groups Industry has few allies or friends Multiple issues and concerns Product review system (including 510(k)) No data demonstrating systemic safety issues FDA hasn’t identified any FDA feels compelled to act Increasing Congressional interest Something will be done Too much pressure and time investment

27. 10 FDA Internal Task Forces Potential to increase industry burden Predicates Indications New technology De novo Evidence Modifications Standards Bundling 3rd Party review Post market data

28. Recent Activities • August 4th FDA releases “conceptual changes” • Oct. 4th comments due • Nov. 5th AEI/Brookings program • IOM meetings and reports • July 29th meeting • Issued and upcoming reports • Increasing advocacy efforts • Development of plans • Administrative changes

29. Reality CheckYes, There Was an Election - But Only the House changed sides 510(k) still under great pressure Industry has some more friends but still has enemies Multiple issues and concerns remain Product review system (including 510(k)) No data demonstrating systemic safety issues FDA feels compelled to act Invested too much to stop now Increasing Congressional interest Something will be done Too much pressure and time investment Scope is open

30. CURRENT CLIMATE “It’s the economy, stupid” Linking 510(k) changes to job losses 510(k) issues are part of broader FDA issues and even broader political issues 2012 is an election year Politics start now Industry getting mobilized Congressional gridlock possible Increasing importance of administrative changes Regulations and guidance Watch for Oversight and Investigation hearings

31. Key Themes

32. Methodology 13 categories for reason for recall • Premarket issues • Design issues • Clinical data gaps • Post-market issues • Manufacturing issues • Labeling mistakes • Sterilization issues • Miscellaneous • Counterfeits and quacks PI reviewed and assigned all reasons for recalls Blind review of 10% of recalls

33. Primary Reason for Recall (N = 118)

34. Very Few 510(k) Clearances Have Been Subject to a Class I Recall Total Recalls 2005 - 2009 Of those 89 Recalls… *Percentages should be viewed as close approximates.

37. Analyzing Recalls by Medical Specialty Demonstrates Same Pattern

38. Understand the ScopeMore than ACTUAL 510(k) review process at issue

39. General Observations • FDA clearly focused on perceived safety issues • 510(k) and predicates viewed as potential safety risks • Ambitious list of changes • Does FDA have capacity to implement these? • Cost and user fee impact • FDA is in “more data” mode • Clinical • Safety and effectiveness • Manufacturing • Product changes • FDA wants more authority overall • Little discussion of innovation • De novo • Information for industry

40. Industry v. study participant demographics Ernst & Young, Pulse of the Industry, Medical technology report ,2010.

41. 510(k) & CE timelines in US & EuropeReported FDA transit times underestimate actual regulatory delay [Office of Device Evaluation, Annual Performance Report, 2009.] US/CE times reported by survey respondents

42. PMA & CE timelines in US & EuropeReported FDA transit times underestimate actual regulatory delay [Office of Device Evaluation, Annual Performance Report, 2009.] US/CE times reported by survey respondents

43. European authorities rank better in clinical competence

44. European authorities rank better in engineering competence

45. European authorities rank better in statistical competence

46. European authorities are viewed as more predictable

47. European authorities are viewed as more reasonable

48. European authorities are viewed as more transparent

49. Combination Products

50. Combination Products • What is a • Drug eluting stent • Prefilled Insulin syringe • Chemically acting product whose label requires an in vitro diagnostic test prior to use? • Fit multiple definitions • Regulatory pathway issues • Critical decision