FDA APPEALS IMPROVING YOUR ODDS OF SUCCESS: TRENDS, EXPECTATIONS, STRATEGIES. Jeffrey Shapiro

Transcription

1 FDA APPEALS IMPROVING YOUR ODDS OF SUCCESS: TRENDS, EXPECTATIONS, STRATEGIES March 21, 2012 Josephine Torrente Jeffrey Shapiro

2 Formal Dispute Resolution with CDER and CBER March 21, 2012 Josephine Torrente (202)

3 Agenda The FDRR Guidance Document Points to Consider for Successful FDRR Case Studies 3

4 The FDRR Guidance Document FDA Guidance for Industry Formal Dispute Resolution: Appeals Above the Division Level CDER/CBER procedural guidance Issued February 2000 Available at: formation/guidances/ucm pdf Many Other Routes of Appeal Available Outside the scope of this webinar 4

5 The FDRR Guidance Document What Can be Appealed Scientific and procedural matters Refusal to approve Clinical hold Refusal to enter SPA Trial design requirements Applicability of statistical principles 5

6 The FDRR Guidance Document What to Submit Written request (letter) and supporting documentation Administrative information Follow details in FDA guidance document Substantive information Set out issue Procedural or scientific Steps taken toward resolution Identify solutions Advisory Committee? State expected outcome 6

7 The FDRR Guidance Document Possible Responses Appeal request granted or denied Plan for Advisory Committee Request additional information Schedule a meeting Request opinion from Office of Chief Counsel Timing (PDUFA Goal) Within 30 calendar days of receipt of the appeal (90%) If by phone, written response 14 days later 7

8 Points to Consider People Division Director or Deputy Director Office Director OND Director (J. Jenkins) or Deputy Director (S. Kweder) Center Director (J. Woodcock) or Deputy Director (D. Throckmorton) Process Must attempt resolution at signatory authority level No new information submitted as part of the appeal Cannot respond to issue in parallel with appeal 8

9 Points to Consider Striking an Appropriate Tone Inform Division/Office of decision to appeal Remove all irrelevant or accusatory language Refer to organizations rather than individuals Stick to the facts Ask how each fact matters to resolution Potential for Retaliation Most Division/Office Directors appreciate potential for scientific/procedural differences of opinion People are people 9

10 Points to Consider It s easy and cheap, I guess, to dispute rather than to actually go off and do the work. - John Jenkins, M.D. (The Pink Sheet Jan. 2, 2012) Suggests skepticism about appeals Appeal should only occur where: Regulatory burden being imposed exceeds time and cost of 2-3 rounds of appeal There is a legitimate basis for overturning the decision below 10

11 Points to Consider Meeting Considerations Unlikely to be beneficial at lower appeal levels May be helpful at OND level New decision makers Input from other OND experts All parties participate Typically delays response by 30 days 11

12 Points to Consider Response Expectations Dispute Appeal Denied Denied does not always mean the sponsor goes away unhappy. - Kim Colengelo Read the letter Well-considered Moves the ball forward Sets out path to resolution On approval issues need to resubmit NDA Appeal is typically of the decision not the action 6-month review clock 12

13 Case Studies Contrave Pixuvri Ryzolt Cayston 13

14 Case Studies - Contrave Background Combination of two approved drugs Seeking approval for treatment of obesity Pre-appeal Discussions 1/31/ CRL issued by Division Requires data from large clinical outcomes trial to rule out CV risk EOR meeting Division required unprecedented not feasible CVOT design 60, ,000 patients Rejected possibility of approval in low CV risk population 2012 General Advisory Committee planned Any agreement on Contrave would be subject to change 14

15 Case Studies - Contrave FDRR 6/3/2011 Appeal Announced Office: outcome not reported OND: 9/20/2011 response Sets forth reasonable and feasible study design criteria (<10,000 patients) Approval possible on interim data 2012 Advisory Committee meeting will not impact the advice provided in this letter and the agency will honor the advice provided Post-appeal 2/6/2012 SPA agreement with Division on study design First round agreement 15

16 Case Studies - Pixuvri Background New molecular entity Seeking approval for relapsed/refractory non-hodgkin s lymphoma Single pivotal trial Pre-appeal Discussions 3/22/2010 unanimous ODAC vote against approval Pivotal study failed trial because of the need to apply a statistical penalty CRL issued at Office level Same issue as ODAC 16

17 Case Studies - Pixuvri FDRR Appeal Filed 12/3/2010 Meeting OND requested additional analyses OND: 5/3/11 response Denied request to find that efficacy had been demonstrated BUT - pivotal study may have been successful Approval not necessarily out of reach Submit information regarding early study stop/ongoing results assessments Ascertain soundness of results after independent radiologic review 17

18 Case Studies - Pixuvri Post Appeal Meeting with review division 6/14/2011 to discuss resubmission Resubmission 10/25/11 ODAC scheduled for 2/9/2012 NDA withdrawn 1/30/2012 Company needed additional time to prepare 18

19 Case Studies - Ryzolt Background Extended release version of approved drug Seeking approval for moderate to severe pain indication Pre-appeal Discussions 9/28/ Approvable letter issued at Division level Method of handling of missing data (LOCF) inappropriate despite prespecification and SPA More conservative method (BOCF) renders results not significant 11/21/ EOR meeting 12/19/ Resubmission Additional sensitivity analyses 19

20 Case Studies - Ryzolt Pre-appeal Discussions (con t) 5/3/ Approvable letter 6/26/ EOR meeting FDRR 10/15/2007 Appeal Office: 11/20/2007 denial Support Division s conclusion 12/19/ appeal to OND: 1/18/2008 response Have not demonstrated efficacy BUT - proposes a third method for handling missing data If positive it could help reassure the Division that the outcome of the study is not biased by imputation Results are significant when third method is used 20

21 Case Studies - Ryzolt Appeal (con t) 3/31/ appeal to CDER - 6/27/2008 Concurs with OND I strongly recommend prompt submission of the statistical analysis suggested by [OND] in the form of a [resubmission] Post-appeal 7/2/ Resubmission Includes analysis by Jenkins Method 12/31/ Approval 21

22 Case Studies - Cayston Background Previously approved drug Seeking approval for treatment of cystic fibrosis patients with P. aeruginosa Pre-appeal Discussions 9/16/ CRL issued at Division level Prespecified pooled analysis of different dosing regimens not acceptable Treatment regimen effect unexplained 22

23 FDRR Case Studies - Cayston 11/24/2008 to Office: Dispute Appeal Denied 2/18/2009 Agreement with Division 3/13/2009 to OND: Dispute Appeal Denied 6/17/2009 4/10/ request for responses to questions 4/22/ response Extensive work to better characterize novel CF endpoint 4/24/ meeting 5/22/ submission New analyses submitted on appeal could not be considered BUT - recommended submission of new analyses to Review Division and consideration by Advisory Committee 23

24 Case Studies - Cayston Post-appeal Resubmission 12/10/ Advisory Committee Advisory Committee vote: 15-2 for approval 2/22/ Approval 24

25 Administrative Appeals March 21, 2012 Jeffrey K. Shapiro (202)

26 Getting past FDA is more challenging today than even 5 years ago Device technology is more complex Data requirements are more demanding Regulatory issues more prominent E.g., drug ingredients, combination products 26

27 FDA makes many decisions in every premarket review that could be disputed Requiring unduly burdensome data Rejecting a 510(k) or PMA Designating a drug primary mode of action (combination product) 27

28 Choose your battles wisely! All reviews involve friction Not possible to appeal all issues You may lose anyway and wind up where you started after a costly delay Appeals are generally slow and inefficient 28

29 Provide the review team with all supporting data and arguments The review team might be persuaded, making an appeal unnecessary It is generally not permissible to present new arguments or data on appeal 29

30 Post-market decisions are appealable Examples: Warning and untitled letters Application Integrity Policy Requirements of a post-approval study Imposition of a section 522 study 30

31 If there is no decision, there cannot be an appeal If a dispute arises during a 510(k) review, sometimes the applicant withdraws the 510(k) to enable further discussions That is fine but a 510(k) withdrawn cannot be appealed 31

32 SUPERVISORY REVIEW 21 CFR

33 Discussion with decision maker ends Goal is to prevent confusion and waste of FDA resources Relationship with Decision Maker Generally, FDA personnel are professionals who do not take appeals personally CDRH has general policy against bias/retaliation And yet must make a judgment whether appeal is worth interruption in relationship 33

34 A supervisory review is not public Under regulations, appeal involves consultation between supervisor and employee, or supervisor s review of the file Review is between CDRH personnel and applicant 34

35 First step: determine who signed the decision General CDRH hierarchy: Branch Division Office Center Commissioner 35

36 Supervisory review moves up the chain of command Example #1: 510(k) AI signed by Branch Chief Division Director Example #2: 510(k) NSE signed by Division Director Director ODE/OIVD Example #3: RFD decision signed by Director of OCP Associate Commissioner, Office of Special Medical Programs 36

37 Rarely, appeal could skip over the supervisor to the next level (telescoped review) Occurs when signatory has already consulted with supervisor, who is in agreement with decision Examples when it might occur: regulatory issue, new policy question or complex scientific question 37

38 Submit the supervisory review request in writing No required format Recommendation: a letter with attachments for background or supporting information 38

39 Ask for a meeting to present the case It is discretionary; usually granted May not be granted for intermediate decisions (e.g., dispute over an intermediate decision like an AI request) Review team may or may not be present (usually are) 39

40 An advisory panel is available Applicant may request scientific advisory panel A panel is cumbersome and rarely used In one case we had, the Director granted a panel, leading the Division to compromise Tip: an alternative might be to request the review authority refer the matter to an external subject matter expert for opinion 40

41 Elements of a good review request Statement of request Level of review and citation to 21 CFR Matter identification (e.g., K number) Request meeting or telephone conference, or expedited review on review of papers Optional: request panel or outside subject matter expert review Clear and concise explanation of dispute and why the decision should be reversed 41

42 Tip: keep it short and simple! Frame the appeal as narrowly as possible to make reversal easier If the dispute appears to be complex, supervisor is more likely to defer to the original decision Focus on defined errors that would justify reversal Don t present the Iliad and the Odyssey, focus on key procedural history 42

43 Potential review outcomes Refusal to hear Reversal, in whole or in part Affirmance, in whole or in part Return to employee for reconsideration under defined conditions Alternative: mediate settlement between submitter and employee 43

44 A supervisory review is an uphill battle Upper management is presumptively reluctant to overrule primary review team Inherent conflict of interest: they must work with these employees every day Tip: don t cast aspersions or blame a single official just present the facts 44

45 Time to decision is uncertain No time requirements in the regulation Upper management is busy, so appeals tend to languish Not part of the MDUFMA performance requirements Informally, upper management says the target is 3 months We have seen numerous appeals far beyond the target, e.g., 8 or 9 months to decision, or longer FDA does not publish information about appeals No public information about the number of appeals processed, time to decision or outcomes 45

46 Negotiating with FDA is slow Key dynamics FDA holds most of the power FDA personnel are busy and any one matter is not necessarily a priority FDA tends to operate by group decision, so there is not a point person with delegated authority to make real time decisions Result: negotiations are slow and iterative These dynamics can apply on appeal as well 46

47 OTHER OPTIONS 47

48 Legal/Regulatory Issue? May be able to characterize some or all of the dispute in legal /regulatory terms Especially if precedents are being disregarded Could present issue to Office of Chief Counsel for opinion Issue must be ripe and not scientific 48

49 Formal Appeal Procedures Citizen s Petition (21 C.F.R ) Petition for Administrative Reconsideration (21 C.F.R ) 21 CFR Part 12 - Formal Evidentiary Public Hearing 49

50 Formal Appeal Procedures 21 CFR Part 13 - Public Hearing Before A Board of Inquiry 21 CFR Part 14 - Public Hearing Before A Public Advisory Committee 21 CFR Part 16 - Regulatory Hearing Before the Food and Drug Administration 50

51 Formal appeal options offer due process but are not usually commercially viable solutions Take months or years to complete Must have deep pockets ($$$), especially for a panel Hardly ever used 51

52 J&J recently invoked formal appeal for SEDASYS Device intended to broaden categories of clinicians who can administer Propafol PMA not approvable (Feb 2010) Invoked statutory right to administrative review via advisory committee Within weeks of panel, latter cancelled based upon agreement of the parties that J&J believes provides a path to market 52

53 Note the length and complexity Feb 2010: CDRH issues not approvable letter per 21 CFR (f) Mar 2010: J&J treats letter as denial and requests administrative review by filing a petition for administrative reconsideration per 21 CFR , Oct 2010: CDRH issues outright denial of PMA per 21 CFR Nov 2010: CDRH grants petition for review per FDCA, sec. 515(d)(4) & (g)(2) Mar 2011: Commissioner refers matter to Medical Devices Dispute Resolution Panel per 2001 guidance and Medical Device Advisory Committee charter This panel may handle referrals of petitions for advisory committee review under sec. 515(g)(2) Dec 2011: Scheduled meeting of the Advisory Committee settlement occurred shortly before Proceedings of panel would have been be governed by sec. 515(g)(2), Federal Advisory Committee Act (FACA), 21 CFR Part 14 governing advisory committees, and the MDAC charter Decision would have come no earlier than 2012 more than 2 years from the decision under appeal 53

54 GUIDANCE 54

55 Existing guidance MEDICAL DEVICE APPEALS AND COMPLAINTS: Guidance On Dispute Resolution (1998) Table (p. 16) outlines types of dispute and associated available processes Resolving Scientific Disputes Concerning The Regulation Of Medical Devices, A Guide To Use Of The Medical Devices Dispute Resolution Panel; Final Guidance for Industry and FDA (2001) 55

56 Draft guidance Draft Guidance for Industry and FDA Staff, CDRH Appeals Processes (Dec. 27, 2011) Will supersede preceding guidance when finalized 56

57 REFORM PROPOSAL 57

58 Reform Proposal Office of Appeals Office of Appeals for Premarket Submissions In the CDRH Director s Office Reporting to the CDRH Ombudsman With dedicated staff Multidisciplinary scientific / medical expertise, and varied premarket review experience Access to dedicated OCC counsel when needed Operating under a written procedure with established milestones and timelines 58

59 Office of Appeals Advantages Regularizes the appeals process Eliminates conflict of interest Develops an experienced team processing appeals more efficiently and consistently Could develop a database with information about dispute and resolution patterns Creates a single office to hold accountable with metrics for timely and fair appeals 59

60 Thank You! Josephine Torrente Jeffrey Shapiro (202) (202)