From: To: Cc: Subject: Date: Califf, Robert Dickinson, Elizabeth (FDA); Sherman, Rachel Conover, Katie; Kraus, Tom Fwd: memo Wednesday, September 14, 2016 5:56:22 PM Ouch 2 From: Jenkins, John K Date: September 14, 2016 at 5:35:44 PM EDT To: Califf, Robert Cc: Jenkins, John K Subject: RE: memo Rob Thanks for providing an opportunity to review your draft memo regarding the eteplirsen dispute.  I am responding just to you since some of the issues I raise below are sensitive.  I would be happy to speak with you privately to discuss my concerns in greater detail if you would be open to that.  I ask that you remove reference to quoting me from the July 12, 2016, e-mail that “reasonable people can disagree.”  I think as used it is mischaracterized and used out of context.  I strongly disagree with Janet’s decision and do not want my words in a single email to suggest that is not the case. As to footnote 7, I think the review team needs to weigh in, but it was my impression that use of corticosteroids has been interpreted based on data to have changed the course of the disease in DMD.  We currently have a pending NDA for use of a corticosteroid in DMD. You note on page 3 that due to the serious defects in the development program, “it is impossible to use much of the resulting trial evidence in regulatory decision-making, including reasonable extrapolation to clinical care.”  Yet you later support Janet’s conclusion that the sponsor has provided data from “two adequate and well-controlled trials.”  I can find no effort to reconcile these very different statements. On page 4, you state “there is also abundant evidence that Dr. Woodcock heard and read FDACDER0001 all the scientific evidence…”  This implies she took these actions BEFORE reaching a decision on the application, which is clearly not correct given her statement to the review team of her intention to overrule them and approve the drug BEFORE they had completed their reviews.  Keep in mind this occurred after an AC meeting at which the majority of the panel voted against both AA and full approval.  It is also clear that she was prepared to approve the drug over the team’s objections by the original PDUFA goal date and only reluctantly agreed to press the sponsor for additional data on dystrophin production from the ongoing open-label trial.  While I am glad she agreed to go along with that request, convincing her to take what seemed like a very logical action was not easy.  So, I find it hard to reconcile your statements about the process with the actions taken.  Keep in mind that the usual course of action would be for the Office to issue a CR letter and then the sponsor could submit a FDRR that would first come to me and only if I supported the Office would an FDRR go to the Center Director.  In this case that process was bypassed. On page 4 you state that Dr. Woodcock “finds no rational basis for identifying a specific threshold value for dystrophin levels that would be needed to support a determination that a particular level is “reasonably likely” to predict clinical benefit.”  This statement defies any sense of scientific reason (would one molecule of dystrophin be enough) and goes directly to Dr. Unger’s concern that “any” level of protein seems to be enough for Janet to support approval.  You then go on to reference Janet’s regression analyses from her memo suggesting a correlation between dystrophin production and clinical outcomes.  As I have noted to you on several occasions, I find this to be a scientifically invalid analysis that compares the endpoint value for dystrophin to a delta in a clinical endpoint.  This analysis simply shows a correlation between higher levels of dystrophin, without regard to drug effect (there is no delta for dystrophin change that is due to drug), and cannot support the conclusion she reached.  Your citation of this analysis is troubling. You make reference in several places to a “totality of evidence” standard.  That is not the statutory standard for demonstration of effectiveness and FDA has always stated that the statutory standard for demonstration of an effect on a surrogate endpoint for AA is the same as for regular approval (i.e., substantial evidence).  Perhaps you are using “totality of evidence” to support the decision that the data provided on the surrogate are reasonably likely to predict clinical benefit, but there must be substantial evidence of the drug’s effect on the surrogate and the data are very weak to meet that standard. You dismiss the concerns about Janet’s level of involvement in this review and her role at the AC by suggesting this is simply part of her leadership style.  I have worked with Janet for over 20 years and I can say without a doubt that her involvement in this case far exceeds her usual “hands on” approach.  You note that there were 14 Center director briefings related to this case, that is clearly not the “norm” for how CDER operates.  You also suggest that because CDER has been successful under her leadership that suggests that her intense involvement in this case does not raise concern.  I see that as true, true, and unrelated.  The FDACDER0002 question in this case is not whether she has overall been an effective leader of CDER, but whether she acted appropriately and without bias in the current case, something I don’t think you effectively address given the evidence and the seriousness of the allegations and concerns expressed. As to your footnote 23, there are direct statements that Janet made to the team that contradict the statements you reference from your interview with her.  I am happy to discuss these statements with you further.  In addition, Janet has had frequent private conversations with the sponsor and the stakeholder community.  To my knowledge, she has not documented the substance of those conversations to the record, as is required under FDA regulations.  That leaves a gap of knowledge to evaluate the concerns raised by the review team and Dr. Borio. I do not find your statements about how this case does not lower the bar for future drug approvals convincing.  I share the concerns voiced by Drs. Unger and Borio about the potential adverse impact on FDA’s ability to reach science-based conclusions on future applications. . On page 9 it would be nice to see you call explicitly for retraction of the publications that have now been discredited.  . Also on page 9 it is ironic that you attribute to Janet the idea of randomizing early in order to generate good evidence.  That is exactly what the review team planned to require of Sarepta after the results of the 12-patient study became available, but it was Janet that pressed that a new randomized trial not be required.  So, if Janet had followed the normal CDER process in this case the review team would have required placebo-controlled trials, as (b) (4) they did for drisapersen and we would have better data on which to make a decision.   I would note that Janet did not and has not involved herself in the drisapersen (b) (4) (b) (4) ases to the same degree as eteplirsen.  Drisapersen arguably ; they had a positive phase 2 trial and a second trial that leaned favorably on a clinical endpoint.  Janet did not object to the division asking for a large phase (b) (4) 3 trial and did not object to ODE1’s decision to to issue a CR letter based on .  I think it is reasonable to question why she devoted so much attention to (b) (4) eteplirsen and not the other drugs.  One could speculate that she too was misled by the early reports on dystrophin production that were later discredited. . The overall tone of your memo seems to say that you conclude that Janet behaved and conducted herself appropriately in this case.  That is at odds with the experience of the review team and is counter to the team-based, collegial working environment that we hope to create at FDA so we can accomplish our important public health mission.  This validation from your level of her actions and behavior is worrisome. While I understand your desire not to undercut her role as Center Director, her actions have at best created a serous FDACDER0003 appearance of bias among the review team members and that has created distrust and a sense of undue pressure to “come around” to her way of thinking.  Even if you uphold her decision I would think you should counsel her about how her behavior and actions have undermined her credibility among the review staff and should be avoided in future similar cases.  Effective leaders must have the trust and respect of their staff.   As I noted in our call last week, there are frequent disagreements about data and actions in CDER, and that is healthy and encouraged so we can ensure we hear all voices as we make decision, what is not healthy is a situation where the actions of a leader creates the appearance of bias since this undermines the trust necessary for the review team to conclude that the action was fair and move on. I understand this appeal has placed you in a very difficult position.  I also understand that you have made your decision.  I hope, that my comments can help you to structure your decisional memo to avoid similar situations in the future.  As you know, I had planned to retire from FDA last spring.  I have delayed my departure for a variety of reasons, but one of the most important reasons is that Janet has told me she plans to serve as acting in my place as head of OND once I leave.  I am very concerned about the impact of that decision on the future of the new drugs review program and would be happy to discuss those concerns further. John     From: Califf, Robert Sent: Tuesday, September 13, 2016 6:40 PM To: Woodcock, Janet; Jenkins, John K; Unger, Ellis; Borio, Luciana Subject: memo   Dear Colleagues, Today I am providing to you a copy of the penultimate draft of my decisional memorandum. Although I believe the contents are self-explanatory, there are a few points that I wish to emphasize. First, I deeply appreciate the dedication to our shared mission displayed by everyone involved in this process. Second, I am heartened that our processes and policies worked as they should, and that we have resolved a matter of great complexity in an orderly and transparent manner. Third, I believe this appeal highlights a critical point: it is precisely in circumstances where FDACDER0004 the evidentiary basis for our decisions is less strong that judgment and opinion necessarily assume greater prominence. We must redouble our efforts to ensure that our system for evidence generation is as robust as possible. Finally, it is precisely because of the complexity of the subject matter and the subtle regulatory judgment required that I have come to the following major conclusions: All applicable processes and procedures were followed; The appealing parties had ample opportunity to present their views; and The decision to grant accelerated approval was made following consideration of all relevant scientific evidence. I elected to review the scientific basis for this regulatory action to ensure that I fully understood the positions of both parties and to evaluate whether an additional expert panel, as recommended in the Scientific Dispute Process Review Board’s memorandum, would be needed. I have concluded that although I believe that both views are rational and reflect extraordinary dedication to the topic, there is no basis upon which I should overrule Dr. Woodcock’s decision, and that additional external review is not indicated. Furthermore, I have evaluated and am satisfied with the post-marketing requirements that have been developed and understand that the Center for Drug Evaluation and Research will closely monitor the sponsor’s compliance with these requirements. I look forward to continued vigorous discussion and debate as we continue to move this field forward. Thank you for your determination, dedication, and perseverance in serving the patient and healthcare communities. I would request that you maintain this memorandum in confidence and do no further distribute it until such time as my decision has been made available in final form. If you identify any significant factual errors in this document, please advise me by COB Wednesday, September 14.   Robert M. Califf, MD Commissioner, Food and Drugs   FDACDER0005 Eteplirsen-- IND 077429 ; NDA 206488 Date Brief Background/Supplemental Information Meeting Forum July 17, 2013 Discussed the suitability to file NDA for Subpart H approval Center Director Briefing October 18, 2013 Overview and background Center Director Briefing Application Review General Discussion October 28, 2013 Continuation of meeting that occurred on Oct. 18 Center Director Follow Up Briefing December 19, 2013 Follow up to the Nov. 15 meeting to discuss the study design of a clinical trial for eteplirsen (Study 4658-301) Sponsor (Type A Meeting) with Sarepta Therapeutics January 17, 2014 Follow up discussion on GSKIND 105284 Drisapersen data findings Center Director Follow Up Briefing February 6, 2014 Update on DMD drugs study design (drisapersen-eteplirsen) Center Director Briefing March 5, 2014 OND team meeting on biomarker data findings and discussion on inviting Sarepta in for a brainstorming discussion Division Meeting re: IND 77429 eteplirsen/biomarker data March 19, 2014 Sponsor meeting to discuss study design and path forward Refer to background April 2, 2014 Post- Brainstorming Debrief Refer to background July 14, 2014 Sarepta Clinical Site Inspection Report Center Director Briefing FDACDER0006 Date Brief Background/Supplemental Information Meeting Forum December 9, 2015 Discussed the current status of eteplirsen review in advance of the AC meeting that occurred on April 25, 2016 Center Director Briefing January 13, 2016 Reviewed slide presentation for the upcoming AC meeting Center Director Briefing February 10, 2016 Discussed the ongoing review of eteplirsen NDA and reviewed what will be presented at the AC meeting Center Director Briefing April 15, 2016 Statistician subgroup presented CINRG data analysis prior to the April 25 AC meeting Center Director Briefing April 25, 2016 Advisory Committee Meeting May 4, 2016 Discussed outcome and plan of action(s) for eteplirsen application Center Director Briefing May 24, 2016 Meeting to discuss eteplirsen decision One-on-one discussion between Drs. Woodcock & Unger May 31, 2016 Discussed reviews conducted by the review team and senior leadership along with any additional information obtained from the sponsor for the eteplirsen application. Center Director Briefing First draft memo from Dr. Woodcock was discussed at this meeting with the division. Comments were also received back from the division Sarepta dct.docx FDACDER0007 Date Brief Background/Supplemental Information July 6, 2016 Ongoing review of the NDA for eteplirsen (e.g. levels of dystrophin, PMR trials and description of the clinical data in the drug label if approved). Meeting notes transcribed by Dr. Woodcock are attached. Meeting Forum Meeting with the division on eteplirsen Eteplirsen application notes-7-6-16.pdf July 7, 2016 Meeting with Commissioner to discuss regulatory review issues and potential formal appeal Commissioner’s Briefing with Unger, Temple, Jenkins July 11, 2016 Draft version of second decisional memo sent to division via email. Comments were also received back from the division N/A Sarepta dct.docx July 14, 2016 Finalized Center Director Review Decisional Memo (signed and uploaded into DARRTS) N/A July 16, 2016 Finalized Office Director’s Decisional Memo (signed and uploaded into DARRTS) N/A July 18, 2016 Finalized Office Director Unger’s formal appeal submitted under SMG 9010.1 N/A FDACDER0008 Center Director Decisional Memo DRAFT (b) (5) 12 pages have been withheld as b(5) (Deliberative Process/Draft) immediately following this page FDACDER0009 742/0.? ?/Z?ee/?P?vprl bit/710% \Jm?t? wry; avx M?oerb B?pzw?ew Cappftauhw a??miea, 1 51?er Una [Md?rubm ETC: Kant?3?, (4: pt?) GI (m 78 718 \l?eom. ME I32]k 77; NW (sick) ?Jack/cf, Mite/KW?? pray/0'6 Iowa/f d7 Am LfSw. (J m?hjw fol} WCJ 7 didacyr?ced WJLL mu) 0% 7C3 +69? . iJ be?. Mw? 6770/) IWU Mam 72.22. @24' GmMith A 0U a blue di 7:9, cf Uppe?o?J. g/Wa?l? Oxk nNcco?m00