Woodcock Wanted Drug Approved Before Review Completed: FDA Records
CDER director Janet Woodcock had made up her mind to approve (see earlier story) Sarepta’s controversial Duchenne drug Exondys 51 (eteplirsen) well before the Center review team had completed its review — in fact, she had written an approval memo before reviewers even submitted their review memo and summary. This and other disturbing actions are detailed in a review summary that illustrates her unprecedented involvement and interference in the NDA review, actions that senior agency officials suggested was driven by her succumbing to Congressional, patient, company and other outside pressures to get the drug approved. Pressure from Woodcock and other outsiders was so bad that at least two members of the review team were leaving FDA or had left the agency, the summary indicates.
When CDER Office of Drug Evaluation 1 director Ellis Unger questioned her involvement in the submission and appealed her decision to override his review team’s opinion that the NDA data did not meet the standard for accelerated approval, Woodcock became defensive and critical of the review team’s expertise. During the appeal, Woodcock told the internal Scientific Dispute Process Review (SDR) Board that the review team did a poor job framing the issues during their advisory committee presentations and that the panel questions were confusing and poorly worded. During her interview with the SDR Board, Woodcock opined that the review team “did not put its best foot forward.” She criticized the review team’s presentation of the IHC data, contending that its failure to highlight the clinical data made the questions on conventional approval and accelerated approval difficult for the committee members to understand.
Unger noted that, to his knowledge, this could be the first time a Center director has overruled a review team (and an advisory committee) on a question of whether effectiveness has been demonstrated. On the suggestion of Office of New Drugs director John Jenkins, Unger urged that FDA commissioner Robert Califf evaluate the appeal too. Califf adjudicated the internal staff challenge in Woodcock’s favor (see story).
In his appeal, Unger said allowing eteplirsen’s accelerated approval would “lower the evidentiary standard for effectiveness to an unprecedented nadir. The amount of dystrophin produced in Study 301 is so meager that it could be considered to be tantamount to any increase in dystrophin. In other words, if a statistically significant change of 0.3% – a mere 3 parts out of a thousand – is considered adequate to support accelerated approval here, then the question arises as to whether there would be any statistically significant change that would be too small to be considered ‘reasonably likely’ to support accelerated approval... If we were to adopt the concept that, for rare diseases, accelerated approval could be supported by any statistically significant change in an appropriate surrogate, or a response in a single patient, we would enable accelerated approval of a myriad of drugs for rare diseases. No doubt there are some who would applaud this as an advance. But a standard this low would undercut FDA’s ability to ensure that drugs that are approved are effective; it would call into question much of what we do. Lowering the bar to this level would be tantamount to rolling back the 1962 Kefauver-Harris Drug Amendments to the Federal Food, Drug and Cosmetic (FD&C) Act, which have served Americans well for some 54 years.
“With accelerated approval of this NDA,” Unger continued, “there would be highly detrimental effects on drug development. Traditional drug development for rare diseases might be replaced by a system where small, baseline-controlled, proof-of-concept studies designed to show any change in a surrogate marker would provide a basis for accelerated approval, assuming that the pathogenesis of the disease was well understood and that the surrogate was directly on the causal path. There would be little reason to pursue adequately controlled clinical trials to support efficacy prior to accelerated approval; in fact, the possibility of failure would provide a disincentive to conduct such trials. For example, a gene therapy designed to produce a missing clotting factor could receive accelerated approval on the basis of a tiny yet inconsequential change in levels of the factor, or a more robust response in a single patient. In short, the precedent set here could lead to the approval of drugs for rare diseases without substantial evidence of effectiveness.”
A review team member (RTM) told the SDR Board that, in his or her view, the review team was never sure whether they were discussing science, policies, or politics. “According to both Dr. Unger and the RTM, Dr. Woodcock frequently conveyed that she thought the review team was being unreasonable and encouraged [the review division] to find a way to approve the eteplirsen NDA,” the summary says. “Both Dr. Unger and the RTM told the SDR Board that Dr. Woodcock seemed focused on the external pressures, from both patient advocacy groups and Congress, and that she frequently talked about the effects of a decision regarding eteplirsen in terms of overarching policy (e.g., the need to be more flexible for ultra-rare diseases).
“Based on my years of experience in Office of Drug Evaluation 1, the Center director’s direct involvement with this drug, compared to other development programs, has been unprecedented,” Unger told the board. He said he found it “unfortunate that the Center director made clear her intent to approve the drug at a briefing with the review team on May 4, 2016, before she had seen drafts of the Division’s final review memorandum or my review memorandum. Prior to reading our reviews, Dr. Woodcock stated that she had already ‘...reached a different conclusion...’ than the review team.”