Bioregnum, Drug Development

Now that Sarepta has bolted out of the barn, the FDA wants to shut the door

John Jenkins, Director, Office of New Drugs

John Jenkins, Director, Office of New Drugs

Now that the FDA has capped Sarepta’s long and controversial campaign to win an approval for its Duchenne muscular dystrophy drug with an accelerated approval, FDA officials would like to send a very clear message to any other biotech looking to slug their way forward using the same tactics: Forget about it.

In a presentation at a summit meeting of the National Organization of Rare Diseases on Tuesday, John Jenkins, director of the office of new drugs at the Center for Drug Evaluation and Research, singled out the eteplirsen case as a new textbook example of what other companies should avoid.

“Path taken by Sarepta NOT a good model for other development programs,” declared one of Jenkins’ talking points under a final section marked “lessons learned” from eteplirsen and other cases.

What followed was a litany of sins that FDA insiders have laid at the door of Sarepta, which gained the FDA’s stamp of approval to sell Exondys 51 for $300,000 a year, despite the heated objections raised by senior officials over the lack of safety and efficacy data laced with barb objections over what was presented. In the end, Sarepta was able to gain an approval after patient advocates and influential players in Washington DC demanded it, with little more than data from a tiny study that was repeatedly challenged by reviewers but endorsed by Janet Woodcock and permitted by Commissioner Robert Califf.

Jenkins had quite a few points to make, and they reflected the laundry list of issues that the agency had spotlighted to criticize Sarepta repeatedly over the course of its review and a defense of its position in light of the biotech’s challenge, plus a few new ones. The FDA, he said, wanted to make clear that badly planned programs could only delay a review and OK; assays, particularly ones that rely on invasive procedures with children, need to be well validated; studies need to be carefully blinded and randomized; evidence of an impact on biomarkers has to be carefully evaluated, excluding ‘any’ effect that might register, reviewers should not be subjected to attacks, and so on.

Since Sarepta won an approval for eteplirsen, there have been some serious concerns that the FDA has lowered its standards to the point that more companies were likely to follow suit, waging a lobbying campaign to back inadequate trial results. NYU bioethicist Art Caplan told Endpoints recently that more developers are bound to use Sarepta as a role model, noting that the industry and regulators need to come up with a new set of rules that could make some sense when it comes to more such pitches on the rare disease front.

Jenkins, though, wants to hold the line with a more traditional approach, leaving Sarepta as the exception that could help prove the rule.

Here’s the full manifesto:

• A poorly planned and executed development program for a rare disease misuses valuable patient resources and serves to delay obtaining the knowledge required to understand the benefits and risks of a drug to support regulatory review and approval

• FDA provides valuable advice and guidance to sponsors, we cannot require sponsors to follow our advice

Path taken by Sarepta NOT a good model for other development programs

• Assays for biomarkers should be well validated before use to avoid obtaining misleading information and wasting clinical specimens

• Particularly true when invasive procedure required to collect tissue in children

• Rigorous blinding and control procedures should be in place to minimize bias in assay interpretation

• Protocol should specify blinding procedures, adjudication methods, independence of readers, etc.

• In many cases, randomized controlled clinical trials represent the fastest way to determine if a drug is effective

• Randomize as early as possible in development to avoid potentially misleading and uninterpretable findings from open-label trials

• Employ methods to limit time on placebo (e.g., dose-response, delayed start, randomized withdrawal, interim analysis)

• Report early trial results accurately, post hoc analyses of failed trials are generally hypothesis generating for next trial, not evidence to support approval

• Knowledge of natural history of disease critical to intelligent design of clinical trials

• Conduct natural history trials before clinical trials begin

• If a natural history external control group is proposed, it should be identified prospectively to ensure comparability to treatment group

• Natural history external control group created post hoc is very difficult to interpret, unless effect of test drug is very large, due to known and unknown confounding

• Use of accelerated approval pathway should be prospectively planned, NOT as a “rescue” for a failed program

• Sponsor and FDA should agree on the surrogate and drug effect considered “reasonably likely” to predict clinical benefit before unblinding data

• “Any” effect of a drug on a biomarker is not a basis for AA

• Ideally, the confirmatory trial to further define clinical benefit should be started before AA is granted to ensure the trial will be completed in a timely manner

• FDA welcomes the engagement of patients and caregivers in helping to design development programs that will result in drugs that provide meaningful clinical benefit to those with disease

• Approval decisions must be based on data from adequate and well-controlled clinical trials, which may include PROs and other patient-derived measures

• Experience of patients enrolled in trials can be very helpful; discordant results between trial data and patient anecdotes are very hard to reconcile

• FDA reviewers are committed to facilitating development of effective and safe drugs for rare diseases

• Upholding statutory standards for approval in face of hopes and desires of patients, families, sponsors, and investors is a very difficult job

• Personal attacks on FDA reviewers creates an atmosphere of distrust and isolation rather than collaboration

• Recruitment and retention of qualified review staff is very challenging in such an environment

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