Senior FDA officials warned that approving $300,000 Duchenne drug will lower agency standards

In the end, Sarepta did many things wrong when it came to developing a new drug for Duchenne muscular dystrophy. But it got one very important part right. The biotech, with the support of a legion of advocates in the patient community, won over Janet Woodcock to their side early on.

The powerful CDER director pushed for an approval even in the face of a heated debate inside the FDA, as senior officials weighed in in opposition to her stand. The acting chief scientist at the agency, Luciana Borio, argued that an approval would lower the agency’s standards and encourage other developers to pursue the same kind of lobbying campaigns employed at Sarepta. And she accused Sarepta of acting irresponsibly by knowingly pushing “misleading” information about the drug. Ellis Unger, director of the office of drug evaluation, scoffed at the data Sarepta offered, calling the drug a “scientifically elegant placebo.”

But FDA Commissioner Robert Califf refused to overrule Woodcock’s decision to OK eteplirsen, despite sharing some of the major objections raised by officials who opposed putting this drug on the market at Sarepta’s price of $300,000 a year.

Califf’s summary review of the extraordinary showdown over eteplirsen point to problems that would have easily killed practically any other marketing application. But with the center director taking a passionate stand in favor of the drug, the commissioner says he decided that he would defer to Woodcock in view of his lack of technical expertise in the matter and a sufficient record of evidence to warrant its move into the market.

Both Unger and Borio opposed Woodcock’s decision to grant an accelerated approval for eteplirsen, according to the September 16 memo from Califf as well as their own memos. Califf set out to determine if the FDA was significantly lowering the bar for an approval, but ultimately decided that Woodcock was pursuing a well established track record for being willing to take tough, ethical stands inside the agency, rather than buckling to a lobbying campaign.

According to Borio, who says that Woodcock was leaning toward an OK in 2014, an approval of this flawed application may set a dangerous precedent that will encourage desperate patients to mount a furious assault in favor of other drug approvals. Her position, outlined in the memo:

Granting accelerated approval here on the basis of the data submitted could make matters worse for patients with no existing meaningful therapies — both by discouraging others from developing effective therapies for DMD and by encouraging other developers to seek approval for serious conditions before they have invested the time and research necessary to establish whether a product is likely to confer clinical benefit. If we were to approve eteplirsen without substantial evidence of effectiveness, or on the basis of a surrogate endpoint with a trivial treatment effect, we would quickly find ourselves in the position of having to approve a myriad of ineffective treatments for groups of desperate patients.

Unger, who warned that the safety profile of eteplirsen is not yet known and that patients taking the drug could die from treatment, was scathing in his assessment of the therapy.

By allowing the marketing of an ineffective drug, essentially a scientifically elegant placebo, thousands of patients and their families would be given false hope in exchange for hardship and risk. I argue that this would be unethical and counterproductive. There could also be significant and unjustified financial costs – if not to patients, to society.

And the review documents included Woodcock’s extraordinary argument that Sarepta needed an accelerated approval to help its stock price, so it could fund additional work.

She opined that Sarepta in particular “needed to be capitalized.” She noted that the sponsor’s stock went down after the AC meeting and went up after FDA sent the June 3, 2016 letter. Dr. Woodcock cautioned that, if Sarepta did not receive accelerated approval for eteplirsen, it would have insufficient funding to continue to study eteplirsen and the other similar drugs in its pipeline. She stated that, without an approval in cases such as eteplirsen, patients would abandon all hope of approval for these types of products and would “lapse into a position of” self-treatment.

Significant deficiencies in the eteplirsen program, says Califf, include a consensus that “the poor quality of many of the biopsies and the failure of the sponsor to implement a high-quality procedure for assay validation” made it impossible to consider much of the data in the application. They all agreed that the drug produced levels of dystrophin that were “small compared with expectations at the outset of trials in humans.”

Sarepta “touted” a study that used unreliable measures of the assay, leading the company to overstate protein expression in follow-up biopsies. That study was debunked by FDA experts, Califf says, and should be corrected or retracted. Borio was much more critical of Sarepta. Her memo states:

I would be remiss if I did not note that the sponsor has exhibited serious irresponsibility by playing a role in publishing and promoting selective data during the development of this product. Not only was there a misleading published article with respect to the results of Study 201/202147 –which has never been retracted—but Sarepta also issued a press release relying on the misleading article and its findings.

There is a distinct possibility, the FDA feels, that increasing the dose would provide enough dystrophin expression, the key biomarker for this disease, to make it work as hoped. But it’s only been tested in animals, never in humans — at least not yet.

And if Sarepta had done what the FDA was telling the company to do, says Califf, then they would probably already have enough compelling data in hand to make a decision based on the merits of the drug.

Woodcock actually decided in favor of an approval on May 4, after taking an “extensive and early involvement” on the drug, which raised concerns about interference with “the integrity of scientific reviews” at lower levels in the FDA. Woodcock completed her final memorandum before Unger had had a chance to complete his own.

Once she determined her position, Woodcock never budged. Ultimately, that was enough. Whatever else happens, Woodcock was proved right about Sarepta’s stock price. Shares are up 86% in mid-afternoon trading. In a call with analysts Monday afternoon, company officials say they will file for an early approval in Europe before the end of this year.

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