T

he run-up to Monday’s approval of a Sarepta Therapeutics drug to treat Duchenne muscular dystrophy was marked by unusual bickering inside the Food and Drug Administration, where debate over a key scientific question morphed into a formal dispute, and the head of the drug review division was accused of being too intensely involved in the process for evaluating the medicine.

Ultimately, the decision to greenlight the drug fell to the FDA Commissioner, Dr. Robert Califf. In a 13-page memo last Friday, he deferred to Dr. Janet Woodcock, the controversial head of the drug review division, who pushed hard to approve the Sarepta medication but clashed with other FDA officials along the way.

“The science is not in dispute beyond the usual types of disagreement that occur when experts review clinical evidence from different perspectives,” he wrote. “It is clear that Dr. Woodcock’s decision utilized the flexibility afforded under the relevant statutory provisions, including consideration of the life-threatening decisions of the disease and the lack of alternative treatments.”

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Califf was compelled to chronicle his decision in response to a formal dispute that was filed by Dr. Ellis Unger, who reports to Woodcock, and disagreed with her decision to approve the drug and the way she went about advocating for approval. The Califf memo was one of several internal FDA documents involving the dispute and the fate of the Sarepta drug that were released Monday.

There is frequently disagreement among FDA staff over the extent to which clinical trial data should support the approval of a new medicine. But the intensity of the dispute surrounding the Sarepta drug underscores the stakes that were involved in this episode. Beyond this one drug, the discord among FDA officials illuminated a wider debate about the pressures the agency faces to endorse medicines from an increasingly aggressive patient population.

In his dispute, Unger identified four deviations from the usual typical decision-making process. He claimed Woodcock was involved in the early stages of the review; she had “extensive involvement” in planning and participating in an expert panel meeting last spring; she made an initial decision last May to approve the drug before the FDA review team completed a draft review memo; and she issued a final decision memo before Unger finalized his own memo.

Unger was not alone. In an Aug. 8 memo to Califf, Dr. Luciana Borio, the FDA acting chief scientist who convened the board that reviewed the dispute, wrote that “we fear that those actions could have chilled scientific debate within (the FDA Center for Drug Evaluation and Review) and reduced the level of participation by the review team during the final stages of the decision-making process.”

“Rather than ensuring that the scientific reviews started at the bottom of the chain of command, Dr. Woodcock made clear from her position at the top that she was pushing for a particular outcome from the very early stages,” Borio wrote. And she noted that at least two staffers were leaving or were about to leave in response to the decision-making process “and the pressures exerted by outside forces.”

Indeed, the dispute centered primarily on a disagreement over whether the Sarepta drug, known as eteplirsen, would produce enough of a protein called dystrophin to generate a clinically meaningful benefit. Boys suffering from Duchenne have a mutation and lack the protein. Sarepta argued that a very small clinical trial demonstrated the drug helped enough boys based on various measures, including a six-minute walking test.

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According to the memos, Woodcock acknowledged some issues with trial data submitted by the company to win approval, but she disagreed with Unger and other FDA staff about the extent to which boys treated with the medicine would experience a meaningful clinical benefit.

Their disagreement, however, also reflected a more fundamental debate over the stance the agency should take toward the Sarepta drug. Until now, the FDA had not approved a drug to treat Duchenne, prompting parents and some lawmakers to argue for accelerated approval, a process that relies on surrogate endpoints instead of actual medical benefits to endorse a drug.

This has been a highly charged issue and has transformed the Sarepta drug into a litmus test for agency approval of new medicines, notably for diseases with unmet medical needs. Seen through that prism, Unger maintained that approving the drug would be detrimental to the FDA approval process on a long-term basis.

“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,” he wrote in a July 18 dispute report. “I argue that this would be unethical and counterproductive. There could also be significant and unjustified financial costs — if not to patients, to society.”

He added that approval “would send the signal that political pressure and even intimidation — not science — guide FDA decisions… 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.”

According to Borio, both Unger and the members of the FDA review team told the dispute review board that 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.”

Ultimately, the review board found that “Woodcock’s extensive, early involvement in the review process troubling. Indeed, her involvement here appears to have upended the typical review and decision-making process. Rather than ensuring that the scientific reviews started at the bottom of the chain of command, Woodcock made clear from her position at the top that she was pushing for a particular outcome from the very early stages.”

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  • Most comments seem to be made by people in the heath field. I’m a young guy with DMD, this drug would not help me personally, because of a slightly different genetic make up. I believe that the choice of a drug should be the responsibility of the individual. The FDA can offer their opinion, but ultimately its your call. Look at cigarettes, slap on a warning from Surgeon General, yet still huge industry.

    I think a lot of the friction is the metrics the FDA wants to see and what the reality of the two are far too different. The sample size is very tiny of any of the Satepta studies. I read theres about 15,000 people in US with this condition and less then 20% of the DMD population will Eteplirsen actually help. I hear on the TV that even Talcom powder is showing a health risk that even FDA was unaware of.

    Personally this drug needs to be the starting point for more research and keep progress growning. I wonder for every disease that was pioneered with some sort of drug intervention, the question of both ethic and science has been raised?

    I don’t think we need to raise concern over the narcotic field. highly doubt people be jumping over for an Eteplirsen high.

    • I understand why you feel this way, but actually this call cannot be made by the individual alone when the price tag is $300,000 a year and the drug does not appear to do much. We all pay for increased insurance premiums and higher taxes to cover government health programs when these expensive drugs hit the market. This may be justifiable when the drug truly has a demonstrable benefit (as in Kalydeco for CF). But when society is asked to pay $300,000 a year for life for an ‘elegant placebo’ it is no longer just within the purview of the individual. If the drug does not work or provides negligible benefit, it is not in anyone’s interest to pay exorbitant prices for it. These marketing and pricing strategies by pharma are ultimately going to interfere with rare disease drug development in general because at some point–probably soon and already starting in some quarters–society is going to cry foul. This is not a win for DMD. You deserve therapies that actually provide significant benefit. It is not a win for other rare disorders, either.

      Another issue of concern is that this approval will potentially direct a lot of future research efforts in DMD towards the development of ‘me too’ drugs because it is much easier for pharma to make a knock-off than to find new targets. The FDA has now essentially told pharma it is okay to be sloppy with their research and lazy with their goals as long as patients demand the resulting flawed product and lobby on behalf of pharma to get it approved. This is not helpful for the DMD community. You deserve better than this.

  • As we used to say in the healthcare products industry “now is far better then perfect”
    This drug has demonstrated its safety and atleast minor efficacy it is NOT the FDA’s position to determine HOW effective it is unless/until there is another approved drug to compare it to. The FDA has currently two missions one is to make sure we don’t get another Thalidomide and the second is to make sure that the drug does what it says it will do and it needs to be as good or better then existing drugs. In this case there are NO existing drugs so ANY positive action should be considered a step in the right direction for these suffering boys. If any of the FDA members had DMD kids they would welcome this as a possible option and then the decision to use it would be based on a decision with them and their physician. the FDA has for too long taken the position that it knows more then we do in the field. I take exception with that and am pretty tired of the FDA withholding their approval all the while I have patients who could very well benefit from the drugs locked in trial prison.
    Safety and Efficacy data needs to be taken out of the power grubby hands of the FDA types and placed in the hands of rolling trials that give access to patients in need all the while returning collected data on use and results and side effects rather then strict and locked clinical trials at selected university facilities who are financially structured to return results to support their end with limited regard for the community at large.
    Dr D (30++ years of surgical Oncology)

    • You’re no Doctor. What you are advocating is open clinical trials with no placebo at the cost of $300,000/year/patient, at the cost of the taxpayer.

    • Dr Wen is right and “Dr Dave” is wrong”. The regulatory standard for approval has always been defined as “two adequate and controlled clinical trials showing substantial evidence of efficacy” and more recently the standard of a single large CONTROLLED trial has been acceptable under certain situations. The Sarepta drug was approved on the basis of a trial that was NOT large, NOT controlled, did DID NOT show substantial evidence of efficacy, and by those measures unarguably inadequate. The approval was political pure and simple, something that FDA has never been shy about doing.

  • Dr. Woodcock has to face one audience that none of her minions has to deal with: The US Congress. No doubt, science notwithstanding that Woodcock sensed early on that failure to approve the drug would be a one way ticket to a congressional inquisition. Don’t blame her a bit. She’s been through this before. Nobody gets praised for approving a drug. On the other hand disapproval will get you drawn and quartered by the 435 men and women who have perfected second guessing to an art form.

    • Agreed. Woodcock mostly likely did overreach in this case, but personally I agree with her decision. Eteplirsen might not be effective (the jury is still out on that), but it is safe, and it is Duchenne’s boys only hope. Sarepta still needs to run a better clinical trial, and the drug might still be withdrawn if it that trial is unsuccessful. Asking DMD patients to wait until the perfect trial is completed means that a lot of them would be dead by the time the results come out. Her decision was politically savvy, yes, but also pragmatic and compassionate.

  • As I read this, I kept thinking: “Oh, no. This is the same phenomenon that got us into the most devastating public health disaster of my medical career – the narcotics addiction crisis.” The Chronic Pain patient advocacy groups, desperate for a viable treatment for their clinical problem, intensely ( and successfully) lobbied to “re-educate” Physicians that : Narcotics were safe, that Physicians were inappropriately fearful of prescribing lg. doses of the drugs to pain patients, that Physicians were at best: ignorant and fearful, and at worst: cruel and judgemental, in refusing to prescribe massive doses of these agents to their patients. Now, it is acknowledged that it was a tragic mistake of incalculable proportions – the death and destruction it has wrought will be with us for many decades.
    I have not studied Sarepta or the studies – I hope an urge to push approval of it, based on a wish to be kind-hearted, is not also a mistake. ( If the drug is only unhelpful to the patients, it is less harmful to those patients and their families than if it is found to be overtly harmful to them. But the ethicists I know would argue that harm is viewed from many different perspectives, eg: giving false hope, driving families into bankruptcy who are heartbroken and desperate, and therefore will take any chance, for a treatment, etc.).
    That is why there are oversight Boards – to assess the benefits and the risks of a drug, in coming to a decision to encourage its’ use. That is what went disastrously wrong with Opioids/Narcotics process.
    What have we learned?

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