Senator Marco Rubio’s essay criticizing the FDA for failing to approve eteplirsen, an investigational drug for Duchenne muscular dystrophy made by Sarepta Therapeutics, highlights a glaring misunderstanding of the drug approval process. Public appeals like Rubio’s and those made by Duchenne families are perfectly appropriate and make for interesting public theater. But they have essentially zero effect on the FDA’s decision-making cascade.

As a former FDA medical officer and senior medical analyst, as well as a former investigational medicine research scientist at Pfizer, I don’t always agree with the regulatory decisions the FDA makes. However, I do support the time-tested process for approving new drugs.

The FDA’s mission requires that it be sure that the drugs it approves are safe and effective. To do this it needs concrete data from controlled clinical data that prove the drug works better than (or, in some cases, at least as well as) an existing therapy. Emotional appeals from the public or from politicians do nothing to establish the parameters of safety or efficacy.

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I can tell STAT readers a secret about the “public speaking” portion of FDA advisory committee meetings: It is all for show. I can recall my FDA supervisors and colleagues checking their emails, doodling, texting, and the like to avoid listening to individuals who would often travel great distances to pour out their hearts to the advisory committee and FDA reviewers, literally begging them to approve a new drug.

The clinical and regulatory review process is extremely complicated and is — or should be — 100 percent based on the safety and efficacy outcomes that emerged from the clinical trial. Even experienced pharmacologists and physicians need years of experience to fully appreciate the complexity of the process. That’s why drug-approval decisions are best left to the experts.

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Right-to-try” legislation makes sense for people who don’t understand the complexities of the drug development process. As a rare Republican working at the FDA and a generally politically conservative person, I am all for more freedom and less government intervention — but not when it comes to drug approval. The truth is, I am not quite ready to entrust the general public (or, for that matter, a senator with no scientific or clinical background) to circumvent the FDA through “right-to-try” and to make independent recommendations regarding clinical pharmacology, pharmacogenomics, biomarkers, and long-term drug safety.

I understand Senator Rubio’s desire to advocate for drugs for rare diseases. But he ought to leave the complexities of drug evaluation and review to experienced FDA scientists.

It’s easy to see why the public, and even politicians like Senator Rubio, are confused by the FDA’s seemingly likely decision to reject eteplirsen in light of several other highly controversial FDA approvals.

For example, last year the FDA gave the green light to flibanserin (Addyi), a drug to treat low sexual desire in women. Although this is a problem for some women, it does not represent a big public health issue, is not debilitating or fatal, and has significant safety issues. What’s more, flibanserin doesn’t work for the vast majority of women, positively affecting only between 8 and 13 percent of those who take it. In addition, flibanserin has potentially fatal drug-drug interactions with alcohol and the most commonly prescribed antibiotics and antifungals currently on the market. Some prominent national health women’s groups have voiced their opposition to its approval.

In contrast, Duchenne muscular dystrophy affects children and young people, robs them of an active life, and is always fatal. Even if eteplirsen, the new drug for Duchenne, has both safety and efficacy issues, the decision not to approve it, in light of the decision to approve flibanserin, has left many people, including most clinical scientists, scratching their heads in confusion.

The FDA’s impending decision isn’t necessarily a death sentence for eteplirsen or for a similar Duchenne drug made by PTC Therapeutics, which was also rejected. A third competitor, BioMarin Pharmaceutical, has just abandoned all of its most advanced Duchenne projects. Many drugs currently on the market required multiple FDA advisory committee meetings, or weren’t approved on the first or even the second review. In fact, flibanserin was one of those — it took three separate submissions to finally gain FDA approval.

If these companies truly believe that their investigational drugs for Duchenne hold clinical promise, they should stick by their compounds and do whatever FDA-required clinical testing is needed to fully comply with the FDA’s requirements for approval. That’s what the makers of flibanserin did, and they were eventually able to convince advisory committees and the FDA, in spite of what can only be described as very poor efficacy and safety profiles.

My advice to these companies: Stop the public relations campaigns, which do nothing to sway the FDA’s decision making process. My advice to my fellow Republican, Senator Marco Rubio: If you are upset with the way the FDA does business, create new legislation to change how it works. Or maintain the status quo and leave the new drug reviews and approvals to FDA scientists, like the ones who approved flibanserin.

David Gortler, PharmD, has two decades of drug development experience. He has been an investigational medicine research scientist at Pfizer, a medical officer/senior medical analyst with the FDA, and a professor of pharmacology at Yale University School of Medicine and Georgetown University School of Medicine. He is now a drug safety expert and FDA policy expert with the consulting group FormerFDA.com.

  • So, this is an interesting commentary. I note a few things here.
    First, if it is true that the FDA reviewers basically ignore the public testimony, despite statements to the contrary that is a significant problem in the process. It was placed there for a reason, presumably.
    Second, you write as if public testimony is all shmucks talking nonsense. Patient testimony is, sometimes, evidence, especially when your n is small and your patient testimony is all the ns. Or, when actual experts in the field of the drug being reviewed or other people directly affected by the review process speak.

    Third, while I agree that most approval decisions are fairly complex endeavors, you do not mention that the advisory committee itself is typically composed of people who are not capable of making an evaluation. You say that the public speakers are for show. I’ll do you one better and state that the advisory committee meeting is often a carnival of grandstanding.

    Some may have “PhD” in their title, but they are often mired in very narrow thinking about a particular drug, and they always have their own agenda. It is evident that many, if not most, do not read the briefing documents. Many also do not even know FDA policy/rules/guidelines, like the 505b(2) pathway. Since we are presumably talking about Sarepta, some in that particular meeting were apparently confused about what evidence they “are allowed” to consider.

    And finally, the advisory committee structure is done in such a way so that when someone on the advisory committee blurts out something that is clearly incorrect although roughly based on FDA slides, it can be taken as fact by others and re-stated over and over, to create a consensus based on incorrect assumptions. Typically the company cannot challenge that in any subsequent statements during the meeting because of the structure of the meeting,… and then the FDA records these advisory committee opinions and uses them to reinforce their opinions of whatever (sometimes slight) issues they may have had with the data. Thus you have a situation where some potential deficiencies in the sponsor’s data get blown up to an artificial significance.

  • This is a terribly misinformed article. It highlights the problem, which is the FDA’s unwillingness to follow current law. The arrogant “we know best” and the law be damned attitude, and failure to adhere to FDASIA flexibilities, including consideration of surrogate and less than perfectly scientific clinical data, in order to avoid type 2 errors. The FDA questions at ACOM are contrary to the law of FDASIA, period, as one or more questions sought yes or no vote recommendations based SOLELY on the clinical studies, which explicitly excludes (contrary to existing law) consideration of the exact evidence that FDASIA mandates be considered. Ironic that the author tells Rubio to change the law if he wants to change the process. Wake up. The law was changed to change the process but the FDA refuses to abide. Moreover, FDASIA is not catering to mass hysteria from self interest groups, rather it simply mandates flexibility of surrogate evidence to meet the same existing FDA standards that have existed for years. Again, the FDA refuses to abide. You think the FDA is above the law, above the legislature, and you disagree with the notion that with the danger of type 2 mistakes, all data should be analyzed more broadly and flexibly, the very purpose of the flexibility set forth in FDASIA. The authors arrogance comes through quite clearly. We at the FDA know best, this is complicated, we have been doing this for years, and want to continue to do it the same way forever. I consider that view to be one of an antiquated dinosaur. The fact is that the ETEP saga is a poster child for the application to receive AA. We all get it that the FDA fears the precedential effect. It is a valid concern. Do your friggin jobs and distinguish this case form all others. It can easily be done. Geez our whole common law system of government in this country is based on decisions by courts, tribunals, and agencies making determinations. Nothing has to serve as any more of a precedent than it should or that the decision-maker wants, as long as the facts and uniqueness of the situation are appropriately emphasized to distinguish this case from past and future ones.

  • The author’s comparison of flibanserin to eteplirsen clearly demonstrates his arrogance and utter disregard for patient welfare. He states that if Sarepta believes their treatment works, they should simply continue down the same incredibly slow path that we require for acne treatments or patients with low sexual desire. Make no mistake, he is advocating that we let kids die while he gets comfortable with the data. As a number of commenters have already noted, he ignores distinctions made for serious conditions with unmet needs in FDASIA already on the books. Somehow it is an “abandonment of science” to grant conditional approval and then later find out a drug is ineffective, but it is simply following “best practices” to allow patients to die for the next five years until we get more “conclusive” evidence.

    If you want to see where the impetus behind right to try is coming from, look no further than this article. I truly believe if the FDA actually followed the letter and spirit of the law, this would not be an issue. Instead, you have bureaucrats with some misguided notion of “science” and “uncertainty” that see no problem allowing patients to die while we conduct trials in the same fashion that we have done for the past 50 years.

  • Why did the FDA change the questions to purposely make it harder than former drugs? If the ques were similiar to previous drugs, they would have been ok’d. Members in there who said they feel the drug works voted it down due to ques wording. Drug is perfectly safe and extends lives. NO reason for rejection.

  • My wife’s life was saved by Kadcyla – the Biggest Blunder by the FDA so far in the 21st century , and not the only one. Check out ” Lorraine’s Story ” on the RTT website. We patients who work for compassionate use reform already knew that the FDA public hearings were a sham . Right To Try is not a pharma ” PR campaign ” . It is a Pt. Rights Movement . RTT is not directly about the 7 – 10 yrs long 20th Centiury FDA drug approval process , but it is fueled by that Slowness and Arrogance . RTT is about individual pt. access to Phase II, III 21st Century drugs . Because the FDA System is so slow . That is why patients, not pharma, protested over the denial of acc. approval to Kadcyla in 2010, the revoking of aproval for Avastin to treat bc in 2011, the denial of acc. appr. for Iclusig, Lemtrada , and the current Pt. support for Duchennes and SMA drugs. The FDA reviewers who stare into computer screens , parsing the data , need to step back and look at the Real Big Picture – your 20th Century 10 year process is making huge mistakes every year since 2009 , with new drugs , derivatives of already established science – antibodies, inhibitors, immuno therapies.. Costing Lives . We Pt. Rights Activists appreciate Sen. Rubio’s questioning of the ” System ” . Support us at the RTT Rally in DC June 16th .

  • Newsflash: Rubio and the rest of Congress already DID change the laws for rare disease drug approval. The FDA is the one who is refusing to follow FDASIA, which is why Congress is paying such close attention. If you want things to go back to the way they were, perhaps you should contact your Congressman and ask them to rewrite FDASIA. Your article completely ignores FDASIA, and the fact that Eteplirsen is a drug intended for a rare disease with a 100% unmet need. My advice to you: Do better research before publishing a biased article that ignores existing laws in order to further your agenda.

  • I too am a pharmaceutical scientist and I must say, your poor attitude is typical of government. Have you even heard of FDASIA? That requires by LAW for FDA to exercise flexibility in taking into account patient experience. It is illegal for FDA to ignore it. Accelerated approval does not require proof of efficacy in a clinical endpoint. It can be a bio marker that is reasonably likely to predict a clinical benefit. Like dystrophin. Get with the program.

  • Respected authors should remember that FDA Type 1 error is better than type 2 error!

    • Your point is simply not true. Type II errors adversely affect every patient denied the efficacious drug for the full term of the delay in approving it. The numbers of patients adversely affected can number in the hundreds of thousands, as has frequently occurred with many cancer drugs delayed for years over statistical minutiae by FDA. The effect of FDA’s common Type II errors has been lethal for millions of patients who were denied access to life extending medicines, ran out of time and died prematurely as a driect result of the error. The effect of Type II errors is even more damaging in the case of rare diseases, where merely increasing the cost and risk of trying to develop a drug for a disease in which cost recovery after approval may be impossible due to the small size of the affected population, causing our system to struggle to fill the drug development pipeline for rare diseases, and forcing companies trying to developing them to abandon them, or even just close their doors. FDA makes many more Type II errors than Type I errors. making them is built into the agency’s culture and processes, and taking a position on the side of continuing to make them is just not acceptable. A lethal error is a lethal error, and FDA needs to stop making them as a matter of course. That is what Congress tried to change with FDASIA, and will more forcefully address if FDA makes a Type II error with eteplirsen.

    • Steven Walker, that’s what he said too. Type 1 error is much worse than a type 2 error, especially for a drug with a clean safety profile. So I think you guys agree.

  • FDA regulations for other products do not specifically require the sponsor to review IRB approved consent documents. However, most sponsors do conduct such reviews to assure the wording is acceptable to the sponsor.

  • This article and the opinions of its author are precisely why Congress directed FDA to incorporate the perspectives of the patient communities affected by its decisions into its drug development and approval decisions, and why Congress also directed FDA to apply its Accelerated Approval authority more broadly and with more flexibility, in a recently enacted law called FDASIA. This author’s description of the disdain FDA staff have for the patients they are supposed to be serving, and his apparent support for it, clearly indicates that Mr. Gortler is part of the problem. Not surprising considering his background as a former FDer. He seems to be ignorant of all the facts surrounding this drug, the disease, the evidence supporting its approval, and the broad support for that approval in both the patient and the expert medical community – specifically the physicians who routinely study and treat Duchenne Muscular Dystrophy, recognized as the leading experts in the field, who openly supported and urged approval of eteplirsen both in writing and during the public hearing portion of the advisory committee hearing. The author, by arrogantly defending a broken process at FDA, amplifies an already compelling argument for fundamentally reforming the FDA and our drug development and approval process. If FDA doesn’t approve eteplirsen it will send a clear signal that the agency is continuing its staunch refusal to modernize, despite the clear direction from Congress that it do so. As a result, FDA will face even more prescriptive direction from Congress, with an increased likelihood that the agency’s power will also be reduced so its failure to act as directed by Congress will be less lethal to the public. The agency has already lost the confidence and respect of the affected patient communities it so callously ignores, and support in Congress for the FDA’s preferred state of endless regulatory stagnation has eroded significantly over the last half-decade. In your comments regarding Right to Try, you also make the classic mistake of assuming that supporters of those laws don’t understand the complexity of FDA’s process, but it is because they do understand that complexity, and the deep, institutionalized dysfunction built in to it over the last half-century, that they support Right to Try laws. The arrogance exhibited in article is typical of a former FDER, but most current and former FDAers know better than to publish an explanation of it. Thanks for explaining so clearly what the FDA thinks of patients fighting serious and terminal diseases. If there are any left who still think FDA is on their side, you just converted them to the truth. If your goal was to somehow defend the FDA should it choose to deny approval to eteplirsen, I think you have done the opposite; therefore, I encourage you to continue. Those of us working to fix the FDA could use someone like you bent on aggressively trying to explain and defend the very FDA failings that are convincing so many that fundamental reform is sorely needed. Steven Walker, Co-Founder,
    Abigail Alliance for Better Access to Developmental Drugs, http://www.abigail-alliance.org

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