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Is the Food and Drug Administration’s approval process broken? At a HUBweek panel hosted by STAT, experts explored that question in light of the FDA’s decision last week to approve a controversial drug for Duchenne muscular dystrophy, a rare disease.

The decision reflected the power of patient lobbying and raised questions about the standards for drug approval, as the FDA’s own medical staffers earlier this year questioned the effectiveness of the drug, which was tested in a small clinical trial. STAT senior writer and Pharmalot columnist Ed Silverman led the panel, calling the Duchenne drug a “litmus test” for the FDA.

The panelists represented all sides of the pharmaceutical world: Diana Zuckerman, president of the National Center for Health Research, a nonpartisan nonprofit; Ira Loss, executive vice president and health care analyst at Washington Analysis, which assesses the impact of FDA decisions on investors; John Crowley, president and CEO of Amicus Therapeutics, who is also the father of two children with Pompe disease, a rare genetic disorder; and Richard Moscicki, deputy center director for science operations at the FDA.


Here are some excerpts of their conversation, edited for clarity.

Let me start off by asking: What do you think needs to be improved in the FDA approval process?

Zuckerman: I am increasingly concerned when the standards and criteria for what’s safe and what’s effective is moving more from the pre-market stage, before approval decisions are made, to the post-market stage. More drugs and devices are being approved on a basis of preliminary data, smaller samples, shorter time frames, and sometimes lacking control groups, as what recently happened with Duchenne muscular dystrophy. When that happens, it has a chilling effect on those who are trying to develop treatments and cures. Why would a company spend all of its energy working to do the best possible research if they can get an approval based on a shorter-term study, less definitive data, as long as they encourage patient groups to advocate and lobby for them?


What about the notion that patients and parents living with the disease are really the only ones who can understand what that’s like, and they should be in a position to assess the benefit and risk?

Zuckerman: I think patient perspectives absolutely should be factored in. And they should be factored in at every level. It’s not just important for patients who are wanting a treatment, it’s also equally important for the patients who get harmed. There are some folks in this room who have been harmed by unsafe medical products. They feel like FDA doesn’t listen to them. It’s really important to listen to patients, both the patients who can talk about the benefits of the drugs, or devices, but also the patients who can talk about the risks and the complications.

John, what do you think? You’ve worked at big and small companies. You run a company that is looking at treatments for [rare] diseases. And you’re a parent of children with a rare disease. What’s your thought on the approval process from a CEO’s perspective, but also from a parent’s perspective?

Crowley: Safety is very important for all of us in industry, and as a parent. But also, we’re battling nature, and we’re battling time. In the rare diseases, sometimes it’s very hard to do placebo control studies technically, or for ethical reasons. I think what we have to think about is we can’t develop all these drugs in a cookie-cutter approach. So it has be individually tailored. And that includes moving away from a paradigm that’s purely safety and efficacy to one where we understand the risks and the benefits. And that’s going to be unique to every disease state.

I absolutely believe it has to be science-driven. You have to reach that threshold of substantial evidence, but, again, I think that’s going to become very custom as we move forward into areas like personalized medicine and smaller and smaller clinical studies.

As a dad of children with a rare disease, the last thing I want is a drug that’s going to make them even sicker or shorten their life any more. But I realize they are sick, and they may have short lives. So as parents we have to balance that. If we take a drug and we’re willing to accept a risk that maybe a general population may not be willing to accept, that is going to employ a measure of flexibility. But ultimately I can assure you that the parents are going to be the first that, if a drug is not working, we’ll be the first to put our hands up and say, look, this doesn’t work.

Going forward, why wouldn’t we be concerned that other companies won’t be emboldened to try and put an application in, and then force the issue? What we saw with this Duchenne episode is that when you have an effective pressure campaign, that can have an effect. And I’m not saying that’s necessarily a bad thing, that introduces a very human element into the discussion, and it can provide additional information.

Crowley: I don’t think so. When I looked at the commissioner’s memorandum, what jumped out at me were his notion’s of flexibility, totality of data, and a patient’s perspective. He was clear that was a one-off. I guarantee you as CEO, the last thing I’m ever going to do is go to my board and hold that up as a model for drug development and say, “Hey, look, we can do this too.” That’s a quick way to make sure that’s my last board meeting.

Zuckerman: I want to get into the specifics of why this particular decision concerned us so much. The scientists all said this drug isn’t proven to work, we don’t know if it works, and therefore it doesn’t meet the legal standards that FDA is supposed to use to make a drug approval decision.

The company said they didn’t have a control group because it would be unethical to have a control group. That is a very frightening statement. If you think that it is not ethical to have a control group to study a drug that you don’t know whether it works or not, then you will never be able to find out if the drug works. You have to have a control group, particularly if you have a small sample like that.

Another big issue is the company announced the same day of the approval that this drug is going to cost $300,000 a year. This is a drug that has to be taken every year for the rest of these boy’s lives. It’s not a cure, it’s management. Now, these patients who have been getting this drug, presumably, for free as part of a clinical trial will somehow have to come up with $300,000 a year to continue to get the drug. I don’t know if insurance companies are going to pay for it, considering that the data show there’s not evidence that it works.

To what extent does an outside group of patient advocates factor into the decision-making process?

Moscicki: I think we have been very interested in the patient perspective. There’s been an increasing movement, both on the patient’s side — patients are empowered today as never before — and I think in general from our side too. I can tell you 20 years ago when I sat across the table and said to an FDA colleague, “You really need  to talk to a patient to understand what they’re trying to tell you.” They said, “No, just the science. Don’t want to be influenced or biased.” Now we’re looking for it, but we understand how carefully this has to be done. We are a science-based organization. We do need science. We will not approve drugs based on acclamation.

  • I enjoyed reading the discussion among the panel. I believe we must be very careful moving forward. Drugs and medical devices need clinical trials. Real trials with a broad spectrum of men and women. The lack of clinic trial on this drug is extremely worrisome. Thank you Diana for the input you took the time to give .

  • This was an excellent panel and event, thank you for this summary. I believe FDA made the right decision on this drug given the circumstances, and the additional information I have learned by following this story, review and approval process, and beneficial impact on young boys with a fatal illness over recent years.

    Please follow up on Diana Zuckerman’s comments and concerns about medical device safety. FDA’s mandate and regulations are much weaker on the device side, where they are supposed to balance benefit and risk to patients, but instead give the benefit of approval to device manufacturers time and again, with the risks, health consequences and costs borne by patients.

    We need a Precision Device framework that recognizes and respects genetic variation in methylation (related to the ability to clear toxins) and other factors. We need prescreening of individual patients for biocompatibility before devices are installed, especially since FDA is stil approving devices made of mercury (dental amalgam), nickel (Essure), polypropylene (mesh), and other materials that are very damaging to those with autoimmune, allergic and/or toxicity reactions to such materials. This is not rocket science.

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