by Deborah Cohen, investigations editorBritish Medical Journal. 2013 347:f6980.
I’ve spent more time than I’d like to admit roaming through the FDA Approvals over the last several years. In spite of being underfunded, I’ve actually been impressed with the quality of the evaluations done by the FDA scientists and the thoroughness of their reports. In my mind, it’s a piece of our government that’s doing its best in a tough circumstance. The place where I’ve been disappointed is not the scientists who evaluate the NDAs [New Drug Applications] and write the reports, it’s in the panel that looks at the reports and makes final approval. There are too many examples where they’ve approved a drug against the recommendations of the FDA scientists on shaky grounds – Zoloft® comes immediately to mind [zoloft: the approval I…, zoloft: the approval II…, zoloft: the approval III…]. The central task of the FDA is safety. Efficacy evaluation is more limited [in spite of what the drug companies would have us believe]. So FDA Approval of an antidepressant says, "this drug has demonstrated antidepressant properties in two short term trials." It says little about clinical relevance or long term usage.
So back to the BMJ interview with an FDA official, a rebel with a cause, Dr. Thomas Marciniak, a veteran investigator at the FDA. He’s less impressed with the FDA process than I am, and has had something of a head-butting career – most recently over Avandia®. Since the interview is there for you to read, I’ll avoid the details. I’ve been trying to think of a way to synopsize what Dr. Marciniak is about, and this is what I came up with. When I started to pore over the FDA reports, I had a preconceived idea of what I might find – sloppiness or maybe even collusion with the pharmaceutical industry. I didn’t find that. I found people being thorough in evaluating the NDAs, checking the findings, questioning confusing parts – in general, doing their jobs as defined. They were neither sloppy nor corrupt. Matter-of-fact, bureaucrats doing what they were supposed to do.
Dr. Marciniak is not such a person. He looks into the clinical trial design, the details of how these studies have been conducted, he worries about missing data and that it’s on the rise. He worries about the long term and thinks the FDA doesn’t do anywhere near enough post-approval investigation. In short, he’s more like you and me – interested in the nuts and bolts and wanting to be thorough in his evaluations. He goes way beyond the extra mile. He wants to know about hidden data. and talks, at times, more like a data transparency activist that a government bureaucrat just doing his job. He steps beyond the FDA’s concrete assignment and wants to look deeply into both the safety and efficacy of a drug, He’s outspoken, or maybe out·speaking, willing to go nose-to-nose with his bosses.
“Drug companies have turned into marketing machines. They’ve kind of lost sight of the fact that they’re actually doing something which involves your health,” Marciniak says. “You’ve got to take away the key components of the trials from drug companies.”
Hear hear! (A comment directed to those who refuse to listen).
FDA History 1-10 (left side, scroll down) –
http://www.doctoryourself.com/
Duane
In the latest New Yorker (December 9), there’s a piece by Ian Parker about sausage-making at the FDA. The candidate for approval is Merck’s potential sleep drug, suvorexant, with a new neurological target, orexin aka hypocretin.
The problems with its competitor, the best-seller Ambien, are extensively reviewed: “….suvorexant ends the dance by turning off the music, whereas a drug like Ambien knocks the dancer senseless.” Difficulty in discontinuing is discussed.
The FDA hero in this piece is neurologist Ronald Farkas, M.D., Ph.D., who terrifies the Merck team with remarks such as “I don’t think we want to raise concerns that suvorexant causes narcolepsy by causing autoimmune death of cells that produce orexins.” (Hmmmm…..good question!!!!???)
How the recommended dosages are negotiated with the FDA will give you the willies. Hint: It isn’t based on science or patient welfare.
Apparently getting a neurologically targeted drug through the FDA used to be a lot easier. Personally, I’m glad FDA regulators like Drs. Farkas and Marciniak have become less inhibited in their discussions with drug companies.
Here’s an article published by Elsevier Business Intelligence (a friend of pharma) about Ronald Farkas and his approach to the suvorexant review http://www.elsevierbi.com/publications/rpm-report/first-take/2013/3/suvorexant
“A predictable risk-benefit framework for FDA drug approval decisions has been a long-term objective of many drug developers. A big step in that direction was adopted as part of the PDUFA V agreement last July. However, FDA’s briefing documents for a review of a Merck insomnia therapy suggest that step may not be heading in quite the way that industry hoped.
….
To Division of Neurology Products’ Ronald Farkas, the new instructions from Center for Drug Evaluation & Research management to reviewers carry the added burden of trying to predict more accurately how a new product may be used and misused in the real world.
In a first draft (PDF) of slides prepared for the May 22 Peripheral & Central Nervous System Drugs Advisory Committee, Farkas cites the new risk-benefit framework in his third slide as a foundation for a scathing review of the Merck application. Citing a paragraph from the prologue to the agency’s February plan for creating a structured benefit-risk assessment program, Farkas declares that the agency must “consider actual, not just ideal use” when reviewing an application.
That’s the foundation for his planned attack on the application, which is centered on the likely behavior of patients while taking the drug – primarily a concern over the potential for “daytime somnolence” and especially impaired driving the next day.
Farkas contends that suvorexant goes beyond making patients “more sleepy” to “much sleepier.” He cites somnolence rates for low-dose suvorexant (15 mg in elders, 20 mg in non-elderly adults) as being 7% with severe somnoloence in a further .2%. For high-dose (30 mg elders; 40 mg non-elderly), Farkas cites figures of 11% somnolence and an added .6% severe somnolence.
Those data, he maintains, suggest “serious risk from drug-impaired driving: falling asleep while driving; driving out of lane; and impaired ability to stay in driving lane.” Farkas noted that the data from clinical trials on driving ability during suvorexant use was generated in a situation where the patients were carefully instructed (“in highly supervised study”) about the operation of heavy machinery.
Looking to the real world use of the drug, Farkas says in shortened Powerpoint syntax: “If instructions about safe driving not effective in highly supervised study, how will drug be safe in actual clinical use?”
….”
How do I suscribe to your blog? I’m really busy and I don’t spend a lot of time weeding through the junk on the internet but your blog came to my attention because you posted an interesting article from the BMJ about the ‘Broken Trial System’ You seem like you have a balanced approach; someone I could follow