Say goodbye and good riddance to FDA approvable letters! And nonapprovables too! Welcome to the new feel-good Center for Drug Evaluation and Research (CDER), where no drug will ever be rejected again.
So is it finally a free-for-all for Big Pharma?
Not quite. If anything, given the agencyâ€™s stepped-up policing of safety signals, the drug approval rate is likely to remain in the dumps. All thatâ€™s really changed is the terminology, but since anything would be an improvement over the current malaise down in Rockville, the drug industry should probably be thankful for this small favor.
The details: As of August 11, there will be no more of those â€œmaybe yes, maybe noâ€ indecisions on new drug applications (NDAs) that have became so popular at CDERâ€”and that have earned it only grief from the drug industry and the media. NDAs that donâ€™t make the grade will no longer suffer the ignamy caused by â€œapprovableâ€ and â€œnonapprovableâ€ letters. Now these losers will get a cheerful â€œcomplete responseâ€ letter (and a pat on the back?) explaining whatâ€™s wrong and recommending actions to be taken to make it right.
“These new regulations will help the FDA adopt a more consistent and neutral way of conveying information to a company when we cannot approve a drug application in its present form,” said CDER czarina Janet Woodcock.
The Context: Last year, the number of â€œapprovableâ€ letters jumped by 40 percent, causing the number of actual approvals to plunge to 19, a quarter-century low. Big-market drugs, me-too drugs, second indications, even priority-review oncology drugs were all delayed or ditched, casualties of a sudden, extreme, and harsh change in safety standardsâ€”a change made even harsher by the agencyâ€™s stubborn refusal to acknowledge what was going on.
An argument could certainly be made that better surveillance of side effects and adverse events was long overdue, but FDAâ€™s silence left Big Pharma feeling whip lashed. Megablockbusters-to-be like Novartisâ€™ Galvus and Sanofi-Aventisâ€™ Acomplia that had promised to cushion one drug giant or anotherâ€™s fall off the patent cliff got the cold shoulder, despite having already been approved in Europe and elsewhere. The situation got so bad that top-10 CEOs have, most uncharacteristically, been lining up to voice their frustration and fury.
But it gets worse. FDA looked like it was trying to hide the fact that it was rejecting so many new drugs behind this flurry of approvable letters. In the past, only NDAs with minor problems got the approvable designation; applications lacking adequate liver and heart toxicology, say, or suicidality data would be dubbed nonapprovable. And the agency would have to answer for its approval and rejection rates.
Accountability took flight as the political pressures on FDA have intensified. Yet rather than admit that politics influences its decisions, the agency has stuck, through it all, to its silly the-scientific-standards-are-the-same story; it blames pharmaâ€™s inspid R&D for the NDA drought. (John Jenkins, head of CDERâ€™s Office of New Drugs, did â€˜fess up to Pharm Exec, however. â€œWe at FDA reflect the approval standards we hear from Congress and the public,â€ he told this reporter last year. â€œWe can set the [safety] bar wherever they tell us they want us to.â€ See â€œFDAâ€™s Approvable Problem.â€
To get with the program, the large-caps have reportedly been ridding their pipelines of experimental drugs with too-dicey toxicity profiles. The result of this dysfunctional arrangementâ€”a decrease in investment in innovationâ€”is likely to worsen the very problem everyone involved claims to be trying to solve. Thatâ€™s government working for you!
The Take-Home: According to the FDA press release, all drugs will get either the stamp of approval or the letter, which carries the designation â€œnot yet approved.â€ (The complete docket is here; the Q&A is here.) We asked some experts what this linguistic sleight-of-tongue might mean in practice.
Not much was the consensus; it was an improvement, if anything, because it did away with the confusion and controversy of â€œapprovableâ€ letters.
Daniel Kracov, head of Arnold & Porterâ€™s pharma and medical device practice: â€œAfter a short period of adjustment, I don’t think it will be very meaningfulâ€”everyone will just shift their expectations. But it does make it a bit harder to parse out what are real rejections or delays versus relatively minor issues.â€
Wayne Pines, head of regulatory and healthcare services at APCO Worldwide: “The change in terminology just ends the use of a misnomer [that] implied that the drug may have been closer to approval than it was. But t will not affect the rate at which new drugs are approved, or the scientific standard.â€
Chris Milne, associate director, Tufts Center for the Study of Drug Development: â€œCDER has had this in place for four years already, so it’s â€˜about time.â€™ On the face of things, it seems like it should be an improvement for both FDA and sponsors in terms of process and perception: FDA won’t have to decide whether the deficiencies reach the level of â€˜not approvableâ€™ and sponsors won’t have to deal with the fallout from receiving such a â€˜branding.â€™â€
Milne emphasizes that a â€œcomplete reviewâ€ letter will not be viewed as a de facto rejection. â€œI think it will be used somewhat like the Black Boxâ€”not categorically (as in high-risk vs. low-risk) but prophylactically to indicate areas of concern,â€ he says.
Is this a way for FDA to get off the hook about being seen as rejecting so many NDAs? â€œThis is an outgrowth of discussions and directions initiated as long as 10 years ago,â€ says Milne. â€œBut it may have the effect of blunting the impact of comparing the numbers of such actions from pre-Vioxx to post-Vioxx.â€
Since the content of the â€œcomplete reviewâ€ letters will be confidential, FDA can be trusted to say nothing in public. It will be up to each drugmaker to decide how much to reveal to investors, analysts, and the media. How this plays out on Wall Street remains to be seen, but one thing is certain: Big Pharmaâ€™s self-proclaimed new transparency will be put to the test.