Good message, wrong occasion to send it
“[T]he agency is establishing new rules for approving drugs to treat some conditions for which other therapies exist, and you can bet drug companies are frantically re-examining their current R&D efforts.”
So writes Dr. Scott Gottlieb, a recent short-term Deputy Commissioner of FDA, to open his commentary “Drug Danger” published in yesterday’s WSJ.
As the late, great Sam Kinison playing Prof. Turgeson in “Back to School” once asked: “Well…Is he right?!?”
In short, no, he’s not right. Not at face value. For one thing, nothing happened at the recent Arcoxia advisory committee hearing that shocked anyone who follows the industry or the COX-2 story closely, and it hasn’t left any competent drug companies scrambling to re-examine their R&D efforts. As Dr. Gottlieb I’m sure knows from his own experience at FDA, industry follows FDA policy-making closely, and when change is afoot, you can bet that drug company execs know it and are either adapting to it if they like it or arguing behind the scenes against it if not.
For another thing, FDA isn’t establishing new rules. Hell, FDA hasn’t even made a ruling on Arcoxia yet. And, even when they eventually rule against marketing approval for Arcoxia, as I’m almost sure they will, FDA dooesn’t set rules by precedent. FDA must consider each new drug application separately, on its own merits. Sure, precedence is considered in NDA reviews, but not in the way it’s considered by courts when interpreting the law. In other words, you can’t view the Arcoxia decision in a vacuum, nor can you assume it portends a policy shift.
But Dr. Gottlieb presumably knows all that. He also presumably knows that FDA has always had latitude to determine what represents an appropriate balance of risk and benefit to the proposed population for treatment. The “default condition” provided by law for investigational drugs filed appropriately with the Agency is approval to market. In order to deny marketing approval, FDA must determine that a drug sponsor has failed to provide adequate evidence that a drug can be used safely as intended. And only FDA (via powers it receives from the Secretary of HHS) determines what is adequate evidence. I’m simplifying a bit, but that’s the gist.
The question of interest that Gottlieb raises with his alarmist opening comment is whether FDA testimony given at the Arcoxia commitee hearings reflects a deliberate and pervasive change in attitude among FDA policy-makers that has influenced (allowed?) its scientific reviewers to be more cautious in their calculations of the benefit:risk equation, so cautious, in fact, that they now violate the rule of law, requiring not only that sponsors demonstrate investigational drugs to be safe for use as intended but also measurably better than drugs that have preceded them. Writes Gottlieb: “In voting 20-1 to reject Arcoxia, FDA’s advisers said that for certain ailments, we have enough medicines. This will ultimately deny patients needed choices and it reflects a dangerous way of looking at drug development, safety, and, more importantly, the practice of medicine.”
Again, that says nothing about the FDA. Advisers are free to say whatever they want and FDA has no obligation to heed their advice. But, for sake of argument, let’s say that Dr. Gottlieb had instead used comments from FDA reviewers to make his point–that FDA believes we have enough medicines for certain ailments and is seeking to restrict approval of new medicines based on some calculation of their relative worth. And that would be a bad thing.
Well…Is he right?!?
Yes, I think he is. I’ve argued as much in these pages and elsewhere several times (funny…no one from WSJ asked me to write an editorial). Patients DO need medication choices, many choices, in fact to provide opportunities for any given INDIVIDUAL patient to find a treatment that she can use safely as intended and to provide market competition that constrains cost. But damn if Dr. Gottlieb didn’t pick a bad opportunity to espouse this view; leave out the Arcoxia bit and the WSJ forum becomes a great opportunity to beat back the likes of Marcia Angell and others who would require demonstrations of “superiority” to older drugs before FDA approval of NMEs.
If Arcoxia is rejected by FDA it won’t be because it’s a “me-too” drug that has not been proven superior to older NSAIDs, it will be rejected because it’s a solidly tested follow-on product that really didn’t look so good when used as the sponsor intended in large Phase 3 trials. Arcoxia might benefit some patients much better than most, and it’s likely that if there were a way to select such patients, the expert advisors would have felt much better about giving Arcoxia the thumbs up. But Merck did not provide evidence that doctors or patients could use to predict with confidence which patients likely would benefit or suffer disproportionately from using the drug.
By criticizing the committee’s decision, Dr. Gottlieb implies that individual-response prediction tests are best left to post-hoc subgroup analyses of pivotal studies and post-approval explorations. Sometimes, like when a debilitating condition is poorly served by existing medicines or when an investigational drug provides a clear margin of benefits compared with risks, it is acceptable to allow post-marketing experimentation to determine who benefits and who doesn’t. And, again, each case must be determined individually. The advisory committee in this case determined that the availability of Arcoxia outside of research use was not advisable based on the totality of evidence they had before them. Their decision was not irrational, induced by fear or revenge, and it certainly was not illegal; it’s also not necessarily a harbinger of ultra-conservative decision-making on the rise at FDA, although, admittedly, Dr. Gottlieb’s insider knowledge of FDA has to make one wonder whether he’s on to something. The pendulum of conservatism is always swinging at FDA, so what’s important to the industry is not where it is today but whether it’s stuck in position–at the wrong end.
When Merck submitted the Arcoxia NDA, it knew it was taking a gamble by relying on a demonstration that Arcoxia was no riskier than an older NSAID, diclofenac, as the key determinant of Arcoxia’s benefit:risk balance. Diclofenac itself has been implicated as risky, leading FDA epidemiologist David Graham to call for its removal from the US market. Merck also had an opportunity in its large Phase 3 program to try to identify sub-populations in its trials that could benefit preferentially (or be exposed to less risk) from Arcoxia, such that the benefit:risk balance would be convincingly favorable. Did they try and fail?
The onus should always, appropriately, be on sponsors to provide compelling evidence before marketing that allows prescribers to have confidence that a new drug can be used safely as intended. It’s unnecessary, inappropriate and (I agree with Gottlieb) even dangerous, to allow regulators to create a higher hurdle than this one.
