The FDA and Alzheimer’s Disease

In The Failure of Solanezumab –How the FDA Saved Taxpayers Billions, an article in the NEJM, Sacks, Avorn and Kesselheim (SAK) defend the FDA by arguing that its high standards prevented the Alzheimer’s drug, Solanezumab, from being approved and thus saved the taxpayers billions in Medicare payments.

It is, of course, not the job of the FDA to approve or fail to approve a drug based on its effect on taxpayers. The FDA has historically stood independent of this kind of politics and that has been all to the good. But the SAK article is a reminder that under socialized medicine every FDA decision moves money from one patient group to another and between patients and taxpayers thus FDA decisions become a tempting leverage point to control allocation through collective choice.

I do not favor collective, which is to say politicized, choice and find much else objectionable in the SAK article–it attempts, for example, to evaluate a rule by examining a single decision when a system-wide, long-run analysis is called for. Rather than go into detail, however, let’s instead point to a much better article by Vradenburg, Fillit, Morgan, Sabbagh, Aisen, and Mohs, a group of leading physicians and scientists who treat Alzheimer patients and research the disease.

Rather than support or criticize an isolated FDA decision, Vradenburg et al. call for a change to the rule/norm currently used to evaluate Alzheimer’s drugs:

The analysis…recommends that the FDA approve new medicines that demonstrate a proven benefit on at least one therapeutic endpoint – either cognition or function. The current FDA standards require a new drug to show benefits on both proven endpoints, an unnecessarily challenging hurdle the authors say may be inhibiting investment in new Alzheimer’s treatments.

The authors make three excellent points about such a change. First:

…the success rate of drugs tested for Alzheimer’s disease has been extraordinarily low when compared with drugs in other therapeutic areas. Of the 244 compounds that were tested in 413 clinical trials between 2002 and 2012, only one resulted in approval of a new chemical entity, in 2003. No others have been approved since that time; the failure rate in clinical trials conducted over the last decade exceeds 99.6%. This staggeringly high failure rate has adversely impacted investment in Alzheimer’s disease research at precisely the time when new advances are most needed.

The failure rate reflects how difficult the problem is but also policy. Either way, when firms look at the billions of dollars in research and development that haven’t led to a single approved drug they are naturally wary about spending more. Breakthroughs don’t happen randomly, however, they happen after lots of trial and error. To stimulate such trial and error firms need revenues and thus to stimulate more swings at the bat it may be justified to approve drugs with relatively small benefits.

Second, as I have noted previously, the FDA needs to be careful not to commit an error of composition. Three ineffective drugs need not add up to an ineffective treatment.

Many drugs in development for Alzheimer’s disease have complementary mechanisms of action. Even if each of these might, individually, deliver a modest clinical benefit, when used in combination or adjunctively, the benefit could become more substantial. If the FDA were to reject, individually, several safe and well-tolerated therapies with complementary mechanisms of action that each demonstrate a modest clinical benefit, it would unwittingly deprive patients of potentially substantial advances in the quality of treatment over the long run with a combination of therapies.

Third, it is ultimately the patient that matters, especially with regard to Alzheimer’s where so much depends on the patient’s internal experiences, and thus we ought to be careful before rejecting their perspective:

The ultimate perspective on clinical meaningfulness, of course, comes from the patient….Efforts to identify what matters, what matters most and how much change matters to patients should become a priority for the field, focused on all stages of the disease. The requirements of the recently-passed 21st Century Cures Act are instructive in this regard.

Hat tip: Abhay Moghekar


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