Setting the standard (and sticking to it)

I have never envied the job that the drug regulatory agencies do, especially those in the US and Europe that much of the rest of the world take their cues from. They are assailed constantly, both as huge pillows into which new drug ideas sink out of sight for months or years, existing only to slow things down while they carefully apply their fingerprints to every step of the process; and as mere pawns of the mighty drug companies, approving all sorts of useless-but-lucrative and even downright toxic ‘treatments’ with little more than negligent waves of their well-manicured hands. You might be surprised at how many people manage to hold both of these opinions more or less simultaneously, or who alternate between them depending on circumstances. (Or you might not be surprised much at all, depending on your views about human nature!)

Those caricatures show the opposite dangers that are waiting in drug approvals, though. You really can let too many or too few things through, and the consequences either way can be very bad indeed. What I think people ask of such an agency, though, is similar to what they ask of a good judge in the legal system. They want consistency, a sense that every case is being judged by the same standards, and that those standards have been made clear to everyone. Changes in the standards will have to be made from time to time, naturally, but those changes must also happen for clearly stated reasons.

We want consistency, a sense that every case is being judged by the same standards, and that those standards have been made clear

I bring all this up because in recent years I have begun to wonder about the US Food and Drug Administration’s (FDA) commitment to these principles. There have been some questionable calls. For example, the small biotech Sarepta has had two ‘exon-skipping’ gene therapies for Duchenne muscular dystrophy (eteplirsen and golodirsen) approved despite, at the time, having no convincing evidence of efficacy for either one. The anti-amyloid antibody Aduhelm (aducanumab) was approved to treat Alzheimer’s disease, even after the agency’s own statisticians came out against the idea, saying again that efficacy had not been proven. Similarly, Eisai–Biogen’s follow-up antibody Leqembi (lecanemab) has also been approved, with what might be slightly better evidence of efficacy (opinions vary on that), but in both cases with some real questions about potentially deadly side effects in some patients.

The British Medical Journal has now reported that the FDA’s 2019 approval of Recarbrio (a three-drug antibiotic combination) seems to have violated its own standards from any perspective. The agency’s reviewers, it turns out, made a strong case that the drug had been studied in the wrong patient population and in the wrong sort of clinical trial design, one that made it impossible to say if it provided any benefit at all – and which made it disturbingly possible that many patients would actually experience worse outcomes than the current standard treatment. To be sure, in the end the drug was not approved for the sorts of patients studied in the trials: it was instead approved for others who had ‘no alternative treatment options’. But those sorts of patients were never tested at all, which means that there is no evidence that Recarbrio has any efficacy to offer them.

These sorts of decisions might seem excusable when looked at one by one, but they are risking the agency’s reputation as a fair judge

There seems to be no way to square this approval with the FDA’s stated standards, and it joins the above-mentioned cases (and several others) in that category. These sorts of decisions might seem excusable when looked at one by one, but they are risking the agency’s reputation as a fair judge that is able to enforce standards. I’m sure that the companies involved are very happy to have received these approvals, but that happiness will not do them (or anyone else) much good if we no longer are quite sure of what it takes to get a drug to market. We have enough uncertainty in this business already – don’t we?

It’s interesting to note that all of these regulatory calls seem to be driven by hopeful thoughts about efficacy and unmet medical need (although in Recarbrio’s case, as the BMJ notes, that unmet need was already filled by the time the drug came to the agency for approval). While I’m glad that the agency has a big heart, I would rather that it have a functioning cerebral cortex. To steal a line from Ernest Hemingway, ‘Isn’t it pretty to think so?’ is not a good regulatory framework. The FDA needs to explain itself, and it needs to realise that it needs to explain itself. But for now, there’s no sign of anything like that happening.