Last week saw the advisory committee meeting for drisapersen, the last of three new candidate treatments for Duchenne Muscular Dystrophy (DMD) to begin the process for approval in 2015. The outcome is clearly important for patients with DMD and their families. Equally, it is important to the companies who have developed these drugs, and their investors. What may be less obvious is that the outcome could be just as critical for the FDA itself.
The mission of drug regulators is pretty simple (at least in theory): to protect the public from quack medicines that are either unsafe or simply don’t work. In practice, it gets a little more complicated because drugs need to be approved before enough patients have been exposed to be absolutely certain about either safety or efficacy. The regulator, therefore, has to make a call as to whether the available data passes the threshold for approval. In addition, the degree of side-effects that are tolerable vary according to the severity of the disease being treated and the degree of efficacy that is observed. As a result, there are no a priori certainties when it comes to the drug approval process.
But until relatively recently, there was an assumption that the mission of the regulators aligned them with the patients they were created to protect. The battle they were adjudicating lay between companies who would benefit from selling a drug even it didn’t work very well and the patients who would be harmed by ineffective or unsafe medicines.
Today, though, that balance seems to have shifted. And the seismic change has come from “activist” patient groups, who seem more concerned that regulators are denying them access to potential medicines than that companies may be trying to polish up ineffective agents for the purpose of profit. Listing to the DMD advisory committee sessions, one could be forgiven for thinking that the battle lay between patients and the white-knight companies on the one side and the beastly regulator on the other.
Such a position seems all the more ironic, given that it comes at a time when the trust of the wider public in pharmaceutical companies has never been lower. The public at large (except, it seems, those with a serious medical condition and their families) view pharmaceutical companies as capitalist profit machines exploiting the monopolies created by both patents and regulators to charge unjustifiable prices for often marginally effective potions and pills – a position that has more than a grain of truth to it, as DrugBaron has discussed many times previously.
Patients and their families, though, clearly have their priorities skewed in a different direction – again, entirely understandably. For them, faced with an incurable condition, the desire to try anything that might help no matter what the cost (whether in dollars or side-effects) is entirely rational.
And set between these two extreme positions sits the regulators. Pity the poor FDA.
The problem looms largest for the FDA with the three DMD drugs now under consideration (Translama from PTC Therapeutics $PTCT, eteplirsen from Sarepta $SRPT and drisapersen from Biomarin $BMRN) because, unfortunately, they do not work (or, at best, do not work very well).
Across the group, the clinical data presented checks almost every box in the “how not to” manual of clinical development. Patient numbers are understandably small (DMD is a rare disease), but the reliance on poorly-conducted biomarker studies, post-hoc selection of data for analysis and in particular the number and severity of the adverse events suggest that, in normal circumstances, there would be no chance for an approval of any of them. Let’s be clear: both Translama and drisapersen failed to meet the primary endpoint for clinical benefit in Phase 3, and eteplirsen has been put forward for accelerated approval on the basis of a Phase 2 result in just 12 patients.
Industry veterans who have seen FDA refuse approvals on the basis of much larger and higher-quality datasets in a range of indications must be wringing their hands at the chatter, which far from viewing rejection as the nailed-on certainty it should be, views approval as possible – even likely. Widely admired analysts, such as Mark Schoenbaum from ISI Evercore, talk of “40% chances” for approval of drisapersen (which objectively seems to have the least favorable dataset under consideration). Markets rewarded Sarepta with a 43% increase in value following the drisapersen advisory committee this week.
What can underpin such an obvious disconnect between the data and the opinions?
Patient power. The advisory committees heard testimony from patient advocates who speak in glowing terms of the cases where individuals in the trials seemed to benefit, and of the desire of the DMD patient community to see these new treatments approved for us as soon as possible. No matter that the trial data is at best equivocal. No matter that the treatments are accompanied by pretty severe side-effects (the thrombocytopenia and vasculo-thrombotic events seen in the drisapersen studies could plausibly result in fatalities if the drug were used in larger populations). In the face of incurable illness, the agents represent the best hope, and for patients and families – understandably – that is sufficient.
Approving any of these agents, though, would set a dangerous precedent. If so little data, of such poor quality, can be considered sufficient to support even a conditional approval, then the point of having a regulator must be called into question. We would have very nearly returned to the days of the snake oil salesman. Every future supplicant at an FDA meeting, armed with slightly more convincing data, could surely point to such an approval as setting the bar they have to leap over. Before long, we will be awash with approved drugs whose safety and efficacy is scarcely known.
This trend is already ubiquitous. Cancer patients, in particular, are demanding access to drugs in trial under the dubious banner of “compassionate use.” Quite what is compassionate about allowing widespread use of untested medicines is unclear, and it will surely hamper the appropriate development of those same medicines as companies come under pressure to supply drug to unsuitable patients putting unpredictable demands for drug product at early stages of clinical development when drug product supplies are likely limited, but also generating impossible-to-interpret data outside the confines of well-controlled studies. And who will pay for such compassionate use? If it becomes a further cost burden to the companies, smaller ones at least could be driven out of the business of innovation altogether.
Regulators have to stand firm against these pressures – even at the cost of being unpopular. Equally importantly, they must explain the reasons for their decisions clearly, in a language that can be understood by the wider public. In the case of the DMD medicines currently under consideration, that surely means requests for further studies rather than approval, together with a clear statement that an approval at this stage carries too high a risk of false hope for patients and higher medical bills for everyone.
Make no mistake, if the regulator folds under pressure from “activist” patient groups, the unlikely alliance between those patients and the companies will instantly invert. As the then-approved drug(s) are launched at eye-wateringly high prices, as they surely would be, the patients’ ire would turn on the companies and on medical insurers or governments who limit access to these drugs. Their message will be “how can you deny us these effective medicines on the grounds of cost?” The answer – that they really are not effective, or at least no where near effective enough to justify their cost – will be all the harder to sustain once the regulators ducked their mission and approved them anyway.
None of this discussion fails to recognize the challenges involved. Who would chose to be the one to explain to the parents of a seven year old boy with DMD or a terminally-ill cancer patient that the drug candidates they recognize as their last or only hope are not available to them? Emotionally (and indeed politically) it is very hard (we may soon discover, impossible). But rationally, it is essential that someone is strong enough to do so, for the good of the patients themselves.
It may seem sensationalist to suggest that failure by the FDA to meet this challenge is an existential threat to the organization. But the chain reaction that would be set in motion by a decision to approve any of these DMD drug candidates will undermine the central rationale of having a regulator to such an extent that society will be forced to ask questions: is a regulator in its current shape, essentially unchanged since the 1960s, still fit for purpose?
On the other hand, a decision to reject these new medicines will unleash a barrage of criticism from the patient groups, who will leverage the strength of the emotional and political positioning to inflict as much reputational damage on the regulators as they can muster. Such an attack may not undermine the rational mission of the regulator to the same extent as a decision to approve, but it may still be enough to cause a re-examination of how we regulate drug approvals in the future.
As we await the decisions of the FDA on these DMD drug candidates in the coming months, the Sword of Damocles hangs large over their heads. Whatever decision they make, it seems likely that drug regulation will be changed forever. And at times of changes like these, it is more important than ever that society engages with the process and shapes what sort of regulation we want to see in the future – preferably before we (or our families) fall ill and our judgment is forever skewed.
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