I recently spoke at an event dedicated to “making clinical trials faster” in the US. Mine was the first talk of the day, so I wanted to set up a framework of thinking about clinical trials that would be useful for further discussion. The attempt was a resounding failure at the level of the talks that followed — more on the specifics of that below — but I still think it’s a good framework so I’ll turn my 5-minute talk into a few paragraphs here in the hopes that more people start looking at the problem from that perspective.
The problem with “making clinical trials faster” is that clinical trials are two very different things with very different purposes to the point that we should probably use a different phrase for one of them. And you can optimize for one or the other, but not both. I am a fan of the mental technique where you figure out the edges of a jigsaw puzzle first — identify the rare extremes — in order to find the more generalizable truth that is somewhere on the spectrum. Here we have the opposite problem: we live in and try to optimize for the middling hodgepodge whereas the two extremes would have been preferable.
These are the two extremes:
- Set 1: Clinical trials that get new drugs and medical devices onto the market, or find new indications for existing drugs.
- Set 2: clinical trials that help guide clinical care and answer practical questions about drugs and devices that are already in use
Set 1 trials are Phase 1, 2 and 3 trials regulated by the FDA with 20-page informed consent forms, lengthy approval processes, strict safety and data monitoring procedures, and costs up the wazoo. The costs are OK since they lead to “value creation” for the economy, of course, but they also contribute to rising cost of health care. And they are especially OK in cases where they are covered by the Sponsor, either a multi-billion-dollar “big pharma” conglomerate or a well-funded biotech. The pembrolizumab KEYNOTE trials are a typical examples but there are too many to count. KEYNOTE-001 in particular is a good example of “speeding up” these types of trials (it was a phase 1 study that lead to accelerated approvals for two indications).
Set 2 trials are “pragmatic” Phase 3 trials that are IND-exempt are they use drugs in their approved indications and should have short, 1-page consent forms, minimal regulatory oversight, and trial procedures integrated into the standard of care to the level that most if not all costs should be covered by medical insurance. And medical insurance companies should be particularly interested in these trials, as they help optimize care and remove ineffective drugs and devices from the market, if not literally then at least by the virtue of physicians not using them any more. As such they are “value-destructive”: imagine a potentially billion-dollar blockbuster drug being found to be no better than a $2-per-dose generic. The RECOVERY trial is the best example of this kind of a trial, leading to quick establishment of standard of care in severe Covid-19. RECOVERY was wholly done in the United Kingdom, and examples of Set 2 trials in the US of A are few and far between.
The outcome of making Set 1 trials faster is more new drugs and devices on the market, including the hypothetical miracle cures that the burdensome FDA approval process is keeping away from patients, leading to large invisible graveyards (for that hypothesis, consider me a skeptic). The outcome of making Set 2 trials faster is fewer ineffective drugs and devices in use. They are the yin and the yang of drug development, creating harmony when they are in sync: new drugs come in, bad ones go out. But at the same time they are diametrically opposed, so it should be no wonder that the tradeoffs required to make one or the other set faster are different.
Of course, clinical trial infrastructure in the US is wholly dedicated to Set 1 trials. This is what the FDA was set up to do, what IRBs are primed for, what the entire ecosystem knows how to do, from clinical research coordinators doing the administrative work at the trial site, to the pharmacovigilance staff monitoring safety, to the administrative and budget offices of universities managing the contracts. But the two sets share the same ecosystem, and all the money being pumped into it by Set 1 makes Set 2 trials nearly impossible: who wants to pay that kind of money for something that could potentially destroy the value of a drug?
And this is my fear for the “make clinical trials faster” project: it will have cheerleaders from both the Set 1 and Set 2 crowd. But there is only one set of tradeoffs to be made, and if I had to bet I would bet that the Set 1 tradeoffs will win if for nothing else then for the major lobbying potential of the pharmaceutical industry. The system is already out of balance, and it wouldn’t take much to tip it completely into disaster territory where so many new but marginally effective drugs overflow clinical practice and it becomes a competition for the best door-to-door salespeople to persuade doctors that their marginal drug is (marginally) better than the other guy’s marginal drug. And if you want to compare the two drugs head-to-head in a Set 2 trial, well, you are out of luck because the regulatory energy of activation and the cost of paying for a trial database and the research coordinator and the data manager is so high that you can’t even… But of course, this is not a hypothetical disaster scenario, this is just modern medicine.
So I gave my 5-minute talk and what followed was a near-perfect encapsulation of Set 1 and Set 2 people talking over each other’s heads. On one hand we should make informed consent forms shorter (Set 2). On the other, let’s use “real-world evidence” to find new indications for drugs and speed up their approval (Set 1). Let’s ease up the monitoring requirements for trials (Set 2). But also do human challenge trials (Set 1). And so on, and so forth.
My gut instinct is to optimize the system for Set 2 trials and to untangle the FDA’s relationship for them. As much as some would like to shoehorn additional responsibility to an already overburdened federal agency, FDA has no place regulating clinical practice. Now, there is another set of federal institutions that have National Health in their name that could maybe lead the way for pragmatic trials, but they too mostly fund small Phase 1–2 studies of marginal drugs whose only distinction is that they came from an academic lab rather than the pharmaceutical industry (and this is because, of course, Phase 3 trials are too expensive to run on a federal budget).
But let’s leave that discussion for a different time.