On my way back from #ASH24 I’ll go back through the abstract book and check out how many cell therapy oral presentations were given by investigators from China. This is the first meeting I’ve attended since 2019 and the difference is striking. Kudos!

PCA maps are the new PET scan, only with zero clinical relevancy instead of at least some. Much more subjective, too! #ASH24

100% of patients developed grade ≥3 neutropenia. “The safety profile was mild” #ASH24

Seeing those PET scans after CAR-T 5–10 years ago was transformative but it has now become superfluous. Yes, yes, that was a nice anecdote, can I now please see some data? #ASH24

Quote of the week is from Adam Mastroianni:

For example, the National Institutes of Health don’t like funding anything risky, so a good way to get money from them is to show them some “promising” and “preliminary” results from a project that, secretly, you’ve already completed. When they give you a grant, you can publish the rest of the results and go “wow look it all turned out so well!” when actually you’ve been using the money to try other stuff, hopefully generating “promising” and “preliminary” results for the next grant application. Which is to say, a big part of our scientific progress depends on defrauding the government.

The article is mostly about Paul Feyerabend, author of Against Method and self-proclaimed scientific anarchist. Recommended.

Some weekend links, old and new:

• A Case Against the Placebo Effect
• Frank Auerbach and the unexamined life
• The Worst Generation (from the year 2000!)
• Merlin Mann on The Great Discontent (2013!)

Yes, yes, reform the NIH. But while we’re in the finger-pointing mode, why not mention the waste in money and time stemming from the way biotech finance works? Beauty contests, herding around fads, billions of dollars wasted on courting KOLs for treatment that will never be approved. It’s all there…

The same week Alexey Guzey proposed abolishing the NIH, two more essays popped up:

• Distinguishing the real from invented problems with the NIH, from Sasha Gusev, himself an NIH-funded geneticist
• The NIH Needs Reform: Here are 10 Sensible Suggestions from Joseph Marine, a cardiologist

A few things came to mind:

• You can clearly see the difference in backgrounds. Gusev’s essay is an “insider-y”, show-me-what-we’re-doing-wrong approach. Marine’s is outward-looking-in, dealing more with perception of the NIH.
• Marine makes several immediately actionable proposals which are the policy equivalent of politicians kissing babies but since these days any politician seen kissing a baby would be called a creep (or worse) I suspect that even those modest proposals would become divisive.
• Neither states conclusively what the NIH is for. Is its mission to give out grants? Advance biomedical science? Or help people live longer and/or better? I’d say it’s that last one and that everything else is means to that end.
• So if we see the NIH as a grant-giving machine, I guess we could give it a passing grade. The awardees certainly seem happy! But in the last 30 years we saw several massive public health crisis, from the obesity epidemic to the opioid murders to the bungled response to the pandemic so from that standpoint at least there is room for improvement.
• Gusev’s essay does not at all consider the opportunity cost of the current system. He lists length of grant proposals as an “invented problem” and unironically writes (emphasis mine):

The last NIH proposal I submitted was about ~150 pages which might indeed seem daunting. But only ~12 pages of that was dedicated to science and will be the focus of study section reviewers (and I can also assure you that I wish I had more than 12 pages to work with). The remainder was some combination of budgets, resumes for all of the personnel involved, descriptions of the data and resources, and contractual language between the NIH and my institution. Nearly all of it was handled by experienced grants administrators in my department who can put these documents together in a matter of hours.

• You don’t have to be an expert in probability and statistics to see how this “invented problem” leads to a winner-takes-all system, the winner being a handful of investigators in a handful of institutions. This is an incredible systemic risk that can lead to billions of dollars wasted and set back an entire field of study by decades.
• I want to read something from Adam Mastroianni on the topic of NIH reform.

Abolish the NIH is an unnecessarily divisive title but the core idea is interesting: sunset extramural NIH funding over 10–15 years through natural expiration of grants and, in parallel, set up alternative mechanisms which otherwise would have no room to breathe. Worth considering.

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.