Finished reading: Fundamentals of Clinical Trials by Lawrence M. Friedman 📚

It is assigned reading for a course I’m helping prepare, so I thought I’d better read the book we’ll ask our students to use. Like many textbooks, it suffers from MANE — many authors no editors — and like many academic texts, it can get way too pedantic. Still, it is hard to argue with its overarching themes: that randomized controlled trials are the pinnacle of medical evidence generation, and that much of the trial paperwork done in the name of quality is unnecessary. I have more comments on that last point, but that is for another time.

I don’t see patients with leukemia any more, but if I did, and was willing to “provide information to [Name Redacted] as it relates to my practice patterns and actively engage in the scientific exchange”, someone is willing to pay me a $1000 “fee” along with providing air travel and a one-night stay at a 4-star Florida hotel. Importantly, that someone states:

As this meeting is not commercially supported, there is no Sunshine Act reporting required.

What this means, as Bing AI will helpfully clarify for those who don’t know, is that:

…the meeting is not funded by any manufacturers of drugs, devices, biologics or medical supplies, and therefore there is no need to report any payments or transfers of value from the manufacturers to the physicians or teaching hospitals who attend the meeting. The Sunshine Act is a federal law that requires such reporting to increase transparency around the financial relationships between physicians, teaching hospitals and manufacturers.

So the clarify further using my non-artificial intelligence: US physicians are required to report payments from drug, device, etc. manufacturers and these reports are available to public. Shell companies insert themselves between said manufacturers and physicians so that they could wine and dine them in the name of “scientific exchange”. Money involved is completely off the books.

And so the letter of the law is followed while the spirit withers away…

The allure to report anything as a medical breakthrough is strong. So strong that even the Financial Times can’t avoid it:

New diagnostic technology that uses fibre optics to find the causes of heart disease has begun ⊕ Emphasis mine. clinical testing at London’s St Bartholomew’s Hospital.

The iKOr device, developed at Barts Health and University College London, measures blood flow around the heart. Researchers say it could eventually help many thousands of patients suffering from cardiovascular symptoms such as chest pains, whose cause cannot be identified with current techniques.

“This new device is a game-changer in how we manage heart disease, making it a lot easier to assess the health of a person’s heart,” said Anthony Mathur, clinical director for interventional cardiology at Barts.

Three patients have undergone testing to date, out of 10 planned in the first phase. Another 100 may, subject to regulatory approval, before the device could potentially become commercially available, if it’s demonstrated to work. There is, it goes without saying, no clinical data published to date.

How does this change the game, exactly, when we don’t yet know if it works? The use of undeserved superlatives in cancer drug reporting is well documented so it’s not a surprise to see cardiology, that other lucrative medical subspecialty, being much the same.

What is a surprise is seeing the usually reliable FT falling down to the level of The New York Times in spreding medical jingoism. How interesting that in both cases it was a local hospital — Memorial Sloan Kettering for NYT, St Bart’s for FT — serving as the source. So interesting that I have to think there were some personal behind-the-scenes goings on.

NIH has always made most of its lectures available to public. With the pandemic, the production values have gotten better, and more people have gotten used to viewing lectures online. Here are a few interesting ones scheduled for this month. Some of them are part of NIH’s Demystifying Medicine series which is open to public and tries to target the curious layperson ⊕ Alas, not always successfully. to the best of presenters' abilities.

Fact Stranger than Fiction: Adventures in the Genomics of Inflammation

• Speaker: Dan Kastner, MD PhD
• Date: Wednesday, February 8, 2023, 12:00 p.m. ET
• Available for viewing here.

Somatic Mutations in “Benign” Diseases

• Speaker: Neal Young, MD
• Date: Tuesday, February 14, 2023, 3:00 - 4:00 p.m. ET
• Register here.

The Use of JAK Inhibitors in Autoimmune Disease

• Speaker: John O’Shea, MD and Angela Christiano, PhD
• Date: Tuesday, February 21, 2023, 4:00 p.m. ET
• Available for viewing here.

Clinical Center Grand Rounds: How Nucleic Acid Structure and Chromatin Environment Influence Gene Transcription

• Speaker: Jason Watts, MD, PhD
• Date: Wednesday, February 22, 2023, 12:00 p.m. ET
• Available for viewing here.

Yes, yes, America has terrible health care — even a tech podcast says so — while paying an order of magnitude more for it than other rich countries. But hear me out: what if the costs are so high because Americans are (unsuccessfully) trying to buy their way out of poor policy decisions, from dependence on cars, to the early 2000s' promotion of opioids, to the widespread availability of cheap but nutrient-less calories, and no amount of fiddling with who pays for what in healthcare will be able to fix that?

Which is to say: it’s fine to look at specific costs and specific outcomes — I have done so myself — but what exactly is the action item after reading a report like The Commonwealth Fund’s cited by Ars Technica?

At the very start of the textbook Fundamentals of Clinical Trials the authors make a distinction between clinical trials — comparing two or more different interventions — and clinical studies, which merely describe an intervention without comparing it to anything. So, there can be no such thing as a “Phase 1 trial”, since they typically involve a single drug at different doses and schedules. The only true trials, according to the authors, would fall under Phase 3, or Phase 2b at the earliest.

This is stupid, misleading, and not at all how the words “trial” and “study” are used by anyone else, including the biggest and most important drug regulatory agency in the world. There are many such pointless exercises of professorial power in medicine, including my favorite: whether the correct pronunciation of “+” in “7+3” is “plus” or “and”. They amount to nothing more than purity tests that award the wielders of the right language a false sense of precision. As Nassim Taleb wrote, nitpicking is the enemy of thought.

The rest of the book is good enough, but more on that later.

After a few months of intermittently kicking the tires on Dave Winer’s FeedLand, I’ve finally had the time to port over a few feeds from my preferred RSS reader. The wonderful thing about FeedLand is that you can easily follow my feed categories and read posts without having an account (which is fortunate, since new signups on Winer’s own server are on hold). The full list of feeds is here. There is even a feed of posts I liked! It’s feeds all the way down.

The Science category has your usual suspects but I had to dig deep for Medicine since many of the blogs I follow haven’t been updated in years and others have turned into HuffPost-level text mills. Fortunately, Substack enabled a resurgence of medical writing, with feeds enabled by default.

Did I mention NetNewsWire is a free, open source RSS reader available on MacOS and iOS, and can sync via iCloud? For the anti-Apple readers, Feedly is there, I guess?

Warning, it’s a press release:

Gaithersburg, MD, January 31, 2023 – Cartesian Therapeutics, a fully integrated, clinical-stage biotechnology company pioneering RNA cell therapies for autoimmune diseases and cancer, has dosed the first participant in its Phase 2b randomized controlled trial (RCT) for generalized myasthenia gravis (MG), an autoimmune disorder that causes muscle weakness and fatigue. The RCT will evaluate the efficacy and safety of the company’s lead asset, Descartes-08, a first-in-class, RNA-engineered chimeric antigen receptor T-cell therapy (rCAR-T).

To the company’s knowledge, this is the first placebo-controlled study of an engineered cell therapy, and the most advanced investigational cell therapy in clinical development for any autoimmune disease. Descartes-08 is administered over 6 weekly outpatient visits and requires no preconditioning chemotherapy.

The manuscript from the open-label study is almost done, but some of the data was presented back in September 2022 (and available on YouTube). I also talked about the study in an MGFA webinar.

RCTs FTW.

Google Scholar alerts are a quick if crude way to be up-to-date with literature. In addition to journal articles and conference abstracts it also looks at U.S. patent applications, and despite the impenetrable legalese something will ocasionally turn up that is at least amusing, if not informative.

Today was one such occasion: a patent for a combination of two already approved drugs to treat toxicity of CAR T-cell therapy, by the group which, admittedly, was the first to give CAR T-cells to humans and the first to treat their side effects.

I may be showing my ignorance of U.S. patent law here but, how is this a thing? These drugs are already commercially available and widely used for exactly this indication. How would they enforce this patent, and how exactly would the patent help with development and commercialization of two drugs which are already on the market?

After reading Steven Johnson’s Where Good Ideas Come From I realized that not everyone makes the distinction between discoveries and inventions, Which is the first website that DuckDuckGo returned, and it is servicable, but I was flabergasted by the long list of nearly identical websites with domain names all some variant of “difference between”. This is how ChatGPT destroys Google. and this may be an example of a discovery masquerading as an invention. Nothing was created — the drugs were already there — the team merely discovered that those two drugs work in a specific indication. If this is deserving of a patent, should every drug combination be patented?

To be clear, I am not a lawyer — caveat lector — but the whole patent system needs an overhaul and making a clearer distinction between discoveries and inventions should be one of the items on the long list of things that need attention.

The beginning of the year was busy enough for a short commentary I co-athored to come out without my noticing.

Briefly, the US government spent $10 billion procuring the anti-Covid drug Paxlovid after a study confirmed its efficacy in unvaccinated people exposed to the delta strain. It then proceeded to hand it out to everyone, including the vaccinated and boosted during the omicron wave, with no data on whether it is actually needed in that setting. A similar drug, molnupiravir, ended up not having any meaningful effect in those who received the vaccine despite preventing hospitalization and death in the unvaccinated.

Could those $10 billion have been better spent? We believe the answer is: yes. For a fraction of the cost, using the same network of local pharmacies as in the Test-to-Treat initiative, the federal government could have randomized the first 100,000–250,000 patients to Paxlovid, Molnupiravir, or usual care — an order of magnitude more than PANORAMIC as many in the American health care system would have been lost to follow-up. The study would have taken mere months to accrue and would have provided valuable information on the efficacy of these treatments in the U.S. population. As importantly, it would have provided an important precedent and infrastructure for more federally funded pragmatic randomized controlled trials of agents under EUA or accelerated approval. The precedent set instead was for government’s full support for use of drugs far outside of the tested indication.

You can read the whole thing here, without a paywall.