Just the other day, I wrote about a scientifically worthless, highly unethical “pay-to-play” clinical trial of stem cells for autism carried out by a quack for-profit stem cell clinic in Panama. Not only was that clinical trial a single-arm, uncontrolled study using subjective measures of improvement highly susceptible to placebo effects as the primary and many of the secondary outcomes. Worse, it was at a clinic that offers stem cell treatment for basically any chronic condition or disease, evidence be damned, and charges huge sums of money for it. Going along with that ethos, the Stem Cell Institute in Panama City charged the parents of children with autism to be on the clinical trial. In any case, I knew at the time I wrote that post a couple of days ago that there was a conference scheduled at the Department of Health and Human Services to discuss the very issue of pay-to-play clinical trials. Conveniently, yesterday there was a story in STAT News by Rebecca Robbins about this conference, held by the Health and Human Services Secretary’s Advisory Committee on Human Research Protections (SACHRP) last week.
What spurred the discussion by the SACHRP is the observation that the problem of pay-to-play goes well beyond quack stem cell clinics abusing the clinical trials process to charge patients to be on their scientifically dubious clinical trials, which are used far more as advertisements than anything else. Here’s what I mean:
Michele Russell-Einhorn has spent 23 years working in the world of institutional review boards, which decide whether to green-light clinical trials. In all that time, she’s never seen quite so many proposals as she has in the past year that rely on an unusual — and controversial — funding mechanism.
Some plan to ask participants to pay $7,000 or so to enroll. Another wanted to ask for upward of $250,000.
In each case, there were “serious concerns about how ethical it was to charge people to participate in the research — and whether it was absolutely necessary,” said Russell-Einhorn, chief compliance officer for Advarra, the second-largest commercial IRB.
You’ll seldom see this sort of thing going on at an institutional review board (IRB) at a university. (IRBs are ethics panels that review proposed human subjects research in order to make sure that it does not place subjects at undue risk and that the potential for harm is low enough to be worth taking for the potential benefit.) That’s not to say you’ll never see it going on at a university. After all, in my last post, I noted two examples of highly dodgy pay-to-play arrangements for clinical trials going on a Duke University and previously carried out at Northwestern University. However, commercial IRBs are far more frequently used by pharmaceutical and biotech companies. Of course, I’ve always had a bit of an issue with for-profit IRBs, because their profits depend on making their customers (companies carrying out clinical trials) happy, and it’s not hard to imagine that a commercial IRB that’s too tough on protocols might lose business to less anal IRBs, but that’s a subject for another time. Let’s just say that if the chief compliance officer for a commercial IRB is bothered by the number of pay-to-play trials coming through her company’s IRBs, that’s a sign that something’s not right, even if, as the story acknowledges near the end, the overall number even this year is “just a handful of the thousands of protocols that she and her team review annually.”
AS noted in the story, these “pay-to-play” studies have caught the attention of the feds. The FDA recently asked a federal advisory committee to consider how the the research community should deal with such trials. Apparently a report with recommendations is being drafted as I type this. Similarly, the NIH asked the committee whether its existing resources are adequate to guide patients considering a clinical trial are up to the challenge of guiding them through the process when they are being asked to pay to be on the clinical trial.
There’s a lot of reason to be concerned, and not just from stem cell trials from for-profit stem cell clinics. (There’s no such thing as a for-profit stem cell clinic that is not a predatory quack clinic; at least, if there is, I’ve yet to encounter one, and it hasn’t been for lack of looking.) Get a load of some other examples:
Last year, STAT reported on a plan in Florida to charge seniors a fee proposed as high as $285,000 to enroll in a clinical trial in which they would get young-blood transfusions to try to forestall aging. That proposal was part of the reason that the Health and Human Services Secretary’s Advisory Committee on Human Research Protections — or SACHRP — decided to take up the issue, according to Holly Fernandez Lynch, a University of Pennsylvania bioethicist who sits on a subcommittee that’s helping draft the recommendations.
In the same field, the startup Ambrosia recently ran a clinical trial that charged about 80 people $8,000 each to get an infusion of blood plasma from a young donor — before halting its business in response to a warning from the FDA. Meanwhile, a clinic in Panama enrolled 20 autistic children in a stem cell trial that charged parents $7,200, the science news site Spectrum reported last month.
That last one was the very trial yours truly discussed in his usual inimitable fashion the other day, but, holy hell, infusions of blood plasma to try to forestall aging? That’s utter pseudoscience. No, it’s worse than pseudoscience. It’s prescientific mystical nonsense based on, in essence, vitalistic beliefs that “younger blood” has potency to reverse aging. Of course, that core belief was gussied up with all sorts of handwaving about cytokines and growth factors in the “young blood,” but at its core, the belief that young blood (or plasma) can reverse aging woo-filled at best. That trial by Ambrosia, in particular, not only used some questionable preclinical studies in mice as the rationale for its study, but it never published its results and has made spectacular claims to various media outlets, such as that an Alzheimer’s patient showed improvements after one treatment; grey hair turned darker for a person in their 60’s; there was a 10% reduction in patients’ blood cholesterol levels and a 20% fall in the level of amyloids; erections resumed in a patient with depleted testosterone levels; and the treatment demonstrated success in treating Parkinson’s patient, arthritis symptoms, sleep, memory, focus, appearance, muscle tone, and energy levels.
It turns out that FDA regulations do allow such “pay-to-play” clinical trials in “extraordinary circumstances.” An example of such “extraordinary circumstances” is a situation when a drug being tested has a price tag so high that the trial can’t otherwise be run. I still have a hard time envisioning such a scenario that wouldn’t be profoundly predatory, but the FDA leaves open the possibility that there might be a situation that isn’t.
Rather than threading the needle with SACHRP, I come down more on this side:
But experts say these trials are ethically fraught for a number of reasons: At worst, they run the risk of being a guise for an enterprise looking to profit from desperate patients. But even when intentions are sound, the trials are likely to only enroll those patients who can afford to participate, thereby skewing the results. There could also be a weak study design, without blinding or a control group, because patients would likely be reluctant to pay for a placebo. And they may reinforce the common misconception among patients that clinical trials are a route to accessing treatments that are guaranteed to help them.
Yes, yes, yes, a thousand times yes to all of those concerns. Selection bias is definitely a major concern, but more importantly, pay-to-play incentivizes (for the company) crappy single-armed clinical trials for exactly the reason listed above. No patient is going to want to be randomized to a placebo or sham group after having paid to be in a clinical trial. I suppose one might envision a scheme whereby the patients who are randomized to placebo get their money back after the unblinding of the trial, but I still doubt that this would persuade many, particularly if the price is steep and the patient has trouble raising the money. I’m sorry, Holly Fernandez Lynch, I’m not persuaded that there are “some where we think we don’t want to have a hard-line stance that says no, never, this could never be appropriate, because sometimes, we think, in rare circumstances, it could be ethically acceptable to ask for this kind of cost-sharing.” I suppose it’s remotely possible that circumstances could justify a pay-to-play design in very rare cases, but I would argue that such cases are so rare as to be unicorn-like and thus not needing a special exception.
In other words, I’m with Dr. Steven Joffe, a pediatric oncologist and bioethicist at the University of Pennsylvania:
“If you open the door to these trials, you inevitably are going to get … exploitative trials, and bad trials, and trials that don’t lead to any useful information,” Joffe said.
Sure, Joffe said, a blanket policy against pay-to-participate trials would mean foregoing a few potentially valuable trials. “But you are also closing the door to a lot of potential abuse that is very likely to happen — and overall the harms of opening the door outweigh the benefits,” he said.
Precisely. The harm of leaving open the door to pay-to-play trials is almost certainly much greater than the good that might come of a rare pay-to-play trial that is ethically acceptable. Still SACHRP is trying to strike a balance, urging IRBs to ask questions like, “Does the study meet relevant thresholds of scientific quality?” and “Is the risk-benefit balance acceptable?” Of course, here’s the problem. IRBs are already supposed to ask these questions about all clinical trials under their consideration. What’s the difference with pay-to-play? I really hope SACHRP can do better by the time it issues its final recommendations after its December or March meeting.
I’ll be waiting to see what SACHRP ultimately says. How will it thread the needle? For my part, I have a very hard time envisioning a situation in which clinical trial that requires patients to pay can be ethical. Maybe there is such a situation, but I need to be convinced.