Yesterday I discussed a highly unethical clinical trial of a new herpes vaccine, based on what appears to be questionable science but backed by über-Libertarian Peter Thiel. The reason the trial is so unethical is because Rational Vaccines, the company that developed the herpes vaccine and is conducting the clinical trial, not only arranged to carry it out offshore but, unlike all American companies carrying out clinical trials offshore for purposes of gathering data to support an application for FDA approval, Rational Vaccines apparently carried the trial out without any oversight by an ethics board, known as an institutional review board (IRB). The reason that this trial bothered me is because it was (and is) so clearly intended as an end-run around the FDA. Indeed, the company basically said that, if the FDA wouldn’t accept its tainted data (tainted because of the way it was obtained), it would continue clinical trials in other countries and that it planned on marketing the vaccine regardless. Meanwhile, Southern Illinois University (SIU), home of the recently deceased scientist who developed the vaccine, William Halford, tried to wash its hands of the whole mess, perhaps realizing that its federal funding was in jeopardy because institutions receiving federal funding must abide by federal Office of Human Research Protections (OHRP) regulations requiring oversight of clinical trials by an IRB.
Clearly, Thiel and Agustín Fernández III, the latter of whom co-founded Rational Vaccines with Professor Halford, are directly challenging the Food and Drug Administration (FDA). However, this is not the only direct challenge to the FDA’s authority by free market fundamentalists and libertarians who bristle at any regulation, but in particular regulation of the FDA, claiming falsely that the FDA is so slow and bureaucratic that it is literally killing people. (No, I am not exaggerating. They really say this.) Perhaps the largest and most successful effort to undermine the FDA and its ability to protect patients comes from the Goldwater Institute, which has promoted so-called “right-to-try” laws at the state level as a way to allow desperate terminally ill cancer patients “one last shot.” (Never mind that the federal government, not the states, control drug approval; right-to-try advocates know state right-to-try laws have no force and that their real purpose is to put pressure on the federal government.) Unfortunately, the price of that “one last shot” is to leave the dying patient entirely on his own. there is no assistance paying for it, and if he suffers a complication insurance companies don’t have to pay to treat it. He can’t sue his physician for malpractice, and the state can’t take away his doctor’s medical license if he practices below the standard of care. I’ve described all these issues before, particularly the ridiculous claim on the part of advocates that drugs that have only passed phase I testing have been shown to be “safe.” It’s not for nothing that I call it a cruel sham. Unfortunately, a version of right-to-try just passed the U.S. Senate and appears on the verge of passing the House of Representatives next month.
I’ve caught flak on many occasions for arguing that the primary purpose of right-to-try isn’t really to help patients, that in reality it’s a wedge with which to pry the process of drug approval away from the FDA, to undermine the FDA’s authority. However, the more I look at right-to-try, the more I become convinced that I’m correct and that it’s really a strategy to let patients and drug companies bypass the FDA. I also predicted that, if right-to-try were to come to pass, the next step would be to increase the number of patients who could bypass the FDA, using right-to-try as the wedge. People scoffed. But in researching the story about the herpes vaccine trial by Rational Vaccines, I came across an article on the Foundation for Economic Education an article by Lawrence W. Reed entitled Herpes Cure Needs Free To Choose Medicine. Not surprisingly, FEE is a libertarian think tank, and not surprisingly Reed portrays Professor Halford as a “genius who challenged conventional wisdom, blazed new trails in scientific research, dedicated his life to helping others, developed promising new tools against a terrible affliction, and lighted a path for the policy changes needed to end the suffering of millions.”
Wow. That’s laying it on thick, isn’t it? I suppose the opinions of the peer reviewers who read his work were so scathing because of professional envy.
After portraying Professor Halford as the brilliant brave maverick scientists who was stymied by the bureaucrats at the FDA who are supposedly trying to keep cures from the people, Reed portrays the herpes vaccine as a reason why a new initiative is needed, which he calls “Free to Choose Medicine” (FTCM):
Here’s where a promising, innovative proposal enters the picture. It’s called “Free to Choose Medicine” or FTCM. It was succinctly explained on FEE.org in this article by Bartley J. Madden a year ago. If Congress won’t reform the FDA or if the FDA won’t reform itself, why not allow a separate track—a competitive alternative that would run alongside the conventional FDA clinical testing track?
Madden suggests that “after a new drug has successfully passed safety trials and shows initial effectiveness in early clinical trials, a drug developer could request that the drug be available for sale. Such an arrangement would allow for new drugs to be available up to seven years earlier than waiting for a final FDA approval decision.” Surely patients for whom conventional drugs and therapies haven’t worked ought to have the freedom to choose a promising alternative. Whose body is it, anyway?
Yes, one has a right to control one’s body, but there is a competing obligation of the government to try to prevent fraud; i.e., to prevent the true believers or the unscrupulous from taking advantage of desperate patients. In any event, Let me remind you that Madden himself was quoted about the unethical offshore trial for Rational Vaccines’ herpes vaccine in a Daily Beast news report on it:
“This is a test case,” said Bartley Madden, a retired Credit Suisse banker and policy adviser to the conservative Heartland Institute, who is another investor in the vaccine. “The FDA is standing in the way, and Americans are going to hear about this and demand action.”
I didn’t know who Madden was when I used this very same quote in yesterday’s post. I do now.
In any case, as I predicted, “right-to-try” is simply a watered down version of FTCM, a version that seems very acceptable to most people who don’t know anything about drug development because the patients for whom it is intended are terminally ill. Instead of asking “Whose body is it, anyway?” right-to-try advocates ask, “What have they got to lose, anyway?” It sounds compelling, but, as I like to say, when discussing the patients of Houston cancer quack Stanislaw Burzynski, they can lose their family’s inheritance, what remaining time they have left if the treatment hastens their death, time away from their families chasing cures, and lack of proper palliative care, among other things. It turns out that FTCM has been around as a concept at least since 2004, as explained on the Freedom To Chose Medicine website. Not surprisingly, the man behind FTCM, Bartley J. Madden is a Policy Advisor for the Heartland Institute, the same libertarian think tank that is so prolific promoting denial of the science concluding that human activity is causing global climate change in which the mean temperature of the globe is rising alarmingly. Indeed, libertarian fingerprints are all over FTCM, which appears to have been, at least in part, the inspiration for right-to-try.
Indeed, Madden himself predicts that the problems with right-to-try will lead people to FTCM:
Assuming there won’t be any federal Right To Try legislation signed into law, the states do not have the legal authority to circumvent the FDA. Moreover, drug developers have a major disincentive to participate because, to survive, drug developers need to secure FDA approvals for their new drugs. And circumventing the FDA by providing not-yet-approved drugs to terminally-ill patients could easily slow or prevent FDA approvals.
Madden presents FTCM as—surprise! surprise!—a “market-based” discipline to the process, based on “competition” that “greatly improves” on right-to-try. In brief, it would create a bifurcated dual track system. One track would be the same FDA process for approval that’s been in place since the early 1960s. The second track would be an “alternative,” which he describes thusly:
First, the Free To Choose track (separate from the FDA’s conventional clinical testing track) enables patients and their doctors to make informed decisions about the use of FDA-approved drugs or not-yet-FDA-approved drugs. Patients, under the guidance of their doctors, would learn about initial safety results and up-to-date treatment results of FTCM drugs. FTCM drugs for a wide range of illnesses (not just terminal illnesses addressed by Right To Try) would be available up to seven years before conventional FDA approval.
Second, FTCM legislation would provide for government oversight of an open-access, Internet-accessible database. It provides up-to-date information for patients and doctors about a FTCM’s drug’s potential benefits and risks before they choose to use it. This is a self-adjusting system wherein more patients use FTCM drugs that work well and vice versa.
Reading the passage above, I asked myself: Where have we heard this sort of idea before? Oh, yes. Balaji Srinivasan, who was considered briefly by Donald Trump for the position of FDA Commissioner. Remember how he was the one who proposed keeping online databases akin to a Yelp or Über for drugs. In fairness, it’s not quite that. Madden represents the database, which he calls the “Tradeoff Evaluation Drug Database” (TEDD) as an “open access database” that would contain “treatment results of FTCM patients including their genetic makeup and relevant biomarkers,” touting it as able to “reveal subpopulations of patients who do extremely well or poorly with the new drug.” Maybe. The problem with such databases is that without a control group it’s hard to know which biomarkers might be useful in the first place. I rather suspect that Mr. Madden doesn’t understand the difficulty and complexity of maintaining such a database, its limitations, or how difficult it is to make conclusions from it.
In any case, this is what the FTCM scheme looks like:
I’ll give it this much, FTCM at least requires a phase II clinical trial. A variant of FTCM published at the Heartland Institute also proposes requiring drug developers to keep working towards conventional FDA approval in order to keep their observational approval status. Clearly, the Heartland Institute also seems unaware that there is already something very similar, a track known as fast track approval that often requires—you guessed it—phase II clinical trials, after which a conditional approval is granted that can be revoked if later trials don’t pan out. In fact, depending on the severity of the disease being treated and the level of unmet medical need, phase II data might be enough, no observational evidence needed.
One potential issue (of many) comes to mind first about FTCM. One of the reasons for clinical trials, besides randomization, is the control part. It’s a randomized controlled clinical trial. That means the treatment protocols are predetermined and carefully controlled. Observations are standardized and carefully controlled. Decision algorithms are carefully controlled. What Madden sees as a strength (“real world” use) is actually a weakness in determining efficacy, at least, because variability makes it harder to detect drug effect. It’s the same reason we generally don’t use pragmatic trials, which are often not randomized and basically never blinded, to approve drugs (and, let’s be honest, what Madden is describing is a pragmatic trial), but rather to determine the efficacy of drugs shown to be efficacious in clinical trials under “real world” conditions. In fairness, TEDD isn’t a bad idea, but it would be far more useful as a complement to the existing clinical trial process, to be used as an adjunct to not as a second track that can be used as the sole basis for drug approval. In fact, the FDA is already moving in that direction without Madden.
Also in fairness, in the PowerPoint presentation on the plan, Madden doesn’t advocate FTCM for all drugs, but rather proposes a “Free To Choose Medicine Advisory Committee … would be established within NIH to determine which experimental drugs are sufficiently promising to merit entry on the FTCM track.” (At least he’s not totally off the rails.)
Be that as it may, what it all boils down to is that Madden wants this second track to lead to a new kind of drug approval by the FDA:
Third, FTCM federal legislation needs to provide a new type of drug approval – Observational Approval – based on treatment results for real-world patients who receive the FTCM drugs. This would motivate drug developers to participate as well as expedite insurance reimbursement for patients.
This is so ludicrous from a scientific standpoint that I am amazed that Madden could say something like that it, except that he’s not a scientists and probably doesn’t realize how ludicrous it is. Yes, with adaptive trials and the use of biomarkers clinical trials are evolving beyond the rigid randomized double-blind placebo-controlled trial, as they need to, given the advances in genomics, proteomics, metabolomics, and whatever other omics you can think of, all of them providing potential predictive biomerkers. That’s not what Madden is describing, though. Basically, he’s describing a free-for-all, full of selection bias, in which the patients who choose “Track 2” are likely different than those who stick with the old-fashioned FDA track.
Of course, the primary idea behind this two-track approach is so obvious as to be painful. The idea of the second track is not to help patients (although Madden might delude himself that it is). Rather, it is to provide a track by which drugs can be much more easily approved than the standard FDA track, and then to put it in direct competition with the FDA track, making it as attractive as possible to drug companies by using observational approval to induce health insurance companies to pay for RTCM drugs and trying to make it so that drug developers would be “motivated to charge lower prices in order to gain increased usage for their FTCM drug.”
Whether right-to-try was inspired by FTCM or not, I don’t know. They certainly share ideas in common, the most prominent of which is the idea that somehow the FDA is an impediment to getting “cures” to the people and that bypassing the FDA in a free market-friendly way would be the best way to overcome this perceived impediment. In right-to-try, the Goldwater Institute appears to have strategically chosen only terminally ill patients to make its case, the better to inspire sympathy and to be able to portray opponents as cold, heartless, and cruel. In RTCM, Madden appears to be going for the whole enchilada by applying to nearly all investigational drugs, regardless whether the disease being treated is life-threatening or not.
I now make another prediction. If right-to-try passes the House and becomes federal law, up next will be RTCM. In the era of Trump, I’m not sure that it wouldn’t ultimately become law.