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Shame! Another front in the libertarian war on the FDA: Rational Vaccines' unethical offshore herpes vaccine clinical trial

I've caught a fair amount of flak over my opposition to so-called "right-to-try" laws. Right-to-try laws have proliferated throughout the US like so much kudzu over the last three and a half years, to the point where 37 states now have some version of these profoundly anti-patient laws on the books. At the federal level, three weeks ago the Senate passed a federal version of right-to-try, with the House scheduled to take up the bill when Congress returns from recess next week. Granted, it's watered down and therefore less horrible than the original version, which Senator Ron Johnson (R-WI_ has been trying to pass for two years, but it's still plenty bad. In this post and a post later this week, I'm going to show you more circumstantial evidence that I was right all along. The first example you've almost certainly heard of, namely the offshore testing of a new herpes vaccine funded in part by über-Libertarian Peter Thiel. The second you probably haven't heard of, and I'll save it for later, given how long this post is.

But first, you need to understand what I mean about right-to-try. Basically, right-to-try laws rest on the false premise that the FDA is so slow and so bureaucratic that cures are being kept from terminally ill patients, or at least drugs that might hugely extend their life expectancies. The situation is presented as so dire that "right-to-try" is necessary, which basically allows terminally ill patients to bypass the FDA and receive experimental therapeutics from companies developing them without having to go through the FDA's Expanded Access program (which basically does the same thing, providing access to experimental therapeutics before they are FDA-approved). It's an idea promoted by a Libertarian think tank, the Goldwater Institute, and the branding has been very successful, to the point where, politically, opposing right-to-try is viewed as the equivalent of taking the terminally ill's last chance away from them, wanting them to die horribly, all while pissing on an apple pie and burning an American flag. (I exaggerate, but not by much.) The Goldwater Institute and right-to-try advocates achieved this effect by cynically parading families of patients with terminal illnesses who were convinced that right-to-try would give their loved ones a shot at life in front of legislators, making it very difficult for them to vote no. Meanwhile, industry and medical groups that might have been able to persuade lawmakers that right-to-try is a terrible idea that is bad for patients, despite the optics created by the Goldwater Institute were cowed and remained silent until very late. For example, the American Society of Clinical Oncology (ASCO), an society to which I belong, spent the last three and a half years saying basically nothing. It was only four months ago that ASCO finally issued a statement opposing right-to-try, when it was basically far, far too late.

I've also caught flak for characterizing right-to-try as being part of a broader war against the FDA (indeed, as part of a broader war against regulation in general) by libertarian-leaning free market fundamentalists, some of whom claim (literally) that the FDA is killing people. Lots of people. How can you say that? proponents of right-to-try would ask, drawing themselves up in their best self righteous fury. This is about helping terminally ill patients! Maybe. But, as I've said before, the FDA already has a Compassionate Use program that achieves the same purpose and rarely turns requests down, a program that's been improved over the last couple of years to be speedier and more responsive, with much less application time. Consistent with its libertarian origins, right-to-try tries to cut the FDA out of decisions between a drug seller and patients, but at the cost of eliminating many protections for patients. For instance, unlike the case in "expanded access" or "compassionate use," the institutional review board (IRB), an ethics panel that oversees clinical trials does not oversee patients in right-to-try. There is no financial help; so only patients whose families are rich or can raise a lot of money fast are likely to be able to benefit. Even worse, as I've described, most right-to-try bills not only do not require insurance companies cover experimental therapeutics (and why should they?), but allow insurance companies not to cover charges for complications from using experimental therapeutics. However, perhaps the most egregiously false argument made by right-to-try advocates is that the laws' allow use of experimental therapeutics after they've been "proven safe" through phase I testing. Yes, you read that right. As I’ve discussed multiple times, there is the requirement that the drug or device has only passed phase 1 trials, which, given how few drugs that have passed phase 1 actually make it through to approval, is a really low bar, especially since most phase 1 trials involve fewer than around 25 patients.

Although not commonly seen as such, right-to-try laws are of a piece with libertarian and radical fundamentalist free market views, some of which claim that the FDA is basically unnecessary or that its role should be vastly constrained. You can see it all there: Minimal requirements for safety testing (phase I), no ethical oversight, the decision entirely up to the company and patient, and, of course, the patient is totally on his or her own. People with such views were even in consideration for the post of FDA Commissioner, for example, two cronies of the aforementioned Peter Thiel, both of whom believe that the FDA stifles their holy grail of "innovation." The first was Jim O'Neill, who has advocated that the FDA test new drugs only for safety, not efficacy, thus returning the FDA to its pre-1962, pre-thalidomide role. The second was Balaji Srinivasan, a Silicon Valley entrepreneur who advocated basically doing away with the current system of FDA regulation and replacing it with online reviews, basically a Yelp or Über for drugs and medical devices. When asked "How do you prevent quacks?" Srinivasan replied, "Scaled Internet reputation systems. Works at massive scale in other areas." So clueless were both of these men that it was a relief when a relatively normal Republican pharma shill named Scott Gottlieb was ultimately appointed. He was the "least bad," most conventional choice, someone any conservative Republican administration might have appointed. Yes, he wants to "streamline" the process by which, for example, vaccines are approved, but he's actually pretty conventional. He's even decided to http://www.npr.org/sections/health-shots/2017/08/28/546719842/fda-crack….

Stymied at the FDA, apparently Peter Thiel is now waging his war on the FDA by other means:

Defying U.S. safety protections for human trials, an American university and a group of wealthy libertarians, including a prominent Donald Trump supporter, are backing the offshore testing of an experimental herpes vaccine. The American businessmen, including Trump adviser Peter Thiel, invested $7 million in the ongoing vaccine research, according to the U.S. company behind it. Southern Illinois University also trumpeted the research and the study’s lead researcher, even though he did not rely on traditional U.S. safety oversight in the first trial, held on the Caribbean island of St. Kitts. Neither the Food and Drug Administration nor a safety panel known as an institutional review board, or an “IRB,” monitored the testing of a vaccine its creators say prevents herpes outbreaks. Most of the 20 participants were Americans with herpes who were flown to the island several times to be vaccinated, according to Rational Vaccines, the company that oversaw the trial. “What they’re doing is patently unethical,” said Jonathan Zenilman, chief of Johns Hopkins Bayview Medical Center’s Infectious Diseases Division. “There’s a reason why researchers rely on these protections. People can die.”

Indeed it is. What Peter Thiel and Rational Vaccines, a company founded by Agustín Fernández III and William Halford (formerly of Southern Illinois University who died recently of cancer) did and are doing is patently unethical—shockingly, horrifyingly so. The very function of the IRB is to protect human subjects in clinical trials. Usually, when a clinical trial is proposed, it goes through two committees, first the scientific review board, or SRB, which determines whether the trial is scientifically justified and soundly designed. The second is the IRB, which is charged with protecting the human subjects. Its function is to examine the clinical trial design and to determine whether it is ethical and whether the risks to human subjects do not outweigh the potential benefits; e.g., that there is clinical equipoise. Once it approves the trial, the IRB continues to monitor the trial, examining reports of adverse events, both serious and minor, and sometimes demanding changes in the trial or even canceling it if it judges that there are too many adverse events or that one group is doing so much better than the other group that it would be unethical to continue the trial. These protections for human subjects flow from the Belmont Report and the Common Rule, both of which were designed to prevent the abuse of human research subjects like what the Nazis did and underlie all the federal regulation regarding human research protection. Unfortunately, these protections are not universal, as they only apply to organizations with federal funding (such as universities) or entities applying for FDA approval for one of its investigational drugs or devices.

Like right-to-try, Peter Thiel's and Rational Vaccines' offshore clinical trial of a new herpes vaccine is an attack on the FDA. Libertarians and free market fundamentalists even admit as much:

The push behind the vaccine is as much political as medical. President Trump has vowed to speed up the FDA’s approval of some medicines. FDA Commissioner Scott Gottlieb, who had deep financial ties to the pharmaceutical industry, slammed the FDA before his confirmation for over-prioritizing consumer protection to the detriment of medical innovations. “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.”

These are exactly the sort of arguments made by right-to-try advocates. Indeed, as I've often pointed out, state-level right-to-try laws are completely toothless because federal law supersedes state law and the FDA regulates drug approval. The real reason for their existence is to put pressure on the FDA and to pressure federal legislators to pass a federal law. Sadly, it appears to have worked, as I doubt that the House will block the right-to-try bill passed by the Senate earlier this month. It will very likely become law next month.

There's also the same sort of snake oil being used to push this approach to Rational Vaccines' approach, which before this trial had resulted in a previous small preliminary trial:

For the initial trial, Halford and Rational Vaccines co-founder Fernández were unable to get federal funding or IRB approval, which oversees human safety. After testing out the vaccine on themselves for safety, they moved the trial to the Caribbean island. They flew 17 patients with pre-existing genital herpes cases there to get three shots of the vaccine. Halford reported that they experienced on average a three-fold reduction in days with symptoms on followup at four to six months after vaccination. Overall, the pair claimed that the trial and self-tests proved the safety and promise of the vaccine. But when Halford attempted to publish the results, scientific reviewers were ruthlessly critical of the data and lack of safety precautions. One reviewer concluded: “This manuscript is partly a vision, partly science, and partly wishful thinking.”

I read the reviews of the manuscript, and I've rarely seen such critical comments from reviewers, ever. Interestingly, the authors apparently tried to slip their clinical trial data into a Perspectives article, rather than as a scientific or clinical report, and they inserted all sorts of extraneous rants and proselytizing into the manuscript, such that Reviewer 2 proclaimed it "part autobiography, part criticism of the herpes vaccine field, part description of autoinoculation studies with the author’s herpes vaccine candidate vaccine, part advertisement for the author’s vaccine company, and part description of preliminary results of a phase I trial." One reviewer explicitly wondered if this was "an end run around the FDA."

Why, yes. Yes it was and is. Very obviously so. So is the current trial. Even so, it's hard to see how this works. Both Both Office for Human Research Protections (OHRP) and FDA regulations explicitly require that clinical trials used in support for an application to approve an investigational new drug (IND) be approved and monitored by an IRB. Even Dr. Gottleib can't change that without changing the regulations (a long and onerous process), and I doubt that even he would want to try, his prior advocacy of "streamlining" the drug approval process notwithstanding. Thus, like state-level right-to-try laws, this stunt by Thiel and Fernández is designed to put pressure on the FDA and lawmakers.

If you don't believe me, listen to Fernández, a former Hollywood filmmaker, himself:

Even so, Fernández, a former Hollywood filmmaker, said he and his investors plan to submit the trial data to the FDA in hopes of getting the vaccine approved for treatment. If the FDA does not respond favorably, he said, the company will continue its trials in Mexico and Australia. Fernández said he hopes to set up an IRB for these next trials. No matter what, he plans to manufacture the vaccine offshore. However, without U.S. approval, the challenges to market such a vaccine in the United States remain significant.

Manufacture and sell the vaccine offshore no matter what the FDA says? This is what quacks do.

Perhaps the worst thing about this is the involvement of the Southern Illinois University. Not only does SIU make excuses, it basically tries to wash its hands of the whole thing, even after having published a glowing press release about the research, promoting it despite how utterly unethical the research was. Now, here's what SIU says:

Nonetheless, Southern Illinois University officials said they had no legal responsibility to ensure safety measures were in place because the university has an arms-length relationship with Rational Vaccines. Fernández said the company licensed two patents related to the vaccine from the university. “SIU School of Medicine did not have any involvement in Rational Vaccines’ clinical trial,” said Karen Carlson, the university’s spokeswoman. “But we are confident that as the chief scientific officer of Rational Vaccines, Dr. Halford followed safety protocols appropriate to the clinical trial.” But other researchers said they were appalled by what they described as the university’s complicity in ignoring more than 70 years of safety protocols.

As am I. For shame, SIU:

One can only wonder whether the feds can do something about SIU's involvement in this, given that the university receives federal funding. Of course, in the anti-regulation governmental era that President Donald Trump has ushered in, I doubt that the FDA or the OHRP will do anything at all, even though SIU richly deserves it for its lack of ethics and disingenuousness. For example:

However, after questions about the lack of IRB approval (a federal requirement), the spokesperson said that the university would “take this opportunity to review our internal processes to ensure we are following best practices.”

Yeah, I hope so. Because clearly SIU wasn't following "best practices" before. Remember OHRP and FDA regulations apply to any faculty of any university receiving federal funds, regardless if the faculty member used federal funds to carry out a clinical trial. SIU dropped the ball here, big time.

There is a multi-pronged war being waged on the FDA by ideological and business interests whose belief in the free market (and profit) as the adjudicator of the value of all things has deluded them into believing that all federal regulation is harmful and represents an undue brake on "innovation," which basically seems to mean whatever people like Peter Thiel want to do to make money, regardless of scientific plausibility and ethics. (The passage of the 21st Century Cures Act is a less egregious example of another front in this war.) If Thiel and Fernández get away with not just taking their clinical trials offshore (which many drug companies do) but of so blatantly flouting FDA and OHRP regulations by not forming an IRB for these trials (which basically no drug company seeking to market a drug in the US does) and manage to win FDA approval for their vaccine, it will be a stake in the heart of the FDA, which is exactly what Thiel wants.

[Next time, to conclude this two-part series: If a federal right-to-try law passes, here's what's likely to be next.]

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