Map of life expectancy at birth from Global Education Project.

Monday, May 21, 2018

With all the turmoil and craziness, too much is flying under the radar

I didn't even know that it appears a truly horrible version of so-called "right to try" is about to become federal law. I have written about this before, but when legislation was only being passed at the state level it didn't really matter. The FDA still controls access to experimental drugs and state law can't preempt it, so state legislation was purely symbolic.

The link is to an essay by the notoriously long-winded David Gorski. Do read it if you want all the details, but I'll try to give a succinct version.

For background, the drug approval process has several stages. First, trials in animals have to show some evidence that a chemical may be promising to treat human disease and establish evidence about safety. People are not mice, however, and unfortunately most agents that show promise in animals turn out not to be useful for human health care, due to lack of efficacy, safety, or both.

So, the next step is a so-called Phase One trial. This involves giving the agent to a small number of human volunteers, starting with very small doses and increasing them until adverse effects are observed. This is not intended to show anything about efficacy, just to get an idea of how much of the drug can be administered safely in a larger study.

Phase Two trials are relatively small trials which are not powered (i.e. do not have a large enough sample size) to really prove efficacy, but do have at least one control arm (a placebo or existing standard treatment) and produce more information about safety (at least in the short term) and enough of an indication of treatment effect to establish the sample size needed for a large scale Phase Three randomized controlled trial. A lot of agents flunk out at this stage, and never make it to Phase Three.

So, in order to get access to an experimental drug you need to enroll in a clinical trial. And of course, you might end up in a control arm and not actually get the experimental drug. Which is at least 50% likely to be good news for you, because the experimental drug might not work and might not be safe. If there already is an established treatment and you have a somewhat serious condition, in the control arm you'll get the standard treatment because placebo control would be unethical. Got that?

The FDA has licensed drugs based on safety and efficacy since the thalidomide catastrophe. But so-called right to try means that terminally ill people will be allowed access to drugs that have only passed Phase One. People intuitively think, "What's wrong with that? Freedom!" Well, there's a lot wrong with it, but it might not be an absolutely terrible idea under some conditions. Unfortunately the legislation that's teed up now is in fact an absolutely terrible idea.

Note the following. Insurance companies will not pay for experimental treatments. People who want them outside of clinical trials will have to pay out of pocket. The drug companies can charge whatever they want. Note also that it is not only the case that evidence for effectiveness is not compelling: there is no evidence of effectiveness whatsoever based on a Phase One trial. The treatment is as likely to make people worse off as it is to help them. Okay, they're dying, what have they got to lose? Other than their children's inheritance, that is. Take it away, Dr. Gorski:

Consistent with their libertarian origin, right-to-try laws also strip away many protections from patients. First, there is no requirement that companies provide the drugs for free or at a reduced price. Indeed, these laws explicitly state that insurance companies are under no obligation to pay, even though such a statement is unnecessary given that insurance companies don’t reimburse for experimental therapies. As a result, the only people who would potentially be able to access right-to-try are the rich or people who are very good at fundraising. A terminally ill person trying to access right-to-try can easily spend away his estate or even go bankrupt before dying. It’s even worse than that. The language in many of these laws can be interpreted to mean not just that insurance companies don’t have to pay for right-to-try but that they don’t have to pay for medical care as a result of complications suffered from using a drug under right-to-try.

Another aspect of these bills is, as Jann Bellamy and I have described many times, how, compared to existing expanded access programs, they strip patient protections away from patients who access them. One way to see this is by comparing what happens when a patient accesses an experimental therapeutic under the FDA expanded access program to what happens when another patient accesses one under a right-to-try law. Under FDA expanded access, patients retain full protections under federal and state laws. They can sue for malpractice if there is any, and their care is still monitored by an institutional review board (IRB), with any adverse events recorded and considered by the FDA. Moreover, the FDA approves nearly all such requests (99%). In contrast, under right-to-try, there is no IRB oversight. It’s all between the company and the patient, a libertarian paradise!

These laws also immunize companies providing right-to-try drugs and physicians overseeing their administration from liability. Right-to-try laws also limit what patients can do in the event of malpractice or negligence. All of them broadly immunize physicians advising or administering right-to-try medications or using right-to-try devices against malpractice suits or actions against their medical license by the state medical board related to their participation in right-to-try. All of them also immunize companies providing experimental therapeutics under right-to-try from liability. All of them contain provisions stating that state employees can’t interfere with a patient seeking right-to-try, which could be interpreted to mean that a doctor at an academic medical center at a state university couldn’t counsel a patient not to seek right-to-try without running afoul of the law. As Jann notes, even if state authorities believe, for example, that an elderly person is being exploited for financial gain by a physician, presumably this provision would prohibit their acting.
Finally, this creates a situation in which legitimate clinical trials may be compromised.  If it isn't possible to recruit enough people who are willing to undergo randomization, because too many people are already clamoring for the experimental drug, we will never know if it really works and is really safe. I will finally note that if a drug shows what appear to be truly miraculous results in Phase One trials, then even a relatively small scale Phase Two trial may who strong evidence of effectiveness, in which case movement toward approval will proceed quickly and expanded access may be offered under existing regulations. This seldom happens. Of course the Koch brothers are behind this particular outrage.

1 comment:

mojrim said...

Perhaps access to post Phase II drugs for those that have failed existing treatments?