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Well said!
If we want cheaper drugs, the FDA should get out of the way. All around the world, people use drugs we do not have access too. How on Earth is a clinical trial better information than decades of use in real life.
Since it is increasingly accepted by courts and legislatures that people have an unlimited right to be killed by their physicians, why can’t they be allowed to obtain and take any medication they like, if it might help them? As a society, we no longer seem to care if people are intentionally put to death by doctors. Isn’t all this concern about safety and effectiveness a bit quaint?
Agreed.
Wish you could make this come to pass.
Back in the day, Great Britain allowed the use of thalidomide by pregnant women. The unborn children were visited with great harm, born with various handicaps.
I have no idea about Kyndrisa™. I don’t know about the testing regime enforced on that company. I don’t know the results beyond Richard’s statement “much evidence from the clinical trials revealed serious complications from the drug’s use, including blood-platelet shortages that were potentially fatal, kidney damage, and severe injection-site reactions. But the no-treatment alternative could prove far worse.”
I understood that the prognosis for this is poor without treatment, but might the treatment be even worse? One presumes we’ll find out because someone somewhere will get access to this treatment and use it for all it is worth.
We keep getting mixed messages on tv about wonder drugs that might do more harm than good, almost to the point where if it doesn’t kill you it may cure you.
Having an acquaintance go through that, ending up killing himself and leaving a widow and two children, there might be something to be said for caution.
Very well put.
There’s a valid concern — especially given how much snake-oil is peddled to desperate people — about wanting to give things as far above board as possible in terms of empirical standards.
But as Epstein says at the end, there are other ways of doing that that don’t have this effect of shutting out people who are informed of the risks from doing what they believe is best for their own health.
Richard,
You have stepped up the level of this debate and asked very fundamental questions pertaining to rights in a free society. For this I applaud you. However, I must try to get myself oriented on this one as this is a very sophisticated situation. That said it doesn’t mean that I won’t be coming down on your side but that I need to take it one step at a time.
I think the law you are referring to set up what was called phase I, phase II, and phase III testing. Phase III was a massive test taking 5-7 years with upwards of 10,000 participants. Its real purpose was to uncover long-term side effects. Phase II was the traditional sized efficacy test taking 1-3 years with 500-1,000 participants. Phase I was the type of test you are talking about with under 100 participants.
I wrote before about the totally bizarre situation during the early 80s where drugs were being forced through phase III before they were allowed to be used at all. Phase II testing was completely adequate to establish a drug’s strong efficacy and anyone facing a disease that was much worse than whatever side effects might crop up obviously should be allowed to use it. Needless to say the hard phase III rule was dropped. Hopefully, there is nobody that insanely doctrinaire left around who actually thinks the hard phase III rule was a good idea.
What you are talking about here is very different. The problem for drugs with only phase I testing completed is no statistical significance of efficacy. Thus the term anecdotal evidence. What I would like to hear is that if we are not going to insist upon hard statistical proof of efficacy before allowing experimental use, do we have a standard by which to judge the phase I situation or are you suggesting that the rights of patients to choose overrides all?
Regards,
Jim
Yes, there is a case for caution. The question is whether we are being overly cautious, especially when it comes to drugs for conditions in such small numbers that it’s extremely difficult to do the kind of studies the FDA requires for drugs that would be made available broadly.
Tom,
So one of the aspects of this kind of argument is that if the total number of sufferers of the disease is low it makes it almost impossible to do the statistically significant studies necessary for current FDA experimental approval.
Again, I’ll ask you instead of Richard. Do you have a standard in mind, non-statistical, for these situations? How would you properly document an anecdotal request? Obviously, the only concern would be to protect people from fraudulent abusers.
Regards,
Jim
Milton Friedman spoke directly to the issue of thalidomide and the justification for the FDA. Interviewed no less by our very own Peter Robinson.
Exactly. If there’s only a handful of people who have the disease, it’s really hard to do a valid trial. The numbers are just too small.
I’d rather one of our doctors answer but I think part of it would be to have very strong disclosure agreements. Also, you could still have reasonably strong regulations regarding who is able to do such trials. This may be a case where it makes more sense to focus on the practitioners than on the product.
Amen.
Clinical trials assess the probability of benefit versus risk for a population. However, in the end, we treat individual patients–family, friends, co-workers–not populations.
Interesting aside: I gained admission to medical school, way back in 1981, on the basis of arguing strenuously against the Kefauver Harris amendment to the Food, Drug and Cosmetics Act.
The professor interviewing me was waxing rhapsodic about the many benefits of the FDA and I, of course, held to a less-well-informed version of the Epstein position. I recall thinking that I was about to throw away my chance of admission to this particular school, but could not resist joining in the argument. We had a thoroughly enjoyable conversation.
Sadly, the Kefauver Harris amendment remains with us to this day.
Couldn’t there be a phased-in process? Such that people who wanted to try it could be given it, perhaps as part of a clinical trial?
If a person is out of options and is looking for hope without a guarantee, shouldn’t that person, as long as the risks are fully disclosed, be allowed to assume the risk?
So the patient is told “This drug has not been approved by the FDA.”
People are taking experimental drugs all the time through clinical trials, right?
I think Professor Epstein is right here.
The European model is sometimes held up as a better way. But didn’t France just halt a drug test after some otherwise healthy test volunteers died suddenly?
There is a reason for bureaucratic cautions when considering new wonder drugs.
George,
I just got back to Ricochet. How would you write such legislation? Would you leave any controls at all? I agree that there are fundamental rights involved and I am tired of letting the left win the argument every time they can make an emotional appeal concerning health care. Still I’d like get your opinion. When it came to Obama Care I asked every physician I knew and shut up and let them talk. Nothing could have been more clear. I couldn’t find one, many who had voted for Obama and some twice, who had the first good thing to say about the ACA.
You tell me.
Regards,
Jim
Phase I trials are powered to look at toxicity only with no promise of cure of improvement. However, if a patient responds, I support the continued use of the drug for that patient. And rare diseases always post a statistical challenge.
This is really the key. Population statistics do an excellent job describing populations, however, we don’t know where the patient in front of falls in that population. Precision medicine is causing the FDA’s head to spin because (no surprisingly) they don’t know how to respond to that type of individualized treatment.
The current process is phased in with strict guidance about what types of evidence each level provides.
PsyL,
This is very interesting. Could you describe the “strict guidance” for us.
Regards,
Jim
Jim, welcome back!
I would prefer to repeal the 1962 amendments in their entirety. Ideally, FDA would require drug makers to publish a drug’s safety profile, would stand ready to intervene in the event of calamitous problems, but would otherwise leave efficacy determination to the market.
I recognize that this is extremely unlikely to happen, so at a minimum I favor Peter Huber’s proposed reforms aimed at bringing the definition of “substantial evidence” into the 21st century. For instance, we now know that clinically identical cancers often differ from one another on a genetic level. What is needed is an updated definition of “efficacy” to mean a demonstrated effect against a marker or pathway, rather than a standalone clinical outcome.
Consider that tumors have redundant pathways for survival (by definition, if a cell depends upon a single pathway for survival, it is unlikely to survive very long). Anti-cancer therapy relies on exploiting differences between healthy cells we need to preserve in order to target and kill only abnormal cells. However, genetic differences mean that different tumors need to be addressed using a variety of approaches tailored for that individual. Rather than a single blockbuster “cure,” we are more likely to employ multi-drug customized cocktails.
Precision medicine requires the FDA to approve drugs based upon adequate safety and performance against the molecular target. Leave clinical outcomes to oncologists and other physicians who will experiment with the right mix for the right patient.
This is how the war against HIV was largely won — a death sentence when I entered training is now, thankfully, just another chronic disease to manage across a long lifespan–by focusing on approving tools rather than cures.
Jim, with the significant caveat that I’m not a treatment/cures researcher. I’m a psychologist and focus on cognition, emotion, decision making usually post-treatment and end of life. However, my work has given me lots of exposure to the clinical trials system.
The standards for what types of questions are answered by a clinical trial are summarized here; Phase 1 are basically very small numbers, examining dosing and toxicities. They aren’t statically powered for cure. The vast majority of these trials, whether funded by Pharma or federal dollars are done in academic research hospital or lab settings. So, it is unlikely, though not impossible thanks to technology, that your local community cancer center is not providing this type of trial.
The trial design and analyses much be constructed with given lab controls, reporting and clinical resources, as well as design and analysis appropriate to the type of question being asked at each phase.
The guidance is strict and then is reviewed by the FDA, so multiple hands touch it and have a interest in it.
Is that helpful?
Phase 1
Purpose:
To find a safe dose
To decide how the new treatment should be given (by mouth, in a vein, etc.)
To see how the new treatment affects the human body
Number of people taking part: 15–30
Phase 2
Purpose:
To determine if the new treatment has an effect on a certain cancer
To see how the new treatment affects the body
Number of people taking part: Less than 100
Phase 3
Purpose:
To compare the new treatment (or new use of a treatment) with the current standard treatment
Number of people taking part: From 100 to several thousand
Some researchers design trials that combine two phases (phase 1/2 or phase 2/3 trials) in a single protocol. In this combined design, there is a seamless transition between trial phases, which may allow research questions to be answered more quickly or with fewer patients.
There are also very early (phase 0) and later (phase 4) phase clinical trials. These trials are less common. Phase 0 trials are very small trials that help researchers decide if a new agent should be tested in a phase 1 trial. Phase 4 trials look at long-term safety and effectiveness. They take place after a new treatment has been approved and is on the market.
Updated: November 2, 2012
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PsyL,
Yes, very helpful. Immediately I realize that I’m just remembering a very old version of this. It has been streamlined and much improved. The big bugaboo of the 80s obsessive Phase III has been moved completely to Phase IV where the drug is already on the market. Meanwhile, Phase I, II, & III have been supercharged to be more effective. I’d be interested in what they mean by Phase Zero.
Now I’m starting to feel like my feet are on the ground. So I’ll ask you the next question. Do you feel given the FDA regime in place or even with any minor improvements still fails the Freedom Test? In other words is a fundamental right of the patient to choose being subverted by FDA even if the regs are as rational as you can imagine them to be?
Regards,
Jim
Noted, and thank you. But I wasn’t even thinking of this interview when I read the post. I do have a position. I think at times the FDA is in a damned-if-you-do and damned-if-you-don’t position. Given the small number of sufferers of this disease, each individual is essentially a clinical trial. I don’t know if the FDA will be involved but actually hope so because someone should be keeping abreast of how well or ill the drug worked – at least for this particular individual. Having at least the beginning of an idea about how and when this might work and what dosages should be meted out might benefit the next patient; and the FDA might be the agency making that information available to the next doctor facing the next diseased patient.