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Sunday, January 13, 2019

The Ethics of Clinical Trials

In a clinical trial the therapy is decided by a pseudo random number generator. How can this be ethical ? People are treated differently for no reason related to different interests different values and priorities or even different merit (assuming merit can differ).

There is a utilitarian rational for clinical trials. Through such trials doctors learn, and that knowledge is useful to future patients. But this rationale is utterly rejected as ethically unacceptable, because it was used to justify depraved experiments.

I think the current discussion of the ethics of clinical trials is based on a mixture which is partly consequentialist and partly deontological, and that it is incoherent, because people feel the need to claim it is totally both, while the two are inevitably in conflict.

So it is asserted that physicians must act in the interest of the patient – each and every patient. It is also argued that clinical trials are morally acceptable. This does not make sense.

It is only possible if the expected welfare of the patients is identical under the two treatments over which one randomizes. Any difference, no matter how tiny, in expected welfare would compel the use of only the current standard therapy, or of only the new experimental therapy.

I think the failed effort to avoid this is to reject the concept of expected welfare. It is argued that it is OK to do one or the other because one does not know which is better for the patient.

It would be OK if one were to say all probabilities must be rounded to 0, 1 or 0.5 so we don’t know means each is exactly equally likely. However, this approach would make life strange and brief. In particular it would rule out general anesthesia for any procedure not necessary to save a life. The chance of death is very low but demonstrably not zero. Don’t operate unless you would operate with a 50% chance of killing the patient would rule out almost all surgery. We must make choices under uncertainty and can’t pretend that all uncertainty is the same and survive for long.

Consider 2 examples.

Another is that there are 2 treatments, and, with best estimates, with treatment A the probability that the patient lives is 50% and with treatment B the probability is 30%.

Another is that there are 2 treatments, and, with best estimates, with treatment C the probability that the patient lives is 50% and with treatment D the probability is 30%.

According to current medical ethics, one must provide treatment A not treatment B but one may chose treatment D or treatment C. This always is based on the assertion that the interests of the patient is all that matters. Yet I have assumed that, for the patient, the two pairs of choices are identical. This can’t make sense.

In the first case there is an unobservable difference between patients of type 1 or type 2 where if they are type 2, then treatment A kills them on the spot. 10% of people are of type 2 (as learned from decades of painful experience). If someone is of type 1, their chance of surviving with treatment A is 5/9. In contrast with treatment B all have a 30% chance of living. With decades of painful experience it is known with essentially complete certainty that the probabilities are 50% and 30%.

In the second case, there aren’t two types, but the evidence on treatment C is preliminary based on a small (phase II) trial. The fraction who survived in the trial was 50% but the 95% confidence interval is 20% to 80%. The null that the true chance is 30% is not rejected at standard confidence intervals. By standard reasoning it is time for a phase III trial with randomization.

In each case, we know that giving A not B might cause a patient to die who would otherwise live and our best estimate of the probabilities of survival are higher with A than with B and higher with C than with D. I think the difference is that one learns something by randomizing and giving half of the patients D and that this outweighs the expected deaths due to the randomization.

I think it is possible to believe people have a right to care, and also conduct randomized trials, if one says there must be a standard of care, and all people have right to that. That one may deviate if the weight of evidence suggests that an experimental therapy is better, but that such deviation is a matter of utilitarian total expected welfare maximization not individual rights which trump average interests.

But it is not easy or comfortable to believe this, so I think that doctors have decided to rely on statistics but reject the very concept of probability. The logical inconsistency might cause some discomfort. It would cause more if the concept of probability weren’t so utterly alien to normal human thought. But in any case the tension between believing in rights and believing those rights don’t always trump utilitarian calculations clearly causes more discomfort.


The Sophist said...

Robert, two comments: (1) your example might have a typo? Both sentences are nearly-identical?

(2) in fact, IIUC, when a treatment in a trial shows signs of being significantly worse than the current standard of treatment, the trial is discontinued. E.g. that happened with at least hormone replacement therapy trial that I remember reading about a while back. Or at least, I think that was the therapy being tested -- I might be misremembering. But it *does* happen.

(3) Furthermore, there *is* a "standard of care" that cannot be breached. This is why (for example) it is *impossible* to test vaccines by randomly vaccinating only some subjects: we have good enough evidence that vaccines protect against infections, that it would be unethical to deprive even willing patients of vaccines.

JimV said...

I too have heard of a case or cases (I am not sure when or where) in which a medical trial was ended early due to first results which were either very promising (in which case everyone got the treatment) or very negative.

I think the general idea is that a trial is done when there is no consensus that a treatment is worth doing but no other good alternatives exist, but I am sure they are misused also.

Let me take this rare opportunity of having a comment marginally worth submitting to also write that this is a great blog--very informative. One wishes you wrote a weekly column for the Washington Post or New York Times.

Robert said...

Thanks JimV.

Yes trials have been stopped because there is strong evidence that one of the two therapies is better than the other, so the trial is no longer ethical. One was the huge mail an aspirin to 10000 MDs and a placebo pill to another 10000.

Yes I know that there is a right to standard of care. I was proposing that if evidence supporting a new therapy isn't strong enough to establish a new standard, then trials are still allowed But (crucially) this is not accompanied by nonsensical assertions that the evidence for the new therapy and the old are perfectly balanced.

The current *justification* for current rules for clinical trials is that statistically signficant evidence from a phase II trial tells us nothing, so with no idea which therapy is better we can conduct a phase III trial.

This is nonsense.

So I object to the clearly false assertions used to justify the current approach to clinical trials. I don't object to the current approach. I just think it shouldn't be defended with lies.

This is actually important. Consider a trial of an off label use of an approved pharmaceutical (required to be allowed to advertise the drug for the new use an IND and clinical trials registration is legally required even if the drug is not a new drug but a new use of an old drug and the company wants to advertise this new use).

It is argued that there is no way to know if the drug is effective for new use. This is argued even if there is phase II evidence that it is effective for the new use. So patients who have the problem and don't meet the conditions for the trial are treated with the old standard of care.

Evidence (which isn't strong enough for approval) that an off label use of a drug is good for the patient is ignored, because if it weren't ignored, the dishonest justification for giving patients in the trial the placebo (or old standard care) could not be used.

The honest statement that we respect your right to standard of care, but, behond that, balance your interests and the interests of science would be good for people who would (more likely than not) benefit from the new therapy and who are not eligible for the trial.

More generally, the assertion that unproven treatments are against the patients interest (even if there is some evidence that they are better than standard of care) may be necessary to protect society from charletans, but it doesn't make any sense given rational calculations of the probability distribution of outcomes.

My concern is that the right approach to trials is defended not with honest but unpleasant ethical arguments (which I consider valid) but with nonsense. Then the nonsense affects care of patients not enrolled in trials.

As a result people die who otherwise would live (and I guess some live who would die) I think more die than would if people thought sensibly about the issues and weren't attached to extreme ethical statements rendered other than catastrophic by nonsensical statements about inference and probability, so the combination of the nice sounding claim that "we consider only the interests of the patient" and the necessary nonsense so this doesn't block all scientific progress kills people.

GC said...

Sophist - Re the misprint: the first "Another" should be "One"

This misprint makes a deliberately odd presentation odder than intended.