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A Painful Application of Medical Ethics

By John Ford - May 5, 2005 12:00 AM

The blogosphere has been increasingly active regarding a young woman, Amanda Twellman-Dieppa and her battle with cancer (see, for example, this post on Hugh Hewitts website). She has been petitioning Medarex Inc. to provide her with their experimental drug MDX-060 on an emergency basis. I have read a number of overly simplistic, even sinister-sounding presumptions for why the company has so far refused. I have no doubt that with the negative publicity generated by those who have come to her defense, Medarex will "come around" and give her the medication.

I have no idea whether she personally will be helped by this drug. I do know that to simply release it will most assuredly not advance the public's health.

This last statement of mine sounds so counter-intuitive that I suspect many people encountering it will immediately dismiss my argument without hearing it. The type of questions raised by this debate are so emotionally divisive that I wonder if I will be able to change even one person's mind. But bear with me.

How do we as physicians know anything about the safety and efficacy of new drugs? Clinical studies. And the gold standard of such studies is the randomized clinical trial (RCT).

In its simplest form, a RCT tests a study drug on a group of patients with a certain condition. The drug is given to half of them. The remainder are given a placebo or the usual treatment for that condition. Patients are assigned to one group or the other in a completely random manner with neither patient nor researcher knowing into which group a patient was placed. This information is maintained by a safety committee not involved in the analysis of the data. (This committee has the option of breaking the randomization for any reason involving the participants' safety.)

A major controversy arises when the condition being studied is uniformly fatal if existing treatments have been exhausted (as is apparently the case in this example). That problem is that an RCT as outlined requires a control group that doesn't get the benefit of even trying the new therapy.

Some might argue that no control group is needed. Give everyone the drug. The problem with this approach is it becomes difficult to analyze the data. With whom do you compare the patients' responses?

If 100% of all patients with the disease die with currently available treatment and some patients with the study drug miraculously survive, then the drug is probably efficacious. Unfortunately few drugs have this kind of dramatic effect. Most drug responses are far more subtle. Hence the need for a randomized control group.

Why not compare the study group to a set of historical controls? In other words, compare the responses to those of pre-study patients getting conventional therapy. This is often done but there are problems with this methodology.

It comes down to comparing apples to oranges. Without the randomization process described above, there is no way of guaranteeing that the study group and the control group (from another study) will be similar with possible confounding factors that could limit the validity of the analysis. Such factors might be age, sex, severity of illness, even factors the researchers had never even considered.

These then are some of the reasons RCT's are the holy grail of medical research. Without such studies, it is impossible to conclude firmly that a given treatment is indeed safe and effective. Without an RCT, one cannot even be sure that the study drug is not deleterious compared with standard treatments.

Ms. Twellman-Dieppa is apparently willing to sign a liability waiver, so why not just give the medicine and take what comes? After all, in her case, the disease is likely to be fatal without an extraordinary intervention.

This approach sounds logical and perhaps represents an admirable expression of human autonomy. Unfortunately, it comes with unintended consequences. When patients volunteer for clinical trials, it is carefully explained to them that they may be randomized into the control group. As one might imagine however, virtually no study participant aspires to be in the control group. If they knew in advance that that might happen, no one would opt to be in an RCT.

What we're left with are competing interests: on the one hand, the need for RCT's to firmly establish safety and efficacy and on the other hand, the understandable fact that no study participant wants to be randomized to the control group.

If a company developing a novel drug were to allow some patients access to it outside an RCT protocol -- as many are presently lobbying for in this instance -- everyone would want to do so and no one would enroll in RCT's. Such a policy may be beneficial for this patient (assuming the unsubstantiated fact that this drug helps and doesn't injure) but it will ultimately prove detrimental to the public at large. We will never be able to determine whether MDX-060 or any new drug is safe and effective in the future.

Certainly there are corporate reasons for not opening the drug to non-study-associated use. This case is gathering a lot of interest from the lay community. If Medarex releases the drug to Ms. Twellman-Dieppa and she has a bad outcome, this will become widely known; clearly not the sort of advertising this company would want.

However, this doesn't lessen the validity of Medarex's position. If, as Medarex claims, the current RCT designed to study MDX-060 is now closed to new enrollment, perhaps an ethical way of possibly helping this patient and maintaining the integrity of the research would be to simply extend the study's enrollment. If she met the study's entrance criteria, she could be randomized like any other patient.

Of course she would have to take her chances of getting randomized into the control group like any other participant. This strikes me as being quite fair in that the others in the study presumably have stories just as gut-wrenching.

John S. Ford, MD, MPH is Assistant Professor of Medicine, David Geffen School of Medicine at UCLA. YOu can find more of his writing here.

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