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Jeanne Lenzer writes: >Could anyone explain the pros and cons of the following: > >Uncertainty principle (absence of proof): Further inclusion >and exclusion criteria are not specified precisely but are >guided by the uncertainty principle (or absence of proof >for that particular patient). If, for whatever reason, the >clinician is convinced that a patient fulfilling the above >criteria should be treated, that patient should be given open >label drug and not randomized. If the clinician is convinced >that a patient should not be treated (for whatever reason), >the patient should not be included in the trial. Only those >patients who fulfill the eligibility criteria AND for whom the >clinician is still substantially uncertain about the balance of >risks and benefits of active drug should be randomized. > >Can this kind of enrollment liberalism cause a failure of true >randomization? Does it introduce spectrum and other biases? > >Thank you any and all for any insight you can give this underfed journalist. > This touches on an issue I am working on right now: the ethics of placebo controlled trials. I have a very rough draft on my web pages: http://www.childrens-mercy.org/stats/plan/placebo.asp I would be very interested in feedback on this page from members of evidence based health. It's an important issue and I want to try to present all sides fairly. I will give a talk on this topic at our hospital on September 12, so your help will be especially appreciated. To address some of Jeanne Lenzer's specific concerns: 1. I prefer the term volunteer bias to spectrum bias because it is more general. Your concern, I suspect, is that the requirements will narrow the spectrum of patients from whom you can randomize. That may be true, but the requirements might create other distortions that are equally troublesome. All randomized trials suffer from volunteer bias. The very process of informed consent will remove many subjects from the pool of available patients. While it is difficult to estimate how much this weakens the evidence, there are specific examples of problems. There was a study of how personality was affected by some biomarkers found in Cerebro Spinal fluid (CSF). You can only get CSF, of course, with a lumbar puncture (spinal tap). What sort of person would volunteer to a research study that required a spinal tap? I'm sure there was some monetary compensation but a spinal tap is painful and carries some risk of medical problems. Well in this case, there was some hard data. The subjects who were recruited for the trial were those who had already participated in an earlier non-invasive trial where they completed various personality tests. When they looked at the scores on these tests, they found a large difference between those who agreed to the spinal tap and those who refused. The volunteers scored half a standard deviation higher on an impulsivity scale. There is also evidence that patients who are drawn from a pool of subjects who have participated in previous research represent a biased sample. These patients, it turns out, are far less likely to have a genetic variant that is associated with a tendency towards adverse drug reactions. Such a subject pool, of course, will understate the risks of many drug therapies. 2. Reading between the lines, I think you are saying that application of the uncertainty principle as stated above might further exacerbate the problems of volunteer bias. This is debatable. If the above requirements were not there, the researchers perhaps would have specified much more detailed inclusion and exclusion criteria so as to avoid randomizing someone who is clearly a candidate for only one of the treatments. Richard Peto has criticized excessively detailed inclusion criteria as a barrier to entering the large number of patients that are needed in mega-trials. 3. In most research, there is an implicit tension between the rights of the individual and the needs of society. The evidence base of a research study is weakened in order to reduce the chance that some individuals are randomized to a treatment that is known or suspected to be inappropriate at the time of randomization. This may mean a delay in discovering an effective treatment for society as a whole. In general, I feel that the rights of the individual to get the best available treatment should trump the need of society for a strong evidence base. A good example of this tension was a recent study of cellular implants for patients with Parkinson's disease. Blinding is important because some of the outcome measures are subjective and drug studies have shown a very strong placebo effect. So the researchers proposed (and got IRB approval) for a study where some patients were randomly assigned to a placebo operation group. These patients underwent the same operation where a hole was drilled in the skull, but no material was inserted into the brain. This made for a strong evidence base, but were the rights of the individuals ignored? Can you justify exposing a patient to the risks of a placebo operation when there is no direct benefit to that patient? 4. Making an experimental or unproven treatment available outside the realm of a randomized trial is itself a controversial issue. The New England Journal of Medicine recently released early the results of a trial of lung volume reduction surgery for patients with severe emphysema. This is a treatment where there was evidence in 1996 of efficacy based on a comparison of 150 consecutive surgeries to historical controls. But the high cost of the surgery and the uncertain evidence basis of the 1996 study caused the NIH and HCFA to bar the use of Medicare funds for this surgery unless the patient agreed to participate in a randomized trial. Patients who wanted the surgery had to either take their chances or pay for the surgery themselves. Should patients who trust the results of a non-randomized study be denied the opportunity to a therapy until others have collected more definitive randomized evidence? Details about this trial can be found at the NEJM web site: http://www.nejm.org It turns out that, at least for some patients, the surgery was actually harmful. Even so, the concept of restricting patient choice seems to be a difficult issue to resolve. William Silverman, in a recently published book, argues strongly against allowing unproven therapies to be available outside a randomized trial. There are some interesting examples involving ECMO and Laproscopic Surgery where these treatments were embraced by many in the medical community before they were tested with randomized trials. Furthermore, those who proposed randomized trials were criticized as unethical. I'm trying to pull together the details on these examples, so any help from the Evidence-Based-Health readers would be appreciated. Steve Simon, [log in to unmask], Standard Disclaimer. STATS: STeve's Attempt to Teach Statistics. http://www.cmh.edu/stats Watch for a change in servers. On or around June 2001, this page will move to http://www.childrens-mercy.org/stats