Clinical trials
Clinical trials are experiments that study the effectiveness of medical treatments on actual patients. Medical treatments can harm as well as heal, so clinical trials spotlight the ethical problems of experiments with human subjects. Here are the starting points for a discussion:
Who owns published data? A researcher gathers data and publishes it. Who owns the data? The U.S. Supreme Court has ruled that “data” are facts and cannot be copyrighted. However, compilations of facts are generally copyrightable. So the answer to who owns data is not always clear. No permission is required for the use of published data or the creative use of a subset of data. Data from a table used to make a graphical presentation or data read off a graph can be used freely without permission. But beyond these guidelines, there is tremendous variation in determining whether permission is needed.
• Randomized comparative experiments are the only way to see the true effects of new treatments. Without them, risky treatments that are no better than placebos will become common.
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• Clinical trials produce great benefits, but most of these benefits go to future patients. The trials also pose risks, and these risks are borne by the subjects of the trial. So we must balance future benefits against present risks.
• Both medical ethics and international human rights standards say that “the interests of the subject must always prevail over the interests of science and society.”
The quoted words are from the 1964 Helsinki Declaration of the World Medical Association, the most respected international standard. The most outrageous examples of unethical experiments are those that ignore the interests of the subjects.
EXAMPLE 4 The Tuskegee syphilis study
In the 1930s, syphilis was common among black men in the rural South of the United States, a group that had almost no access to medical care. The Public Health Service recruited 399 poor black sharecroppers with syphilis and 201 others without the disease in order to observe how syphilis progressed when no treatment was given. Beginning in 1943, penicillin became available to treat syphilis. However, the study subjects were not treated, even after penicillin became a standard treatment for syphilis. In fact, the Public Health Service tried to prevent any treatment until word leaked out and forced an end to the study in 1972.
The Tuskegee study is an extreme example of investigators following their own interests and ignoring the well-being of their subjects. A 1996 review said, “It has come to symbolize racism in medicine, ethical misconduct in human research, paternalism by physicians, and government abuse of vulnerable people.” In 1997, President Clinton formally apologized to the surviving participants in a White House ceremony.
The Tuskegee study helps explain the lack of trust that lies behind the reluctance of many blacks to take part in clinical trials.
Because “the interests of the subject must always prevail,” medical treatments can be tested in clinical trials only when there is reason to hope that they will help the patients who are subjects in the trials. Future benefits alone aren’t enough to justify any experiment with human subjects. Of course, if there is already strong evidence that a treatment works and is safe, it is unethical not to give it. Dr. Charles Hennekens of Harvard Medical School, who directed the large clinical trial that showed that aspirin reduces the risk of heart attacks in men, discussed the issue of when to do or not to do a randomized trial. Here are his words:
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On the one hand, there must be sufficient belief in the agent’s potential to justify exposing half the subjects to it. On the other hand, there must be sufficient doubt about its efficacy to justify withholding it from the other half of subjects who might be assigned to placebos.
Why is it ethical to give a control group of patients a placebo? Well, we know that placebos often work. Patients on placebos often show real improvement. What is more, placebos have no harmful side effects. So in the state of balancing belief and doubt described by Dr. Hennekens, the placebo group may be getting a better treatment than the drug group. If we knew which treatment was better, we would give it to everyone. When we don’t know, it is ethical to try both and compare them. Here are some harder questions about placebos, with arguments on both sides.
EXAMPLE 5 Placebo controls?
You are testing a new drug. Is it ethical to give a placebo to a control group if an effective drug already exists?
Yes: The placebo gives a true baseline for the effectiveness of the new drug. There are three groups: new drug, best existing drug, and placebo. Every clinical trial is a bit different, and not even genuinely effective treatments work in every setting. The placebo control helps us see if the study is flawed so that even the best existing drug does not beat the placebo. Sometimes the placebo wins, so the doubt about the efficacy of the new and the existing drugs is justified. Placebo controls are ethical except for life-threatening conditions.
No: It isn’t ethical to deliberately give patients an inferior treatment. We don’t know whether the new drug is better than the existing drug, so it is ethical to give both in order to find out. If past trials showed that the existing drug is better than a placebo, it is no longer right to give patients a placebo. After all, the existing drug includes the placebo effect. A placebo group is ethical only if the existing drug is an older one that did not undergo proper clinical trials or doesn’t work well or is dangerous.
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EXAMPLE 6 Sham surgery
“Randomized, double-blind, placebo-controlled trials are the gold standard for evaluating new interventions and are routinely used to assess new medical therapies.” So says an article in the New England Journal of Medicine that discusses the treatment of Parkinson’s disease. The article isn’t about the new treatment, which offers hope of reducing the tremors and lack of control brought on by the disease, but about the ethics of studying the treatment.
The law requires well-designed experiments to show that new drugs work and are safe. Not so with surgery—only about 7% of studies of surgery use randomized comparisons. Surgeons think their operations succeed, but innovators always think their innovations work. Even if the patients are helped, the placebo effect may deserve most of the credit. So we don’t really know whether many common surgeries are worth the risk they carry. To find out, do a proper experiment. That includes a “sham surgery” to serve as a placebo. In the case of Parkinson’s disease, the promising treatment involves surgery to implant new cells. The placebo subjects get the same surgery, but the cells are not implanted.
Placebos work. Patients on placebos often show improvement and their inclusion produces a better experiment. As more doctors recognize this fact, more begin to ask, “If we accept a placebo in drug trials, why don’t we accept it in surgery trials?” This is a very controversial question. Here are two arguments about whether placebos should be used in surgery trials.
Yes: Most surgeries have not been tested in comparative experiments, and some are no doubt just placebos. Unlike placebo pills, these surgeries carry risks. Comparing real surgeries to placebo surgeries can eliminate thousands of unnecessary operations and save many lives. The placebo surgery can be made quite safe. For example, placebo patients can be given a safe drug that removes their memory of the operation rather than a more risky anesthetic required for the more serious real surgery. Subjects are told that they are in a placebo-controlled trial, and they agree to take part. Placebo-controlled trials of surgery are ethical (except for life-threatening conditions) if the risk to the placebo group is small and there is informed consent.
No: Placebo surgery, unlike placebo drugs, always carries some risk, such as postoperative infection. Remember that “the interests of the subject must always prevail.” Even great future benefits can’t justify risks to subjects today unless those subjects receive some benefit. We might give a patient a placebo drug as a medical therapy because placebos work and are not risky. No doctor would do a sham surgery as ordinary therapy because there is some risk. If we would not use it in medical practice, it isn’t ethical to use it in a clinical trial.
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STATISTICAL CONTROVERSIES
Hope for Sale?
We have pointed to the ethical problems of experiments with human subjects, clinical trials in particular. Not doing proper experiments can also pose problems. Here is an example. Women with advanced breast cancer will eventually die. A promising but untried treatment appears.
The promising treatment is “bone marrow transplant” (BMT for short). The idea of BMT is to harvest a patient’s bone marrow cells, blast the cancer with very high doses of drugs, then return the harvested cells to keep the drugs from killing the patient. BMT has become popular, but it is painful, expensive, and dangerous.
New anticancer drugs are first available through clinical trials, but there is no constraint on therapies such as BMT. When small, uncontrolled trials seemed to show success, BMT became widely available. The economics of medicine had a lot to do with this. The early leaders in offering BMT were for-profit hospitals that advertise heavily to attract patients. Others soon jumped in. The New York Times reported: “Every entity offering the experimental procedure tried a different sales pitch. Some promoted the prestige of their institutions, others the convenience of their locations, others their caring attitudes and patient support.” The profits for hospitals and doctors are high.
Should we have waited for controlled clinical trials to show that the treatment works, or was it right to make it available immediately? What do you think? What are some of the issues that should be considered?
NOW IT’S YOUR TURN
Question 7.4
7.4 Ethics and scientific research. The authors of a paper on clinical research and ethics stated the following.
For a clinical research protocol to be ethical, the methods must be valid and practically feasible: the research must have a clear scientific objective; be designed using accepted principles, methods, and reliable practices; have sufficient power to definitively test the objective; and offer a plausible data analysis plan. In addition, it must be possible to execute the proposed study.
Do you think this rules out observational studies as “ethical”?