Placebo Control Group Not Required
FDA doesn't require that a drug study include a placebo control group, DeLap says, only that its design be capable of establishing a drug's safety and effectiveness. Non-placebo types of drug studies include "head-to-head" studies, which compare the experimental drug to an existing treatment, and historically controlled studies, which compare the new drug's effects with information gathered in the past about the expected progression of a medical condition.
Often, however, a placebo control can provide the clearest insight into what a treatment can accomplish, according to DeLap, especially with some psychiatric and other drugs in which the placebo effect is known to play a particularly weighty role. In fact, DeLap says, in some cases the placebo effect "makes it almost hopeless, statistically" to use studies that test a new treatment side-by-side against an existing one and determine whether the new treatment works.
The placebo controls that have traditionally been used to test medications have recently been used, too, to test the effectiveness of surgical procedures. In one well-publicized study sponsored by the National Institutes of Health, half of the Parkinson's disease patients enrolled in the trial underwent a sham surgery in which doctors drilled holes into their skulls but didn't implant the potentially beneficial human fetal tissue in their brains.
While FDA doesn't evaluate the safety or effectiveness of most surgical techniques, the agency does regulate surgical implantation of animal cells or re-engineered human tissues. The agency has approved at least one sham surgery-controlled trial, which will study the effectiveness of implanted pig fetal cells for Parkinson's.
Even with the powerful scientific advantages of including a placebo control, researchers and FDA must look at each treatment individually to decide if the use of placebos is appropriate and ethical. In fact, much medical research does not involve a placebo control because "it's just not an option, ethically," DeLap says.
To determine whether a placebo-controlled trial is acceptable, drug company and FDA experts ask:
- For what condition is this drug being tested?
- What is the natural progression of the disease?
- How serious is the risk if a patient gets a placebo rather than an active treatment?
In DeLap's specialty, oncology, placebo-controlled studies are often unacceptable because of the great risk to cancer patients of any treatment delays. For a headache, on the other hand, patients in a study may be uncomfortable for a time, but are not at risk of a lasting health impact. So, for those conditions in which the downside of being on placebo is modest and short-lived, DeLap says, it's an individual's prerogative to say, "I know what I'm getting into, and I want to further this scientific research."
To help ensure that patients know the pros and cons of enrolling in a study, each participant must sign an "informed consent" form, which clearly explains:
- the purpose of the study
- what enrollees will be asked to do (take a pill twice a day for three months, for example, and visit the doctor once a week for blood and other laboratory tests)
- the possible benefits and known adverse reactions associated with the experimental treatment
- other therapies that are available for their condition.
Even willing participants can't sign away their right to a well-designed study, though, DeLap points out. "We can't fall into the trap of thinking that, once someone says 'I'm willing to participate,' their consent covers us for deficiencies. Our responsibilities go way beyond getting informed consent." One such responsibility: As a study progresses, researchers monitor results so if major positive or negative drug effects are seen, the study can be stopped. The first major clinical study of the AIDS drug AZT (zidovudine), for example, was halted early when researchers saw that AZT patients were living significantly longer than others in the study.
Still, some critics say today's safeguards are not sufficient and oppose the use of placebo-controlled studies in almost all drug research. Patients desperately seeking to end their suffering, some say, may not be capable of giving true informed consent.
DeLap and other FDA experts view any far-reaching ban on placebos in research as paternalistic. "We at FDA don't have an ethical blind spot, as some would suggest," DeLap says. "A patient's right to the best treatment is always paramount. But the social hope is that careful scientific research can help us learn beyond a shadow of a doubt what works and what doesn't, so that these patients' kids will have better treatments available to them."