Placebo trials require special care by IRBs
Placebo trials require special care by IRBs
Standard of care, crafting informed consent are key
Many IRBs rethink their organizational structure to provide for more efficient review; some decide the time is right to create a second IRB and divide their studies into different areas of expertise.
The ethics of approving a placebo-controlled clinical trial can be tricky for IRBs. While a trial that employs a placebo can provide scientifically valuable information, IRBs must weigh the potential harm of leaving a patient with a medical condition untreated during the course of the study.
As the number of drugs available for previously untreatable conditions continues to increase, it would seem logical that the number of placebo-controlled trials would decrease.
But Ana Iltis, PhD, an ethicist at St. Louis University, St. Louis, MO, says that's not necessarily the case. The particulars of available treatments, FDA requirements, and even the possible risks of an active-control trial can all lead researchers to believe that a placebo is warranted.
"For example, if you're doing an active-control trial, do you need to involve a much larger number of subjects? Is it going to take a much longer amount of time to have data?" Iltis says. "There's also been debate over when the FDA requires placebo controls. So there are some scientific questions at stake, too.
"Those I think are the most challenging cases, where we really have to ask questions about whether that's appropriate."
Clinician vs. investigator
Iltis says the IRB she serves on at St. Louis University does review placebo-controlled studies and has, on occasion, rejected them, even after researchers have attempted to justify them or to add additional safeguards.
She says that one important ethical concern about placebos is a duty to provide care, which is particularly important when physicians are enrolling their own patients in a study.
"I don't think patients generally see their physician as an investigator — it's their doctor," Iltis says. "And I do think there tends to be a recognition that the physicians involved in these cases, by and large, are not only researchers, but somebody's clinician, and you need to account for that in deciding whether or not a placebo control is appropriate."
She says it can be difficult for an IRB to judge what the standard of care is for a condition, particularly if standard treatments are not very effective or have serious side effects.
"They'll say, 'We have standard treatments, but they don't work,'" Iltis says. "When you're at an IRB and you're given that kind of answer and you don't have the expertise yourself, it's hard."
Pregnant subjects can bring an added degree of difficulty to the decision-making, simply because there has been so little research done with them. "So, there are a lot of unanswered questions. You may know what the standard of care is, but it hasn't been tested."
When confronted with a placebo-controlled study, Iltis recommends asking very detailed questions about the standard treatment.
"Is there a standard intervention available? Sometimes the answer is 'Yes, but . . . it's really burdensome, it's not that effective, and it has really bad side effects.'
"Then I ask, well, if you had a patient who rejected this [standard] treatment, what would you do? Would you say OK? Would you insist that no, no, no — you have to get this?"
If a physician would be comfortable with his patient declining the standard treatment, then Iltis says the use of a placebo is less problematic.
"But if you say, 'I would never let somebody just altogether reject this treatment,' then I think you've got some real concerns about a placebo," she says.
Bringing in experts
Iltis says it's important for an IRB to have sufficient depth of expertise on the disease being studied.
"And this is always an issue because often the people with the expertise are on the study and so they have a conflict," she says. "If you can't answer it within your own IRB, then you start asking questions."
In addition to tapping experts within the institution for help, Iltis says her IRB has actually paid for outside expertise to help better understand a study.
"Because everybody at the institution was on the study, we took their word for whatever we could, but at some point, we felt like there was an obligation to go beyond that," she says. "Even after people with medical expertise on the IRB had gone out and done their homework, we were still left with pretty significant questions and didn't feel comfortable proceeding based on just what they knew.
"And that's another piece of it — IRB members have a responsibility of doing due diligence and going out and looking. But sometimes that's not enough. And knowing your limits is really important."
In cases where placebo is found to be justified, Iltis says the researchers often must put in safeguards, such as physician rescue provisions, to prevent serious harm to the subject as a result of going untreated too long.
"This often happens with studies of diabetics — you'll say, 'At what level of hemoglobin A1c are you going to pull them out?"'
Another safeguard would be to keep the trial as short as is feasible, so the patient is not potentially off medication long enough to cause lasting harm.
"If you have somebody who's had a disease for maybe 10 years now, and it hasn't been treated and it's just been caught, what's another six weeks without treatment?" Iltis offers as an example.
She says that in any case, informed consent documents in placebo-controlled trials must clearly spell out that some subjects will receive placebos, what that means, and that there are alternative treatments that a patient could pursue outside the study.
"The alternatives should always be spelled out, but there's some debate about how much they should be spelled out," Iltis says. "Is it OK to say, 'There are alternative treatments and your doctor can discuss these with you?' Or should you list them in detail?"'
"I'm an advocate for listing at least some detail because I think people need to know that."
But Iltis says there's a limit to how much detail is appropriate.
"To be honest, there are cases where the investigators want to include the downfalls of standard treatments in the research consent forms, and I've typically seen that discouraged," she says. "Some people have seen it as a way of trying to tell people the standard really isn't very good, that you ought to be in research instead."
Many IRBs rethink their organizational structure to provide for more efficient review; some decide the time is right to create a second IRB and divide their studies into different areas of expertise.Subscribe Now for Access
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