Placebo-controlled trials that limit supplementation potentially place people at risk of undue harm, warn researchers. It is essential to balance the need for identifying significant treatment effects against ensuring that patients are not harmed by being denied access to therapeutic treatment, say the review authors writing in Nutrients.
Placebo-controlled trials that limit supplementation potentially place people at risk of undue harm, warn rearchers.
It is essential to balance the need for identifying significant treatment effects against ensuring that patients are not harmed by being denied access to therapeutic treatment, say the review authors writing in Nutrients.
The research team was a collaboration between The George Washington University School of Medicine and Health Sciences (GWU), Washington, DC and The University of Chicago Pritzker School of Medicine, Chicago.
Adequate vitamin D status has been proven beneficial for bone health and has been increasing recognised as important in a wide variety of health outcomes. The area of vitamin D intervention trials is therefore one where ethical consideration of placebo arms should be given high priority in study design, argued the researchers.
“The potential adverse effects of withholding vitamin D supplementation in known cases of deficiency may include diminished bone health (short or long term) as well as increased risk of infection, autoimmunity, cancer, chronic disease, or even mental illness,” commented lead author Dr. Leigh Frame, Program Director of Integrative Medicine at GWU.
The possible conflicting objectives of identifying a significant effect of the treatment, versus excluding vulnerable individuals from potentially beneficial treatment, occurs in two principal types of trial design, explained the researchers.
Firstly, where there is an active control arm, but no placebo group and secondly, where there is a placebo group with supplementation restrictions.
The first case can lead to a situation where “the potential benefit of a research study can be diminished if lack of placebo leads to non-significant results. It would then be less ethical to expose participants to risk, even if minor, when it is unlikely for the study as designed to show significant benefit,” said Frame.
In the second case, the use of placebos has often yielded valuable information but raises ethical questions.
“Since vitamin D has a known benefit and vitamin D deficiency a known harm, it can be argued that withholding adequate supplementation poses an undue health risk to participants, especially those with known deficiency,” proposed Frame.
“The potential benefits of understanding the ideal dose of vitamin D may not outweigh the possible harm being inflicted on participants who are withheld vitamin D supplementation,” she added.
The authors proposed two potential solutions, which could enable significant outcomes to be identified, while avoiding harm to those potentially most in need of active treatment.
Firstly, trials could be designed with a placebo group but without supplement restrictions, the researchers argued. The VITamin D and OmegA-3 TriaL (VITAL) allowed participants to supplement up to 400IU/day (the Recommended Daily Allowance (RDA) at the time of commencement) to ensure the safety of those in the placebo arm.
The VITAL study researchers were thereby able to reduce the possibility of harm from vitamin D deficiency. By monitoring serum vitamin D concentrations in both groups, the study also achieved an effective control group, even though it had slightly higher background vitamin D levels.
“Allowing participants to consume additional vitamin D supplements addresses to some extent the ethical concerns raised by not doing so,” said Frame.
The second possible solution might be to use a placebo group with a rescue repletion program given to participants on a routine basis at the end of the trial.
Under this approach, placebo receivers may experience vitamin D deficiency during the course of the study, but would subsequently be given doses that reduce the risk of serious or irreversible harm, the scientists explained.
The scientists suggested that this alternative would preserve methodological robustness and would meet the 2001 Declaration of Helsinki qualifications for ethical use of a placebo group.
Nevertheless, the adequacy of risk reduction to placebo group participants would depend on the nature of the outcome being studied, the researchers cautioned. The suitability of this strategy in long-term vitamin D trials must also be addressed.
The researchers suggested a number of recommendations to promote the ethical use of placebo groups.
“The nutrition research community should establish guidelines for the ethical use of placebo-controlled supplementation studies. Before placebos are used in a study, investigators should engage in robust discussion over the ethical implications.
“Nutrition researchers should understand the relationship between ethical and methodologic challenges. Arguably, it is unethical to enroll any participants in a clinical trial that is not powered to detect a difference.
“Journal editors and funding agencies should also demand thorough ethical justifications of the use of placebos, especially in cases of known vitamin D deficiency or in vulnerable populations,” Frame proposed.
Establishment of such ethical guidelines could be used to set the standard for use of placebo groups in other areas of clinical treatment, the researchers concluded.