Ethics of Placebo-Controlled Studies: Pediatric Study Challenged
​​[Posted on: Thursday, February 15, 2018]

A doctor with competing interests complained that a NIH-funded study similar to his earlier trial was unethical because it involved giving placebo to children. This prompted NIH to call an urgent meeting of the DSMB for the placebo-controlled trial and some changes to the trial to address the concerns. However, this case points to some important questions about the regulatory and ethical challenges with conducting placebo-controlled studies. Placebo-controlled studies are the gold-standard to demonstrate the efficacy of an investigational product. The need for placebo-controlled studies is widely accepted and written within the regulations for creating data to support market approval of all new drugs. Placebo-controlled studies are hard to recruit subjects for, require additional procedures for blinding and data management, and require DSMB to monitor for safety issues in a blinded study. Over the last 30 years, concerns have been raised over the safety and welfare of trial participants when given placebo but most concerns are alleviated with well designed studies and the need to confirm the utility of a new drug. There are cases where placebo-control can be challenging. The case in question concerns a study to evaluate the efficacy of high dose vitamin D therapy in preventing asthma attacks in children. The study involves 400 subjects, 6-14 years old, deficient in vitamin D, to either receive 4000 IU of vitamin D or placebo daily for almost a year (48 weeks). Previous studies have indicated that high doses of vitamin D therapy can reduce the frequency of asthma attacks in vitamin D-deficient children; however the results would likely not meet the standard of clinical evidence needed by FDA to allow asthma prevention claims on vitamin D due to the lack of placebo-control. The challenger to the study cited risk to children whose vitamin D is withheld for the year on the trial. The challenger, Dr. Bruce Davidson, is not involved in this study. Rather he conducted a similar study outside US where all participants were treated with different amounts of vitamin D. He claimed that his study already demonstrated the benefit of vitamin D therapy and hence the new placebo-controlled study subjected children to unnecessary and dangerous risk. There are a few interesting issues that should put this discussion in context. Vitamin D is widely available as a supplement and an additive in various foods. But any claim to treat asthma with vitamin D would require FDA approval as a drug and hence the need for controlled clinical trials. Controlled clinical trials are expensive and not practically feasible by supplement manufacturers hence the study in question is funded by NIH. The informed consent of the study clearly lets the parents of the children know about randomization to placebo and there are adequate measures in place to address any adverse events for participants. The DSMB and IRBs involved in the study agreed that the risk to the study participants was adequately addressed and that the study should continue. It is anyone’s guess if Dr. Davidson was motivated by genuine concern or publicity for filing the compliant with NIH. FDA has aggressively pursued supplement companies making medical claims forcing either to withdraw claims or do controlled clinical trials. Most supplements companies withdraw claims as doing a clinical trial is not financially feasible for them leaving most consumers not aware of the potential benefits of treatments with supplements. We need trials like this; can vitamin D supplementation truly reduce asthma attacks instead of expensive prescriptions. Without trials like this, we will never know, for sure.