What's in the placebo?

We tried to find out what was in the “placebo pill” of one of the most controversial statin trials ever conducted.

A recent conversation between popular podcaster Joe Rogan and presidential candidate, Robert F Kennedy Jr ignited an international discussion about placebos in clinical trials. Here, we document the difficulty in determining the details (formulation and testing) of the placebo used in a controversial cholesterol-lowering trial of Crestor (rosuvastatin) – adapted from our earlier publication in JAMA Internal Medicine.

The basis for a “placebo” controlled trial is to reliably assess the safety and efficacy of a therapeutic drug or vaccine against a placebo – they can be active or inactive placebos.

An active placebo can be used to mimic the side effects of the intervention, with no therapeutic effects on the condition being treated.  For example, atropine may be used as a placebo in antidepressant trials to mimic the symptoms of “dry mouth” often experienced after using antidepressants, with no therapeutic effect on depression. The aim is to mitigate the risk of unblinding trial participants.

More commonly, placebos are intended to be inactive or inert. Inactive placebos should ‘match’ the sensory and visual aspects of the experimental drug to maintain blinding throughout the trial. In other words, a placebo needs to be equal in shape, size, colour, texture, weight, taste, and smell. 

Drug companies keep details a secret

Drug companies will often manufacture their own placebo for use in clinical trials. The technical data and analytical methods used for the placebo are detailed in the certificate of analysis (CoA), which is part of the dossier submitted to the relevant drug regulator as part of a licensing application.

Drug regulators are expected to analyse the CoA to ensure the placebo and the experimental drug are appropriately matched, to eliminate an unknown variable. However, the details relating to the contents of a placebo are often unknown to independent researchers and remains proprietary information of the drug manufacturers.  For example, the in trials of Gardasil (HPV vaccine), the manufacturer often used a placebo containing amorphous aluminium hydroxyphosphate sulfate (AAHS) – an adjuvant to enhance immune response – and has kept the formulation a proprietary secret.

In fact, the exact formulation of a placebo is rarely disclosed in the peer-reviewed publication of a clinical trial.  Further, medical journals do not require authors, nor drug manufacturers, to disclose the contents of a placebo or publish the CoA. Placebos may contain excipients such as chemicals, dyes, or allergens, which might unintentionally cause side effects, raising concerns about the reliability of trial data and the transparency of important information.