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.
July 17, 2023
BY MARYANNE DEMASI, PHD and TOM JEFFERSON, MD
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. [https://jamanetwork.com/journals/jamain ... ct/2776287]
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 remain proprietary information of the drug manufacturers. For example, in the 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.
In 2017, Robert Shader, physician and editor-in-chief of Clinical Therapeutics, raised concerns when a study on people with multiple sclerosis published in the New England Journal of Medicine, injected one group of people with a monoclonal antibody (ocrelizumab) and the other group with a ‘matching’ placebo. But what was in the placebo?
“Was it saline? Was it the same vehicle in which the monoclonal antibody was dissolved?” asked Shader.
Shortly after, he made the following announcement to prospective authors:
Effective January 1, 2018 (Issue 1, Volume 40), we will require that a full description of any placebo (PBO) or matched control used in a clinical trial be given in the Methods section. It will no longer be sufficient to simply indicate that a PBO was used. This means that color; type (capsule or pill or liquid); contents (eg, lactose), including dyes; taste (if there is any); and packaging (eg, double-dummy) must be noted. For solid PBOs, shape must also be described, as well as whether the PBO is active or inactive. In addition, any efforts to study the success of matching should be included. For example, could subjects/patients or evaluating/rating clinicians guess assignments? Sham procedures must also be described in detail. We are instituting this change as part of our ongoing effort to facilitate replication of findings from trials. All too often this valuable information is omitted from published trial results.
Inappropriately matching a placebo to the experimental drug or vaccine can lead to under-reporting of harms or misleading trial outcomes as well as raising ethical questions about whether patients are properly consenting to participate in trials.
Even when one of us (TJ) found evidence that an ‘active’ ingredient in the placebo of a pivotal HPV vaccine trial had been misreported as ‘inert,’ neither the authors nor the editors acted to correct the error.
Placebo in the JUPITER trial
The JUPITER trial investigated the effects of 20 mg rosuvastatin (Crestor) in ‘healthy people’ at low risk of heart disease. It was a highly controversial study because - despite major criticisms - it underpinned the decision to grant regulatory approval for rosuvastatin for the prevention of “a first cardiovascular event.”
One aspect of the JUPITER trial piqued our interest. While muscle aches were similar in the statin and placebo groups, the reported rate of muscle aches in the placebo group (taking the ‘inert’ pill) was much higher (15.4%) than in the placebo group of other statin trials (<5%).
Therefore, we sought to obtain the CoA of the placebo pill used in the JUPITER trial, in the hope that it might explain why the ‘healthy subjects’ at low risk of heart disease in the placebo group, experienced an unusually high rate of muscle harms.
The process of obtaining the CoA for the placebo used in the trial turned out to be arduous.
The peer-reviewed publication in the New England Journal of Medicine contained no information about the contents of the placebo, nor did the study protocol, which only described it as a ‘matching’ placebo.
We then contacted the lead investigator - Paul Ridker, Professor of Medicine at Harvard University and Brigham and Women's Hospital - but he did not respond to our emails.
We made enquiries to the European Medicines Agency since it allows access to certain regulatory data. However, the agency informed us that it had not licensed any single statin (only two statin-fibrate combination products) so we turned to the individual member states of the European Union.
The Dutch drug regulator - i.e. Medicines Evaluation Board (MEB) - had licensed rosuvastatin and confirmed that it held the data relating to the JUPITER trial. But after multiple emails over several months requesting access to the CoA, the regulator finally conceded that it did not have that particular document in its possession.
We also lodged a request with the Australian drug regulator - the Therapeutic Goods Administration (TGA) - which informed us that the information we requested was “not publicly available and the TGA would not be in a position to release this information…without the permission of the sponsor (AstraZeneca Pty Ltd)”.
The TGA also stated that we could apply through a formal Freedom of Information (FOI) process, however, it would not guarantee the release of any information “if the sponsor raised valid objections” or if the documents were classified as exempt under the FOI Act. The TGA suggested that we approach the drug manufacturer directly, so we did.
After multiple emails and lengthy delays, we finally obtained a response from AstraZeneca stating that we could ‘apply’ for access to the information but that we could not share the data with any third parties without restrictions. The company stipulated in its conditions that we could not publish the CoA in the peer-reviewed literature and that any analysis of the CoA by us, would have to be “pre-reviewed” by the drug company since they were owners of the information.
We refused to abide by AstraZeneca’s conditions of access. This type of oversight, whereby research needs to be vetted by drug companies or where researchers are required to sign confidentiality agreements, can stifle open science.
Lack of transparency
Our attempts to independently analyse the formulation of the placebo used in the JUPITER trial to eliminate an unknown variable was time consuming, convoluted and ultimately, unsuccessful. Since the contents of the placebo remain unknown, we were not able to elucidate whether the absence of any increase in musculoskeletal harms in the JUPITER trial was a reliable outcome. Further, we are left with questions over whether this document was properly scrutinised by the drug regulators before making the decision to license the statin. We are concerned that significant aspects of clinical trials funded by the pharmaceutical industry are kept secret, with drug manufacturers having the final word on the trial outcomes of these widely used public health drugs.
SOURCE:
https://maryannedemasi.substack.com/p/w ... t/20951580