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The history and role of randomized controlled trials in medicine

Drawing on his experience of being part of a Covid vaccine trial, Senior Medical Writer Guy Karger, explains why RCTs have become the ‘gold standard’ for vaccine and drug development, but also their limitations, especially when applied to rare diseases.

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15 February 2022

By: Guy Karger

As we ride yet another wave of the SARS-CoV-2 coronavirus, I think back to just over 1 year ago when I fell victim to it. Although my symptoms were very mild, I was told to go to the hospital – not to the emergency department but to a nondescript Portakabin in an underground car park – and call someone to meet me on arrival. The reason for my special treatment? Well, my contact was a clinical trial coordinator and I was a volunteer in a Covid vaccine clinical trial. As she worked her way through her examination in full PPE, including taking multiple vials of my infected blood, it occurred to me she was in quite an unusual situation for a clinician. She could take my history but have no way of knowing my vaccine status. She sent my blood to be tested for antibodies but would never know the results, and neither would I. In a double-blind, randomised controlled trial (RCT), it is the blind leading the blind.

In the flood of data the pandemic has brought since the SARS-CoV-2 genome was published, one aspect of medicine that has remained somewhat above the fray of claim and counter-claim is the status of the RCT as the ‘gold standard’ examination to declare a vaccine or drug for the betterment of human health. So, it is worth knowing a bit of how this came about because this status was not really secured until the last quarter of the 20th century. The first RCT with positive results was published in 1948 and, although considered a seminal piece of work, it was not placebo controlled. The leap it took was to randomly allocate patients with tuberculosis to a group receiving experimental streptomycin or a group just resting in bed. The investigators took great care to blind themselves and also their patients even though they did not give them a placebo – they simply didn’t tell their patients they were part of a trial and placed them in a separate ward to the treatment group. Modern informed consent protocols ensure such dubious ethics could not take place today!

The Origin of RCTs

The idea of a randomised trial did not originate in interventional medicine. Indeed, it took more than half a century to take root after being practised first in psychology. One early experiment in 1884 used a method of randomisation as familiar to gamblers or magicians then as now: a shuffled pack of playing cards. They were used to determine in what order a higher or lower pressure was applied to a subject’s finger so as to test how accurately the subject could perceive differences in sensation. Modern methods of random allocation use computers but the principle is the same, as is the objective: to minimise bias and prejudice in subjects and investigators concerning an experimental action and its outcome.

International guidelines and ethical principles surrounding clinical research were established during the 1960s. However, it was not until a US Supreme Court ruling in 1973 upheld regulations introduced by the US Food and Drug Administration (FDA) to tighten criteria for clinical trials in the wake of the thalidomide scandal that RCTs were seriously integrated into drug development efforts by the pharmaceutical industry. The new rules led to thousands of drugs having their approval withdrawn on the basis of lack of efficacy, and a new era of patient protection was born.

Recruitment challenges and the use of placebos

But there are drawbacks to RCTs. The need for sufficient statistical power to divine small treatment effects drives a need to recruit sometimes thousands of patients at great cost, and long-term effects can be difficult to ascertain, especially if it becomes ethically impossible to withhold a treatment from the control group. The need for homogeneous patient characteristics between treatment and control groups means that external validity can be reduced – how applicable the results are to patients outside the trial who might be sicker, older or of different ethnicity. In some disease areas, the use of a placebo can be difficult to justify if the standard of care is ineffective and the experimental treatment has shown great promise in earlier uncontrolled trials. In other cases, the standard of care might be administered by a different, more invasive route to the experimental treatment, one which is difficult to justify blinding with a sham control, for instance, lumbar puncture.

Rare diseases and accelerated approvals

Some innovative treatments for rare diseases and cancers have fallen foul of these difficulties, yet they have managed to gain approval with the results of uncontrolled or ‘open-label’ trials. In most, but not all cases, these conditions are terminal with very little hope offered by the standard of care. Both the FDA and European Medicines Agency (EMA) have pathways for accelerated approval of drugs where there is obvious need and, in some cases, the approval is conditional on randomised trials in the post-marketing setting. In some cases – imatinib in chronic myeloid leukaemia, for example – the efficacy of a drug is so great in uncontrolled trials that the RCT is never conducted and the confirmatory evidence comes from real-world patients. However, gefitinib is an example of a drug approval being rescinded after evidence from an RCT post-approval showed no survival improvement. There can also be glaring inconsistencies in approvals for different drugs for the same condition. Taliglucerase alfa was approved for Gaucher disease, a rare metabolic condition, without controlled trial results, whereas velaglucerase alfa was evaluated 2 years earlier in an active-controlled trial. Sometimes, the absence of approved therapies as standard of care is a barrier for one developer (e.g. alemtuzumab in chronic lymphocytic leukaemia) but another may be happy to use off-label controls to satisfy the demands of RCT design (pixantrone in non-Hodgkin lymphoma).

My participation in the Covid vaccine trial continued for a further 9 months officially, although I was unblinded as soon as I was offered a vaccine as part of the national rollout. It turned out I had been given the placebo and so I took my place as an ‘event’ in the control group as part of the final analysis of an authorised Covid vaccine. Through a design that was unheard of in the medical world at the time of the Spanish ‘flu pandemic in the early 20th century, a single RCT was enough to convince scientists across the world that the vaccine was safe and effective. But whether we ordered a polymerase chain reaction (PCR) test, talked to a Test and Trace operative or took part in a clinical trial, the story of Covid will be written in the data built from the contributions of billions of people all over the world, and may yet herald a new era of participation in medical science.

 

References:

Shultz KF, Grimes DA. Allocation concealment in randomised trials: defending against deciphering. Lancet. 2002;359(9306):614–618. https://en.wikipedia.org/wiki/Randomized_controlled_trial#cite_note-Schulz-2002-46

Streptomycin Treatment of Pulmonary Tuberculosis: a Medical Research Council investigation. Br Med J. 1948;2:769. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2091872/pdf/brmedj03701-0007.pdf

Bhatt A. Evolution of clinical research: a history before and beyond James Lind. Perspect Clin Res. 2010;1(1):6–10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149409/

Peirce CS, Jastrow J. On small differences in sensation. Mem Natl Acad Sci. 1884;3:75–83.http://psychclassics.yorku.ca/Peirce/small-diffs.htm

US Food and Drug Administration. Milestones in U.S. Food and Drug Law. Available at: https://www.fda.gov/about-fda/fda-history/milestones-us-food-and-drug-law. Accessed February 2022.

Hatswell AJ, Baio G, Berlin JA, et al. Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999-2014. BMJ Open. 2016;6(6):e011666. https://bmjopen.bmj.com/content/6/6/e011666

Tsimberidou AM, Braiteh F, Stewart DJ, et al. Ultimate fate of oncology drugs approved by the US Food and Drug Administration without a randomized trial. J Clin Oncol. 2009;27(36):6243–6250. https://ascopubs.org/doi/10.1200/JCO.2009.23.6018

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