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This month in pharma

Exploring the industry's most important dates, we recall October 1948: The publication of the first modern randomised clinical trial

This month - randomise clinical trialArguably the first ever randomised trial comes from the Book of Daniel in the Old Testament where Daniel, resisting instruction from King Nebuchadnezzar II, followed a diet of pulses and water while a separate group of children consumed meat and wine. Observing greater health and fitness in Daniel after ten days of these differing regimens, King Nebuchadnezzar made everyone eat what appeared to be the healthier alternative.

It may be a story with a simple process, and an ostensibly logical – if scientifically unfounded – conclusion, but it highlights the rationale behind the modern randomised clinical process that remains the foundation for getting a drug approved and available to market. That is, to work out both if a treatment is effective and safe to offer patients, and if that treatment is more safe and effective than another currently available option.

It was 1946 before the scientific method caught up with the logic, however, with the UK Medical Research Council's (MRC) study into the use of antibiotic streptomycin as a treatment for tuberculosis patients seen as the first true randomised clinical trial, complete with control groups and blind assessment.

As stated in the control scheme section of the study's paper, published as 'Streptomycin Treatment of Pulmonary Tuberculosis' in the British Medical Journal (BMJ) on October 30, 1948: 'Determination of whether a patient would be treated by streptomycin and bed-rest (S case) or by bed-rest alone (C case) was made by reference to a statistical series based on random sampling numbers drawn up for each sex.'

This process involved sealed envelopes containing details of what trial arm the patient was involved in, with patients receiving only bed rest remaining unaware that they were participating in a trial.

At the end of the six-month observation period, 7 per cent of patients taking streptomycin had died, whereas 27 per cent of bed-rest patients had died. Radiology results noted considerable improvement in 51 per cent of streptomycin cases compared to 8 per cent of bed-rest cases.

It was a study that paved the way for a future of evidence-led clinical observation, but some of its most important ideas had been around for years.

Indeed, randomisation was first introduced into the field of trials in RA Fisher's 'crop variation' experiment in 1923 although, debatably, its first medical use was in 1926 in another tuberculosis trial when J Burns Amberson used the flip of a coin to decide which of 24 patients would receive the active treatment and which would be the control group.

Before this, such experiments were even less methodological, although they did manage to lead to some important, life-saving advancements. These included Scottish physician James Lind's attempt to prove citrus could cure the nutritional deficiency disease scurvy with what some see as the first use of control groups in experiments.
A set of scurvy patients was given the same general diet, with a select group receiving additional foods such as oranges and lemons. It was noted that the conditions of patients eating fruit were noticeably improved after just six days, although it took another 50 years before the Royal Navy made lemon juice a necessary part of the men's diet.

The past 60 years have seen trials develop and expand to cover tens of thousands of people across countries and continents. However, while it has come at a huge cost to the pharmaceutical firms, healthcare organisations and governments that fund them, trials are a vital necessity to ensure the drugs used do what they are intended to do and that they are the best available option.

Patient safety is not left to the flip of a coin nowadays either, and updated codes and regulations requiring informed consent from all participants are a staple part of the process, with evolution of the regulatory process seeing the formation of both the Committee for Medicinal Products for Human Use (CHMP) and European Medicines Agency (EMA) in Europe, as well as the continued development of the US Food and Drug Administration (FDA).

The MRC's streptomycin trial was one that led to many more TB studies that have helped find and develop treatments to save countless lives around the world. It is the same basic aim that Lind, Amberson and many others had with their own studies, and it is something that needs to remain at the heart of clinical trials today.


Tom MeekThe Author
Tom Meek
, web editor at PMLiVE

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31st October 2011

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