Clinical Trials 101: Unpacking the Fundamentals - Part 1

An introduction to clinical trials, including an overview of its history and definitions

Clinical trials now form a major milestone in the translational journey of a new medicinal compound or medical technology, and although as junior researchers, sometimes accompanying a new compound to that final, celebratory destination of a randomised clinical trial (RCT) can seem impossible, we must take heart from the fact that clinical trials have been documented well before our foray into science. To be exact, clinical trials have been on the scene since biblical times. That’s right. The first ever publication of a clinical trial, albeit without the peer review process that we all know and love in this age, was documented in The Book of Daniel. King (and not Professor) Nebuchadnezzar was documented to have ordered his troops to eat only meat and drink only wine, a vegan’s nightmare diet that the mighty King believed was most nourishing. However, several young men in his army, of royal blood objected to this diet, preferring instead to eat vegetables. Thus, the benevolent King allowed this group to only eat a diet of legumes and water for 10 days. To the King’s surprise, at the end of the 10 days, the legume and water group appeared to be better nourished than the meat-eaters. Based on these findings, the King allowed the Biblical vegans to carry on including vegetables in their diet. For the first time in human history, The Book of Daniel had recorded an open uncontrolled dietary study that directly influenced a public health decision¹.  

It wouldn’t be until the middle of the 1700s before the first randomised control trial was documented. The revolutionary, Dr Lind holds the honour of being the first physician in the modern era to conduct a randomised controlled trial². In 1747, Dr Lind, a surgeon on board the Salisbury ship noted, with concern, the high mortality among sailors with scurvy. In his seminal work titled ‘Treatise for Scurvy’, Dr Lind divided 12 sailors affected with scurvy into 6 treatment groups. He then proceeded to treat each group with a different treatment option, ranging from sea water and vinegar to oranges and limes. Whilst any modern-day ethics committee would baulk at Dr Lind’s experimental protocol, his study incorporated many features still applied in randomised clinical trials to this day. Dr Lind’s contribution to randomised clinical trial is celebrated annually on the 20th of May, designated World’s Randomised Clinical Trials Day, and the date when Dr Lind began the world’s first ever (ethically challenged) documented randomised clinical trial.

Fast forward another century and humankind stumbled upon the concept of a placebo. This time the hero to introduce this important aspect into clinical trials arena was an American by the name of Austin Flint³. In 1863, Dr Flint treated 13 patients with rheumatism with a dummy treatment made from herbal tea extract. In his study entitled ‘A Treatise on the Principles and Practice of Medicine’, where Dr Flint noted that patients treated with the dummy treatment reported a reduction in symptoms, an effect he attributed to the ‘placeboic remedy’.

In 1900, the Medical Research Council of the United Kingdom, an institute steeped in prestige and still operational today, conducted the first ever double-blind controlled trial to investigate the treatment of the common cold with an extract of penicillium patulinum. In 1943, in the middle of wartime, the MRC set out to enrol over a thousand British office and factory workers suffering from a common cold. The study enlisted the help of several key experts by forming a Clinical Trials Committee chaired by Sir Harold Himsworth and employed statisticians. Despite its novelty in trial set-up, the investigators did not find any beneficial effect of patulin in the common cold⁴.

The negative results from the patulin trial did little to curb the snowball now in place for clinical trials, as 3 years later, the MRC conducted the first ever randomised curative trial- the RCT of streptomycin in pulmonary tuberculosis⁵. Once more, a Clinical Trials Committee was assembled, this time chaired by Sir Austin Bradford Hill. Streptomycin was imported from the US and due to its shortage, it was considered ethically acceptable to administer it to only patients enrolled in the treatment group. During this trial, the first ever randomisation process was set up by Dr Hill and was statistically more robust than the previously employed alternate allocation system. Meticulously planned and executed, the Streptomycin trial continues to be referred to as ground-breaking even today, despite the development and increasing sophistication of clinical trials over the intervening years.

Since the biblical trial first noted in The Book of Daniel, clinical trials have developed into a regular and well-accepted procedure in healthcare, focusing on scientific evaluation and efficacy of novel therapeutic compounds, diagnostic modalities, and medical technologies. Not only do clinical trials aim to assess these, just as importantly, they must also safe-guard patient safety. Thus, there will remain the need to balance medical advancement with patient safety. As our scientific knowledge continues to develop, especially in the domain of artificial intelligence and its application in healthcare, so too will there be a need to develop new procedures and protocols in ethical and legal framework of clinical trials. The story of clinical trials is far from over, in fact some would say it’s only just beginning.

Read also: 

Part 2: The design, implementation, and execution of clinical 

Part 3: Essential principles in data analysis and interpretation in clinical trials