Part Two: Design Issues: A Concise History of The Clinical Trial*

The term Clinical Trial comprises research activity which evaluates treatments of diseases. These treatments may be accepted and well established treatments, and also new candidate treatments. The Clinical Trial evolved over a long period of time, and the concept continues to evolve.

Some Important Examples:

The Pare Trial (1537)

For the times, the standard battlefield treatment to seal wounds was the use of boiling oil. Pare evaluated a non-boiling preparation of egg yolks, oil of roses and turpentine. He observed that the non-oil treated group suffered less than the boiling oil treated group. This was not a strict clinical trial, but did incorporate a comparison of treatments.

Fun with Fruit Juice and Scurvy (1600-1795)

East India Shipping Fleet (1600)

Four ships, one equipped with lemon juice. Lemon Ship crew almost free of scurvy, compared to other three ships. Company attributed difference to lemon juice.

James Lind's Salisbury Study (1747)

Trial run on board the Salisbury. Compared several treatments concurrently (at the same time), including a orange/lemon ration. The sailors under the orange/lemon ration fared the best.

A variety of evidence pointed to the effectiveness of citric juice in preventing scurvy; however, providing for this type of ration on long naval missions was expensive. Finally, a preponderance of evidence forced the point, or perhaps citric juice rations became more cost-effective.

British Navy provides for lemon juice rations for the prevention of scurvy in 1795.

Haygarth's Placebo Trial (1799) - Spare the Rods,…

Perkins' Tractors were metallic rods. These rods were stroked along a patient's body in the treatment of arthritis, joint pain, open wounds, gout, pleurisy, and tumors, as well as for sedating violent cases of insanity. These rods were widely accepted and used.

Haygarth was not convinced that Perkins' Tractors were effective. His trial compared false tractors, which precisely resembled Perkins' Tractors, but were made of wood. Both types of tractors (Perkins' and fake) were evaluated on cases of arthritis (chronic rheumatism). Both types of rods worked equally well in relieving patient pain.

Haygarth demonstrated the idea of a placebo treatment. The effect of a placebo treatment is based solely on the patients' perception that they are being treated, and so there will be an improvement. It is also called spontaneous improvement, improvement not related to an active treatment.

Gull and Sutton on Placebos (1865)

"The cases show that too much importance has been attached to the use of medicines, especially those acute cases where the tendency to a natural cure is the greatest."

H Sutton, 1865

Medical Research Council, United Kingdom (1930-1)

"The Medical Research Council announce that they have appointed a Therapeutic Trials Committee, as follows, to advise and assist them in arranging for properly controlled tests of new products that seem likely, on experimental grounds, to have value in the treatment of disease…."

The Lancet (1931)

The US Polio Trials (1953)

Polio Myelitis vaccine evaluated in a US large scale pediatric clinical trial. Positive results obtained in these trials led to use of polio vaccines (Salk, Sabin) which led to virtual eradication of polio in US and worldwide.

The Food and Drug Administration (1938, 1962)

United States Food, Drug and Cosmetic Act of 1938 provided FDA mandate for monitoring and regulating food, drug and cosmetic products in the US.

Kefavaur-Harris amendments (1962)

Added muscle to the FDA act by explicitly requiring adequate and well-controlled investigations. These amendments empowered the FDA to use the controlled clinical trial as the gold standard for evaluating medical treatments.

* paraphrased from Clinical Trials: Design, Conduct and Analysis, C Meinert and S Tonoscia, Oxford University Press, 1986.