605-562 BC

King Nebuchadnezzar II carries out the first clinical trial when he orders that a strict diet of meat and wine be followed for three years. However, four children of royal blood convince Nebuchadnezzar to allow them to exchange bread and water for the required meal. After only ten days, those who have switched to bread and water appear more resplendent and well nourished than those who have stuck to wine and meat.

1537

Renaissance surgeon Ambroise Parè mixes a concoction of oil of rose, turpentine and egg yolk as a replacement for the accepted medicament for treating open wounds. One day after the unintentional trial, Parè observes that the wounds treated with the traditional formula are swollen and extremely painful, while the wounds treated with the experimental mixture are not painful. Parè deduces that the new balm is more favorable than the oil usually applied.

1600

Seafarers setting out for the East Indies make the chance discovery that adding sour oranges and lemons to their diet improves general health and saves lives. But it isn't until 147 years later that Lind conducts his famous study.

1747

James Lind proves the effectiveness of lemon juice in preventing scurvy. His experiment is known as one of the first widely known controlled clinical trials: a trial with a parallel control group that is given an alternative treatment.

19th century

Trials utilizing the placebo emerge. In medicine, a placebo "is any intentionally non-effective medical treatment, especially an inactive or inert substance, prescribed to replace medication that is desired by a patient but which cannot be given or which would be inappropriate. Placebos are often given to control groups used in experimental research to compare the results with those of the experimental drug." (Placebo is Latin, literally meaning, "I will please.")¹

1912

The USA Congress prohibits labeling medicines with false therapeutic claims intended to defraud the purchaser, a standard difficult to prove. However, it acts as a stimulus to clinical studies.

20th Century

Trials utilizing randomization develop. Randomization is a process by which subjects in a clinical trial are randomly assigned to receive one of the treatments offered. In a 'blind' trial concerning the effects of sanocrysin on tuberculosis, patients are randomly divided into two separate groups of equal size. One group receives the sanocrysin and the other receives placebo. The patients do not know who is getting the test drug.

1930s

Experts from Great Britain establish a Therapeutic Trials Committee with the idea of managing clinical trials to study new drugs.

1938

After 107 people die after taking sulfanilamide (which contained anti-freeze ingredients), the US Food, Drug, and Cosmetic Act enforces the need for manufacturers to demonstrate safety.

1941

The FDA is required to analyze and attest the potency and purity of insulin, the life-saving drug for diabetes.

1944

Introduction of multicenter studies. These are several studies conducted at different sites but all using the same protocol; this allows the results to be pooled, so that the greater numbers give increased statistical 'power'.

The UIS Public Health Service Act is passed, encompassing a broad spectrum of health concerns, in addition to regulation of biological products and checks on infectious diseases.

1947

The Nuremberg Codex establishes ten points for the protection of subjects and patients in clinical trials. These tenets require a voluntary declaration of consent by trial participants; the right of trial participants to comprehensive information on the nature, purpose, and potential risks of the experiment; and the right of trial participants to withdraw from the trial at any time (link to section 9). Performance of a trial must be based on anticipated beneficial results, and the risk involved must be proportionate to the social and humanitarian significance of the problem being addressed.

1957

The Surgical Adjuvant Chemotherapy Projects are developed; these projects are focused on testing the ability of thiotepa as an adjuvant to excision treatment of breast, stomach, and colon cancer.

1962

Passage of the Kefauver-Harris Drug Amendment in the USA; proof of efficacy required for new drug approval, in addition to proof of safety.

US President Kennedy pronounces the Consumer Bill of Rights. Congress is informed of the peoples' right to safety, the right to be informed, the right to choose, and the right to be heard.

1964

The World Medical Association develops the Declaration of Helsinki. This serves as a statement of ethical codes to provide direction for physicians and other participants in medical research involving human subjects. "Medical research involving human subjects includes research on identifiable human material or identifiable data." The Declaration is subsequently amended in the years 1975, 1983, 1989, 1996, 2000, and 2001.²

1970

In Upjohn v. Finch, the Court of Appeals upholds enforcement of the 1962 drug effectiveness amendments by ruling that commercial success alone does not constitute substantial evidence of drug safety and efficacy. In other words, this must be provided by well-conducted, well-controlled clinical trials.

1986

Individual countries such as Great Britain, France, Germany, and the Scandinavian countries issue Good Clinical Practice recommendations. These were soon ordered in 1989 into th GCP recommendations of the European community.

1987

Revision of the investigation drug regulations is carried out in the United States. The goal of this is to expand access to experimental drugs for patients with serious diseases with no alternative therapies - i.e. availability without evidence of efficacy from well-controlled, well-conducted clinical trials.

1988

The US FDA is given even broader responsibility and authority regarding the approval of new drugs.

1991

Passage of a European Union directive. Compulsory criteria for the authorization of a medicinal product for sale on the European market are quality, safety, and efficacy. Safety and efficacy must be demonstrated in humans in clinical trials.

1991

Regulations are issued to accelerate the examination of drugs for life-threatening diseases.

With the establishment of the Women's Health Initiative (WHI) the era of large clinical trials is begun. The three major components of WHI studies are: "a randomized controlled clinical trial of promising but unproven approaches to prevention; an observational study to identify predictors of disease; and a study of community approaches to developing healthful behaviors." Evidence from such large prospective studies are clearly superior to retrospective epidemiologic surveys, and sometimes contradicts well-established concept (e.g. the results of the WHI Hormone Replacement Study contradict previous beliefs concerning the potential benefit of this therapy on heart disease risk.)³

1997

The US Prescription Drug User Fee Act is reaffirmed by the FDA Modernization Act. This Act dictates wide-ranging reforms in agency practices. Provisions include measures to regulate health claims for foods, regulate advertising of unapproved uses of approved drugs and devices, and expedite review of medical devices.

2001

Under its "accelerated approval" regulations, the FDA approves Gleevec, a promising new oral treatment for patients with chronic myeloid leukemia in less than three months - a record for this sort of therapy. Accelerated approval allows the FDA to approve drugs for serious or life-threatening illnesses on the basis of clinical trials that indicate the drug is reasonably likely to be of real clinical benefit.

The Declaration of Helsinki is revised to reaffirm its position that extreme care must be taken in making use of a placebo-controlled trial, and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

• Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or
• Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.