Clinical trials in neurology

K K Jain MD (Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.)
Originally released March 8, 1999; last updated February 7, 2017; expires February 7, 2020


Controlled clinical trials are now necessary for the approval of new therapies. Besides academic centers and large pharmaceutical companies, individual practicing physicians may also be involved in clinical trials. This article reviews the basics of clinical trials, including design and methodology, with special emphasis on neurologic disorders. The role of the United States government in the database of clinical trials is described, along with problems and limitations of clinical trials.

Key points


• Clinical trials are essential for new drug development as evidence of efficacy and safety is required for approval by regulatory authorities.


• Biomarkers and pharmacogenomics are playing an important role in the design and monitoring of clinical trials.


• Basic methods of clinical trials are applicable in neurology, but there may be specific problems associated with clinical trials of disorders such as multiple sclerosis.


• Some problems with clinical trials, such as the lack of publication of negative results, still need to be resolved.

Historical note and terminology

Traditionally, clinical drug development has been based primarily on observational and empirical studies. In the 17th century, drugs were licensed by governments in Europe based on evidence from experiments in animals and humans. Trials conducted in the 19th century usually consisted of an investigator administering a trial medication to 1 or a few patients. If they improved, the drug was believed to be efficacious. During the 20th century, many open-label studies have been conducted to assess the efficacy of drugs. Although these studies were an improvement over the casual observational studies of the 19th century, they were subject to many confounding factors and biases.

Potential bias in allocating patients to active and control treatment is one of the main problems with uncontrolled studies. The Danish Nobel laureate, Johannes Fibiger, was the first to use randomization to control selection bias in 1898 (Hrobjartsson et al 1998). He allocated patients, on alternate days, to receive treatment with either antidiphtheria serum or control therapy. However, this may have allowed physicians who understood the process to selectively choose the patients for entry into the trial.

Application of statistics in medicine and randomized controlled clinical trials were developed in the second half of the 20th century. Results of the first clinical trial, which dealt with the treatment of pulmonary tuberculosis with streptomycin, were published in the United Kingdom in 1948 by the Medical Research Council (Yoshioka 1998). This article was the first to describe in detail the control of bias through randomization. This was accomplished by placing random numbers in sealed envelopes when assigning treatments to patients. Bradford Hill, a statistician who pioneered clinical trials, wrote the early accounts of clinical trials (Hill 1951; Hill 1952). Randomized, controlled clinical trials became prevalent in clinical medicine in the past 30 years. Open-label studies, though still performed occasionally, are no longer regarded as capable of providing the most valid information. Single patient studies persist in the form of case reports in the literature.

Drug development starts with identification of a candidate molecule and is followed by preclinical animal testing before proceeding to human clinical trials. The total process takes 10 to 15 years, with the last 5 years devoted to clinical trials. A clinical trial is a prospective study in human subjects, either in patients or nonpatient volunteers. The International Committee of Medical Journal Editors defines a clinical trial as any research project that prospectively assigns people or a group of people to an intervention, with or without concurrent comparison or control groups, to study the cause and effect relationship between a health-related intervention and a health outcome. The term “clinical trial” is more specific than “clinical study” because it emphasizes clinical investigation rather than all clinical evaluations made in a clinical study (such as those that may be carried out during the phase 4 of a clinical trial). The purpose of the controlled clinical trial is to provide valid evidence of the effects of therapy, including study of areas such as absorption, distribution, metabolism, and excretion of the drug. Later, the controlled clinical trials compare the effect and value of intervention against a control (standard treatment or placebo) in human subjects to determine the efficacy and safety.

Passing of an amendment to the Food, Drug, and Cosmetic Act by the United States Congress in 1962 authorized the FDA to ask the pharmaceutical manufacturers to provide results of randomized clinical trials prior to drug approval, and by 1970, the submission of these results with a new drug application became a requirement (Bothwell and Podolsky 2016). Presently, no new drug is approved by the health authorities worldwide without evidence of efficacy and tolerability obtained from controlled clinical trials. Controlled trials have also been applied to evaluation of nonpharmacological methods of treatment such as radiotherapy and surgery. This article will describe the basic principles of clinical trials and their application to neurology.

The content you are trying to view is available only to logged in, current MedLink Neurology subscribers.

If you are a subscriber, please log in.

If you are a former subscriber or have registered before, please log in first and then click select a Service Plan or contact Subscriber Services. Site license users, click the Site License Acces link on the Homepage at an authorized computer.

If you have never registered before, click Learn More about MedLink Neurology  or view available Service Plans.