History of clinical research ethics at a glance

Clinical research, notably randomized controlled trials (RCTs) are nowadays considered as the holy grail of evidence based medicine. Since results from lab tests and animal experiments are not enough to be extrapolated to humans, conducting trials involving human subjects is necessary for the marketing approval of new drugs and for advancing medical practices. The conduct and ethics of clinical research are now closely regulated to ensure the proper protection of trial participants. However, this was not the case in the past where clinical research was often subjected to violation of human rights.

One of the first trial involving human subjects was thought by James Lind, a British surgeon in the 16th century. He studied scurvy – a disease known now to be caused by the deficiency of vitamin C – using a an interventional trial design. He was able to show that sailors in the control arm (not provided with fresh fruits) were more likely to develop scurvy compared to sailors who were given fresh fruits. Afterwards, similar human experiments were conducted by scientists in attempt to prove their hypothesis. Later on, in the 19th century, the concept of blind experiment was introduced by the french physiologist Claude Bernard in order to ensure the objectivity of scientific observation.

Behind the success of human trials lied many abuses, the most notable ones were the medical experiments conducted by Nazi doctors on war prisoners during World War II. These experiments have been recognized as “crimes against humanity” during the Nuremberg trials in 1946 and led to the establishment of the Nuremberg code as the first code of ethics for medical research involving human subjects. The 10 principles of this code introduced the concepts of voluntary informed consent, free withdrawal, absence of coercion and positive benefit/risk balance. This was a major steps in history to protect human rights in medical research.

Nearly two decades later, in 1964, the World Medicine Organization adopted the Declaration of Helsinki. The declaration expanded the principles of the Nuremberg code. It also clarified the informed consent principle stating that potential subjects should only give consent after being fully informed about the study design, objectives, risks and benefits. In addition, it allowed the informed consent to be given by the ‘legal guardian’ in cases of ‘legal incapacity’. The declaration was revised in 1975 to introduce the need to assess research protocols by an independent research ethics committee. Since its creation in 1964, the declaration has been amended seven times, most recently in October 2013.

During 1970’s and 1980’s Japan, UK and other European committees had each developed their independent set of guidelines based on the Declaration of Helsinki. In the US, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued in 1978 the Belmont Report. In addition, in 1982, the World Health Organization (WHO) and the Council for International Organizations of Medical Sciences (CIOMS) jointly issued the International Guidelines for Biomedical Research Involving Human Subjects mainly to help developing countries, that did not have their own legislation for clinical trials, apply the principles of the Declaration of Helsinki. This created different standards of practice worldwide and repetition of clinical trials in different countries, which resulted in delay in drug marketing approval. The solution to this problem came about in 1996 when a series of meetings known as the International Conference on Harmonization of Good Clinical Practice (ICH – GCP) took place in order to standardize the conduct and ethics of clinical research worldwide. The GCP provided detailed ethical and scientific recommendations for designing, conducting, monitoring, recording and reporting clinical trials involving medicinal products. The GCP have been later transposed into regulations in many countries. In the face of the rapidly evolving complexity of clinical research, this guideline has been updated in 2016 to add clarifications to the areas of data management, risk-based monitoring and sponsor and investigator responsibilities. 

Despite the past scandals related to human experiments, clinical research has allowed tremendous improvements in medical treatments and is nowadays regarded as a cornerstone for advancing medical practice. In the last decades, the perpetual development of international guidelines and country-specific legislations for clinical research has improved subject protection and restored the public’s trust in medical research. In the face of the rapidly progressing field of clinical research, ethical codes should be constantly revised in order to improve human morals and values.

References

• International Conference on Harmonization of Good Clinical Practice: http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html
  
• Muthuswamy V. Ethical Issues in Clinical Research. Perspect Clin Res. 2013 Jan-Mar; 4(1): 9–13.
• Nardini C. The Ethics of Clinical Trials. Ecancermedicalscience. 2014; 8: 387.
• World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/