In the era of numerous civilization diseases and other threats to human life and health, patients worldwide expect new therapies which are both effective and safe. However, access to modern drugs would not be possible without clinical trials, which are a necessary element of the drug marketing authorization process. Clinical trials have been a part of the medical landscape for over 275 years, creating opportunities for scientists to find viable treatments for a range of conditions.
A gradual, historic progression of scientific methods such as comparison of interventions, randomization, blinding, and placebo controls in clinical trials demonstrates how these techniques are collectively responsible for a continuous advancement of clinical care. Developments over the years have been ethical as well as clinical. Along the way, there have been challenges but also triumphs. The clinical trials of decades – or even centuries – past brought the industry to where it is today.
The early milestones
It is often suggested that the world’s first clinical trial is recorded in the “Book of Daniel” in The Bible around 500 BC, in which a nutritional experiment utilized a control group.Several young men of royal blood were assigned to a diet of only vegetables and water for 10 days and were compared with the men complying with the King’s Nebuchadnezzar diet of meat and wine, which was intended to keep warriors in top physical condition. When the experiment ended, the vegetarians appeared better nourished than the carnivores, so the King permitted the group to continue with their diet (3). While the Babylonian ruler was not able to decidedly resolve the question of which of the diets is preferable, we cannot fault him for this – the question has not been fully answered up to this day. However, the King certainly deserves credit for introducing two major components of a clinical trial: separate groups following different prescriptions and a finite length of the trial, upon which the results are evaluated.
Attention shall be given also to the contribution made by the great Persian physician Ibn Sīnā – known in the West as “Avicenna”. In his encyclopedic Canon of Medicine published in 1025, he suggests that in the clinical trial, the drug should be used in its natural state in disease without complications. He recommends that two cases of contrary types be studied and that a study be made of the time of action and of the reproducibility of the effects (2). These rules reflect a contemporary approach to clinical trials.
Let us not forget the work by the French 16th century surgeon Ambroise Paré who undertook an unintentional trial for battlefield wounds when the standard supplies for treatment, boiling oil, ran out. Alternatively, he applied a digestive mixture of turpentine, egg yolk, and oil of roses for the sealing of soldiers’ wounds. The antiseptic properties in the turpentine meant that this group of soldiers were overall in better condition than the soldiers who had received the hot oil. Although unplanned, Paré’s innovation provided a method much more effective than the standard treatment (3). Thus, we begin to encounter the idea of advancement of care through experimentation.
The modern era- from James Lind’s scurvy trial to randomization
Any historical treatise on clinical trials would be incomplete without the mention of the Scottish surgeon James Lind, who is considered the first physician to have conducted a controlled clinical trial of the modern era. Looking for a solution to avoid the high mortality rate of scurvy among sailors, he selected twelve patients with scurvy into different groups and had each group follow a particular dietary regimen. During this trial, he determined oranges and lemons (sources of vitamin C) gave the best result, creating a way to keep sailors safe from scurvy in the years to come. Although the results were clear, Lind hesitated to recommend the use of oranges and lemons because they were too expensive. It was nearly 50 years before the British Navy eventually made lemon juice a compulsory part of the seafarer’s diet, and this was soon replaced by lime juice because it was cheaper (3, 4). In 2003, Royal College of Physicians established The James Lind Library to commemorate the 250th anniversary of the publication of Lind’s pioneering contribution “Treatise on Scurvy”. The Library was created to improve public and professional general knowledge about fair tests of treatments in healthcare and their history. The publicity and popularity of the James Lind Library has made 20 May designated International Clinical Trials Day – because James Lind’s celebrated controlled trial began on that day in 1747. The Association of Clinical Research Professionals (ACRP), which is the non-profit organization dedicated to representing, supporting, and advocating for clinical research professionals, has promoted and organized Clinical Trials Day since 2014 as a joyful opportunity for the clinical research community to pause in reflection, recognition, and admiration of all that has been accomplished thanks to clinical trials and the people behind them. More information about the ACRP community of clinical researchers and celebrating Clinical Trials Days can be found on www.clinicaltrialsday.org.
The next stage was the introduction of the obligation to carry out toxicological tests. Such a decision was made after the Sulfa Craze of 1937 – where for several years in the late 1930s hundreds of manufacturers produced tens of thousands of tons of myriad forms of sulfonamide drugs (known widely as “sulfa drugs”) without oversight, leading to 107 deaths relating to improperly prepared sulfa (9). This brought about the passage of the Federal Food, Drug, and Cosmetic Act in 1938. It outlined requirements for new drugs to ensure safety before releasing them to the market.
The arrival of the placebo marked another important breakthrough in the history of clinical research. The term first entered the landscape in the early 1800s, including the 1811 edition of Hooper’s Medical Dictionary. However, the first known use of a placebo in a clinical trial didn’t occur until 1863, when Austin Flint conducted a trial involving patients with rheumatic fever, and compared the results of the active treatment with that of a placebo. Flint discovered that there was no difference in the natural history of the disease, indicating that the symptoms associated with rheumatic fever subsided naturally over time, not as a result of the orthodox drug treatment (3). The implementation of a placebo marked a shift in medicine in which identifying the positive benefits of active drug treatments was centralized in importance.
Looking for a treatment for the common cold, the Medical Research Council (MRC) of the UK in 1943 conducted the first double-blind comparative clinical trial with concurrent controls in the general population. The study was rigorously controlled by keeping the physician and the patient blinded to the treatment – patulin, an extract of Penicillium patulinum. The treatment allocation was done using an alternation procedure. A nurse allocated the treatment in strict rotation in a separate room (filling the record counterfoil separately, and detaching the code label for the appropriate bottle before asking the patient to visit the doctor). While the study itself didn’t prove patulin as an effective option, it did serve as a foundation for future double-blind clinical trials (5).
After almost 200 years since the first clinical trial conducted by James Lind, the first randomized control trial of streptomycin in pulmonary tuberculosis was carried out in 1946 by MRC of the UK. The MRC Streptomycin in Tuberculosis Trials Committee conducted tests of the promising antibiotic, but had an extreme shortage of the drug. To manage their limited supply of streptomycin, participants were randomly assigned to control groups and treatment groups. Randomization eradicated the frequently observed bias in which clinicians placed healthier patients in the experimental group and sicker patients in the control group (5, 6). The results of the study began the virtually universal use of randomization in clinical trials and were regarded as welcoming a “new era of medicine”.
Evolution of ethical and regulatory framework
Over several hundred years, the scientific aspects of conducting clinical trials and the associated medical advances continued to improve at a seemingly exponential rate, especially in the early 1900’s. However, in the 1930s and 40s disgraceful experiments took place that put science over humanity, such as deliberately infecting a 12-month-old baby in California with herpes simplex virus or infecting prisoner ‘volunteers’ in an Indiana prison with sexually transmitted diseases for drug testing, not to mention the countless experiments carried out in World War II concentration camps. These experiments proved that a greater focus on the ethical aspects of clinical trials was necessary.
The first international guidance on the ethics of medical research involving humans – the Nuremberg Code – was formulated in 1947, following the Nuremberg trials in Germany in which Nazi physicians were tried for crimes committed during experiments on concentration camp prisoners. Dr. Leo Alexander outlined six points – later expanded to ten – that defined genuine medical research, giving the War Crimes Counsel a basis for assessing the actions of the physicians on trial in regard to their treatment of prisoner human subjects. Those points became known as the Nuremberg Code, creating the first official and broadly accepted basic elements of research ethics (8).
The ten essential conditions of experiment requirements focused on the protection of human participants in clinical trials. The document specified that voluntary consent was essential and that the benefits of research must outweigh the risks. The Nuremberg Code had succeeded in solidifying a predominant acceptance of ethical research, but there continued to be violations by some investigators. The hallmark of unethical research practices is the “Tuskegee Study of Untreated Syphilis in the Negro Male” which began in 1932 and continued for forty years without any regard to the standards established at Nuremberg. The blatant disregard for humanity in the name of science consequently led to deaths and infections of participants’ partners and children. The Tuskegee study exemplifies the necessity of providing protections for research subjects and is a reminder of the fact that humanity must be put above science. This kind of led the World Medical Association (WMA) to draft in 1964 ethical principles for medical research involving human subjects called the Declaration of Helsinki.
It aimed to promote the ethical conduct of research and to protect human subjects from associated risks. The Declaration of Helsinki was the first set of international research guidelines that required research participants to provide informed consent (1).It has since been regularly revised, most recently at the General Assembly in October 2013. At the WMA Council meeting in April 2022, a workgroup was established to begin another revision of this important document. The first regional expert meeting to discuss this revision was started with the Asian region in Tel Aviv, Israel, on 9-11 December 2022 and the Latin American region in Sao Paulo, Brazil on 24-25 February 2023. More meetings are also planned in order to bring regional and international experts together to consider the next steps of the revision.
It should be noted, that research has been evolving since the Declaration of Helsinki was adopted. Large collections of data and human specimens allow for the development of new research strategies and models, as well as new predictive types of research and analysis. The combination of large amounts of data, the possibility of combining large databases and the application of information technology is already changing many aspects of research. The potential of such databases is vast, but so are the dangers. The analysis of scenarios that already exist for the use (and misuse) of health data and biobanks showed that the major risk scenarios may not result from science, but from the commercial, administrative or political use of such data. Thus, since 2016, the Declaration of Taipei on Ethical Considerations regarding Health Databases and Biobanks has complemented the Declaration of Helsinki. This policy aims to address any use of health databases and biobanks excluding individual treatment and is not restricted to research.
The ICH-GCP guidelines – the ‘Bible’ of clinical trials
The Declaration of Helsinki formed the basis for the ethical principles that underlie the Good Clinical Practice (GCP) guidelines, which have become the universal standard for the ethical conduct of clinical trials. Other important milestones in the formation of the GCP guidelines were:
- the Kefauver-Harris Amendments that required the Food and Drug Administration (FDA) to evaluate all new drugs for safety and efficacy, which was implemented in response to the severe fetal limb deformities linked to the use of maternal thalidomide. This drug reaction was only discovered after 10,000 infants were born in over 20 countries worldwide (7);
- the Belmont Report which was issued in April 1979 by the National Commission for Protection of Human Subjects of Biomedical and Behavioural Research. The principles of this report are: Respect for Persons, Beneficence, and Justice.
In 1982, the World Health Organization (WHO) and the Council for International Organizations of Medical Sciences (CIOMS) issued a document entitled ‘International Guidelines for Biomedical Research Involving Human Subjects‘. This document was released to help developing countries apply the principles of the Declaration of Helsinki and the Nuremberg Code (7). Worldwide, many organizations and committees issued various documents and guidelines on the same issue, therefore, in an effort to overcome international inconsistencies throughout the countries, the International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued the ICH Guidelines: Topic E6 Guidelines for GCP. These guidelines were approved on 17 July 1996 and implemented for clinical trials from 17 January 1997. The participants of these guidelines were representatives of the European Union, Japan, and the United States as well as those of Australia, Canada, the Nordic countries, and WHO. The ICH-GCP guidelines have become a harmonized standard that protects the rights, safety and welfare of human subjects, minimizes human exposure to investigational products and improves quality of data. Compliance with this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected and consistent with the principles of the Declaration of Helsinki, and that the clinical trial data is credible. The ICH-GCP guidelines are therefore considered the ‘Bible’ of clinical trials and have become a global law which safeguards humanity as we know it today. It should be noted that ICH-GCP guidelines are constantly evolving. Since 2016, the year of finalization of the ICH guideline for GCP E6(R2), the clinical research field faced advances in technology that came along with rising complexity of trials, and global challenges. Thus, ICH prepared in May 2023 a draft guidance for the industry “ICH E6 (R3) Guideline on good clinical practice (GCP)”to address the growing gaps between the existing regulations and real-world processes, such as growing variety of study types and data sources, as well as quality concerns.
The ten essential conditions of experiment requirements focused on the protection of human participants in clinical trials. The document specified that voluntary consent was essential and that the benefits of research must outweigh the risks. The Nuremberg Code had succeeded in solidifying a predominant acceptance of ethical research, but there continued to be violations by some investigators. The hallmark of unethical research practices is the “Tuskegee Study of Untreated Syphilis in the Negro Male” which began in 1932 and continued for forty years without any regard to the standards established at Nuremberg. The blatant disregard for humanity in the name of science consequently led to deaths and infections of participants’ partners and children. The Tuskegee study exemplifies the necessity of providing protections for research subjects and is a reminder of the fact that humanity must be put above science. This kind of led the World Medical Association (WMA) to draft in 1964 ethical principles for medical research involving human subjects called the Declaration of Helsinki. It aimed to promote the ethical conduct of research and to protect human subjects from associated risks. The Declaration of Helsinki was the first set of international research guidelines that required research participants to provide informed consent (1).It has since been regularly revised, most recently at the General Assembly in October 2013. At the WMA Council meeting in April 2022, a workgroup was established to begin another revision of this important document. The first regional expert meeting to discuss this revision was started with the Asian region in Tel Aviv, Israel, on 9-11 December 2022 and the Latin American region in Sao Paulo, Brazil on 24-25 February 2023. More meetings are also planned in order to bring regional and international experts together to consider the next steps of the revision.
References:
- Bhatt A, Sewlikar S. India Steps towards Globalization-Reforms to Schedule Y Regulations. CR Focus. 2007;18:21–26Collier R. Legumes, lemons and streptomycin: A short history of the clinical trial. CMAJ. 2009;180:23–24.
- Bull JP. MD Thesis: University of Cambridge; 1951. A study of the history and principles of clinical therapeutic trials.
- Collier R. Legumes, lemons and streptomycin: A short history of the clinical trial. CMAJ. 2009;180:23–24.
- Dodgson S J. The evolution of clinical trials. The Journal of the European Medical Writers Association. 2006;15:20–21.
- Hart PD. A change in scientific approach: from alternation to randomised allocation in clinical trials in the 1940s. BMJ. 1999 Aug 28;319(7209):572–573.
- MRC Streptomycin in Tuberculosis Trials Committee. Streptomycin treatment of pulmonary tuberculosis. BMJ. 1948;2:769–83.
- Otte A, et al. Good Clinical Practice: Historical background and key aspects. 2005;26:563–74.
- Sparks J. Timeline of laws related to the protection of human subjects Office of History National Institutes of Health. [Accessed 20 Sep 09]. http://history.nih.gov/about/timelines_laws_human.html.
- Wax PM. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med. 1995 Mar 15;122(6):456-61.