The History of Clinical Research

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605BC Book of Daniel

The very first recorded example of what could be described as a simple, experimental design was found in the book of Daniel, following Nebuchadnezzar (King of Babylon) in his attempts to keep his people healthy. Nebuchadnezzar went on a 10-day long vegetable-based diet, while the other ‘participants’ were enjoying meat and wine, on a quest to test the effects and benefits of a vegetarian diet. Although the design and assessment would receive quite a few criticisms nowadays, Nebuchadnezzar was found to be healthier than the other subjects, suggesting that a vegetarian diet is more beneficial than a meat- and wine-based diet. 

500BC The Hippocratic Oath 

Hippocrates, often referred to as ‘the father of Western Medicine’ created an oath all physicians and healthcare professionals need to swear to. By taking the oath, healthcare professionals agree to practice medicine in a just and ethical way. The same responsibility carries over to clinical research – not only is practicing medicine ethically, looking after participants’ protection and wellbeing in trials is vital.

History Clinical Trails Past Present Future

1537: Ambroise Pare and the Wound Oil 

Ambroise Pare was a surgeon and used to treat soldiers’ wounds with oil. However, when he ran out of oil he applied ‘egg yolks, oil of roses and turpentine’ on the wounds of some soldiers, and the next morning he realised that the wounds of the soldiers on the ‘experimental mixture’ were looking and feeling much better than those treated with oil. Although using experimental mixtures is prohibited nowadays, many of the discoveries (e.g. Penicillin) are owed to similar ‘accidents’. 

 

1747 James Lind: The Scurvy Experiment 

Vitamin deficiencies have been associated with many neurometabolic disorders, as well as neuropsychiatric symptoms. When sailors spent a long time on the boats, they would suffer from poor wound healing, skin changes, loosening of teeth, and eventually die. British Nave James Lind believed that citric acids could prevent and cure this condition known as scurvy. He thus decided to divide 12 sailors into six groups each of which were given a different supplement in addition to their regular diet. James Lind tested the effects of cider, sulfuric acid, vinegar, seawater, oranges, lemons, and a spicy paste with barley water. He observed that sailors receiving the citrus fruit immediately began recovering. This supports the suggestion that vitamin C, e.g. citrus fruit, is necessary for a healthy immune system.

1863: Placebo 

In 1863 scientists introduced the ‘placebo’ – a key feature in most clinical trials to this day. Researchers use inactive substances (e.g. starch or sugar) that look like the real drug used in the trial. Placebo pills allow researchers to understand the effects a new drug or treatment may have on a certain condition. 

1887 National Institute of Health (NIH)

The NIH, previously known as the Hygienic Laboratory, invests $30.9 billion on an annual basis to support global scientific advances. It was founded in 1887 by Joseph J. Kinyoun.  With so many needs to expedite research, understand symptoms, discover treatments, the NIH is undoubtedly the largest public founder for medical research. Some of the projects they have founded are ‘Neurostimulation Technologies: Harnessing Electricity to Treat Lost Neural Function’, ‘Childhood Hib Vaccines: Nearly Eliminating the Threat of Bacterial Meningitis’, and ‘Understanding Immune Cells and Inflammation: Opening New Treatment Avenues for Rheumatoid Arthritis and Other Conditions’

History Clinical Trails Past Present Future

1887 National Institute of Health (NIH)

The NIH, previously known as the Hygienic Laboratory, invests $30.9 billion on an annual basis to support global scientific advances. It was founded in 1887 by Joseph J. Kinyoun.  With so many needs to expedite research, understand symptoms, discover treatments, the NIH is undoubtedly the largest public founder for medical research. Some of the projects they have founded are ‘Neurostimulation Technologies: Harnessing Electricity to Treat Lost Neural Function’, ‘Childhood Hib Vaccines: Nearly Eliminating the Threat of Bacterial Meningitis’, and ‘Understanding Immune Cells and Inflammation: Opening New Treatment Avenues for Rheumatoid Arthritis and Other Conditions’

1906 FDA Pure Food and Drug Act 

Although drugs contribute to the management of symptoms and diseases, they may have unwanted side effects. In 1906 US President Theodore Roosevelt signed the FDA Pure Food and Drug Act law. The FDA law prohibited interstate transportation on unlawful food and drugs, and banned trade of products for indications outside the labeling. The FDA is now responsible for approving new drugs, but also removing them from the market if and when adverse effects are observed. Temafloxacin (Omniflox) is an example of a withdrawn antibiotic from the US market; initially approved for treatment of lower respiratory tract infections, genital, urinary and skin infections, it was associated with severe allergic reactions and hemolytic anemia in over 100 patients within 4 months of its use, and three patient deaths. 

1928: Sir Alexander Fleming Discovers Penicillin 

His cluttered and untidy lab led to the growth of mold on a stack of staphylococci cultures. This unintentional result led to the discovery of penicillin, which soon thereafter was globally recognised as an efficacious life-saving drug. Fleming’s discovery of the penicillin was a turning point in the treatment of bacterial infections. 

History Clinical Trails Past Present Future

1932-1972: The Tuskegee Syphilis Study 

The US Public Health Service recruited 600 participants to study the effects of syphilis. The sample included syphilis-positive African Americans and 201 health controls. The longitudinal study was unethical and would have not received approval today given the maltreatment of subjects, the lack of informed consent and ability to withdraw, as well as denied access to Penicillin – which is a treatment for syphilis. Participants not only died and infected others, but they congenitally passed it to their children. Not only is this study highlighting the need of looking after participants’ wellbeing and only designing ethical protocols, it also sheds light to the ingrained systemic racism in science and the need for a radical change. 

1937: Elixir Sulfanilamide Disaster 

S.E. Massengill Company was a pharmaceutical founded in the late 1890s. The company was responsible for the 1937 Elixir Sulfanilamide disaster, one of the deadliest mass poisonings of the 20th century. Elixir Sulfanilamide was liquified by dissolving it into diethylene glycol, a toxic compound, ignoring its dangerous properties. The drug was released without any safety testing and killed Americans across 15 different states. The Chief Chemist died while awaiting trial and the company was only charged a minimal fine for mislabelling the product – the only penalty they were subject to under the 1906 FDA Act. To prevent similar scandals, the 1938 Federal Food, Drug, and Cosmetics Act was created.

1938: Federal, Drug, and Cosmetic Act 

Failure to prove drug safety prior to its release led to one of the deadliest poisonings (Elixir Sulfanilamide) of the 20th century. With the 1938 law change, the FDA’s primary focus of seizing production and marketing of adulterated drugs was changed. The FDA became a regulatory agency involved with supervising the evaluation of all new drugs. The 1938 Act was extensively amended but remains the principal foundation of FDA regulatory authority to this day. All drugs need to have safety demonstrations prior to market approval, and must have clear labels with adequate directions for safe use. 

History Clinical Trails Past Present Future

1939-1945: World War II Experiments 

While people around the world were experiencing the social, economic, political consequences of global tension, the German Nazi Party was also conducting a series of monstrous experiments on its concentration camp prisoners. The experiments, which were part of the Holocaust, aimed to develop new weapons, treatments for the injured German soldiers, and to advance their eugenic racial ideologies. The prisoners often died, or suffered disfigurement, or permanent disability. Such experiments should not be conducted, and informed consent should be obtained prior to involvement in trials. Although scientists are not allowed to carry out grotesque medical experiments, they now need to ensure that their publications do not encourage racist assumptions – instead science should be used as a weapon to re-educate people and fight racial injustice. 

1943: Patulin and the first double-blind controlled trial 

The first double-blind controlled trial, i.e. a trial in which neither the researcher nor the participant know whether they are being administered a drug or a placebo, was recorded in 1943. The UK Medical Research Council (MRC) tested patulin for the treatment of the common cold, and while the procedure was carried out very carefully patulin treatment was deemed ineffective. Although the researchers did not obtain the results they had hoped, the patulin trial was a pivotal moment and paved the way for the first randomised control trial in 1946.

1944: Multicentre Studies 

Conducting studies with small sample sizes has several limitations, such as lack of generalisability, and inability to control for factors significantly affecting outcomes. By introducing multisite studies researchers were able to use the same protocol at different centres and assess all results together. This allowed researchers to not only recruit larger numbers of participants, but also to recruit a wider range of populations, strengthening the experimental designs and analyses. Most large trials are now being carried out at multiple clinical research centres. 

1944-1974: Human Radiation Experiments 

Over 4,000 secret studies were sponsored by the US government during the Cold War era and exposed thousands of naive US citizens to atomic radiation to study its effects on the human body. Thousands of victims, the majority of whom belonged to vulnerable groups (e.g. prisoners, pregnant women, patients, children), were exposed to harmful doses. What patients often thought was ‘just another injection’ was actually toxic radioactive material injections which led to the development of life-threatening conditions.

1946: The first randomised controlled trial 

In 1946 the UK MRC conducted the first randomised controlled trial (RCT), investigating the effects of streptomycin in pulmonary tuberculosis. RCTs allow reduction of biased sources when testing the effectiveness of new treatments as subjects are randomly allocated to 2 or more testing groups. Those involved in the trial carefully monitored and assessed participants throughout a 15-month period. The trial became a model of design and policy implementation. 

History Clinical Trails Past Present Future

1947: Nuremberg Code 

A pivotal moment in the history of protocol approval and informed consent for participation in experiments was the outcome from the Nuremberg Trials. German Nazi Party members were tried for their inhumane acts against the victims of their experiments, in particular on their unwilling prisoners of war. A set of 10 ethical principles for human experimentation was created and the Code demands that all experiments include participant informed consent, clear and appropriate designs, no coercion, and beneficence towards all participants. Nowadays, no researcher is allowed to carry out an experiment unless ethical approval has been granted and faces serious consequences if fails to do so.

1951: Henrietta Lacks 

Henrietta Lacks was receiving treatment for cervical cancer when George Otto Gey, a researcher, took cells from her tumour and realised that he could keep them alive in culture. Her cells are known as the HeLa immortal cell line and are used in biomedical research. Over 20 tons of cells have been grown from the HeLa line and researchers from all over the world are using them to develop and test new treatments. The HeLa cells were used to test for the first polio vaccine in the 1950s, and have been used for AIDS and cancer research, among many other experiments. Henrietta Lacks never found out about her impactful contribution to science – at the time permission to harvest cells was not required. After her death some family members expressed some concerns and studies resulting from the cells’ DNA sequence should acknowledge her contribution. Two family members were also given a place to the 6-member committee which regulates access to the sequence data.

1950s: The “Thalidomide case” and the importance of human clinical trials

Thalidomide was a drug released on the market in the 1950s, given to pregnant women to treat morning sickness. The drug was only tested in animal trials before it became available to the public. Unfortunately, it was soon observed that when given in the first trimester of pregnancy, it caused significant birth defects to infants from moderate malformation to life threatening conditions. The “Thalidomide case” changed the way treatments were approved by regulatory authorities. Following the scandal, it became mandatory that all human clinical trials received regulatory approval before starting to trial the protocol.

1960’s: Harvard Psilocybin Experiments 

Timothy Leary and Richard Alpert, two Harvard professors, gave psilocybin (a psychedelic drug) to students and prisoners to examine whether the then-lethal drug could lead to radical, and positive behaviour changes. The two professors’ research was heavily questioned as they were taking the drugs with the students during the experiments, and two students were admitted to a psychiatric hospital. The professors were invited into a meeting which turned into a trial against them, and a controversial article was later published in the Crimson in 1962. Although the state authorities decided to approve use of psilocybin in experiments under the conditions that a (sober) physician is always present during the study, Alpert refused. It is believed that Alpert and Leary were stocking up for another experiment, the Zihuatanejo Project. They were both dismissed by the university soon after that and their advocacy of psychedelic use made them significant figures in the nascent counterculture, an anti-establishment cultural phenomenon in the Western world between the mid-1060s and the mid-1970s.

History Clinical Trails Past Present Future

1960s: The Polio Vaccine

Polio is a disease caused by the poliovirus, a virus that can infect the nervous system and cause significant limb paralysis. The polio vaccine was tested in the largest human clinical trial in history with approximately 1.8 million children taking part. The large number of participants provided strong evidence that the vaccine was both safe and effective and was quickly approved and distributed to the wider population.

1962: Kefauver-Harris Drug Amendment

The Kefauver-Harris Drug Amendment ensured that drug manufacturers provided proof of effectiveness and information about all side effects to avoid marketing of cheap and dangerous drugs as expensive ‘breakthrough’ drugs. 

1964: Declaration of Helsinki 

The World Medical Association used the 10 principles from the Nuremberg Code to develop a detailed document on human research ethics. It has been revised six times from June 1964 until 2008 and focuses on respect for the subject, their right to self-determinate, and their right to make informed decisions regarding their participation in research. It highlights that human rights should not be compromised for science’s sake. 

The NIH, previously known as the Hygienic Laboratory, invests $30.9 billion on an annual basis to support global scientific advances. It was founded in 1887 by Joseph J. Kinyoun.  With so many needs to expedite research, understand symptoms, discover treatments, the NIH is undoubtedly the largest public founder for medical research. Some of the projects they have founded are ‘Neurostimulation Technologies: Harnessing Electricity to Treat Lost Neural Function’, ‘Childhood Hib Vaccines: Nearly Eliminating the Threat of Bacterial Meningitis’, and ‘Understanding Immune Cells and Inflammation: Opening New Treatment Avenues for Rheumatoid Arthritis and Other Conditions’

1974: The National Research Act

After the appalling treatment of participants in the Tuskegee Syphilis Study, President Richard Nixon signed the National Research Act which demands all research using human participants to be reviewed by an Institutional Review Board. This was another step to protecting the rights of human participants. 

History Clinical Trails Past Present Future

1974: FDA Bureau of Medical Devices and Diagnostic Products & 1976: Medical Device Amendments 

To meet the needs of the rapidly-growing medical device field, the FDA created the Bureau of Medical Devices and Diagnostic Products, as they were not previously covered by the regulations from the 1938 Federal Food, Drug, and Cosmetic Act. President Gerald Ford then signed the Medical Device Amendment to increase the FDA’s power over the production of new devices. The new legislation introduced the concept of risk-based classifications for medical devices. All devices need to be proven safe and effective prior to entering the market. 

1979: The Belmont Report 

The Tuskegee Syphilis study also led to the development of the Belmont report, which brings attention to unethical research conducts and explains the three principles to guide human experiments: Respect for persons, Beneficence, and Justice. It is now used as a primary ethical framework for protection of US research participants. 

1981: FDA Regulations Title 21

Title 21 was created in addition to the Belmont Report (1979) and includes regulations for the Protection of Human Subjects (Part 50), Financial Disclosure (Part 54), IRBs (Part 56), Investigational New Drug Applications (Part 312), Investigational Device Exemptions (Part 812), and Electronic Records (Part 11).

1990: International Conference on Harmonisation Guidelines 

The ICH guidelines were created in April 1990 in response to the global harmonisation plans of many European countries, Japan, and the US. With several products being marketed globally, nations had to reduce redundant, and expensive procedures while ensuring safeguards on quality, safety, and efficacy – the three basic criteria for approval of new medical products. In 1996 the ICH released the Good Clinical Practice (GCP) Guidelines, one of the most significant documents in clinical research. 

1990: The Safe Medical Devices Act 

The Safe Medical Devices Act is an extension of the Medical Device Reporting Legislation, and highlights the importance of patient safety when using medical devices. The act requires hospitals and healthcare professionals to always report any serious injury or death incidents caused by the devices to the FDA and manufacturers. In turn, the FDA is allowed to order device product recalls and take action when a device may be defective and dangerous.

History Clinical Trails Past Present Future

1991: The Common Rule 

The Common Rule is a set of ethics rules for the protection of human participants in biomedical and behavioural experiments. Its main elements include: requirements for assuring compliance by research institutions, obtaining and documenting participant informed consent prior to participation, and requirements for Institutional Review Board (IRB) membership, function, operations, review of research, and record keeping. It additionally protects vulnerable subjects, including pregnant women, prisoners, foetuses, and children.

1993: MedWatch 

The MedWatch was launched by the FDA – the MedWatch allowed collection of data regarding adverse events in healthcare settings. When an adverse event involving a medical product is reported, the FDA issues safety alerts or orders product recalls, and may also withdraw the product or make label changes to protect the general public health. From 1993 to 2011 40,000 hazards were detected. 

1996: Health Insurance Portability and Accountability Act 

In 1992 President Bill Clinton signed the Health Insurance Portability and Accountability Act but the final HIPAA rule only went into effect in 1996. The HIPAA ensures that all patients are informed of how their health data will be stored and kept confidential when participating in research trials.

History Clinical Trails Past Present Future

1996: National Bioethics Advisory Commission 

The National Bioethics Advisory Commission looks into any ethical issue which may arise in science and medicine, and in turn advises the President on bioethical issues. The Commission created by President Bill Clinton examines topics such as cloning, human stem cell research,  and research with human participants.

1996: The World Health Organisation Guidelines for Good Clinical Practice 

The GCP Guidelines are one of the most significant documents in clinical research, addressing justifications for a trial and protocol, protection of participants, all investigators’, sponsors’ and monitors’ responsibilities, assurance of data integrity and product accountability, and the roles of regulatory authorities. One way the guidelines facilitate understanding and implementation of GCP is by explaining in detail how each GCP Principle is routinely applied and implemented. 

1996: Hoiyan (Nicole) Wan 

In 1996 a 19-year-old girl, Hoiyan (Nicole) Wan took part in a minimal-risk study on smoking and air pollution. The girl underwent bronchoscopy to obtain brush biopsies from lung tissue. The girl died two days after the procedure from complications. It was later revealed that she was administered four times the maximum tolerated dose of lidocaine, a topical anaesthetic. The physician involved was found guilty as the protocol failed to clearly state the maximum dosages, the stated guidelines were violated, and the girl’s condition post-bronchoscopy was not carefully and properly monitored. 

1999: IMARC Research, Inc. 

In 1999 Sandra Maddock founded IMARC Research, Inc. IMARC started as a monitoring company and is now a leading full service medical CRO (Contract Research Organisation), delivering high-quality clinical research monitoring, auditing and training, as well as development and consulting to any companies looking to correctly follow legal and ethical guidelines for research trials.

1999: Jesse Gelsinger 

Researchers’ and investigators’ failure to strictly adhere to protocols may lead to serious adverse consequences. In 1999, Jesse Gelsinger, a sufferer of a rare x-linked genetic disease of the liver was enrolled in a university-based gene therapy. At the time of recruitment Jesse did not suffer any effects, however the 18-year-old boy died four days after partaking in the procedure. The University of Pennsylvania had a financial interest in the trial and did not report serious side effects experienced by other patients, and the informed consent Jesse received prior to participation did not disclose known deaths during animal trials. Jesse had high ammonia levels as his body was unable to metabolise it. Although his ammonia levels should have been an exclusion criterion, the investigators enrolled him in the trial, leading to multiple organ failure and brain death.

History Clinical Trails Past Present Future

2004-2007: Ketek

Ketek was an antibiotic used to treat a type of pneumonia caused by bacteria. Although the drug received FDA approval in 2004, it was linked to numerous severe liver injury cases and four patient deaths. The drug received a series of urgent safety warnings and the Congress investigated the FDA’s acceptance of fraudulent safety data despite being reviewed three times. The FDA was accused of using inappropriate safety review methods, and failure to present any issues of data integrity. 

Recent Years

Technological advancements increased scientific knowledge, greater funding and improved equipment are few of the factors that have significantly contributed to the improvement of current clinical trials – from study conception to execution. Although the clinical research community has been affected by delays in protocol design, recruitment of eligible participants, coordination of administrative work, amongst other challenges, COVID-19 has expedited collaborative and innovative trials, and promising changes in clinical research practices. Specifically, COVID-19 has propelled the clinical research industry toward a need for streamlined and expedited drug development. The discovery of a vaccine against COVID-19 proved that accelerated trial approval, in conjunction with timely participant recruitment, funding and training of trial managers and staff would lead to significant improvements in the timeline of drug development. Recent, global collaborations have underlined the importance of transparency in clinical trials, sample diversity for generalisable results, raising awareness and educating the public – this would increase the likelihood of engagement and participation – and finally, adopting decentralised practices. 

Conclusion 

To conclude, the history of clinical trials – from the very first recorded example of a trial to today’s practices – has evolved dramatically. Ethical and safe practices, together with improved transparency and digitalised, decentralised designs could positively shape the future of clinical trials, improving drug development, and ultimately refining patient experience, prognosis and quality of life.  

References

Bhatt, A.

(2010). Evolution of clinical research: a history before and beyond James Lind. Perspectives in clinical research1(1), 6.

FindMeCure.

 2018. The History of Clinical Trials. [online] Available at: <https://www.findmecure.com/blog/the-history-of-clinical-trials/> [Accessed 3 February 2022].

Junod, S. W.

(2008). FDA and clinical drug trials: a short history. A quick guide to clinical trials, 25-55.

Khera, A.

2021). Clinical research in 2021: A new era of collaboration and innovation –. Pharmaphorum.com. Retrieved 3 February 2022, from https://pharmaphorum.com/r-d/views-analysis-r-d/clinical-research-in-2021-a-new-era-of-collaboration-and-innovation/

Maddock, S.

The History of Clinical Research. Retrieved 3 February 2022, from https://cdn2.hubspot.net/hub/149400/file-410979295-pdf/docs/CRT_Timeline_download.pdf

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