The Development of Clinical Trials

In modern medicine, clinical trials are the gold standard of clinical research. Clinical trials are well-controlled, function under a strict regulatory environment, and are a type of research study that is performed on people to evaluate a medical, surgical, or behavioral intervention. This intervention could include drugs, cells, other biological products, surgical procedures, radiological procedures, medical devices, behavioral treatments, and preventive care. People of all ages can take part in clinical trials, and they are a primary way for researchers to find out if new treatments, drugs, or medical devices are safe and effective. They also can be used to test ways to find diseases earlier while others find ways to prevent health problems altogether.

There are four phases of clinical trials:

Phase I

This phase typically tests a new drug or treatment on a small group of people (20-80) to evaluate safe dosage ranges and identify side effects

Phase II

This phase introduces a larger group of people (100-300) to test for effectiveness and monitor for any adverse effects. This stage can last several years.

Phase III

This phase is used to gather more information about safety and effectiveness by studying larger populations (up to 3,000 people) in different regions using different dosages. This is the step before approval with positive test results. This stage can also last several years.

Phase IV

This phase is after FDA approval when a device or drug’s effectiveness and safety are monitored in wide, diverse populations over a longer time frame.

Typically, a clinical trial will look something like the following:

1. Research staff explain the trial and gather personal information.
2. You sign a consent form.
3. You are screened to make sure you qualify.
4. If you accepted, you schedule a first visit or baseline visit where research conducts cognitive or physical tests.
5. You are randomly assigned to a treatment or control group.
6. You follow the trial procedures and report any issues or concerns to researchers.
7. Some trials require you to visit the research site at regularly scheduled times for new cognitive or physical evaluations or discussions with staff. This is also when the research team will collect information about the effect of the intervention, your safety, and your well-being.
8. You continue to see your regular physician for the usual healthcare.

The Beginning of Clinical Trials

The definition of a clinical trial according to the International Committee of Medical Journal Editors is “any research project that prospectively assigns human subjects to intervention and comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome.” With this definition in mind, some versions of controlled clinical trials have existed for thousands of years with the first recorded manifestations as a variety of attempts to compare interventions before later incorporating randomization, blinding, and placebos.

The First Documented Trial

The first documented evidence of an actual clinical trial that fit this definition occurred in 500 BC and was outlined in the book of Daniel from the Old Testament. This trial was a nutritional experiment where Daniel and his three brothers were assigned to a diet of only vegetables and water and were compared with men who followed the king’s diet of meat and wine. Daniel and his brothers were documented as the healthier group based on their diet. The accuracy of the trial and account has not been confirmed but this has been the basis of a clinical trial that was clearly demonstrated and documented.

The First Formal Trial

The first formal clinical trial was documented in 1025 AD by Persian physician and philosopher Avicenna who established groundbreaking rules for testing drugs and remedies. While these rules may have changed and adapted, this is still considered one of the first real descriptions of formal clinical trials.

James Lind

In 1747, Naval surgeon James Lind famously conducted the first controlled clinical trial. This trial was conducted to find a remedy for a group of sailors who were suffering from scurvy. In this trial, he divided the 12 sick sailors into six pairs and gave them each a different dietary supplement: cider, vinegar, seawater, sulfuric acid, oranges, and lemons. His documented results revealed that the sailors who received oranges and lemons were able to recover, proving that citrus is a critical part of a sailor’s diet.

Introducing Placebos

By the 1800s, the concept of placebos was first mentioned and defined in Hooper’s Medical Dictionary of 1811 as “any medicine adapted more to please than benefit the patient.” Placebos went on to play a critical role in blind clinical trials as a psychological aspect. When used, patients are not told if they received the placebo or experimental drug.

Ethics and Consent

With clinical trials becoming more common by 1964, the World Medical Association drafted an internal manuscript called “Declaration of Helsinki”, due to a few ethical issues in a variety of clinical trials, which promoted voluntary involvement and informed consent in human subject research. While this document is not legally binding, it serves as the basis for laws that govern medical research, and in 1979, in The United States, the National Commission for Protection of Human Subjects in Biomedical and Behavioral Research drafted the Belmont Report which outlined the basic ethical principles: respect for persons, beneficence, and justice and laid out guidelines for conducting research.

The 1970s

The Society of Clinical Trials was conceived in 1978 where they began to develop and discuss the clinical trial design and the analysis of clinical trials in the government. The FDA also assisted during the late 1970s by working with external advisory committees and conducting FDA industry workshops. These workshops support the development of 30 drug-class clinical guidelines.

Public Access

In 2000, with input from the FDA and other organizations, the NIH National Library of Medicine developed clinicaltrials.gov, a database of privately and publicly funded clinical trial studies conducted globally. It was made public on February 29, 2000, and won the Innovations in American Government Award in 2004. This site allows the public to find, learn and submit studies and offers a variety of other resources about clinical trials.

In response, in 2005 the Internal Committee of Medical Journal Editors began requiring trial registration as a condition of publication. By 2006, the World Health Organization stated all clinical trials should be registered and in 2007, they launched the International Clinical Trials Registry Platform which provides a search portal for a single point of access to the trials that are registered. Also in 2007, the requirements for submission to clinicaltrials.gov were expanded after Congress passed the Food and Drug Administration Amendments of 2007 which required more types of trials to be registered, additional trial registration information, and submission of summary results.

What’s Happening Now?

Clinical trials and research have gone on to discover groundbreaking treatments and have evolved into standardized procedures that adhere to strict regulatory and ethical requirements that are reviewed and updated frequently. As clinical research grows, there are some exciting clinical trials to watch out for this upcoming year including:

• A diabetes drug for Parkinson’s disease
• ADC (antibody-drug conjugate) for ovarian cancer
• CRISPR-Cas9 for muscular dystrophy
• Safe treatment for sleeping sickness
• Circulating tumor cells
• Lecanemab for Alzheimer’s disease
• Gene editing for sickle-cell disease