Defining Clinical Trials
This is a multi-part article on clinical trials. This first article is intended to provide an overview of clinical trials, definition, participation, identifying trials and a brief discussion of the trials. In later articles, we will explore in detail the high standards set for clinical trials as promulgated under the Code of Federal Regulations as administered by the US Food and Drug Administration.
According to the National Institutes on Aging (NIA), a division of the US National Institutes of Health, “clinical trials are research studies performed in people that are aimed at evaluating a medical, surgical, or behavioral intervention. They are the primary way that researchers find out if a new treatment, like a new drug or diet or medical device (for example, a pacemaker) is safe and effective in people”.1
Why Participate in a Clinical Trial?
There are many reasons why people choose or not choose a clinical trial. Some of the reasons behind their choices include:
Prior treatments for their health problem did not work.
Others participate because there is no treatment for their health problem. Participants sometimes find that being in a clinical trial opens up new treatment opportunities.
Some studies are designed for or include people who are healthy but want to help find ways to prevent a disease, such as those who may have a genetic predisposition for a particular malady.
Many people participate in a clinical trial in order to play a more active role in their own health care.
Other people say they want to help researchers learn more about certain health problems.
“Whatever the motivation, when you choose to participate in a clinical trial, you become a partner in scientific discovery. Major medical breakthroughs could not happen without the generosity of clinical trial participants—young and old.”1
Phases of clinical trials
A clinical trial is initiated after preclinical work is completed and the sponsor of the therapy submits a request to the FDA to conduct a Phase I (first-in-human, FIH) clinical trial.
The figure shown above is a pictorial summary of the drug discovery/drug development process. Historically, this type of drug development was the domain of small molecules but as medicine moves forward, healthcare is focusing more on patient-centric precision medicine and the interplay of “omics” in translational medicine.
Prior to initiating a clinical trial, drug developers, or sponsors, must submit an Investigational New Drug (IND) application to the FDA before beginning clinical research.5
In the IND application, developers must include:
Animal study data and toxicity (side effects that cause great harm) data
Clinical protocols (study plans) for studies to be conducted
Data from any prior human research
Information about the investigator
The following is a brief summary of the clinical trial phases. A later article will address the regulatory aspects and requirements of each trial, as well as preclinical work required.6
Phase 0 trials are the first clinical trials done among people. This trial involves very few people and only small doses are utilized to see how the medication might metabolize and what effects are seen at low does. This phase involves up to 10 – 15 patients.
Phase I trials focus on identifying a safe dosing range for the drug, involving as few side effects as possible. The physician begins with extremely low doses and increases the dose until side effects, sometimes severe, are observed. The drug is tested in a small group of 15 to 30 patients. The drug may help patients, but Phase I trials are to test a drug’s safety. If a drug is found to be safe enough, it can be tested in a phase II clinical trial.
Phase II trials further assess safety, but this trial sometimes referred to Phase IIa and IIb attempt to determine drug efficacy. For cancer patients, the drug is often tested among patients with a specific type of cancer. Phase II trials are done in larger groups of patients compared to Phase I trials. Often, new combinations of drugs are tested. Patients are monitored carefully for efficacy and safety.
Phase III trials compare a new drug to the standard-of-care drug. These trials assess the side effects of each drug and which drug works better. Phase III trials enroll 100 or more patients.
Often, these trials are randomized. Randomization essentially means that there is a control group that receives a placebo (not often) or the standard of care drug and another group that receives the test drug. Double blind randomized trials means that neither the physician nor the patient know which drug they will receive. A computer program is often used to randomly assign people to the trial arms. Every patient in a phase III study is watched closely. The study will be stopped early if the side effects of the new drug are too severe or if one group has much better results. Phase III clinical trials are often needed before the FDA will approve the use of a new drug for the general public.
Phase IV trials test new drugs approved by the FDA. The drug is tested in several hundreds or thousands of patients. This allows for better research on short-lived and long-lasting side effects and safety. For instance, some rare side effects may only be found in large groups of people. Doctors can also learn more about how well the drug works and if it is helpful when used with other treatments.
Finding a Clinical Trial
There are several avenues down which new patients can go in order to find a clinical trial. Most often once a diagnosis is given, the patient discusses treatment options at that time. Certain companies like xCure Inc. have developed an AI-based precision oncology platform that tightly integrates cancer research and care to offer the patient a precision medicine based approach to therapy.2 Perhaps the most well known of websites offering current and past clinical trial information on innumerable diseases and their subsets is ClinicalTrials.gov. Physicians and patients alike often go to this website for up-to-date information.3 In addition many people seek support groups and websites that focus on a particular condition.4
Written by: Lawrence D. Jones, Ph.D.
Keywords: Clinical Trials, FDA, Precision Medicine, Clinical Studies, Phase 1, Phase 2, Phase 3, Phase 4