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On the heels of the COVID-19 pandemic, many people are familiar with the concept that a new drug or vaccine undergoes clinical trials, and some may even have a sense that there are different phases of testing, but the details may be less certain. So, we thought we would take a closer look at what happens, when, and why.

Moving from the lab to people
Every day, scientists in research laboratories around the world work on developing new treatments and preventions to improve the lives of patients. They conduct experiments to understand how diseases occur and progress, in whom, and how to treat them. This work may use cells; chemicals; and animals such as mice, rats, rabbits, dogs, or monkeys, before any testing can occur in humans. Institutions that conduct research using animals must have oversight committees dedicated to protecting the health and welfare of the research animals. These committees make sure that the animals do not experience unnecessary stress or pain and that only the minimal number of animals needed are used in any experiment. Animal testing is necessary to understand how a potential treatment or vaccine performs in a living system. In addition to making sure the potential product is safe, scientists use animals to understand things like whether the potential product works in a biological system, what dose might work best and be safe, and the relative timing that might be needed between doses. While researchers can learn a lot from studies in animals, few human diseases can be perfectly modelled in non-human animals. Thus, animal studies provide only so much information. This is where clinical trials come into the process. Clinical trials are carefully controlled, regulated experiments conducted in groups of people. These trials can involve studies of potential new vaccines, drugs, medical procedures or diagnostic tools, or they can evaluate novel ways of using existing treatments, medications or procedures.    

A brief historical perspective on clinical trials
Many examples exist throughout medical history in which study participants, and society at large, benefited from participation in clinical trials, but it is also important to note that human testing has, at times, been used to commit abhorrent and contemptible violations of human rights.

For example, medical experimentation was historically performed on individuals or groups unable to meaningfully resist or decline participation, including children; people experiencing incarceration or physical or mental limitations; and members of disadvantaged or disenfranchised racial, ethnic, religious, and socioeconomic groups. One infamous example is the Tuskegee syphilis experiment in which the study population of Black men with syphilis was denied information about their diagnosis and, even more tragically, denied treatment once it became available. The researchers denied treatment because they wanted to study how the disease progressed, but it is wholly unethical to withhold treatment that is available and known to work. The racial disenfranchisement of the study participants rendered them systematically vulnerable to such medical abuses. This type of unethical behavior made clear the need for stringent clinical trial rules, especially the need for robust protections for people participating in research. Today, the protection of human rights and patient welfare are top priorities when conducting clinical research. Transparency is also critical for ensuring public trust in the integrity of clinical trials. In the United States, the U.S. Food and Drug Administration (FDA) is responsible for regulating clinical trials and subsequently approving new products.

First things first: Informed consent
Any scientist or clinician who wants to conduct research in people must complete a series of trainings before they can do so. They must also repeat these sessions every few years to continue doing this type of research. The trainings outline the ethical conduct of research involving people; introduce core principles, like respect, beneficence (acting in people’s best interests), and justice; and dictate the requirements of such research. One particularly critical requirement is that participants only be enrolled in a clinical trial by choice and without coercion. To make sure this is the case, clinical researchers must obtain what is known as informed consent. Informed consent requires that any participant in a clinical trial: 

• Recognizes that they are joining a research study
• Fully understands the nature and purpose of the study
• Knows the risks and benefits of participating 
• Is made aware of any alternative treatments that exist
• Is aware that their participation is completely voluntary and that they can withdraw from the study at any time 

Researchers must provide interpreters or translators if needed to ensure that the participant understands each of the above points, and they must be available to answer any questions or concerns that the participant may have. If an individual is unable to provide informed consent on their own behalf, such as a child, they can participate by providing their assent, or approval, alongside consent, or permission, from their parent or legal guardian.

Designing a clinical trial
When planning a clinical trial, researchers must define a specific goal. This allows them to design the study in a way to measure what they want to learn, so that the findings are clear and easy to interpret. For example, as with any scientific experiment, clinical trials must include appropriate control groups so observed outcomes can be attributed to the intervention and not chance alone. 

The control group does not receive the trial drug or treatment. Instead, they may receive the current best alternative or, if none exists, they may get a placebo. A placebo is important in the absence of another alternative, so that the individuals in each group and, ideally, the researchers themselves, cannot tell which group they are part of. This process controls for the observed phenomenon of patients experiencing side effects or resolution of symptoms as a result of simply believing they’ve received treatment, even if they haven’t. This phenomenon is known as the “placebo effect.” Likewise, the delivery of the intervention or placebo should be randomized, such that there is not a known pattern of delivery that might tell researchers who has or has not received treatment. Randomization of this process helps to avoid bias when assigning treatments to participants. 

If randomization occurs and steps are taken to prevent both the participant and the researcher from knowing which group an individual is in, this is called a “randomized, double-blind, placebo-controlled” study. This is the gold standard because participants and researchers can inadvertently influence the results if they know who got the intervention and who got the placebo. To successfully conduct a double-blind study, a separate researcher or group of researchers prepare the study intervention codes and ensure that, for example, the vials look similar and are labeled with the intervention code and no identifying information that would indicate whether it is the intervention or placebo. In this manner, the people administering the intervention do not know whether they’re providing the trial intervention or a placebo. At the end of the study, or if an issue arises with a participant, the intervention code is “broken,” and that is when the study team and the participant find out which group they were in. 

Depending on the type of intervention, double-blind trials are not always possible (e.g., if the intervention is a specific type of surgery), so when designing the study, scientists need to take all these things into consideration and design the most robust study possible given the realities of the situation. 

Study designs must then pass steps mandated by the FDA, including review by an Institutional Review Board (IRB). An IRB is a group of experts, including at least one non-scientist and one expert from outside of the institution performing the study. IRB approval is required to begin a clinical trial. This group ensures that: 

• Federal regulations are followed 
• Informed consent is obtained and appropriate 
• Participants are exposed to minimal harm
• The study design is strong 
   

In pursuit of these goals, the IRB can require modifications to a clinical trial protocol, approve it, or reject it. The process of controlling a clinical trial is more complicated than controlling experiments in a research lab. While it’s simple to see differences between populations of identical mice living identical lives in all ways except which treatment they were given, humans are incredibly diverse, and live complex lives full of thousands of independent variables for which researchers cannot control. The best way to control a clinical trial, therefore, is to enroll a large and diverse population to take part in the study. By making sure the study includes individuals of diverse ages, sexes, races and ethnicities, the researchers do their best to ensure that the findings will not only be accurate, but that all communities will benefit equally.

The phases of clinical trials
Once a treatment has been developed, a trial designed, and IRB approval obtained, it’s time for the trial to begin. The FDA has strict regulations related to the phases (or steps) of clinical trials that must be completed before the product can be considered for approval or distribution to the public. These regulations are designed to ensure that the product or treatment is both safe and effective. If any phase fails to show safety or efficacy, the trials are halted. Although the phases of clinical trials typically span many years, they can be expedited during a public health emergency as was done for COVID-19 vaccine trials. (For more information on accelerated trial timelines, please see “How Can COVID-19 Vaccine Development Be Done Quickly and Safely?” in the resources section of this article.) 

Four phases of clinical trials are stipulated (numbered I through IV). Their goals and brief descriptions of each, are as follows: 

• Phase I clinical trials are small and short, usually involving fewer than 100 volunteers. Their main goal is to establish the safety of the product as it is given to people for the first time. Sometimes, it will include different doses to start establishing the lowest dose that works while also causing the fewest side effects. Participants in phase I trials are generally healthy volunteers who want to contribute to the pursuit of public health. About 70% of drugs proceed to phase II.
   
• Phase II clinical trials increase in size and begin to establish whether the treatment works. Whereas phase I trials evaluate how healthy volunteers respond, phase II trials typically involve several hundred patients with the condition of interest. Even with several hundred volunteers, the sample size is still too small to definitively prove whether a treatment will be beneficial. Researchers therefore continue to focus on whether the treatment is safe, particularly now that the participants more closely represent the target population. They also continue to work toward establishing optimal dosing. Only about 33% of drugs move to phase III.
   
• Phase III clinical trials determine whether a product is ultimately approved for use among the general population. In phase III, the trials involve several thousand participants with the condition, and they incorporate the use of placebos or standard therapy controls to make a direct comparison between people who did or did not receive the intervention. With larger pools of participants, phase III trials also help uncover side effects that occur more rarely and, therefore, weren’t apparent in the small groups who participated in phases I and II. Phase III studies also last longer than phase I or II studies, allowing researchers to look for prolonged side effects or delayed benefits. Just over 25% of treatments are approved following phase III studies.
   
• Phase IV clinical trials are undertaken after FDA approval has been granted. Rather than a randomized, controlled, double-blinded trial, phase IV trials are “observational,” and take place after the treatment has been released for use among the public. Observational studies are more natural in that they follow what happens as the product is used by the general population. People are not recruited by informed consent or placed into intervention versus control groups, and the product is not administered by study staff. The treatment sponsors can also monitor the data for side effects or adverse reactions that are too rare to encounter in the smaller clinical studies. Additional studies are also conducted by groups such as the Centers for Disease Control and Prevention (CDC) and large medical networks that have access to large patient populations. Transparency about scientific findings and clear communication about the potential risks and benefits of a medical product are critical components of this process. 

In sum
The birth of clinical testing and regulation came out of the need to protect citizens from harmful products and treatments that found their way to an unregulated market (See “A Closer Look: The History and Authority of the FDA” in the resources list.). Even as medical testing helped to protect the public, tragic instances of medical abuse persisted. Over time, the process of testing drugs, products, and treatments in the United States has advanced to include strict regulation and oversight, including formalized phases of clinical trials. These protocols are designed to maximize the benefits to the public and minimize the risks to clinical trial participants. Although these regulatory systems are well-established, continuing work to ensure enforcement, transparency, and quality is critical, particularly in light of past historical incidents and current disinformation campaigns that can sow doubt.


Related resources

Biomedical Research and Animals (high school 2-lesson unit) 

FDA Regulations Relating to Good Clinical Practice and Clinical Trials (webpage)

Key Concepts of Clinical Trials: A Narrative Review (scientific paper) 

Patient Recruitment & Ethics in Clinical Research (webpage)

The Untreated Syphilis Study at Tuskegee Timeline (webpage) 

Making Vaccines: Process of Vaccine Development (webpage)

The Journey of Your Child’s Vaccine (infographic)

A Closer Look: The History and Authority of the FDA (article)

How Can COVID-19 Vaccine Development Be Done Quickly and Safely? (webpage)