Clinical Trials: The Basics
In this section you will learn what a clinical trial is, why it is important, who can participate, what the phase of a trial means, and how trials for rare diseases can be different.
What is a clinical trial?
Clinical trials are organized research studies that test the effects of new medicines in people. The trials help to determine better approaches for disease prevention, screening, diagnosis, and treatment. Clinical trials are conducted only after initial laboratory studies are successful. Trials are generally sponsored by a variety of individuals and organizations, including researchers,
physicians, academic medical centers, pharmaceutical companies, and government agencies.
Participating in a Clinical Trial
Choosing to participate in a clinical trial is an important decision. Some people choose to join a clinical trial so they can play a more active role in their own health care, while others are seeking treatment options that are not yet widely available, and many hope to help others by contributing to research. Participation can require extra time and effort (e.g. doctor visits
hospital stays). When considering the pros and cons of participating in a clinical trial, it can be helpful to talk to your doctor, family, and friends.
All clinical trials have requirements for who can participate in the study (inclusion criteria) and who cannot (exclusion criteria). These criteria are based on factors such as age, gender, type and stage of disease, medical history, laboratory test results, and other health related categories. Depending on the stage of testing, some studies enroll patients with illnesses while
other studies seek healthy individuals. The inclusion and exclusion criteria are used to identify appropriate participants. The criteria help ensure that researchers will be able to answer the questions they plan to study.
The 4 phases of clinical trials
A clinical study can usually fit into one of four phases. A Phase I study is typically the first time the medicine is being tested in human volunteers. Typically, these volunteers are not sick and simply help researchers understand how the body reacts to a new medication. As more is understood about the medicine, more complex trials are designed to test the medicine in patients
who suffer from specific diseases. These are called Phase II and III studies and are usually required for a new medicine to be approved. Phase IV studies are conducted after the medicine has been approved for sale and tend to test specific risk and benefits of that medicine.
Overview of the phases of clinical trials
- Initial stage for testing an experimental treatment (usually in healthy humans)
- Usually enrolls healthy volunteers however, actual patients are often enrolled in trials of rare or chronic diseases (when other treatment options are not available)
- Examines initial effects and safety
- Evalates the safety of increasing doses
- Assesses how the drug interacts with the body (pharmacokinetics and pharmacodynamics)
- May provide preliminary evidence of effectiveness
- Second stage for testing an experimental treatment in humans with a specific disease
- Usually enrolls patients and in larger numbers than Phase I
- Evaluates initial efficacy
- Continues safety assessments from Phase I
- Phase IIA studies dosing requirements; Phase IIB studies efficacy
- Some trials combine Phases I and II
- Third stage for testing an experimental treatment in humans with a specific disease
- Randomized, controlled, multicenter trials* in larger numbers, sometimes more than a thousand patients
- Confirms the effectiveness of the product and general safety (versus a placebo or another treatment)
- Two or more successful Phase III trials are typically required for regulatory approval of a treatment
- Fourth stage of evaluation of drugs. Phase IV studies occur following the regulatory approval of the treatment.
- Collects additional evidence on risks and benefits
A few helpful definitions: A randomized trial is one in which study participants are randomly assigned to different treatment groups. A controlled trial is one in which one group receives a "control" treatment—such as a placebo (an inactive substance) or another medicine or medical intervention—to allow comparison with
the group receiving the test treatment under evaluation. A multicenter trial is one that is conducted at multiple study locations.
Clinical Trials for Rare Diseases
Clinical trials study important research questions, follow careful methods to ensure accurate results, and respect ethics that minimize risks to people. Whenever possible, clinical trials use standard trial designs and large sample sizes (numbers of study participants). This helps to ensure adequate statistical power for detecting treatment benefits and risks.
In clinical trials for rare diseases, however, the sample size is unavoidably small due to so few patients having a particular disease, requiring innovative approaches to optimizing the study design and data analysis. Here are some ways that clinical trials for rare diseases differ from clinical trials for other conditions:
- Use of Natural History Studies: A natural history study does not involve any treatment or medicine, but is simply an observational study designed to learn more about how the disease or condition progresses in a population without treatment. Sometimes a natural history study will be conducted before a phase I trial when little is known about the symptoms of the
condition being studied.
- Use of patients instead of healthy volunteers during Phase I. Phase I clinical trials for rare diseases often enroll patients with the targeted disease rather than healthy volunteers. Commonly, other treatment options are not available for patients with rare diseases.
- Fewer patients. In all phases of clinical trials, the number of patients required for studying rare diseases is much lower than for other diseases. For example, whereas a Phase III study of a common disease such as diabetes may enroll thousands of patients, a Phase III study of a rare disease may include fewer than 100 patients. When study results are analyzed,
the small sample size in rare-disease trials can make it challenging to prove true treatment effects. Study design and statistical methods used in larger clinical trials to ensure reliable results (for example, inclusion and exclusion criteria, randomization, and results analyses) may be less useful in smaller trials.
- Statistical power and generalizable results. Typically, the statistical power of a study—and the reliability of the results—increases as the number of study participants increases. Also, well-conducted larger studies typically produce more generalizable results, meaning that the results would also be expected in similar patients who did not participate
in the study. Small patient populations can present study design challenges for clinical trials of rare diseases.
- Combined phases. In clinical trials for rare diseases, the phases are sometimes combined, such as Phase I/II or Phase II/III, in order to maintain enrollment of the relatively small number of patients and expedite progression of all phases of the study program.
- Efficacy versus placebo within a specific time frame. Rare disease clinical trials must prove that the product is more efficacious than placebo within a specific time frame, which can sometimes be a challenge in a population with a rare genetic disease. As a result, study inclusion criteria may be strict in order to ensure the best chance for success.