People expect doctors to use treatments that work well and to stop using those that do not. However, it is often difficult for doctors and other scientists to tell which treatments work. Making this distinction is part of the science of medicine and usually involves studying the effects of treatments in clinical trials.
Clinical trials are experiments designed to find out whether an intervention is safe and effective. The intervention is most often a drug but can also be a device, such as a pacemaker or stent, or a diagnostic tool, such as a blood test. Participation in a clinical trial is an option for many people who have serious illnesses, especially when no good treatments are available. Thousands of clinical trials are conducted each year and may take place at a variety of locations, including universities, hospitals, clinics, doctors’ private offices, and professional clinical research sites.
The people who conduct clinical trials are called clinical researchers, or investigators. Investigators are usually doctors who are paid to conduct the trials by the National Institutes of Health (NIH) or by a pharmaceutical, biotechnologic, or medical device company. Investigators follow a detailed protocol (list of instructions) that dictates who is eligible to participate in the trial, what interventions will be given or used, how often participants will be evaluated, and how data will be collected. Several thousand people typically participate in clinical trials for each new intervention before it becomes available to the general public.
Clinical trial design can be complicated but typically follows the principles described in The Science of Medicine.
All interventions must be approved by the U.S. Food and Drug Administration (FDA) before they can be prescribed or used (see FDA: The Drug Development Process). The FDA’s goal is to allow an intervention to be given to the general public only after that intervention has proved to be safe and effective in carefully designed clinical trials. The FDA requires three phases of clinical trials before approval is granted. An optional fourth phase is often done after an intervention is approved.
Phase I trials assess the safety of an intervention but not its usefulness in treating a disease. A phase I trial is the first time an intervention is used on people. Tests are conducted on a small group of healthy people to learn how the intervention acts in humans, including the side effects, and to learn what doses of drugs are safe. Because phase I trials involve healthy people, the participants receive no direct medical benefit, but their contribution to the health of others is significant. These participants receive monetary compensation, with the amount dependent on the time commitment and the nature of the drug or procedure being tested.
Phase II trials are conducted if the intervention seems safe in a phase I trial. In phase II trials, the intervention is tested in a larger group of people who have the disease that the intervention is intended to treat. Phase II trials help researchers determine whether the intervention is safe for sick people and give an early determination of whether the intervention is effective. If the intervention is a drug, phase II trials help researchers determine what dose might be appropriate.
Phase III trials are conducted if safety is still satisfactory in phase II and the intervention seems effective. In phase III trials, the intervention is given to or tested in a large group of people who have the disease being studied. In phase III, the new intervention is usually compared with the standard treatment, a placebo, or both.
It takes an average of 10 years from when a drug is initially discovered until it is approved for market. About seven years of this time is for the clinical testing process. Many drugs, medical devices, and diagnostic tools never complete all three phases. Others do complete the three phases but are not approved for use because they fail to be effective or safe or both.
Phase IV trials are conducted to evaluate interventions that have already been approved for use. One type of phase IV trial is done to compare two or more approved interventions or to test an approved intervention on a disease for which it is not approved. When an intervention is tested for a new disease, three phases are not needed, but the clinical trial design is similar.
Postmarketing surveillance is another type of phase IV trial, which is done after the drug or device has been approved and is in widespread use in the general public. This study uses information from medical health records and doctors' reports to identify any side effects that were not detected in the first three phases of clinical trials. Postmarketing surveillance is particularly important in detecting side effects that are uncommon (and thus might not show up even in a phase III trial) or that occur mainly in a unique group of people, such as pregnant women or people of a certain ethnic origin who might not have been part of the original trials. If new side effects are identified and are serious, use of the drug or device might be restricted, or the drug or device might even be removed from the market.
People have different reasons for wanting to participate in clinical trials. Some want the newest treatments, which they hope will be more effective than the current standard of care. Others participate out of a desire to contribute to science or to receive money. Still others may want access to free drugs and medical care.
Merely wanting to be in a clinical trial is not enough. Only people who are eligible for a particular trial can participate. Every trial has specific criteria that spell out the characteristics a participant must have to join, such as a type and stage of cancer, a certain minimum cholesterol or blood pressure level, a specific age range (between 40 and 65, for example), or the absence of pregnancy or certain diseases. Participants may be required to undergo an extensive screening process involving blood tests and other medical procedures.
Sometimes a person’s doctor recommends participation in a clinical trial. This recommendation is particularly common for people who have cancer.
Trial recruitment ads run routinely in most major newspapers and on many local radio stations. Some local newspapers and newsletters now publish dedicated weekly sections listing clinical trials. Many communities have one or more research centers that consumers can call directly to get information or to get on a mailing list. Almost all clinical trials are listed at www.clinicaltrials.gov, a web site sponsored by the NIH. Some web sites help match people to specific trials. For example, the NIH has an internet-based registry called Research Match, which people can use to connect with researchers seeking participants for their studies. CenterWatch is another service that contains thousands of trials that are currently enrolling people.
Some people find it tedious to participate in a trial, especially if it lasts many months or requires frequent visits to the research site or frequent blood tests. Some trial protocols require participants to regularly telephone the trial nurse to report symptoms or to keep a medical diary at home as a condition of remaining in the trial.
Some trials are delayed, canceled by the sponsoring organization, or even stopped early once underway because certain participants do not fare well while taking or receiving the experimental treatment. Delays or cancellations can be hugely disappointing to people to whom the treatment brings relief. Also, after a clinical trial has ended, participants may no longer have access to an experimental treatment that was providing a real benefit.
Deciding whether to participate in a clinical trial is an important and complicated decision. Both risks and benefits must be carefully considered.
First, participants should be aware that they are not guaranteed to receive the new treatment and may instead receive a placebo or older treatment.
A trial drug may have side effects and cause bad reactions ranging from headaches and sleeplessness to breathing difficulties or, on very rare occasions, even death. Although the researchers try to warn participants of all known side effects, unanticipated problems may develop.
The experimental treatment might not work as well as intended, possibly not even as well as standard treatment.
There are also some very real benefits to clinical trial participation. If a treatment works as expected, participants could have a better outcome than with other treatments normally available to them. In some instances, participants have even been cured.
Volunteers typically receive excellent care in a manner that might otherwise cost thousands of dollars. Because participants are so well monitored, they tend to learn a great deal about their overall health and any underlying medical conditions. Sometimes there is an opportunity to build camaraderie with other participants, which may be particularly welcome by people who have rare or uncommon diseases. At a minimum, clinical trial participants can be sure that they are helping to advance medical science and public health.
In a very small fraction of situations, investigators in charge of clinical trials and studies have acted unethically. One particularly shameful example is known as the Tuskegee experiments. Conducted around Tuskegee, Alabama, from 1932 to 1972, this study enrolled about 400 poor, mostly illiterate, African-American sharecroppers who had syphilis. These participants were not told that they had syphilis, and despite the widespread availability of the effective treatment penicillin, the Tuskegee investigators withheld penicillin and information about penicillin purely to continue to study how the disease progressed. Participants were also prevented from accessing syphilis treatment programs that were available to other people in the area. As a result of this horrendous breach of ethics and trust, several safeguards were put in place. Included in these safeguards are the establishment of Institutional Review Boards and the concept of informed consent.
Institutional Review Boards (IRBs) are specific committees in each medical institution that participate in clinical trials. Committee members must include at least one non-scientific member and at least one member who is not affiliated with the institution at which the research is being done. IRBs review all proposed clinical trials involving humans. The purpose of these committees is to ensure that trials are conducted in an ethical manner and to avoid any unreasonable risks associated with the trial design. Only trials that have been approved by the IRB of an institution are allowed to proceed in that institution. Each institution's IRB may evaluate and approve studies independently from other IRBs. Alternatively, when many different institutions participate in a study, the FDA permits use of a Central IRB that performs the review for that study. Using a Central IRB can eliminate a lot of duplicated effort by separate committees and also ensure a consistent set of protections and requirements at all the study centers. The Central IRB for a study may be the individual IRB at one of the study sites or a private, independent IRB. Central IRBs must still follow all local requirements at each participating site.
Informed consent means that a person is given all the information needed to make an educated and informed decision as to whether to participate in a clinical trial. Information should describe all aspects of the trial, from its purpose to a statement about who pays for medical care to treat any research-related injuries. Informed consent documents tend to be lengthy (in some cases, dozens of pages long), technical, and hard to read. However, it is essential that participants read the documents carefully.
Participants should take the informed consent documents home, read them over several times, and discuss them with their personal doctor and family members. The doctor can help clarify some of the participation risks. Family members and friends particularly need to be involved if they will be providing transportation to the research center. After reviewing the informed consent documents carefully, participants should return to the investigator and trial coordinator and ask any further questions.
The protection of the safety and rights of clinical trial participants is a task shared by several government agencies as well as the IRBs. However, to a large extent, participants—with the help of their doctor, family, and friends—must play an active part in their own protection. The Clinical Trial Participant’s Bill of Rights can help people understand how to protect their rights during participation.
Clinical trial participants can always quit a trial if it proves to be uncomfortable or too inconvenient. In addition, a vigilant investigator and trial coordinator will insist that participants drop out if there are changes in their health—such as an allergic or strongly negative reaction to the trial intervention—that make the trial too risky for them to continue. Investigators may also stop a trial if participants in one of the groups seem to be having very positive or very negative outcomes compared with participants in the other group. For instance, if the trial intervention is very effective, the trial may be stopped so that all participants may receive the intervention and benefit. If the trial intervention is ineffective or harmful, the trial may be stopped so that no more of the participants are harmed.