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 there are no good treatments 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.

Key Questions to Ask Before Participating in a Clinical Trial What is the main purpose of this trial? Does the trial involve a placebo or a treatment that is already on the market? How will the treatment be given to me? How long is the trial going to last? What will I be asked to do as a participant? What has already been learned about the trial treatment and have any trial results been published? Do I have to pay for any part of the trial? Will my insurance cover these costs? Is there any reimbursement for travel costs, parking, or childcare? Will I be able to see my own doctor? If the treatment works for me, can I keep using it after the trial has ended? Can anyone find out whether I am participating in a clinical trial? Will I receive any follow-up care after the trial has ended? What will happen to my medical care if I stop participating in the trial? Do the trial doctor and investigator have any financial or special interest in the trial? What are the credentials and research experience of the trial doctor and trial staff? Adapted from: The Center for Information and Study on Clinical Research Participation, www.ciscrp.org.

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 or by a pharmaceutical, biotechnologic, or medical device company. Investigators follow a detailed protocol that dictates who is eligible to participate in the trial, what interventions will be given or performed, how often participants will be evaluated, and the manner in which data will be collected. Several thousand people typically participate in clinical trials for each new intervention before it becomes available to the general public.

Types of Clinical Trials: Clinical trial design can be complicated but typically follows the principles described above (see The Science of Medicine and Clinical Trials: How Doctors Try to Learn What Works).

All interventions must be approved by the U.S. Food and Drug Administration (FDA) before they can be prescribed or performed. The FDA's goal is to allow an intervention to be given to the general public only after that intervention has proven to be safe and effective in carefully designed clinical trials. The FDA requires three phases of clinical trials before approval is granted.

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 the actions of the intervention 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.

If the intervention seems safe in a phase I trial, then phase II trials are conducted. In phase II trials, the intervention is tested in a larger group of people who have the disease 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.

If safety is still satisfactory in phase II, and the intervention seems effective, then a phase III trial is conducted. 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 to the standard treatment, a placebo, or both.

It takes an average of 7 years for a promising drug to make its way through the clinical testing process. Many drugs, medical devices, and diagnostic tools never complete all 3 phases. Others do complete the 3 phases but are not approved for use because they fail to be effective or safe or both. Doctors also perform clinical trials with interventions that have already been approved for use (sometimes termed phase IV trials). These trials may be done to compare two or more interventions, or to test an intervention on a different disorder. In this case, 3 phases are not needed, but the clinical trial design is similar.

The Participation Experience

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. 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.

Finding a Trial: 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 for information or to get on a mailing list. Almost all clinical trials are listed at www.clinicaltrials.gov, a web site sponsored by the National Institutes of Health. Some web sites help match people to specific trials. For a list of top-rated organizations and web sites offering useful information about clinical trials, refer to Appendix IV (see CLINICAL TRIALS).

In the Trial: 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 get 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 for those whom the therapy 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.

Risks and Benefits

Deciding whether to participate in a clinical trial is an important and complicated decision. Both risks and benefits must be carefully considered.

Risks: 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 cause side effects and 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.

Benefits: 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 found a cure.

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 assured that they are helping to advance medical science and public health.

Problems and Safeguards

In a very small fraction of situations, investigators in charge of clinical trials 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 or 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 are specific committees in medical institutions that review 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 Institutional Review Boards are allowed to proceed.

Informed consent is a principle in which 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.

Elements of Informed Consent Documents Major Elements A statement explaining the trial's purpose, the procedures to be followed, the duration of participation, and any investigational treatments or procedures A description of foreseeable risks and discomforts to participants A description of benefits that the participant can reasonably expect A disclosure of any alternative treatments or procedures that might be advantageous to participants A statement about how participant confidentiality is maintained An explanation of compensation and whether medical treatments are available if injury occurs A list of contacts to answer study-related questions and to help with research-related injuries A statement that participation is voluntary and that there is no penalty and no loss of benefits for refusing to participate Other Elements When Appropriate A statement that there may be unforeseeable risks to the participant, embryo, or fetus—if the participant is or may become pregnant A list of circumstances under which the investigator may terminate a participant's enrollment A description of additional costs to the participant An explanation of the consequences and procedures if a participant decides to withdraw A statement that participants will be informed of significant new findings that might affect their willingness to participate A description of the number of participants enrolled in the trial Adapted from: The Food and Drug Administration, Code of Federal Regulations, Title 21, Section 50.25 (www.fda.gov).

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 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 Institutional Review Boards. 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.

The Clinical Trial Participant's Bill of Rights Any participant who gives consent to participate in a clinical trial or who is asked to give consent on behalf of another has the following rights: To be told the purpose of the clinical trial To be told about all the risks, side effects, or discomforts that might be reasonably expected To be told of any benefits that can be reasonably expected To be told what will happen during the trial and whether any procedures, drugs, or devices are different than those that are used as standard medical treatment To be told about available options and how they may be better or worse than what is being studied in the clinical trial To be allowed to ask any questions about the trial before giving consent and at any time during the course of the trial To be allowed ample time, without pressure, to decide whether to consent to participate To refuse to participate, for any reason, before and after the trial has started To receive a signed and dated copy of the Informed Consent form To be told of any medical treatments available if complications occur during the trial Adapted from: The Center for Information and Study on Clinical Research Participation, www.ciscrp.org.

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.

Last full review/revision December 2006 by Kenneth A. Getz, MBA; Oren Traub, MD, PhD