• Why choose to participate in a clinical research trial?
• What is a clinical trial?
• What is a clinical research protocol?
• What are the phases of a clinical trial?
• What protections are in place for those who choose to become a clinical research subject volunteer?
• What is an Informed Consent Form (ICF) or Informed Consent?
• Who can participate in a clinical trial?
• Who pays for or sponsors a clinical trial?
• What happens during a clinical trial?
• What is a placebo?
• What is a comparison or control group?
• What is a masked or blinded study?
• What is a double-blind study?
• What are side effects, adverse reactions or Adverse Events (AE)?
• What are the risks, benefits and alternative treatment options when one considers joining a clinical trial?
• What should I know before I join a clinical trial?
• Should I continue working with my primary health care provider if I participate in a trial?
• Can I leave a trial after it has begun even if it is not over with yet?
• Will I be paid for participating in a clinical trial?
• Glossary of clinical research terminology
• Clinical research trial overview and summary

Why choose to participate in a clinical research trial?
 Choosing to participate in a clinical trial is an important personal decision. The following frequently asked questions will provide you with detailed information about clinical trials. In addition, it is often helpful to talk to your health care provider, family members, or friends about deciding to join a trial. After you have identified some trial options, the next step is to contact the study research staff and ask questions about specific trials.
What is a clinical trial?
 A clinical trial is a research study to answer specific questions about vaccines or new therapies or new ways of using known treatments. Clinical trials (also called medical research and research studies) are used to determine whether new drugs or treatments are both safe and effective. Carefully conducted clinical trials are the fastest and safest way to find treatments that work.
 Ideas for clinical trials usually come from researchers. Once researchers test new therapies or procedures in the laboratory and get promising results, they begin planning Phase I clinical trials. New therapies are tested on people only after laboratory and animal studies show promising results.
What is a protocol?
 All clinical trials are based on a set of rules called a protocol. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study. While in a clinical trial, participants are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment.
What are clinical trial phases?
 Clinical trials of experimental drugs proceed through four phases:

• In Phase I clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
• In Phase II clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
• In Phase III studies, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
• Phase IV studies are done after the drug or treatment has been marketed. These studies continue testing the study drug or treatment to collect information about their effect in various populations and any side effects associated with long-term use.

What protections are there for people who participate in clinical trials?
 The government has strict guidelines and safeguards to protect people who choose to participate in clinical trials. Every clinical trial in the U.S. must be approved and monitored by an Institutional Review Board (IRB) to make sure the risks are as low as possible and are worth any potential benefits.
 An IRB is an independent committee of physicians, statisticians, community advocates, and others that ensures that a clinical trial is ethical and the rights of study participants are protected. All institutions that conduct or support biomedical research involving people must, by federal regulation, have an IRB that initially approves and periodically reviews the research.
What is informed consent?
 Informed consent is the process of learning the key facts about a clinical trial before you decide whether or not to participate. These facts include:

• Why the research is being done.
• What the researchers want to accomplish.
• What will be done during the trial and for how long.
• What risks are involved in the trial.
• What benefits can be expected from the trial.
• What other treatments are available.
• The fact that you have the right to leave the trial at any time.

 If you are considering joining a clinical trial, the research staff will give you informed consent documents that include the details about the study. If English is not your native language, you can ask for the consent documents in languages other than English. Since joining a clinical trial is an important decision, you should ask the research team any questions you may have about the study and the consent forms before you make a decision.
 It is also a good idea to take the consent documents home and discuss them with family members or friends. Talking about your options can help you to feel comfortable with your decision. If you decide to join the clinical trial, be sure to ask for a copy of the informed consent documents so you can review them at any time.
 Remember informed consent is more than signing a form. It is a process that continues through the study. You should feel free to ask the research team questions before, during, and after the study. Informed consent continues as long as you are in the study.
Who can participate in a clinical trial?
 All clinical trials have guidelines about who can get into the program. Guidelines are based on such factors as age, type of disease, medical history, and current medical condition. Before you join a clinical trial, you must qualify for the study. Some research studies seek volunteers with illnesses or conditions to be studied in the clinical trial, while others need healthy volunteers. Healthy volunteers participate in Phase I trials, vaccine studies, and trials on research on preventive care for children or adults.
 The factors that allow you to participate in a clinical trial are called inclusion criteria and the factors that keep you from participating are called exclusion criteria. It is important to note that inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to study.
Who sponsors clinical trials?
 Clinical trials are sponsored by government agencies: such as the National Institutes of Health (NIH); pharmaceutical companies; individual physician-investigators; health care institutions such as health maintenance organizations (HMOs); and organizations that develop medical devices or equipment. Trials can take place in a variety of locations, such as hospitals, universities, doctors' offices, or community clinics.
What happens during a clinical trial?
 The clinical trial process depends on the kind of trial you participate in. The team will include doctors and nurses as well as social workers and other health care professionals. They will check your health at the beginning of the trial, give you specific instructions for participating in the trial, monitor you carefully during the trial, and stay in touch with you after the study.
 Some clinical trials involve more tests and doctor visits than you would normally have for your illness or condition. For all types of trials, you will work with a research team. Your participation will be most successful if you follow the protocol carefully and stay in contact with the research staff. Some terms that will help you understand what happens in a trial are defined below.
What is a placebo?
 A placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the treatment's effectiveness. In some studies, the participants in the control group will receive a placebo instead of an active drug or treatment.
What is a comparison or control group?
 A control group is the standard by which experimental observations are evaluated. In many clinical trials, one group of patients will be given an experimental drug or treatment, while the control group is given either a standard treatment for the illness or a placebo.
What is a blinded or masked study?
 A blinded or masked study is one in which participants do not know whether they are in the experimental or control group in a research study. Those in the experimental group get the medications or treatments being tested, while those in the control group get a standard treatment or no treatment.
What is a double-blind or double-masked study?
 A double-blind or double-masked study is one in which neither the participants nor the study staff know which participants are receiving the experimental treatment and which ones are getting either a standard treatment or a placebo. These studies are performed so neither the patients' nor the doctors' expectations about the experimental drug can influence the outcome.
What are side effects, adverse reactions, or adverse events?
 Side effects are any undesired actions or effects of drug or treatment. Negative or adverse effects may include headache, nausea, hair loss, skin irritation, or other physical problems. Experimental treatments must be evaluated for both immediate and long-term side effects. If a side effect is mild, it is called an Adverse Event or AE. If it is severe, it is referred to as a Serious Adverse Event or SAE.
What are the benefits and risks associated with clinical trials?
 There are both benefits and risks associated with clinical trials. By participating in a clinical trial, you can:

• Take an active role in your own health care.
• Gain access to new treatments that are not available to the public.
• Obtain expert medical care at leading health care facilities during the trial.
• Help others by contributing to medical research.

Clinical trials have risks:

• There may be side effects or adverse reactions to medications or treatments.
• The treatment may not be effective for you.
• The protocol may require a lot of your time for trips to the study site, treatments, hospital stays, or complex dosage requirements.

What should I know before I join a clinical trial?
 You should know as much as possible about the research study. It is important for you to feel very comfortable asking questions and the staff should answer them in a way you can understand. A list of sample questions appears below.
How should I prepare for the meeting with the research coordinator or doctor?

• Plan ahead and write down the questions you want to ask.
• Ask a friend or relative to come with you for support and to hear the responses to your questions.
• Bring a tape recorder so you can replay the discussion after you get home.

What questions should I ask?
 Some questions you might ask about the research include:

• Why is this research being done?
• What is the purpose of the study?
• Who is sponsoring the study?
• Who has reviewed and approved this study?
• Why does the research team think the treatment, drug, or medical device will work?

 Some questions about your participation in the study include:

• Where is the study site?
• What kinds of therapies, procedures, and/or tests will I have during the trial?
• Will they hurt? If so, for how long?
• How will the tests in the study compare to tests I would have outside the study?
• How long will the study last?
• How often will I have to go to the study site?
• Who will provide my medical care after the study ends?
• Will I be able to take my regular medications during the trial?
• What medications, procedures, or treatments must I avoid while in the study?
• What are my responsibilities during the study?
• Will I have to be in the hospital during the study?
• Will the study researchers work with my doctor while I am in the study?
• Can anyone find out that I am participating in a study?
• Can I talk to other people in the study?
• Will I be able to find out the results of the trial?

 Questions about risks and benefits include:

• How do the possible risks and benefits of the study compare with approved treatments for me?
• What are the possible immediate and long-term side effects?
• Other questions include:
• What other treatment options do I have?
• Will I have to pay anything to participate in the study?
• What are the charges likely to be?
• Is my insurance likely to cover those expenses?

Should I continue working with my primary health care provider if I participate in a trial?
 Yes. Most clinical trials provide short-term treatments related to a designated illness or condition, but not extended or complete primary health care. In addition, by having your health care provider work with the research team, you can ensure that your other medications or treatments will not conflict with the clinical trial protocol.
Can I leave a clinical trial after it has begun?
 Yes. You can leave a clinical trial at any time. If you plan to stop participating, let the research team know why you are leaving the study.
Will I be paid for participating in a clinical trial?
 Some clinical trials will pay you for joining the trial, while others will not. In some programs, researchers will reimburse you for expenses associated with participating in the research. Such expenses may include transportation costs, child care, meals, and accommodations.
GLOSSARY OF CLINICAL TRIALS TERMINOLOGY
 Clinical Trial: The most rigorous method for evaluating the safety and efficacy of a new drug, device, or surgical procedure on a group of individuals who are willing to participate and meet the eligibility requirements to be randomized. (See Randomization, below.)
 Clinical Research Associate (CRA): A representative of either the sponsor or contract research organization (CRO) that is responsible for monitoring the quality of the conduct of the clinical trial.
 Contract Research Organization (CRO): A company funded by the sponsor to manage the day-to-day aspects of the clinical trial.
 Control (Comparison) Group: The group of participants in a clinical trial who have been randomly assigned to the treatment group receiving the usual standard of care. (See Standard of Care, below).
 Coordinator: An investigator who supervises the operations of the clinical trial with respect to coordinating patient visits and trial procedures.
 Data and Safety Monitoring Board (DSMB): An external, independent, multi-disciplinary group of experts who monitor a clinical trial's progress as well as accumulating data for the emergence of any early benefit or harm. The DSMB usually recommends continuation, but may recommend alteration or early termination in which case there is immediate reporting of findings.
 Food and Drug Administration (FDA): The US government regulatory agency responsible for monitoring and enforcing policies that regulate the manufacturing, testing, and marketing of the drugs and devices. The FDA must approve all drugs and devices prior to their commercial availability.
 Informed Consent: A process by which the researcher explains all potential risks and benefits of a clinical trial to potentially willing and eligible participants. The Institutional Review Board (IRB) must approve the informed consent and all potential participants must sign the form in advance of starting the clinical trial.
 Institutional Review Board (IRB): IRBs are composed of medical professionals as well as non-medical professionals and lay persons who review all research to protect participants. Specifically, they try to uphold three principles, namely respect for persons, beneficence and justice.
 Intervention Group: The group of participants in a clinical trial who have been randomly assigned to the treatment strategy of the product under investigation.
 Investigator: A health professional involved in the design, conduct, analysis, or interpretation of the clinical trial, generally including doctors, nurses, pharmacists, and coordinators.
 Placebo: An inactive or inert substance, which is identical in appearance to the product under investigation.
 Principal Investigator: The medical researcher who has the overall authority and responsibility for the clinical trial.
 Protocol: The outline for the clinical trial, which includes the specific objectives, the eligibility criteria, and the procedures to be completed. An IRB must approve the protocol before a participant can be randomized into the clinical trial.
 Randomization: The method of assigning patients by chance (luck of the draw) to either the treatment under investigation or to the existing standard of care. This is the only reliable means of verifying the small to moderate benefits of new treatments.
 Sponsor: The pharmaceutical, research, or health organization that funds the clinical trial.
 Standard of Care: The current best available drug, device, or surgical procedure in medical practice.
CLINICAL TRIALS — AN OVERVIEW
 Clinical trials are the most reliable research studies available for proving whether new drugs, devices, or surgical procedures are beneficial in the treatment and prevention of human illness.
 For the results to be widely applicable, clinical trials need to include a broad range of people — men, women, and children of different races and ethnicities.
 Clinical trials typically compare a new drug, device, or surgical procedure against usual care (the best treatment currently available). They have an important impact on clinical practice as well as the health of the general public regarding the treatment and prevention of human illness. Participants in clinical trials are randomly assigned (randomized, meaning assigned by chance, or luck of the draw) to a treatment strategy. They receive either the new treatment under study (assignment to Intervention Group) or usual care (the Control or Comparison Group). Because neither the patient nor the researcher knows which group offers the better treatment until the trial has concluded, randomization provides the most powerful test as to which strategy is ultimately the most beneficial to humans.
 Clinical trials are different from basic research (laboratory or animal studies). Basic research answers crucial questions about why, not whether a drug, device, or surgical intervention may reduce premature death or disability. Basic research has great precision but always has questionable relevance to humans.
 The Informed Consent process, whereby the researcher explains potential risks and benefits of a clinical trial to willing and potentially eligible participants, should be completed before any individual is randomized into a clinical trial.
 Participation in a clinical trial may well turn out to benefit you individually. Beyond this, it can certainly benefit society by filling in a gap and extending knowledge about the best treatment or preventative strategy for a given illness or condition.
 Clinical trials have helped medicine make great strides in treating and preventing human illness. As more knowledge accumulates, the quantity and quality of treatment and prevention strategies available to all of us will continue to improve.
WHAT IS AN IRB?
 An Institutional Review Board is a committee of people appointed to function as a watchdog over participants in clinical trials. The Food and Drug Administration (FDA), requires that these committees periodically review all research. IRBs try to assure that patients enrolled in a trial are protected. No patients can be enrolled in a trial without the prior approval of the IRB. Many hospitals appoint their own IRBs, but smaller institutions (the facility providing your care) that do not have their own IRB, often use an independent IRB who serves the same purpose.
 What is the basic objective of IRBs? IRBs are comprised of medical professionals as well as nonmedical professionals and laypersons who review all research with the basic objective to protect trial participants. Specifically, they try to uphold three principles, respect for persons, beneficence, and justice.
 Respect for persons requires them to assure that patients are provided with all of the information they need in order to decide if they should enroll.
 Beneficence requires them to protect the patients from harm, and maximize the potential benefit.
 Justice requires that participants not assigned at random to the new drug, device, or procedure be offered usual medical care of proven benefit.
 Why are they qualified to do it? The FDA requires that the IRB should be diverse in terms of gender, ethnicity, and professional experience. An IRB must be composed of a minimum of five members. Many are health professionals — physicians, nurses, pharmacists, and other scientists. They must have at least one non-science committee member, and it is common to see legal professionals and clergy members on an IRB. Also, there must be at least one member not affiliated with the institution either directly or through family ties.
 Additionally, no one who may directly benefit financially from the approval of a new therapy may be a voting member of an IRB. In other words, employees of any sponsoring company cannot participate in IRB decisions concerning a particular trial. Further, investigators conducting a trial likewise cannot participate in IRB decisions concerning that trial.
INFORMED CONSENT
 Before you enroll in a clinical study, the physician — principal investigator, or his/her representative — responsible for your care while on the study must execute what is known as informed consent. This is the information that must be provided to the patient detailing all study obligations, procedures, and potential risks/benefits, as they are known.
 The language must be understandable and may not be exculpatory, meaning that you will not waive your legal rights, and the physician, the investigating institution, and the sponsoring company are not released from liability or negligence.
 The physician or study coordinator will review the informed consent document in detail with you. This document is required under federal law to include information pertaining to the following:

• A statement that the study involves research including the purpose of the research, the duration of your involvement, and the procedures that will be completed.
• A description of any known risks or foreseeable discomforts to the patient.
• A description of any expected benefits to the patient or to others as a result of participation in the trial.
• A disclosure of appropriate alternative treatments or procedures that might be beneficial to the patient.
• An explanation of whom to contact with any questions or concerns pertaining to the research, your rights as a research subject, and to report any events you feel may be related to the research.
• A statement that participation is voluntary, and that you may discontinue participation at any time without penalty.
• A statement regarding confidentiality, explaining that your identity will be guarded, but that blinded medical records will be available to the Food and Drug Administration for their review.
• Should the research involve more than minimal risk, a statement explaining what compensation or treatment will be available to you should injury occur during the trial, and where you may obtain further information concerning compensation and treatment.
• The above information has been reviewed by an Institutional Review Board (IRB) prior to the enrollment of any patients. The purpose of the IRB is the review, approval, and continuing review of all clinical investigations. Specifically, the goal of this continual review is the protection of the study subjects.

 Before the facility conducting the study is able to enroll any patients, these documents must be carefully prepared, reviewed, and approved; all specific to each individual clinical trial. The physician, or their representative is required to review this with you, and you are encouraged to clarify any questions or concerns you have at this time. This is not a contractual agreement, and you may still decide to withdraw from the study at your discretion. This is simply a statement which demonstrates that the details of the study were disclosed to you, and that you elected to participate. If you decide to participate and sign the consent form, you should receive a copy of the consent with all the appropriate signatures, such as your signature, the person who performed the consent discussion with you and the investigator who is running the trial.
THE FOUR PHASES OF CLINICAL TRIALS
 Phase I: Phase I trials are the first step in testing a new treatment in humans and are primarily concerned with assessing safety by monitoring for any harmful side effects. In these trials, researchers look for the best way to administer a treatment; such as whether by mouth (orally), by injection into the blood (intravenously), by injection into the muscle (intramuscularly), and also look at the frequency at which a treatment should be administered (e.g., how many times a day, etc.). Phase I trials typically require a relatively small number of participants.
 Phase II: Phase II trials continue safety monitoring, as for example, dosage levels are increased to determine the optimal benefit to risk range (the range of doses at which humans receive optimal benefits with minimal risk). As in Phase I, these trials also typically require a relatively small number of participants.
 Phase III: Phase III trials typically compare the outcome of participants randomized to the new treatment (the Intervention Group) with those assigned to the best available standard drug, device, or surgical procedure (Comparison or Control Group).
 Many Phase III trials utilize a placebo, an inactive or inert substance that appears identical to the product under investigation. The use of the placebo allows for an unbiased assessment of side effects from the new treatment.
 Many Phase III trials use a double-blind design, meaning that neither the participant nor the researcher knows who is getting the new intervention and who is getting usual care. However, if some extreme effect emerges (either beneficial or harmful) the external Data and Safety Monitoring Board (DSMB), which oversees the clinical trial, can recommend either its early termination or alteration of the design.
 Phase III trials typically enroll large numbers of participants, ranging from hundreds to tens of thousands of people. They may be conducted simultaneously at many sites across the United States as well as in other countries, at facilities including major medical centers, community hospitals and clinics, doctors' offices and veterans' and military hospitals.
 At the end of the Phase III trial, researchers analyze the data to assess the benefits of the new treatment, inform the participants, and publish their findings in peer reviewed medical journals for the medical community as well as the general public. If the new treatment is beneficial, the clinical trial results are submitted to the US Food and Drug Administration (FDA), which considers whether to grant approval for its use.
 Phase IV: Phase IV trials are conducted after the FDA has granted approval to monitor long term effectiveness of a treatment and its impact on quality of life, as well as to compare its cost effectiveness relative to other treatments.