Clinical Trials

What Is It?

Every drug that makes it to the pharmacy shelf must leap over numerous hurdles, starting with experimentation in the lab, followed by clinical trials in humans and culminating with the scrutiny of the U.S. Food and Drug Administration (FDA), which must review and approve all proposed new medications for safety and effectiveness before they can be sold to consumers.

A clinical trial uses human volunteers in planned research to increase medical knowledge. A trial look at an "intervention," such as a drug, medical device, procedure or participants' behavior (such as diet and exercise), to assess its merit. The researchers measure the effects of the intervention on the participants. The goal is to see if a new drug, device, procedure or behavioral modification is effective and safe.

For example, a clinical trial might look at the effects of a new drug on participants to see if it effectively and safely lowers high blood pressure.

There is another kind of clinical study, called an observational study, in which participants are also observed to assess health outcomes, but they are not assigned specific interventions, such as a drug or procedure. For example, researchers conducting an observational study might observe a group of older adults to see how exercise affects their cardiac health. (Find out more about observational studies.)

In the United States, research usually starts with lab experiments and sometimes with animal testing or computer modeling. This may be followed by clinical trials in humans.

Currently, more than 150,000 studies of drugs and other treatments are in active clinical trials in 185 countries. They may be done in cities and towns of any size and can be conducted at universities, community clinics, hospitals and doctors' offices.

The federal government maintains a website called ClinicalTrials.gov that provides information on publicly and privately funded clinical studies of drugs, diseases and conditions. The site has information about what trials are being conducted or coming up and which ones are seeking participants.

All clinical trials must have a study design plan called a protocol. This plan is presented to the U.S. Food and Drug Administration (FDA) as part of the Investigational New Drug (IND) application. The FDA and a research ethical review board or an institutional review board (IRB) must approve a protocol for each study site. After the study begins, the review board advocates for the volunteers. Anyone who volunteers to participate in a study must first sign a written informed consent, which says that you have been given information about the study and understand it. (Find out more about oversight of clinical trials and informed consent.)

Once a trial is completed, the results are examined by the FDA. Before approval is given, the clinical trial results of safety and effectiveness must be "statistically significant." That means the results are analyzed to show that they are highly likely to be "true" and not the result of chance.

The process can take more than 10 years, and many new products and procedures never make it through the process and never reach the market.

Pharmaceutical companies also test drugs that have been approved to continue checking long-term safety and effectiveness. If the company wants to market the drug for new uses or add labeling claims, more clinical trials are required.

Reasons for Conducting Clinical Trials

Any question a health care professional might have about how best to diagnose, treat or prevent a medical condition may be addressed scientifically by a clinical trial. For example, a study might ask whether using a particular drug in addition to surgery is better than surgery alone or whether earlier, more aggressive treatment of a condition produces a better outcome. Trials are often used to compare a new drug's safety and effectiveness to a placebo or to existing drugs used for the same purpose.

While some may have goals of testing potential cures for diseases or ways to prevent them, others may be aimed at improving quality of life for those living with a disease or condition.

Here are a few reasons for conducting clinical trials:

• Evaluating a way to treat or manage a disease or a condition, such as drugs, medical devices or approaches to surgery or treatment
• Finding ways to prevent development or recurrence of a disease or condition, such as testing new medicines, vaccines or lifestyle changes
• Evaluating ways to identify or diagnose a disease or condition
• Examining ways to identify a condition or the risk factors for that condition
• Looking for ways to improve the comfort and quality of life of people with a chronic illness and measuring the success of those methods

When a company or agency proposes a new drug or medical device, it usually conducts some trials using animals or computer models. If those results prove promising, it submits an Investigational New Drug (IND) application to the FDA asking to begin testing with humans in a clinical trial.

The IND includes a design plan called a protocol. This includes, for example, study locations; how long the study will last; how many people will participate; eligibility requirements; and a schedule of tests, procedures, medications and dosages.

Before the clinical trial can begin, the FDA and a research ethical review board or an institutional review board (IRB) must approve a protocol for each study site. The review board will advocate for the volunteers. Its job is to be sure that the clinical trial is designed to answer the scientific question and to assure participants' safety.

Many trials include multiple "arms," or groups of participants who are given different treatments for the purposes of comparison. One group might receive an experimental drug, while another receives a standard treatment or a placebo.

Some words you may hear used to describe clinical trials include:

• Open-label: A drug trial in which both the researchers and the volunteers know what drug is being administered and at what dose. It is also called a non-blinded trial. Sometimes such studies are conducted while a drug is awaiting review; during that period, participants or insurers may be required to pay the wholesale cost of the medication.
• Placebo-controlled: A trial in which some participants are given the drug that's being tested and others are given a placebo, or inactive compound. A placebo can have many forms. In addition to the familiar pills, a placebo may be an injected saline (inactive) solution in the case of an injected or infused drug or an inactive cream or nasal spray. The placebo will look exactly like the experimental medication.
• Double-blinded or double-masked: Usually participants don't know if they're receiving the treatment being tested or not. Such studies are termed single-blinded. But in some cases, health care providers also don't know which group is receiving the drug and which a placebo. These studies are called "double-blinded."
• Randomized: A randomized trial is one in which participants are randomly selected for either the experimental group or the control group. Often, researchers use a computer program to determine who goes into which group. Neither the researcher nor the volunteer has any input or control into which group you enter.

Phases of Clinical Trials

Clinical trials have several phases. The initial trials, usually small (20 to 80 volunteers), are called Phase I trials. Some Phase I trials use the same dose of a drug throughout the trial, but others may increase the dose to determine the maximum safe dosage and to discover what, if any, side effects result as the dose is increased. Additionally, researchers sometimes take note of effectiveness data gathered during Phase I trials: Did participants stabilize or get better? The primary purpose of these studies is to measure the drug's safety.

In Phase II trials, researchers again look at safety, but also gather data on effectiveness. Some Phase II trials compare the drug to existing treatments, others to a placebo. Phase II trials target volunteers with a specific disease to evaluate the potential benefits of the new drug in this select population. Phase II trials are usually larger than Phase I studies and may include up to several hundred participants.

Phase III trials are the make-or-break tests of effectiveness and safety and the first time the drug (or other intervention) is used in a broad population. These trials gather additional information on the overall risk-benefit relationship. The results of Phase III trials also affect FDA labeling of a drug or device. These studies may recruit from 1,000 to 3,000 participants and are designed to evaluate effectiveness, compare the experimental treatment to other treatments (if any) or placebo and monitor safety. Because Phase III trials are so much larger than other studies, they provide the best data on overall effectiveness and safety of the treatment.

Phase IV trials are conducted after the FDA grants marketing approval. These studies can provide valuable insight on the effects of long-term use of a treatment or procedure in the general population. They can be designed to accomplish many things. Some are ongoing safety trials, some are registry trials examining the long-term impact on a disease process and others look at the cost/benefit analysis.

An observational study is not a clinical trial in the traditional sense, although it still requires IRB review and approval and compliance with the federal Health Insurance Portability and Accountability Act (HIPAA) in most cases. It is a study that tracks, but does not interfere with, health-related behaviors.

For example, an observational study might ask a series of questions to women diagnosed with cancer at an early age and compare the responses to those of women not diagnosed with cancer.

Results from observational studies might point the way toward a clinical trial. For example, if oral contraceptives appear to reduce ovarian cancer rates in observational studies, a clinical trial may be designed to verify that observation. Why not just accept the conclusion of the observational study and avoid the added expense of a trial?

Observational studies tend to be inconclusive because it is difficult to exclude all other factors that may play a role in outcomes. For example, women who use birth control pills might be more likely to follow a healthy diet or less likely to smoke or have other behaviors that influence cancer rates. A clinical trial is a structured process that seeks to exclude variables (such as diet, fitness, etc.) and answer specific questions by randomly placing participants in treated or untreated groups to help control for such factors.

Participation in an observational study is often less demanding than a clinical trial (although some studies require elaborate diaries of food choices, exercise tracking, etc.) and usually carries very little or no risk.

If you are interested in participating in a clinical trial, you may have to do some of the legwork yourself. This may mean searching the Internet, asking friends and colleagues or directly asking your health care provider about possible participation. Some trials are advertised, but most are not.

Physicians may be reluctant to refer patients to a trial if there is an existing treatment or if they are concerned about losing a patient to another physician. Additionally, insurance companies may refuse to pay for care provided as part of clinical trials. Indeed, recruitment of participants is a major hurdle for researchers.

Currently, less than 5 percent of eligible cancer patients take part in clinical trials. The more people who participate in clinical trials, the faster scientists can answer questions that will lead to better prevention, diagnosis and treatment of cancer.

Until a few years ago, it was difficult for people to find out about clinical trials, but now there are resources you can use to find out about trials for a particular condition. People who have cancer can contact 1-800-4-CANCER, an information service sponsored by National Cancer Institute (NCI) that provides information on the more than 8,000 clinical trials that are NCI-funded. The information is available online at www.cancer.gov/clinicaltrials.

For information on more than 150,000 federally and privately funded studies, go to www.clinicaltrials.gov. Patient advocacy organizations are another good resource. CenterWatch Clinical Trials Listing Service (https://www.centerwatch.com/), a Boston-based publishing and information services company, also contains trial listings. There are many other websites available, but be aware that not all have credible information.

The main criterion for most clinical trials is that you fit the indication—that is, you have the condition the researchers want to treat. All trials define specific participant-selection criteria. A study may look at participants of a particular age range or those with a certain level of disease severity. Some trials may prohibit participation because you have another medical problem, such as high blood pressure or diabetes. Many trials, such as those designed to evaluate the value of preventive care, seek healthy volunteers.

Risks and Benefits of Taking Part in a Clinical Trial

So, why do people participate in clinical trials? Some people who are very ill or who are not responding to standard treatments join clinical trials to receive new, investigational treatment. They are hoping that this treatment, possibly a new drug, medical device or procedure, will work better for them than standard therapy. Others participate in clinical trials to contribute to medical science.

Participation in a clinical trial brings many potential benefits and possible risks. The benefits include access to new treatments otherwise unavailable, as well as an opportunity to help others by contributing to medical research. Sometimes, it also means access to top medical care, although the majority of FDA-approved clinical trials are conducted in community practices. If a treatment proves effective, all participants in the clinical trial may be offered the treatment, even if they were in the control group during the trial.

If you enroll in a clinical trial, you should be aware of the potential risks. You may be signing up for some inconveniences. The treatment may have side effects or produce adverse reactions with other medications or foods. You may receive a placebo (although they are never used in cancer trials when cancer patients would be put at risk by not having effective therapy for their cancer), or you may receive the experimental treatment but not derive any benefit.

If there is an existing effective therapy, it is important that you weigh your options carefully because you may get only a placebo treatment or the experimental treatment may not be as beneficial as the current standard treatment for your disease. Also keep in mind that the design of the trial may require frequent trips to the study site, hospital stays or additional procedures, some of which may be difficult or uncomfortable.

Clinical trial sponsors may include government agencies, such as the National Institutes of Health (NIH); pharmaceutical or medical device companies; individual physicians; or health care institutions.

If you participate in a clinical trial, you may have more clinic visits and tests than you would if you were not taking part in a study. That's because the research team needs to gather detailed data on the progress of your treatment. They may need frequent blood tests, for example, to measure the medication in your bloodstream or to measure markers of disease severity (glucose, for example, in diabetics) or disease progression. You may be asked to keep a diary, fill out forms about your health or other tasks. Some studies may follow your progress even after the treatment ends.

In addition to doctors, the clinical trial team may include nurses, social workers, clinical research associates, data monitors, data entry technicians and other health care professionals. If you participate in a trial, they will review your health history and current medications with you at the beginning of the trial, give you instructions for participating, monitor you during the trial and possibly contact you after the study is completed.

Every U.S. site that conducts human clinical research trials must submit the protocol to an institutional review board (IRB). An IRB reviews trial protocols for safety, sound science and other issues and monitors ongoing trials conducted by the site or institution. Such committees include physicians and other health care professionals, statisticians and laypersons who work together to make sure trials adhere to ethical standards and respect for participant rights.

The IRB is set up to make sure that:

• participant risk is kept to a minimum
• informed consent is obtained from every participant or a legal guardian or representative of the participant; the IRB also makes sure participants who are incompetent or otherwise vulnerable (prisoners, for example) are protected
• participant selection is fair
• the potential value of the knowledge or participant benefit gained from the trial outweighs the risks
• participant privacy is protected

The Office of Human Research Protections, a division of the U.S. Department of Health and Human Services, inspects IRB records and operations from time to time to make sure the proper procedures are being followed. It may impose penalties if problems are uncovered.
Many trials also have Data and Safety Monitoring Committees, which review studies in progress. During a study, if the committee finds that the treatment is harmful or of no benefit, it will stop the study. The committee may also stop a study if there is clear-cut evidence the treatment being studied is superior. All participants then receive the better treatment.

Informed Consent

Before joining a clinical trial, you, or a person legally responsible for you, will have to provide informed consent. (An exception is made for certain emergency treatments.) In most cases, the information will be written and you will be asked to sign a document stating you have been given information and understand it.

Researchers are required to share the following information with clinical trial participants:

• The study involves research of an unproven drug, device or procedure.
• The purpose of the research.
• How long the study is expected to take.
• What will go on in the study and which parts of the study are experimental.
• Possible risks or discomforts.
• Possible benefits.
• Other procedures or treatment options available instead of the proposed treatment.
• The FDA, the sponsor, the IRB or their designees may inspect study records, but records will be kept confidential.
• Whether medical treatments are available if an injury occurs, what those treatments are, where they can be found and who will pay for the treatment.
• The person to contact with questions about the study.
• Participants' rights and injuries related to research.
• Participation is voluntary.
• Participants can quit at any time without losing the rights or benefits to which they would normally be entitled.

During the informed consent process, ask any questions that may affect your decision to participate. Consider writing down questions in advance, asking a friend or relative to join you during the risks/benefits discussion with a health care professional or bringing a recording device so you can replay the discussion later.

Before you sign informed consent documents and join the trial, make sure you've thought through the issues and discussed them with family and friends. Once you join a trial, remember that informed consent is a process that continues throughout the study. You may ask questions even after signing the forms.

You can drop out of a trial at any time. But it is important that you talk with your research team to tell them why you want to drop out. Sometimes problems such as lack of transportation or child care can be resolved or side effects better managed. Even if the problems can't be resolved and you drop out, the information you give the researchers can be helpful, especially if it pertains to side effects. Even if the cause seems less serious—for example, a dosing regimen so complicated it doesn't seem worth the bother—be sure to let them know. Sometimes such input prompts changes that may make the product more patient-friendly.

Increasing Diversity in Clinical Trials

In recent years, researchers have stepped up efforts to include women, minorities, the elderly and children in clinical trials. In the past, Caucasian men were disproportionately represented in clinical trials. One factor that limited women's participation was an FDA ban from 1977 to 1993 on early stage testing of most medications in women of childbearing age, for fear of causing birth defects.

Women's health advocates worked for years to change this and other policies that stifled research involving women's health, noting that many women of childbearing age use contraception, are not sexually active or have chosen not to have children. The issue was important because if gender affects the way a drug works in the body and these differences are identified in early phases of research, then subsequent studies can be tailored to explore these differences and figure out how best to use the drug in both men and women. Moreover, the advocates argued, women should be allowed to weigh the risks and benefits and make their own choices about their bodies.

One result of this political pressure was the creation of the NIH's Office on Women's Health, charged with setting an agenda for research and ensuring adequate representation of women and minorities in NIH-funded trials.

Today, women are recruited for trials even if they are of childbearing age; however, they are also informed of the potential risks to the fetus of untested medications. Researchers reduce the risk of fetal exposure by counseling women about the potential risk (if any) to the fetus and giving the drug during or immediately after the menstrual period or only after a negative pregnancy test. Some trials may require that a woman use one or more methods of birth control to ensure that pregnancy does not occur during or immediately after the trial period.

Even aside from the fertility issue, women have often been underrepresented in clinical trials, most notably in cardiovascular clinical trials, despite the fact that cardiovascular disease is the leading killer of women.

A 1993 federal law, which was amended in 2001, requires that women and minorities be included in every clinical trial involving a disease that affects them and that the NIH makes sure studies are designed to collect and analyze data on gender and racial differences. Drugs often work differently in men and women due to differences in such factors as body size, body fat distribution and hormones. Many drugs, for example, linger in the body longer in women than in men.

Unfortunately, gathering enough data to detect meaningful gender differences often means substantially increasing the size and cost of a trial. Rather than starting with mammoth trials, some experts suggest gathering data in smaller trials that may suggest trends that could be further examined in subsequent, more targeted trials.

In late 2003, Congress passed the Pediatric Research Equity Act (PREA), which enables the FDA to require testing of drugs for pediatric use when drug firms do not test them voluntarily. PREA closely followed the Best Pharmaceuticals for Children Act (BPCA), which rewards drug companies with six months of additional market exclusivity after the completion of studies in children as requested by the FDA. Then in 2007, with strong support of the American Academy of Pediatrics, Congress reauthorized both the PREA and the BPCA and increased the authority of the FDA to require studies on drugs and medical devices used in children.

Determining who pays for participant care in a clinical trial can be a delicate matter. The costs associated with participating in a clinical trial fall into two categories:

• Usual or standard-of-care costs, such as doctor visits, hospital stays, clinical laboratory tests, X-rays and so on, which occur whether you are part of a trial or receiving standard treatment. These costs are normally covered by insurance, if you have it, or by you, if you don't.
• Extra care or study-related costs associated with trial participation, such as additional tests that may not be fully covered by the trial sponsor or research institution or by insurance.

The sponsor of the clinical trial usually covers research costs, such as data collection and management, research physician and nurse time, analysis of results and tests performed purely for research purposes.

Some studies provide free services and medications and even pay volunteers for participating and/or reimburse them for expenses associated with trial preparation, such as travel costs, meals and accommodations. In studies of a new medication, the drug may be provided free from the manufacturer, but you or your insurance company will be charged for other costs, such as physician appointments and other services. Other trials will require you or your health insurance provider to pay as usual, even for the experimental service.

Make sure you know what charges you will be responsible for before participating, and check with your insurer before joining a trial in which the health plan will be billed.

If you want to participate in a trial, you should:

• Find out about the costs associated with the trial and determine which are covered by the sponsor or institution or physician practice.
• Find out about your health plan's policy on experimental or investigational treatments. Read your policy closely; if the answers are not clear, call the customer service line, check the website or write to them asking for specific information about clinical trials coverage.
• Work with your health care professional to ensure the health care team meets its obligations in terms of paying for certain parts of the treatment as provided for under your benefit plan. You may want to ask your health care professional or hospital to send an information package to the plan that includes the following:
  • the results of previous studies, especially any data published in a peer-reviewed medical journal
  • a letter that cites the insurance contract's language to explain why the service should be covered
  • letters from researchers explaining the trial
  • support letters from patient advocacy groups
• Work closely with your company's benefits manager. Often, they serve as your advocate should disagreements arise.
• Give your health plan a deadline to make a coverage decision.

Health plans usually cover only established services and medications—those for which there are sufficient data to demonstrate safety and effectiveness. Most are reluctant to pay for experimental (also called investigational) services or medications. If your insurer learns you are in a clinical trial, you may experience payment denials even for services or medications that would ordinarily be covered.

But some states now require insurance companies to provide some coverage for clinical trials.

If you live in a state that doesn't require clinical trial coverage, your insurance provider may still offer coverage. In any event, contact your insurance company to find out what they will and will not cover before you get involved in a clinical trial.

Insurers usually look at several factors in determining whether participant costs will be covered:

• Sponsorship—Some plans set standards of scientific rigor and oversight that a trial sponsor must meet to qualify for coverage.
• Trial phase and type—Some plans cover participant costs only for experimental treatment deemed "medically necessary" for the individual participant. They may also consider the phase of the trial; some plans cover Phase III trials, because the treatments that reach that stage of testing have a track record of efficacy. Some plans may allow participation in a Phase I or II trial with documentation of effectiveness.
• Cost—Some plans may provide coverage if trial care is not significantly more expensive than standard treatment.
• Availability of effective treatment—Coverage may be provided only for conditions for which no standard therapy is available.
• Qualifications—A plan requires that the medical staff and facility meet guidelines that show they are qualified to perform unique or unusual services associated with the trial.

If your claim is denied, review your insurance to find out about the appeals process. In the battle to win coverage, you and your doctor may have to demonstrate:

• The therapy is not just part of a research study but also a valid procedure that benefits participants.
• Your situation is similar to that of other participants participating in clinical trials as part of a covered benefit.
• Possible complications have been anticipated and can be managed.

Your state likely has an insurance customers' hotline or advocacy office that may be able to help. The insurance commissioner's office is another option. Keep copies of all materials you and your doctor send to the health plan, as well as all information the plan sends you.

If Medicare is your primary health plan, there is good news. Medicare now covers the routine costs of qualifying clinical trials. Medicare will pay any charges normally covered, including tests, procedures and doctor visits. The plan will also pay normally covered charges associated with the experimental treatment (for example, Medicare would pay for anti-vomiting medication administered in conjunction with an experimental cancer chemotherapy drug). If an experimental drug or procedure causes a side effect whose treatment is covered by Medicare, the plan will pay those charges as well.

Like other insurers, however, Medicare still does not cover:

• the new item or service the study is testing (except for certain medical devices) unless Medicare would cover the item or service even if you weren't in a study
• items or services used only to collect data and not for direct medical care (such as monthly CT scans for a medical condition that would normally only require a yearly scan)
• coinsurance and deductibles
• materials provided free by the trial sponsor

In addition, many state Medicaid programs now also cover all or some of the costs of clinical trials.

1. Clinical trials may study new drugs, medical devices or procedures or new uses (or doses) for previously approved drugs, devices or procedures.
2. Clinical trials of new drugs must be approved by the FDA and by an oversight committee—the institutional review board—at each trial site.
3. Clinical trials are conducted in four stages: Phase I, II, III and IV; Phase III trials are the largest and provide the best data on effectiveness and safety among the general population.
4. To find out about clinical trials that are recruiting for your condition, ask your health care professional, contact a patient advocacy group and check out https://www.clinicaltrials.gov.
5. If you participate in a clinical trial, you may have more doctor visits and tests than you would if you were not taking part in a study. That's because the research team needs to gather detailed data on the progress of your treatment.
6. From 1977 to 1993, the FDA forbade early stage testing of most medications on women of childbearing potential for fear of causing birth defects. (The ban applied regardless of whether the woman planned to bear children.) Now, thanks to years of pressure by women's advocacy groups citing the need for gender-specific information about drugs and diseases, women are recruited for trials, even if they are of childbearing age, but are informed of the potential risks of untested medication on fertility and pregnancy (if any).
7. When a manufacturer believes a treatment may have exceptional promise, the FDA can issue what is called fast track or "priority review" status. If the treatment survives this accelerated scrutiny, it can be brought to market—and benefit people—much sooner.
8. Some states have passed laws that require health insurance companies to provide coverage for clinical trials.
9. Medicare now covers many costs associated with participation in clinical trials.

Review the following Questions to Ask about clinical trials so you're prepared to discuss this important health issue with your health care professional.

1. What is the purpose of this trial?
2. Who is sponsoring the study?
3. Who has reviewed and approved the study?
4. Why do you think this treatment will work?
5. Will I have to go to different clinics or facilities over the course of the study?
6. What kinds of therapies, procedures and/or tests will I have done during the trial?
7. How will the treatment and tests I receive in the study differ from treatment and tests I would have outside the study?
8. How often will I have to make medical appointments?
9. What will happen after the study ends? Will there be follow-up care and contact? For how long?
10. Are there any medications, procedures or treatments I should avoid during the study?
11. What responsibilities will I have during the study?
12. Will I still see my regular doctor during the study?
13. Will I be able to find out the results of the trial?
14. What are the approved or standard treatments and how effective are they?
15. What are the possible side effects?
16. How will expenses be handled?
17. Is my insurance likely to cover my costs? Will I be billed for any procedures or medications?
18. What are the charges likely to be?

For information and support on Clinical Trials, please see the recommended organizations and Spanish-language resources listed below.

National Institute of Aging Alzheimer Disease Study
Website: https://www.nia.nih.gov/health/alzheimers/dementia-research-and-clinical-trials

Pharmaceutical Research and Manufacturers of America
Website: https://www.phrma.org
Address: 950 F Street, NW
Washington, DC 20004
Hotline: 202-835-3400

Women's Health Initiative (WHI)
Website: https://www.whi.org/
Address: 2 Rockledge Centre
Suite 10018, MS 7936 6701 Rockledge Drive
Bethesda, MD 20892
Phone: 301-402-2900
Email: nihinfo@od31tm1.od.nih.gov

ClinicalTrials.gov
Website: https://clinicaltrials.gov/

Spanish-language resources

Medline Plus: Clinical Trials
Website: https://www.nlm.nih.gov/medlineplus/spanish/clinicaltrials.html