A patient you are admitting to the hospital tells you that he is in a clinical trial. Your friend is a participant in a clinical trial and tells you that she’s not sure she understands what the study is about. Your neighbor has cancer and wants to locate a clinical trial but tells you she doesn’t want to be a “guinea pig.”

Each year, thousands of people are subjects in clinical trials, and millions follow the results in the media. The National Institutes of Health lists more than 66,000 active clinical trials categorized by disease condition, drug intervention, sponsor and location.¹ Do you know how to respond to questions that patients, friends and neighbors might ask? Read on to find some answers.

From Lab to Prescription Pad

A clinical trial is a research study involving human participants whose purpose is to answer specific health questions about how to cure or control disease and how to enhance health. Clinical trials are sponsored and funded by a number of organizations, such as medical institutions, foundations and pharmaceutical companies, as well as government agencies, such as the National Institutes of Health, the Department of Defense and the Department of Veterans Affairs.¹ Clinical trials are conducted in hospitals, universities, physicians’ offices and community clinics.

Treatment trials test experimental treatments, new drug combinations or new approaches to surgery or radiation therapy. Prevention trials, often conducted over long time periods, study how to prevent disease or how to prevent disease from recurring. These types of studies may involve drugs, vitamins and minerals, vaccines or lifestyle changes.¹ Quality of life or supportive care trials evaluate ways to improve comfort and quality of life for those with a chronic illness.^1-3

Many clinical trials are aimed at the development of drugs. Developing a safe and effective new drug often takes years and is an enormous financial investment.²

Once a promising compound has been identified and has completed initial testing in the laboratory, the company developing the drug files an application with the FDA for an investigational new drug number. The application gives the FDA information supporting the hypothesis that it is reasonable to begin testing with human subjects.^1,2

Clinical trials occur in four phases, with each addressing specific questions:^1-3

• Phase I: Is the treatment safe?
• Phase II: Does the treatment work?
• Phase III: How does this treatment compare with existing treatments?
• Phase IV: Are there other potential uses for this treatment, and what are the long-term adverse effects?

A Phase I tests a drug or device for the first time in a small number of people. The effective dose of the drug and adverse effects in humans are not known. In a Phase I trial researchers test an experimental drug or device to evaluate safety, determine a safe dosage range and identify side effects.^1,4

In a Phase II trial the experimental drug or treatment is given to a larger group of subjects to see if the drug or treatment is effective and to further evaluate its safety.⁴ If a drug or treatment appears promising based on participants’ response rate and the duration of the response, further development may be pursued in a Phase III trial. Phase III trials are usually large, multi-center studies that involve thousands of people. The purpose of a Phase III trial is to confirm the effectiveness of a drug or treatment, monitor side effects, compare it to commonly used treatments and to collect information that will allow the experimental drug or device to be used safely.⁴ Each treatment tested in the trial is called a study arm.^2,4 Participants are assigned to a specific arm of the study by randomization — a process often described to those participating as being like “the flip of a coin.” In a randomized study, the experimental therapy is known as the treatment arm. The treatment that is not part of the drug being tested is called the control arm. To prevent researcher bias, some randomized studies are double-blinded — neither the research team nor the subject knows what treatment the subject is receiving.

Phase IV trials are done after a drug has received FDA approval and is commercially available. This phase assesses other uses for the drug, known as off-label uses, and further evaluates adverse effects.^1,2 Before the FDA approves a drug as safe, it’s tested on several thousand people, a sample size usually large enough to identify serious adverse effects. However, when drugs are used commercially by millions, rare but potentially lethal consequences can occur. For example, safety concerns related to popular anti-inflammatory drugs, such as refocoxib (Vioxx) and celecoxib (Celebrex), prompted the FDA to announce a plan to strengthen its Phase IV postmarketing drug safety program.¹

Clinical trials are conducted in a specific way. Each study protocol includes a background statement of the health problem and its significance, a hypothesis proposing how the drug or device will solve the problem, the study design and procedures, inclusion and exclusion criteria and potential benefits and risks, including adverse effects.

Inclusion criteria are the factors that allow someone to participate in a clinical trial; factors that eliminate someone from participating are exclusion criteria.^1,2 Inclusion and exclusion criteria may include factors such as age, gender, the type and stage of a disease and the patient’s previous treatment history and other medical conditions.² Defining inclusion and exclusion criteria helps the study produce reliable results.^1,2

In some situations, patients don’t qualify for a clinical trial but may benefit from using the drug being studied. An FDA process known as expanded access allows drug manufacturers to provide the experimental drug to people with a life-threatening or serious illness for which there is no alternative treatment.¹

Who’s Who

The principal investigator is the leader of the research team; he or she is responsible for conducting the clinical trial following good clinical practice guidelines. A study coordinator or clinical research coordinator handles all the details of the study. Healthcare practitioners have an excellent background for working in research and often serve as study coordinators.² Healthcare practitioners interested in this field should contact the Association of Clinical Research Professionals, an international organization that provides educational, certification and networking opportunities for research professionals. The designation CCRC indicates a person is a certified clinical research coordinator.

The research team assesses the health of each participant at the beginning of the trial; gives instructions for participating in the trial; monitors the participant carefully during the trial; ensures informed consent; reports to the FDA, pharmaceutical companies and/or institutional review boards; and continues to follow the person after the trial is completed.

To Participate or Not

People should carefully consider the advantages and disadvantages of enrolling in a clinical trial. On the plus side, participation allows people to play an active role in their own healthcare, and if a person is assigned to the experimental or treatment arm of the study, he or she may receive a treatment that is more effective than current therapy.^1,2 People involved in clinical trials also have access to expert medical care at leading medical facilities and receive more intense monitoring than they would if they were receiving a similar standard of care therapy. For some trials, medications will be free to the study participant, and for some people, this might be the only way they could receive such medication.

Participants must also consider the disadvantages of participation. Although an experimental treatment has been tested in the laboratory and in animal studies, there may be unknown adverse effects, ranging from unpleasant symptoms to potentially life-threatening adverse effects.² In addition, a participant may be randomized to the control arm of the study and thus receive no additional therapeutic benefit. Alternatively, the study treatment may not be effective. Following the research protocol usually requires more time and attention than customary treatment, including trips to the research study site, physician visits, laboratory and radiological tests, completion of study logs to record symptoms, complex dosing regimens, and in some instances, hospital stays.^1,2 Clinical trials may not cover the costs of medical care involved, and there may also be insurance co-payments or deductibles for which an individual participant may be responsible.^1,2 Some health plans don’t cover costs associated with clinical trials if they consider the treatment approach experimental. The National Cancer Institute provides information on insurance coverage for people enrolling in studies that involve patients with cancer. Many states require health plans to cover the costs of some clinical trials. Consumers can find information about their state’s laws or policies at www.cancer.gov/clinicaltrials/education/laws. Federal programs such as Medicare and the Department of Veterans Affairs also help pay costs associated with some clinical trials.4

Protecting Participants

Today a number of safeguards are in place to protect the rights of people who participate in research. These safeguards arose out of significant human rights abuses. In the United States, the abuses that were part of the Tuskegee Syphilis Study resulted in dramatic changes in the protection of human subjects. As a result of the abuses, great effort was devoted to ensure that people who were part of any investigational treatment had their rights as human subjects protected. At the end of World War II, the Nuremberg Code was adopted as an internationally recognized code of research ethics.^1,2 The Declaration of Helsinki, issued in 1964, is also internationally recognized as a worldwide standard for the conduct of clinical trials.² In 1974, the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research was established. The commission’s findings and recommendations were published in 1979 in the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects.² All research supported by the U.S. government adheres to the ethical principles of respect for persons, beneficence and justice.² Respect for persons acknowledges the dignity and freedom of each individual and requires that research subjects give informed consent before participating in a clinical trial. Beneficence requires that researchers maximize benefit and minimize risks and aim for a reasonable balance between risks and benefits. Justice requires that individuals and communities have equal access to clinical trials and that the rights of vulnerable populations, such as members of minority groups, children and the developmentally disabled, are protected.

As a result of federal regulations, all studies involving human subjects in the United States must be reviewed and approved by an institutional review board. An IRB consists of people with varying backgrounds, such as physicians, research scientists, pharmacists, nurses and social workers. At least one member of the IRB is a community member not affiliated with the research institution.^1,2 The IRB has several important responsibilities:

• To assess that risks to participants are minimized and are reasonable in relation to potential benefits and new knowledge
• To ensure that informed consent is obtained
• To ensure that patient selection is fair and that safeguards are in place to protect vulnerable populations
• To determine that subjects’ privacy is protected.

In addition to a thorough initial assessment, the IRB regularly reviews the ongoing clinical trial to ensure the rights, safety, and the well being of subjects are protected. An IRB can stop a clinical trial if researchers are not following the protocol or if the trial appears to be causing undue harm to a patients.⁴ Principal investigators and study coordinators are required to inform the IRb of any adverse events that may occur with participants. 

Subjects Really Informed?

Before deciding whether to participate in a clinical trial, people should know as much as they possibly can about the trial and have the opportunity to have their questions answered. Research subjects should know the following —^1,2

• Why the study is being done
• Who is conducting the study and are they qualified to be running the study
• Who is going to be in the study
• Why researchers believe the new treatment being tested may be effective
• What kinds of tests and treatments are involved
• How the possible risks, adverse effects and benefits of the study compare with current treatment
• What the alternatives are to participation
• How long the study will last
• Who will pay for the study; Will the participant be responsible for any costs during the study
• What type of long-term follow-up care is needed
• How participants will learn about the results of the study
• Who is in charge of participants’ care and who should be contacted for questions, problems or concerns

Study participants must be informed that participation in a clinical trial is voluntary and that they have the right to withdraw from the trial at any time without jeopardizing their rights to future care.

Informed consent is a key to ethical research and is required by federal law; a valid informed consent requires that research participants truly understand to what they are consenting.³ The informed consent document is often considered the legal foundation of the informed consent process. However, informed consent involves more than disclosing the required legal elements in writing. The goal of the process is to provide potential research subjects with the information they need to decide whether to participate in a clinical trial. This process should include a continuing exchange of information between the research team and the participant through the entirety of the study. The informed consent document that describes the study should be the starting point for an ongoing exchange of information between the researcher and the research subject.

Keep It Simple

One key aspect of the research consent is that it be written (or read to the subject or the subject’s representative) in a language the subject understands. This is a formidable challenge because an informed consent for a clinical trial contains highly complex information that requires a level of comprehension beyond that required for consent for customary medical care.⁴ A large body of literature indicates that most Americans do not understand the language used in informed-consent forms.^4,5 One study showed that about 30% of subjects in a cross-section of oncology clinical trials believed that their treatment had already been proved to be the best treatment for their type of cancer.⁶

Nearly half of all Americans read at or below the eighth-grade level.⁴ Lower educational level, mental illness, and in some instances, advanced age are associated with less understanding.³ According to the National Cancer Institute, research consents should be at the sixth- to eighth-grade reading level.⁷ Here are two examples of consent information about voluntary participation, the first at the sixth-grade reading level and the second at the 12th-grade reading level:

• Taking part in this study is your choice. If you decide not to take part or drop out, this will not harm relations with your healthcare providers.
• Your participation in this study is strictly voluntary. You have the right to choose not to participate or to withdraw your participation at any point in this study without prejudice to your future healthcare or to other services to which you are otherwise entitled.⁷

Determining how to improve research consent comprehension is a national concern. A systematic review of interventions to improve research participants’ understanding of informed consent for research concluded that multi-media and enhanced consent forms have had limited success.⁵ Having a study team member or an educator spend time talking one-to-one with a potential study participant may be the most effective way to ensure that participants really comprehend to what they are consenting.⁵ An extended personal discussion promotes more active engagement and is based on the premise that informed consent is more than just the action of reading a form and signing it.

Answering Questions

What about the newly admitted patient who tells you he is involved in a clinical trial? In this situation, the goal is to protect the patient through procedures that ensure his safety and that also promote his continuing participation in the clinical trial while he is hospitalized. Make sure that your agency has policies and procedures that address the following questions: Does the patient’s primary provider know the patient is in a clinical trial? Where is the research protocol located? Do you know the adverse effects of the investigational drug? What help does your pharmacy provide in educating you about the investigational drug and its potential adverse effects? Who administers the drug — you or the patient? Was this admission due to an adverse event?

Tell your friend who needs more information about the study she is in to contact the principal investigator with her questions. If after that conversation she still has questions, she should contact the chair of the IRB that approved the protocol. The names and contact numbers of both of these people are found on her copy of the consent. Advise your neighbor who wants to find a clinical trial to go to www.clinicaltrials.gov. This site lists thousands of active clinical trials. Individuals can view types of trials cross-referenced to health problems and can find information about inclusion criteria, trial locations and sources of more information.

As patient advocates, healthcare practitioners have an ethical responsibility to advise people about their rights when they participate in clinical trials. Whether at work or in the community, healthcare practitioners can serve as valuable resources for information about clinical trials.

For More Information

• Lists of clinical trials: www.clinicaltrials.gov
• The Association of Clinical Research Professionals: www.acrpnet.org
• States requiring coverage of clinical trial costs: www.cancer.gov/clinicaltrials/education/laws
  

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