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1 Clinical trials 101

Publication Date: April 2012 Vol. 7 No. 4

Author: Elizabeth Ness, MS, RN; Linda K. Parreco, MS, RN; Annette Galassi, MA, RN;
Ann M. O’Mara, PhD, RN, FAAN

Editor’s note: This is the second in a four-part series on clinical trials written by nurses at the National Cancer Institute at the National Institutes of Health. Read Part 1 “Are you ready to care for patients in clinical trials?

Nurses are front-line care providers for many patients who might be eligible to participate in a clinical research study, more specifically, a clinical trial. We can play a key supportive role in patients’ awareness of, understanding of, and decision making about clinical trial participation. However, we can only do so if we understand the process, ethics, and requirements of clinical trials. This article, the second in a series, provides that information.

A brief history of clinical trials

Clinical trials date back farther than you might expect. One of the earliest recorded clinical trials, documented in the Old Testament, describes how Daniel tested two diets to see which was healthier—a vegetarian diet or a diet rich in meats and wine. After 10 days, the vegetarian diet was judged as being healthier.

In 1537, Ambroise Parè unintentionally conducted the first clinical trial of a novel therapy. He used a mixture of turpentine, rose oil, and egg yolk to prevent the infection of battlefield wounds, noting that the new treatment was much more effective than the traditional formula.

James Lind is often credited as the father of clinical trials because he was the first to introduce control groups into his experiments. In 1754, he discovered that citrus fruit prevented scurvy.

The first clinical trials using placebos were conducted in 1863, and the idea of randomization was introduced in 1923.

Since then, clinical trials have rapidly grown and contributed valuable knowledge to the medical field.

Types of clinical trials

A clinical trial is a type of research that seeks to answer a scientific or medical question about the safety or potential benefit of an intervention, such as a medication, device, teaching concept, training method, or behavioral change. Many clinical trials are conducted to assess the safety and efficacy of new/investigational drugs, devices, or procedures. Typically, researchers first test new therapies or procedures in the laboratory and in animals. The treatments that show promise are moved into clinical trials. Usually, the results from one clinical trial will provide data about safety and efficacy to inform continued research.

The National Institutes of Health identifies five types of clinical trials:

  • Treatment: Test new treatments or devices, new combination of drugs, or new approaches to surgery or radiation therapy. Treatment trials are often categorized by phases. (See Phases of clinical trials.)
  • Prevention: Evaluate the effectiveness of ways to reduce the risk of developing a disease or preventing a disease from returning by either “doing” something (for example, lifestyle changes, including diet, exercise, smoking cessation) or “taking” something (for example, medications, vitamins, vaccines)
  • Diagnostic: Develop better tests or procedures to identify/diagnose a particular disease or condition more accurately (for example, imaging tests, laboratory correlatives, tumor markers)
  • Screening: Assess new or better ways of detecting disease or health conditions earlier in healthy people (for example, tissue sampling or procurement, laboratory tests including genetic testing, imaging tests, physical exams, health history including family history and pedigree)
  • Quality of life (or supportive care): Evaluate measures to improve comfort of and quality of life for people with chronic illnesses through better therapies or psychosocial interventions. Focus can be on the patient, families, caregivers, or a combination.
Click to read Phases of clinical trialsAdapted from:

Kummar S, Gutierrez M, Doroshow J, Murgo AJ. Drug development in oncology: classical cytotoxics and molecularly targeted agents. Br J Clin Pharmacol. 2006;62(1):15-26.

Understanding clinical trials. ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/info/understand#Q01.

U.S. Food and Drug Administration. Code of Federal Regulations. Title 21, Subpart B: Investigational New Drug Application. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312.

 

The clinical research enterprise

The individuals and groups that fund, conduct, monitor, and benefit from clinical research are referred to as the clinical research enterprise. The major stakeholders in this enterprise include:

  • sponsors, including private and public funding organizations
  • government agencies (for example, National Institutes of Health, Department of Defense, and Department of Veterans Affairs)
  • academic medical centers (AMCs)
  • pharmaceutical and biotechnology companies
  • device manufacturers
  • research organizations (for example, AMCs, private research institutes)
  • clinical research team, including, but not limited to: investigators, research nurse coordinators/study coordinators, and clinical data managers
  • research participants
  • regulatory and government groups
  • institutional review boards (IRBs)
  • U.S. Food and Drug Administration
  • Agency for Healthcare Research and Quality
  • Centers for Medicare & Medicaid Services
  • healthcare providers (for example, physicians, physician assistants, nurses, nurse practitioners, medical residents and fellows)
  • volunteer health associations (for example, American Cancer Society, Alzheimer’s Association)
  • consumers
  • public
  • healthcare delivery system
  • payers and purchasers of health care.

Those involved in the clinical research enterprise work together to ensure that the rights, safety, and welfare of the research participants are protected and respected and that the data generated by the clinical trial are accurate, verifiable, and reproducible. The protection of research participants and generation of quality data are referred to as Good Clinical Practice, which is the standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials.

Here is a closer look at the clinical research team and the research participant.

Roles of the clinical research team

Every clinical trial has at least one investigator (for example, physician, nurse, pharmacologist, psychologist) who is responsible for the conduct of the clinical trial. Most clinical trials have more than one investigator. When this occurs, one investigator is designated the “principal investigator” (PI) and has overall responsibilities for the clinical study. The others are referred to as sub-investigators or co-investigators.

See Overview of clinical research team responsibilities for information about other team members.

Click to read Overview of clinical research team responsibilitiesAdapted from:

Grady C, Edgerly M. Science, technology, and innovation: nursing responsibilities in clinical research. Nurs Clin North Am. 2009;44(4):471-481.

Office of Human Research Protections. Investigator responsibilities—Frequently asked questions. http://www.hhs.gov/ohrp/policy/investigatorfaqsmar2010.pdf.

U.S. Food and Drug Administration. Form 1572: Statement of investigator. http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm214282.pdf.

Role of the research participant

The research participant is a partner in the clinical research enterprise. It is important that participants understand their role and how it impacts their safety and welfare. Some of the participant’s responsibilities include:

  • reading the entire informed consent document and asking questions if he or she does not understand something about the study
  • following directions for proper use, dosing, and storage of self-administered study medications
  • accurate and timely reporting of information about side effects, hospitalization, missed doses, and pregnancy
  • keeping scheduled appointments or if unable to do so, informing the staff as soon as possible
  • notifying staff when contact information (for example, phone number, address) changes
  • informing staff members if he or she chooses to withdrawal from the protocol.

Several steps are taken to protect clinical trial participants, including adhering to ethical principles and following the informed consent process.

Adhering to ethical principles

It was not until 1947 that society began to look at protecting research participants who are referred to as human subjects. The Nuremberg Code was the first ethical code for the conduct of biomedical research. Since then, other international guidelines have been developed. Laws and regulations have also been enacted to provide protection for human subjects.

One of the key developments was The Belmont Report in the 1970s. In 1973, the U.S. Congress convened a hearing on the Quality of Health Care and Human Experimentation to examine several clinical research studies conducted in the United States where there were issues related to protecting human subjects. The consensus of this hearing was that federal oversight was required to protect rights and welfare of research subjects. In 1974, the National Research Act was passed, which established both the National Commission for Protection of Human Subjects of Biomedical and Behavioral Research and the IRB system. Among other duties, the Commission identified the important ethical principles that should be followed during research involving human subjects:

  • Respect for persons: protecting the autonomy of all people and treating them with courtesy and respect and allowing for informed consent
  • Beneficence: maximizing benefits for the research project while minimizing risks to the research subjects
  • Justice: ensuring reasonable, nonexploitative and well-considered procedures are administered fairly (the fair distribution of costs and benefits to potential research subjects)

Named for the conference center in Elkridge, Maryland, where the Commission meets, The Belmont Report is a statement of basic ethical principles and guidelines that help resolve ethical problems that surround the conduct of research with human subjects. (See How the principles of The Belmont Report are applied in clinical research.)

Click to read Overview of clinical research team responsibilitiesFrom: U.S. Department of Health & Human Services, Office of Human Research Protections. The Belmont Report. http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html. Accessed March 14, 2012.

Informed consent process

Informed consent (IC) is an ongoing process of communication and mutual understanding between the potential research participant and investigator. IC is not just a piece of paper, a moment in time, or a contract. The IC process includes:

  • information sharing about the nature of the research, expected side effects, and possible outcomes, if appropriate
  • comprehension of that information
  • voluntary participation.

His or her signature on the IC document demonstrates the research participant’s voluntary agreement. In rare circumstances, a waiver may be granted to allow for verbal consent. The IC document must contain the following elements:

  • Statement saying that the study involves research
  • Explanation of the purpose of the research
  • Invitation to participate
  • Statement regarding the voluntary nature of participation, including that refusal to participate will not involve any penalty or loss of benefit to the patient
  • Expected duration of participation
  • Description of procedures to be followed
  • Identification of procedures that are experimental (for example, investigational drug)
  • Description of any foreseeable risks/discomforts
  • Description of any benefits to participant or others
  • Disclosure of any appropriate alternatives to study participation (for example, standard comfort measures)
  • How confidentiality will be maintained
  • Contact people for questions related to research and the research participant’s rights
  • Anticipated additional costs from participation
  • Consequences of the participant’s decision to discontinue research participation
  • Statement that participant will be notified of significant new findings that may affect his or her decision to continue participation.
  • Financial conflict of interest with investigator, if appropriate

It is the investigator’s responsibility to ensure the research participant gives voluntary consent that is free of coercion or undue influence. If anyone other than an investigator will be conducting the consent process, the IRB must approve this first. The investigator or designee should be:

  • knowledgeable about the IC process
  • knowledgeable about the protocol
  • able to determine if the subject is well informed and making his or her own decision
  • able to identify and resolve outstanding questions.

Consent is obtained before any protocol-specific procedures are conducted. The discussion needs to include a summary of the purpose of the research, procedures involved, potential risks and benefits, and alternatives to participation. (See Steps in the informed consent process.) This conversation should occur in a quiet and private location.

Steps in the informed consent process

Step 1: Investigator (or Institutional Review Board/Independent Ethics Committee–approved designee) explains the study to the patient verbally, providing all pertinent information (purpose, procedures, risks, benefits, alternatives to participation, and so on) and must allow the potential subject ample opportunity to ask questions.

Step 2: A copy of consent is given to the patient for further review before he or she makes a decision. The patient is given sufficient time to discuss the possibility of participating in trials with family, friends, and other physicians. “Sufficient time” can range from hours to days, depending on the type of trial.

Step 3: After allowing the patient time to read the consent form, an investigator (or IRB-approved designee) meets with the patient and answers any additional questions the person may have.

Adapted from: Office of Human Research Protections. Informed consent. http://www.hhs.gov/ohrp/policy/consent/index.html.

Two special considerations for IC are vulnerable individuals and pediatric assent.

According to The Belmont Report, vulnerable individuals are those who are incapable of protecting their own interests. More formally, they may have insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own interests or may experience unfair coercion. Examples include, but are not limited to: pregnant women, neonates, fetuses; children; institutionalized individuals; the cognitively impaired, intellectually disabled, or mentally ill; prisoners; and persons with potentially disabling, life-threatening, or terminal illnesses/diseases. There are additional laws and regulations to provide additional protection for these individuals.

Pediatric assent is the child’s affirmative agreement to participate in research. The failure of the child to object should not be construed as assent. The IRB may waive the requirement for assent if the child doesn’t have sufficient capacity to participate in the decision or there is direct benefit to the child.

Age appropriateness needs to be considered, including maturity level; psychological state; medical condition; level of comprehension and reasoning, which can be altered by anxiety; and physical and emotional disturbances. The IRB determines if a separate assent document is required rather than a verbal assent. Once a child has agreed to participate in the clinical trial (that is, has given his or her assent), the child’s legal representative (parents or guardians) is consented using the same process as described above. They must give legal permission for the child to enroll. A separate document, an assent document, may be required, especially for older children. The child, rather than just giving his or her verbal assent, will need to sign the assent document.

Another important part of the clinical trials enterprise is the research protocol.

Protocol development, review, and approval

The protocol is a written document that outlines the plan for the clinical trial. It is the “recipe” for ensuring that the procedures/measures outlined in the research study are carried out in a consistent, reproducible manner. The common elements of a protocol document include a background describing purpose and objectives; description of the trial design, interventions, and procedure; pharmaceutical information; considerations for supportive care; and instructions for data collection and reporting.

Multiple steps are required before a protocol is ready to enroll participants. This process is commonly referred to as “protocol development’” and includes writing, review, and approval. The protocol development process requires thoughtful planning and consultation with others, such as a statistician. Either the sponsor or the investigator may write the protocol.

Once a protocol is written, a variety of reviews and approvals are required before it can be implemented. The type of review and approval may vary according to location or intervention, but all clinical trials will have an ethical review. The success of the research study depends on the quality and clarity of the protocol.

Institutional review board

The ethical review is conducted by an IRB, a committee that prospectively and regularly reviews and approves the protocol to make sure that it follows ethical principles and meets federal regulations for the protection of research participants. The primary responsibility of the IRB is to protect and safeguard the rights and welfare of human subjects—to balance the rights of individual subjects with development of knowledge to further society as a whole.

IRB membership consists of a minimum of five members with diverse backgrounds in terms of race, gender, and culture as well as experience, expertise, and sensitivity to community issues. The IRB should be able to determine the acceptability (approval) of the proposed protocol in terms of institutional commitments, regulations, applicable laws, and standards of professional conduct and practice.

Using The Belmont Report as its guide, an IRB will approve a protocol if:

  • risks to participants are minimized
  • risks to participants are reasonable in relation to anticipated benefits
  • selection of patients is fair
  • protocol includes a plan for data and safety monitoring
  • informed consent will be obtained
  • Protection of privacy and confidentiality will be maintained
  • Additional safeguards for vulnerable subjects are applied.

Though the IRB has many other responsibilities beyond the initial protocol review and approval, including annual review of study progress and risk-benefit review for unexpected severe side effects or deaths, discussions of these are beyond the scope of this article.

Clinical trials and third-party reimbursement

As part of the informed consent process, participants should be aware of what costs they might incur as a result of participating in a clinical trial.

For industry/pharmaceutical company trials, the investigational agent is usually supplied at no cost to the participant, and additional trial-related procedures might also be covered. However, costs due to complications of participation may not be covered, so these costs are then the responsibility of the participant and should be addressed in the IC document.

Health plan coverage for clinical trial participants varies from plan to plan. There are typically two types of costs associated with a clinical trial:

  • Patient-care costs
    • Routine/standard of care costs (expected costs related to having the disease) are typically covered by most health plans.
    • Additional protocol or study-related care costs (for example, additional lab tests, ECG, additional doctor visits) might require resolution between the patient’s health plan and the sponsor. These additional costs can be incorporated into a clinical trial budget and requested of the sponsor/institution.
  • Research costs (for example, data collection, research staff time, data analysis, tests conducted purely for research purposes) are usually covered by the sponsor/institution.

Some health plans consider clinical trials as “investigational” or “experimental” and will not cover routine care costs while others may provide limited coverage for trials they consider cost-neutral (meaning they are not significantly more expensive than the treatments considered standard) or cover patient-care costs for Phase III trials but not Phase I or II clinical trials.

Since 2000, Medicare has covered beneficiaries’ routine standard of care patient-care costs in clinical trials. The 2010 Patient Protection and Affordable Care Act ensures coverage for individuals participating in clinical trials, prohibits insurers from dropping coverage because an individual chooses to participate in a clinical trial, and prohibits insurers from denying coverage for routine standard of care that they would otherwise provide just because an individual is enrolled in a clinical trial. All clinical trials that treat cancer or other life-threatening diseases are included.

Finding a clinical trial

Clinical trials are no longer exclusively conducted in academic medical centers or dedicated research centers or research units. Clinical trials have moved into the community (for example, community hospitals, private practices) and more are being conducted outside the United States.

There are many ways individuals can learn about clinical trials, including searchable websites. The National Library of Medicine (www. clinicaltrials.gov) provides up-to-date information including eligibility criteria and contact information for locating federally and privately sponsored clinical trials for a wide range of diseases and conditions conducted in the United States and around the world. Currently, there are more than 14,000 clinical trials recruiting research participants registered with the National Library of Medicine in the United States alone.

Clinical trials have been very beneficial in identifying more effective treatments for disease prevention and treatment and symptom management. By understanding the basics of clinical trials, you can more confidently answer your patient’s questions, which will assist them in making an informed decision about participation in research.

Elizabeth Ness, Linda K. Parreco, Annette Galassi, and Ann M. O’Mara work at the National Cancer Institute, National Institutes of Health, in Rockville, Maryland. Elizabeth Ness is the director of staff development at the Center for Cancer Research; Linda Parreco and Annette Galassi are public health advisors for the Office of Communication and Education; and Ann O’Mara is the head of Palliative Care Research in the Division of Cancer Prevention.

Selected references

Department of Health and Human Services. Code of federal regulations. Title 45, Part 46: Protection of human subjects. http://www.hhs.gov/ohrp/policy/ohrpregulations.pdf. Accessed March 14, 2012.

Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA. 2000;283(20):2701-2711.

National Cancer Institute. If you have cancer and have Medicare…you should know about clinical trials. http://www.cancer.gov/clinicaltrials/payingfor/medicare-and-cancer-trials. March 14, 2012.

National Cancer Institute. States that require health plans to cover patient care costs in clinical trials. http://www.cancer.gov/clinicaltrials/payingfor/laws. Accessed March 14, 2012.

Office of Human Research Protections. Investigator responsibilities—Frequently asked questions. http://www.hhs.gov/ohrp/policy/investigatorfaqsmar2010.pdf. Accessed March 14, 2012.

Providing clear and consistent information to consumers about their health insurance coverage. Healthcare.gov. http://www.healthcare.gov/news/factsheets/2011/08/labels08172011a.html. Accessed March 14, 2012.

Rice TW. The historical, ethical, and legal background of human-subjects research. Respir Care. 2008;53(10):1325-1329.

Understanding clinical trials. ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/info/understand-Q01. Accessed March 14, 2012.

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