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Conducting Clinical Trials

  • Updated: 06/03/2013

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Recommendations

The Problem
Purpose
Background of the Issues
Recommendations
Conclusion
Endnotes

These "Recommendations for the Development of Informed Consent Documents for Cancer Clinical Trials" were prepared by the Comprehensive Working Group on Informed Consent in Cancer Clinical Trials for the National Cancer Institute in October 1998.

The Problem

Many informed consent documents have become too long and complex, and do not provide a sound basis for informed decision-making. 1,2,3

Purpose

These recommendations are intended to provide a clear template for informed consent documents and supplemental materials used in clinical research. The goals of the recommendations and accompanying template are to increase potential research participants'* understanding of proposed studies and better enable them to make decisions about participation.

The recommendations are intended to assist: (1) sponsors and/or investigators who write consent forms and (2) local Institutional Review Boards (IRB) which oversee research projects and consent documents at their institutions (45 CFR 46.109 and 21 CFR 56.1096).

Although the recommendations are focused on treatment studies, they may also apply to prevention, early detection, diagnosis, and other types of trials. The recommendations are relevant to all phases of clinical research; however, each phase may generate additional specific considerations to be addressed in the informed consent document. (The template highlights some of these considerations and the sample consents serve as examples of specific study considerations.)

The recommendations are not intended to address issues for genetic testing and tissue banking. These are being addressed in other forums.


* This document uses the term "research participant" to mean "research subject," the term used in the Federal regulations. Please see Appendix 1 for additional definitions of terms.


Background of the Issues

The goal of the informed consent process is to provide people with sufficient information so they can make informed choices about whether to begin or continue participation in clinical research. The process involves a dynamic and continuing exchange of information between the research team and the participant throughout the research experience. It includes discussion of the study's purpose, research procedures, risks and potential benefits, and the voluntary nature of participation.

The informed consent document provides a summary of the clinical study and the individual's rights as a research participant. The document acts as a starting point for the necessary exchange of information between the investigator and potential research participant. Also, research participants and their families may use the consent document as an information resource and reference throughout participation in the trial.

The informed consent document is often considered the foundation of the informed consent process; it does not, however, represent the entirety of the process. Nor is the informed consent document a risk-management tool for the investigator and/or institution.

Development of a consent document that provides useful and understandable information has become more challenging due to the increased complexity of medical research and care. Such challenges require careful consideration of what information is useful to participants and how to provide it in clear and simple language.

Recommendations

The Comprehensive Working Group on Informed Consent in Cancer Clinical Trials* has developed: (1) recommendations related to specific Federally-required elements in the consent form,** and (2) general recommendations to enhance the research participant's understanding of the consent form.

In addition, the Working Group recommends that relevant agencies such as the National Institutes of Health and the Food and Drug Administration facilitate the development of methods to enhance the informed consent document and process in clinical research.


*Appendix 6 lists the participants in the Comprehensive Working Group on Informed Consent in Cancer Clinical Trials.


** Federal regulations require that the informed consent document include certain basic elements and provide for inclusion of additional elements when appropriate (45 CFR 46.116, 21 CFR 50.20, and 21 CFR 50.25). Please refer to the Code of Federal Regulations and Appendix 2 for the list of Federally-required elements of informed consent.


Recommendations for Specific Federally-Required Consent Elements

The following recommendations provide guidance in the interpretation of the Federal regulations related to specific elements of the informed consent document and are outlined in the accompanying template. Although the Comprehensive Working Group considered all of the Federally-required consent elements, it chose only to develop recommendations for the following elements. The template, however, does address all of the Federally-required elements for informed consent. See Appendix 2 for the complete list of Federally-required elements.

Purpose of the Study

The consent form should clearly and simply explain the purpose of the research study and state why the potential research participant is eligible to enroll. The main objective of the proposed study should be placed in the context of standard care. For example:

The purpose of this research study is to find out whether adding the drug Taxol to a commonly-used chemotherapy is better at preventing your cancer from coming back than the commonly-used chemotherapy by itself. The study will also see what side effects there are from adding Taxol to the commonly-used chemotherapy. Taxol has been found to be effective in treating patients with advanced breast cancer. In this study, we want to see whether Taxol will be a useful addition to the treatment of patients with early-stage breast cancer and to see if the side effects seem to be worth the possible benefit.

Research Regimens

Research participants should be able to: (1) understand what is going to happen to them in the research study, (2) distinguish what is standard care from what is investigational care, and (3) understand what additional standard care, that otherwise would not be given, is provided because they are in the research study.

The consent document should include a simple schema, clearly list and describe the research regimens of the protocol, and explain how it will be determined which regimen the research participant will receive. If the study involves randomization, the chance of a participant being placed in a particular group should be stated clearly.

When the comparison between procedures or therapies is the primary objective of the study, the consent form should describe both approaches, even if one is considered standard. If comparison is not the objective of the study, standard therapies should be listed but need not be described in the research consent form.

Risks

Physical risks of participation should be described. Nonphysical risks should be included when they could affect the patient's decision about participation. Examples of relevant nonphysical risks of participation may include: increased time commitments and travel considerations, financial implications, risks related to insurability and employment, and psychological effects.

The risks associated with the trial should be described and compared to risks of common standard therapeutic alternatives (if available) and to the option of no treatment. Specifically, the consent form should describe risks that are:

  1. very likely, regardless of severity, and
  2. less likely but serious, or rare but relatively severe as compared to the severity of the disease and/or risks of alternative options.

Interpretation of these terms is subjective and should be determined by the investigators and IRBs.

The risks associated with standard medical therapy that would be delivered regardless of participation in the clinical trial (such as placement of a central venous catheter) should not be included in the research consent document. Information about the risks of standard medical procedures should continue to be provided in separate informed consent documents as part of usual (nonresearch) medical care. Investigators and IRBs, however, may choose to include risks of standard medical practice in the research consent document if such inclusion would clarify: (1) the distinction between the standard and investigational therapies and/or (2) the cumulative or additive risks associated with the research trial.

Risks should be presented for the entire regimen rather than listing the risks for each specific drug or procedure that comprise the intervention. This will provide a more accurate and comprehensive summary of the research risks and reduce the repetition of side effects common to different agents or modalities in the trial.

Benefits

Potential benefits to the research participant and to others should not be overstated in the consent form. Because positive outcomes cannot be guaranteed, any statements regarding potential therapeutic benefit should be based on available data. No investigational approach should be identified as the only chance for cure, or contrasted with standard approaches that offer no chance of cure. When relevant, the consent form should state that the investigational therapy may be no better than or may even be inferior to standard therapy or have no therapeutic effect. This issue is of particular relevance to early phase trials where there are limited human data.

Alternatives

The informed consent document should list the alternatives to participation in the clinical trial, including the option of no anticancer treatment at the current time, or treatment with standard therapy, when appropriate.

Confidentiality

The confidentiality section of the informed consent document should state that although measures will be taken to protect the privacy and security of personally-identifiable data, absolute confidentiality cannot be guaranteed. The consent document should list the organizations that will have access to personally-identifiable data and that personally-identifiable information may be disclosed as required by law. When listing organizations that will have access to research records, describe for what purposes the information will be disclosed to these organizations.

Other Information

Information not required by the Federal regulations should not be included in the informed consent document unless it is necessary for the potential participant's understanding of the proposed research.

Drug information sheets and information explaining access devices and supportive care should be provided separately (as supplemental materials), and not in the research consent forms. Information that is not required for the basic understanding of the research purpose, procedures, risks, or possible benefits by the potential participant, but is intended for the benefit or legal protection of those conducting the research, should be presented in a separate document.

General Recommendations

Readability

Informed consent documents should be understandable to the patient population at the local facility. Documents should be written at an eighth grade or lower reading level. Investigators are also encouraged to use computer software applications or other techniques that assess reading level. Technical and legal jargon should be avoided.

Use of active voice, short sentences, personal pronouns, clear page layout with "white space" borders, and large fonts make documents easier to read. 4,5 The use of simple outlines, flow charts, diagrams, study schemas, calendars, and other graphics are encouraged. Consent forms should use the second person because it reflects the conversation between the investigator and potential research participant. (See Appendix 3 for suggestions for developing easy-to-read informed consent documents.)

Supplemental Information

The research participant should be informed about and provided access to supplemental information during the initial decision-making process and throughout the research trial. This approach should minimize the length and complexity of the informed consent document and allow the essential elements of consent to be better highlighted in the consent document. Supplemental materials may enable the potential research participant to more effectively read the consent form and ask questions of the investigator at the initial informed consent discussion or during participation in the trial. Supplemental materials that can be used with consent forms for a variety of protocols may need only a single IRB review, depending upon local IRB review procedures.

Supplemental materials may include: information sheets developed by investigators and IRBs; Web-based information such as the NCI clinical trials Web site (http://cancertrials.nci.gov) and Physician Data Query (PDQ); booklets, videos, and other materials provided by NCI's Office of Cancer Communications; pharmaceutical information materials written for the lay public; and copies of the complete research protocol.

Investigators should consider the use of a variety of communication techniques that complement the informed consent document to enhance the potential research participant's understanding. (See Appendix 4 for some suggested communication methods.)

Consent Comprehension in Diverse Populations

It is essential to include diverse populations in cancer research. This important and complex issue requires cultural sensitivity in developing the informed consent document and communicating with the potential research participant and family members. The standards for valid consent should not be compromised in the face of language, cultural, or physical challenges.

Oral and written translations are only part of the process of presenting informed consent information to non-English-speaking persons. Culturally-appropriate consent documents and supplemental materials such as videos, audiotapes, and interactive computer programs may be especially helpful in communicating information to individuals from diverse populations, whether or not English is their primary language. Consent documents should also be adapted to the needs of individuals with limited literacy skills and those who are vision impaired. A single research trial may require several versions of the informed consent document to tailor the information to a variety of populations.

Notification of New Information

When new knowledge emerges that is likely to affect a research participant's willingness to continue participation in the trial or might have affected the decision to enter the trial in the first place, the participant should be informed and written consent may need to be documented again. The urgency of notifying the research participant of new toxicity data, for example, depends on the likelihood and severity of the risk. New information regarding relatively minor risk or low severity may be presented orally at the next routine visit. In any case, the IRB should be notified and consulted as soon as possible to assist the investigator in determining the appropriate form of notification.

When a Phase III study includes review by a Data Safety and Monitoring Board, potential research participants should be informed of its existence in the consent document. For example:

A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the data from this research throughout the study. We will tell you about new information from this board or other studies that may affect your health, welfare, or willingness to stay on this study.

Conclusion

The informed consent document is only one part of the larger process of informed consent that occurs between the potential research participant and members of the research team. The informed consent document should be understandable to the research participants involved.

The informed consent process should involve an ongoing dialogue between investigators and research participants. Investigators should address the research participants' concerns and questions and should confirm that research participants understand the basic purpose and conduct of the study. Only in this way can researchers ensure that the rights of research participants are protected and that the integrity of the informed consent process is maintained.

Endnotes

1 S. Grossman et al., "Are informed consent forms that describe clinical oncology research protocols readable by most patients and their families?" J Clin Oncology 12 (1994): 2211-5.

2 R. Joseph, "Viewpoints and concerns of a clinical trial participant," Cancer 74 (1994): 2692-3.

3 C. Meade et al., "Consent forms: How to determine and improve their readability," Onc Nursing Forum 19 (1992): 1523-8.

4 National Cancer Institute, Clear and Simple: Developing Effective Print Materials for Low-Literate Readers NIH Pub. No. 95-3594 (December 1994): 22-37.

5 National Cancer Institute, Making Health Communications Programs Work: A Planner's Guide NIH Pub. No. 95-3594 (April 1992): 37-8.