|NIH Guidance on Informed Consent
For Gene Transfer Research
In addition to the resources within this guidance, the following resource materials may be valuable. Some of these materials are specific to human gene transfer research. Others deal with informed consent and other research ethics issues that are particularly salient in these trials (e.g., therapeutic misconception).
These materials were selected because they provide additional information on the topics discussed in the guidance that may assist investigators, institutional review boards, and institutional biosafety committees in developing consent forms or aiding the consent process for gene transfer. Materials that report the results of empirical research without providing such assistance have not been included. This list is not exhaustive and will be periodically updated.
The author asserts that current human subjects research protections are in need of reform. Changes should focus on using informed consent as an educational process. Issues are raised that relate specifically to educating potential study participants about genetic research.
This publication offers ethical commentary regarding the authors' research on therapeutic misconception. The authors suggest ways to improve the informed consent process, including the use of a trained, neutral educator to guide the consent process. This third party would focus discussion on information regarding the subject's personal care, dispel the therapeutic misconception, and better explain the purposes of the study, randomization, and use of placebos.
The author discusses the ethics of experiments that do not confer direct benefit on participants themselves. Several case studies are analyzed with respect to shared difficulties with informed consent. Suggestions are made which may help researchers provide a more thorough and effective consent process.
The author considers informed consent for study participants who are desperately ill and for whom a clinical trial may falsely offer a "last hope." To protect this vulnerable population from coercion, a decision to participate in a clinical trial must be based on a careful weighing of risks and benefits.
The author asserts that informed consent must strike a compromise between promoting moral values and ensuring risk management. This can be accomplished by using the informed consent process to encourage autonomous decision-making. A study participant's intentionality, voluntariness, and understanding are essential to this approach.
The authors suggest that, given the rapid pace of research in this area, human protocols for in utero gene transfer research may be seriously considered in the foreseeable future. Federal guidelines for fetal research rely on minimizing risk and informed consent to protect the "rights and welfare" of both the fetus and pregnant woman. However, in utero gene transfer research poses special challenges to informed consent. An expectant parents' comprehension of, and voluntariness for participation in, research may be easily undermined, leaving the fetus unprotected from undue research risks. To compensate for this limitation, a greater emphasis should be placed on the benefit/harm assessment.
An empirical study that explores the kinds of potential benefits IRBs look for when reviewing a study and how they prioritize particular benefits. The authors conclude that there is a great deal of heterogeneity in how IRBs consider benefits in research and that standards and common tools for assessment would be helpful in defining and clarifying the critical assessment elements.
After the release of the Belmont Report, the volume of information disclosed to potential study participants increased substantially. To make sure this information is conveyed thoroughly, researchers should approach this task with a commitment to open communication and collaborative decision-making.
Daugherty C, et al. A feasibility study of informed consent and medical decision-making: Employing an interactive patient choice design in phase I trials. Presented at the 1996 Annual Meeting of the American Society of Clinical Oncology 1996.
A report on a study in which participants chose from a range of predetermined dose levels after extensive information regarding risks and potential toxicities of drugs was provided. Participants were then surveyed after giving consent. Results show that allowing participants to choose their dosage level is feasible and does not interfere with the overall informed consent process. Authors assert it may even provide participants with an additional sense of control, empowerment or self-worth, and could facilitate rapid dose escalation n some Phase I studies.
A study revealed that most patients who participate in Phase I trials are strongly motivated by the hope of therapeutic benefit. Accordingly, only a minority of participants appears to have an adequate understanding of the purpose of Phase I trials as dose-escalation/dose-determination studies. The implications of these results are discussed.
The meaning and historical development of informed consent are analyzed from the standpoint of Phase I clinical trials for cancer. The author reviews empirical studies of informed consent in these Phase I trials, and calls for further research on the intricacies of communication between investigators and research participants.
Ethical issues associated with informed consent are reviewed on the basis of personal experience and reviews of current research. The ethical underpinnings of informed consent are discussed and the inadequacies of some informed consent documents are highlighted. Suggestions for future research are made which may help investigators and study participants maximize the educational value of informed consent.
The authors discuss the possibility that the current system for informed consent places a researcher's need for impartiality in direct conflict with his or her fiduciary obligation to a sick patient. The roles of the FDA and the NIH in resolving these conflicts are discussed, as is the importance of adverse event reporting.
This article proposes a framework for reviewing human gene therapy protocols for clinical trials. The author provides a description of gene transfer techniques along with a checklist of issues commonly faced by IRBs. Major points of controversy regarding gene therapy are discussed as well, including national and local review, risks to society and individuals, and the ethical quandaries raised by the prospect of germ line intervention.
To avoid the therapeutic misconception, researchers and IRBs should make sure that study participants who enroll based on potential benefits stand a reasonable chance of obtaining them. Throughout this process, researchers and IRBs must carefully distinguish between the different types of benefit and, in doing so, must discuss the nature of the potential benefit, its potential magnitude and the likelihood that it will occur, while acknowledging any uncertainty.
Investigators preparing to engage in human gene transfer research must use the NIH guidance document, "The Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA Molecules into the Genome of One or More Human Subjects," written by the Recombinant DNA Advisory Committee, to prepare for the submission of a research protocol. Several corrections in the terminology (like using "gene transfer" instead of "gene therapy" and "subject" instead of "patient") employed by this guidance document could help to avoid misconceptions about gene transfer research and clarify both the promise and the limits of the research enterprise for investigators and subjects.
This article emphasizes the importance of follow up for participants in gene transfer trials. Each investigator is responsible for ensuring that participants receive proper long-term follow-up. This is especially important for gene transfer, a cutting edge technology for which public support is often tenuous. Also, the merits of a system for participant tracking are evaluated.
This article explores what happens when a physician assumes the role of researcher. In these cases, a physician's fiduciary duty to individual patients competes with a new obligation to contribute to generalizable knowledge. When conflict arises, individual IRBs can choose to introduce a third party to educate the potential study participant regarding possible risks and the expectation of benefit.
The author suggests that nonfinancial conflicts of interest are intrinsic to human subjects research. Institutions must emphasize proper behavior. IRBs should conduct widespread audits of ongoing research so that conflicts are exposed before they become problematic.
A look at some of the questions raised by minor modifications in medical practice. Focusing on the example of a change in the administration of chemotherapy for ovarian cancer, the author considers whether such innovations should be considered research and whether they should undergo review by an IRB.
This source suggests that physicians receive training in both research techniques and ethics in before they assume the role of investigator. Furthermore, when a potential participant is also the physician's patient, the physician should enlist a third party to assist in the informed consent process. Also, any financial compensation must be commensurate with the tasks performed by the physician-investigator and disclosed to the public.
NIH Recombinant DNA Advisory Committee. Assessment of adenoviral vector safety and toxicity: report of the National Institute of Health Recombinant DNA Advisory Committee. Human Gene Therapy 2002. 13(1): 3-13.
This source focuses on the gene transfer community's response to the death of Jesse Gelsinger. Particular areas of focus include adverse event reporting and information sharing as means of increasing the safety of vector use.
Sorscher EJ, et al. Informed consent to participate in a research study - gene therapy for cystic fibrosis using cationic liposome mediated gene transfer: a phase I trial of safety and efficacy in the nasal airway. Human Gene Therapy 1994. 5(10): 1271-7.
The authors provide an example of an informed consent document used in a gene transfer trial for cystic fibrosis. It may be of more general interest as a model, since the document covers the major topics raised by Appendix M for all gene transfer studies, such as the purpose of the study, procedures, follow-up, risks and discomforts, benefits, confidentiality, alternatives, and the right to withdraw from the study.
Issued by the Kennedy Institute of Ethics, this web site compiles gene transfer bibliographies on topics ranging from general information to philosophical and religious perspectives. "Quick Bib" search engine provides the most recent literature on this topic.
Some of the most recent articles about informed consent in clinical studies are referenced.
Berg JW, et al. Informed Consent: Legal Theory and Clinical Practice. Oxford University Press, 2001.
An overview of informed consent, emphasizing the practical issues facing both physicians and investigators. The historical and ethical underpinnings of informed consent are discussed, along with the challenges faced when applying current legal theory in the clinical setting.
Brody BA. The Ethics of Biomedical Research: An International Perspective. Oxford University Press, 1998.
This book analyzes the major issues of research ethics, including human subjects research protections, via a review of official policies from throughout the world.
Faden RR and Beauchamp TL with King NMP. History and Theory of Informed Consent. Oxford University Press, 1990.
Current ways of thinking about informed consent are explained from a historical perspective. Philosophical and legal frameworks are used to explore informed consent as it pertains to clinical medicine, federal policy and research involving human subjects. Autonomy is considered the foundation of current informed consent theory.
Fletcher JC. The Evolution of the Ethics of Informed Consent. In: Research Ethics. New York: Alan R. Liss, Inc., 1983, pp. 187-228.
This book addresses the philosophical, historical, and societal touchstones of informed consent. It begins with the biological and social basis for altruism (which is at the core of human concern for ethics and others), applies those concepts to the notion of consent in the practice of medicine, reviews the abominable practices of Nazi physicians at Nuremberg and the outcome of the Nuremberg trials, and closes with the more recent development of Public Health Service policy.
Getz K and Borfitz D. Informed Consent: The Consumer's Guide to the Risks and Benefits of Volunteering for Clinical Trials.
This guidebook provides the information that may help potential participants and their advocates make well-informed decisions about participating in clinical trials. Participants' rights and reasonable expectations are illustrated. Special focus is attributed to various ways participants can seek recourse if an adverse event occurs.
Katz J. Experimentation with Human Beings: The Authority of the Investigator, Subject, Professions and the State in the Human Experimentation Process. New York: Russell Sage Foundation, 1972.
This publication explores the rights and responsibilities of the various participants in clinical research. The roles of investigators, subjects, medical professionals and the state are portrayed through a case-based analysis of legal precedent.
Levine, RJ. Ethics and Regulation of Clinical Research. 2nd ed. Baltimore: Urban and Schwarzenberg, 1988.
This resource presents an overview of the medical, ethical and regulatory underpinnings of clinical research. Fundamental concepts like balancing harms and benefits are discussed, along with proper methods for selecting participants and protecting their privacy. The responsibilities of IRBs are illuminated through a case study based on Yale-New Haven Medical Center.
Veatch RM. The Patient as Partner: A Theory of Human Experimentation Ethics. Bloomington: Indiana University Press, 1987.
A review of the general ethics of experimentation and the federal regulations governing research with human subjects. Ethical dilemmas in research design and recruitment are examined, along with potential ethical problems inherent in investigations involving particular risks or patient populations. The author calls for participants to be regarded as partners in research who are well informed regarding purposes, methods, and alternatives.
Developed by the NIH Office of Biotechnology Activities, this brochure is directed at individuals who are considering participating in a gene transfer study. It provides a brief overview of gene transfer research and a list of questions for individuals to ask the study investigators and to consider themselves as they make a decision about whether to participate.
Assembled by the National Hemophilia Foundation, this brochure discusses both positive and negative aspects of enrolling in gene transfer trials. The need for potential study participants to gather a significant amount of information prior to making their decisions is stressed.
A guide to understanding the process of informed consent through which potential study participants can learn about possible risks and benefits as well as their rights and responsibilities. Contains some sample forms and templates.
This patient reference guide, published by the American Association of Health Plans, highlights key issues for adult patients who are thinking about enrolling in a clinical trial.
This pamphlet provides important questions that potential study participants should ask before participating in a clinical trial.
This site provides a glossary pertinent to rare diseases and conditions that was compiled by the NIH Office of Rare Diseases. It also provides links to other sources of information about clinical trials more generally.
The University of Michigan IRB compiled definitions of scientific terms that frequently appear in informed consent documents but may be unfamiliar to potential study participants. In addition to helping potential study participants, this is a useful tool for researchers and IRB members as they write and evaluate informed consent documents.
The National Human Genome Research Institute (NHGRI) created this database to help potential study participants better understand the terms and concepts used in genetic research. One click on the term of interest reveals information ranging from term's pronunciation, audio information, images and additional links to related terms.
Government Guidelines and Regulations
Subpart A provides the basic federal policy for the protection of human subjects. Subparts B, C, and D, respectively, set forth additional protection for research, development and related activities involving fetuses, pregnant women, and in vitro fertilization; research involving prisoners; and research involving children.
Part 50 sets forth the Food and Drug Administration's requirements for informed consent, while Part 56 outlines the agency's provisions for IRBs. Though largely similar, the FDA regulations differ in several key respects from the "Common Rule" (45 CFR Part 46) adopted by other agencies and administered by the Department of Health and Human Services. For research falling under the purview of both HHS and FDA, the requirements of both sets of regulations must be met.
This document represents the FDA's current guidance on protection of human subjects involved in clinical research. While this document is not intended create or confer any rights and does not operate to bind the FDA or the public, it is meant to serve as an aid to IRBs as in effectively protecting human research subjects.
This document recommends ways to attain higher levels of harmonization in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines. The objective of such harmonization is a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines while maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health.
IRBs confront many complex issues. Familiarizing oneself with the pertinent regulations is a challenge, and understanding the concepts involved, how they relate to human subject research, and how they should be applied can be equally difficult. This document offers an explanation of the legal and ethical constructs that form the basis for human subjects research regulations which researchers and IRB members may find helpful.