Safeguarding Healthy Research Subjects: Protecting Volunteers from Harm

Guidelines for Institutions, Institutional Review Boards, and Researchers Regarding Biomedical Research with Normal Healthy Subjects
New York State Department of Health
March 1999

The following guidelines were developed to enhance protection of individuals who participate in biomedical research in New York State, with particular focus on normal healthy subjects. The purpose of the guidelines is to

  • enhance the capability of institutional review boards (IRBs) to ensure the protection of human research subjects;
  • educate researchers about key principles for maximizing the protection of research subjects;
  • encourage institutions to provide adequate fiscal and resource support to IRBs and training for researchers in principles of human subject protection.

These are guidelines, not regulations. They are intended as a framework to provide IRBs, researchers, and institutions with a broad range of considerations for designing, reviewing, and implementing protocols involving normal healthy subjects. IRBs and researchers are encouraged to adapt these guidelines to the specific circumstances of individual studies. The guidelines are fully consistent with existing federal and state regulations.

Research with normal healthy subjects who will derive no direct benefit from participation is fundamentally different from research with patient-subjects who may derive personal benefit from the study. Nonetheless, while the focus of these guidelines is the normal healthy research subject, many of the principles are applicable to human research subjects in general.

Table of Contents

WORKGROUP ON IRB GUIDELINES

Chairperson

Nancy Neveloff Dubler, LL. B.
Director, Division of Bioethics Member,
Institutional Review Board Montefiore Medical Center and
Professor of Bioethics
Albert Einstein College of Medicine
Bronx, New York

Members

Gary L. Chadwick, Pharm. D., M. P. H.
Associate Professor of Medical Humanities and Executive Director,
Research Subjects Review Board University of Rochester
Rochester, New York

Benjamin K. Chu, M. D.
Vice President of Clinical Affairs
New York University Medical Center
New York, New York

Jeffrey A. Cooper, M. D.
Professor of Radiology and Pediatrics and
Chair, Institutional Review Board
Albany Medical Center
Albany, New York

Dale E. Hammerschmidt, M. D.
Associate Professor of Medicine and Chair,
Institutional Review Board
University of Minnesota
Minneapolis, Minnesota

Cassandra E. Henderson, M. D.
Associate Professor of Obstetrics and Gynecology
Albert Einstein College of Medicine and
Member, Institutional Review Board Montefiore Medical Center
Bronx, New York

Leonard D. Hudson, M. D.
Professor of Medicine Head,
Division of Pulmonary and Critical Care Medicine
University of Washington
Seattle, Washington

Corinne L. Leach, M. D., Ph. D.
Associate Professor of Pediatrics Director,
Neonatal-Perinatal Medicine Program
State University of New York at Buffalo
Children’s Hospital of Buffalo
Buffalo, New York

Arthur A. Levin, M. P. H.
Director Center for Medical Consumers and Member,
Institutional Review Board Psychiatric Institute
New York, New York

Carol Levine, M. A.
Director Families and Health Care Project
United Hospital Fund
New York, New York

Robert J. Levine, M. D.
Professor of Medicine and Chair,
Institutional Review Board
Yale University School of Medicine
New Haven, Connecticut

Hermann Mendez, M. D.
Associate Professor of Clinical Pediatrics
SUNY Health Science Center
Brooklyn, New York

Jonathan D. Moreno, Ph. D.
Kornfeld Professor and Director
Center for Biomedical Ethics
University of Virginia
Charlottesville, Virginia

Christine O’Dell, R. N., M. S. N.
Clinical Nurse Specialist
Pediatric Neurology/ Epilepsy Center and
Member, Institutional Review Board
Montefiore Medical Center
Bronx, New York

William M. Sage, M. D., J. D.
Associate Professor
Columbia Law School
New York, New York

Ex-Officio Members

Christine Grady, R. N., Ph. D.
Acting Director Department of Clinical Bioethics
National Institutes of Health
Bethesda, Maryland

Charles R. MacKay, Ph. D.
Project Clearance Officer
National Institutes of Health
Bethesda, Maryland

Observer

J. Thomas Puglisi, Ph. D.
Director Division of Human Subject Protection
Office for Protection from Research Risks
National Institutes of Health
Rockville, Maryland

Staff

Carl H. Coleman, J. D.
Executive Director New York State Task Force on Life and the Law
New York State Department of Health
New York, New York

Elysa Gordon, J. D.
Legal Consultant
New York State Department of Health
New York, New York

Monica Meyer, M. D.
Physician Consultant
New York State Department of Health
Albany, New York

Jean Pohoryles
Health Program Aide
New York State Task Force on Life and the Law
New York State Department of Health
New York, New York

Marianne Zarelli
Secretary to the Director
Bureau of Hospital and Primary Care Services
New York State Department of Health
Albany, New York

The Workgroup wishes to thank the following individuals who reviewed drafts of the document and offered editorial suggestions: Guthrie Birkhead, M. D., Director of the AIDS Institute at the New York State Department of Health; Philip A. Ludbrook, M. D., Chairman of the Institutional Review Board at Washington University School of Medicine in St. Louis, Missouri; Sonja Noring, a consultant to the AIDS Institute at the New York State Department of Health; and Robin Levin Pennslar, editor of the most recent Guidebook to the federal regulations for the protection of human subjects (45 C. F. R. § 46).

EXECUTIVE SUMMARY

The following guidelines were developed to enhance protection of individuals who participate in biomedical research in New York State, with particular focus on normal healthy subjects. The purpose of the guidelines is to

  • enhance the capability of institutional review boards (IRBs) to ensure the protection of human research subjects

  • educate researchers about key principles for maximizing the protection of research subjects

  • encourage institutions to provide adequate fiscal and resource support to IRBs and training for researchers on human subject protection

Two key principles underlie these guidelines:

  • IRBs, researchers, and institutions must recognize the special vulnerability of normal healthy subjects enrolled in studies in which there is no direct personal benefit to offset risk and must provide protections appropriate to the unique qualities of each individual subject and the risks of the protocol.

  • While IRBs and their sponsoring institutions are responsible for establishing and promoting “cultures of compliance” with regulations and policies to safeguard human research subjects, researchers have the primary responsibility to protect the safety and welfare of individual subjects. Researchers have an obligation to monitor the risk experiences of individual subjects and to modify or terminate an intervention when a subject’s experiences differ substantially from what was described in the protocol or informed consent.

RISK-BENEFIT ASSESSMENT

  • An IRB may approve a research protocol if and only if it determines that risks are minimized and reasonable in relation to anticipated benefits

  • In assessing risk, the IRB should consider

    • the magnitude of any harm that subjects might encounter, as well as the probability that it will occur

    • additive effects of each element of risk in a protocol

    • cumulative risks associated with participation in sequential protocols or more than one protocol at the same time

    • what may be perceived as ordinary discomfort or inconvenience for some subjects could be experienced as significant harm by others

    • the distinction between known risks and uncertainties in research

  • Because there are no anticipated direct individual benefits to subjects in the studies addressed in these guidelines, the IRB must judge whether the benefit of new knowledge anticipated by a study justifies inviting healthy persons to undertake the risks

  • While clinical standards of practice are often based only on empirical conventions, IRBs should decide whether research interventions not designed to benefit subjects directly should be restricted to methods and procedures supported by published data

  • IRBs should not approve any research with normal healthy subjects in which researchers deliberately inflict a serious harm

  • If the IRB does not have the expertise to evaluate a protocol’s risks and/ or benefits, it should obtain the advice of one or more expert consultants or request consultation from another IRB with more relevant experience

  • IRBs should periodically review ongoing research to ensure that there are no changes in the risk-benefit assessment

INFORMED CONSENT

  • Basic elements of informed consent are set forth in the Code of Federal Regulations (45 C. F. R. § 46 and 21 C. F. R. § 50), Protection of Human Subjects

  • Researchers must assure the IRB that full disclosure will occur and that subjects can readily understand the information provided and have sufficient opportunity to consider whether to participate

  • If the investigator is the subject’s health care provider or has any other special relationship to the subject, the IRB should require that the consent process draw a clear distinction between the role of health care provider and the role of researcher

  • The IRB should make certain that the subject’s right to withdraw is protected throughout the study

  • Researchers should inform IRBs about the funding source and terms of funding for the research, and the IRB should consider whether researchers should be required to disclose this information to prospective subjects

  • IRBs can safeguard the informed consent process by suggesting such strategies as the following:

    • limiting the target group to individuals with sufficient expertise to understand the protocol

    • requiring a waiting period after recruitment before informed consent is given

    • ensuring an ongoing consent process over the course of the study

    • using noninvestigators to obtain informed consent

    • ensuring subjects’ comprehension of research procedures through questionnaires or other methods

    • familiarizing prospective subjects with the research environment

  • IRBs should ensure that researchers are sensitive to the language and cultural differences of potential subjects

RECRUITMENT

  • IRBs should scrutinize recruitment strategies for the possibility of coercion or undue inducement

  • Researchers should generally not recruit individuals whom the researcher is in a position to penalize or reward

  • Institutions should establish standards for recruiting students or staff at the same institution as the investigator

  • General advertising for subjects is preferable to direct solicitation

  • If an advertisement refers to remuneration, it should state only that there will be reimbursement for time, inconvenience, and out-of-pocket costs

  • Advertisements should generally not state that subjects will receive “free medical care”

  • In general, IRBs should not approve finder’s fees

REMUNERATION

  • Remuneration should be proportionate to time, effort, and inconvenience and should not provide an undue inducement to participation

  • IRBs should ensure that the financial incentive does not compromise the subject’s right to withdraw from participation; they should consider stipulating that full or prorated payment be made even if the subject does not complete the study

RESEARCHERS’ OBLIGATIONS

  • Researchers have independent obligations for safeguarding human subjects that transcend the IRB’s general informed consent and protocol review process

  • Researchers must identify individual inclusionary and exclusionary characteristics of potential subjects

  • As appropriate, researchers should attempt to identify subjects who participate in multiple studies

  • Researchers should carry out ongoing monitoring and assessment of risks and discomforts based on individual subjects’ perceptions and experiences

  • When studies are complex, involve a number of procedures, and/ or take place over a protracted period of time, researchers should reaffirm the informed consent at key junctures

  • Researchers should terminate interventions when risks or discomforts appear to escalate, even in the absence of the subject’s request

INSTITUTIONAL RESPONSIBILITIES

  • An institution that conducts research involving human subjects has an obligation to promote their protection through support and training of IRB members, education of researchers, teaching of students, and other measures

  • Institutions should strongly consider establishing systems for payment of direct medical expenses incurred by subjects who are injured as a result of their participation in research

  • Institutions should consider maintaining a registry of individuals who participate in research protocol
Go to Introduction chapter