The National Bioethics Advisory Commission (NBAC) was established by Executive Order 12975, signed by President Clinton on October 3, 1995. NBAC’s functions are defined as follows:

a) NBAC shall provide advice and make recommendations to the National Science and Technology Council and to other appropriate government entities regarding the following matters:

1) the appropriateness of departmental, agency, or other governmental programs, policies, assignments, missions, guidelines, and regulations as they relate to bioethical issues arising from research on human biology and behavior; and 2) applications, including the clinical applications, of that research.

b) NBAC shall identify broad principles to govern the ethical conduct of research, citing specific projects only as illustrations for such principles.

c) NBAC shall not be responsible for the review and approval of specific projects.

d) In addition to responding to requests for advice and recommendations from the National Science and Technology Council, NBAC also may accept suggestions of issues for consideration from both the Congress and the public. NBAC also may identify other bioethical issues for the purpose of providing advice and recommendations, subject to the approval of the National Science and Technology Council.

National Bioethics Advisory Commission

     6705 Rockledge Drive, Suite 700, Bethesda, Maryland 20892-7979 Telephone: 301-402-4242 • Fax: 301-480-6900 • Website: www.bioethics.gov

ISBN 1-931022-17-8

Ethical and Policy Issues in Research Involving Human Participants

Volume II

Commissioned Papers and Staff Analysis

Bethesda, Maryland August 2001

National Bioethics Advisory Commission

Harold T. Shapiro, Ph.D., Chair

President Emeritus and Professor of Economics and Public Affairs The Woodrow Wilson School of Public and International Affairs Princeton University Princeton, New Jersey

Patricia Backlar

Research Associate Professor of Bioethics Department of Philosophy Portland State University Assistant Director Center for Ethics in Health Care Oregon Health Sciences University Portland, Oregon

Arturo Brito, M.D.

Assistant Professor of Clinical Pediatrics University of Miami School of Medicine Miami, Florida

Alexander Morgan Capron, LL.B.

Henry W. Bruce Professor of Law

University Professor of Law and Medicine

Co-Director, Pacific Center for Health Policy and Ethics University of Southern California Los Angeles, California

Eric J. Cassell, M.D., M.A.C.P.

Clinical Professor of Public Health

Weill Medical College of Cornell University New York, New York

R. Alta Charo, J.D.

Professor of Law and Bioethics Law School and Medical School University of Wisconsin Madison, Wisconsin

James F. Childress, Ph.D.

Kyle Professor of Religious Studies Professor of Medical Education Director, Institute for Practical Ethics Department of Religious Studies University of Virginia Charlottesville, Virginia

David R. Cox, M.D., Ph.D.

Scientific Director Perlegen Sciences Santa Clara, California

Rhetaugh Graves Dumas, Ph.D., R.N.

Vice Provost Emerita, Dean Emerita, and Lucille Cole Professor of Nursing University of Michigan Ann Arbor, Michigan

Laurie M. Flynn*

Senior Research and Policy Associate

Department of Child and Adolescent Psychiatry Columbia University New York, New York

Carol W. Greider, Ph.D.

Professor of Molecular Biology and Genetics Department of Molecular Biology and Genetics Johns Hopkins University School of Medicine Baltimore, Maryland

Steven H. Holtzman

Chief Business Officer

Millennium Pharmaceuticals, Inc. Cambridge, Massachusetts

Bette O. Kramer

Founding President

Richmond Bioethics Consortium Richmond, Virginia

Bernard Lo, M.D.

Director

Program in Medical Ethics Professor of Medicine

University of California, San Francisco San Francisco, California

Lawrence H. Miike, M.D., J.D.

Kaneohe, Hawaii

Thomas H. Murray, Ph.D.

President

The Hastings Center Garrison, New York

William C. Oldaker, LL.B.

Senior Partner

Oldaker & Harris, L.L.P. Washington, D.C.

Co-Founder and General Counsel NeuralStem Biopharmaceuticals Ltd. College Park, Maryland

Diane Scott-Jones, Ph.D.

Professor

Psychology Department Boston College Chestnut Hill, Massachusetts

*Resigned on May 10, 2001.

CONTENTS

Research Ethics in Australia A-1

Donald Chalmers

University of Tasmania

Location of the Office for Protection from Research Risks Within the National Institutes of Health: Problems of Status and Independent Authority

John C. Fletcher

University of Virginia

B-1

Privacy and Confidentiality in Health Research C-1

Janlori Goldman and Angela Choy

Georgetown University

An Examination of Issues Presented by Proposals to Unify and Expand Federal Oversight of Human Subject Research

C.K. Gunsalus

University of Illinois at Urbana-Champaign

The History, Function, and Future of Independent Institutional Review Boards

Erica Heath

Independent Review Consulting, Inc.

The Danish Research Ethics Committee System—Overview and Critical Assessment

Søren Holm

University of Manchester

D-1

E-1

F-1

Vulnerability in Research Subjects: A Bioethical Taxonomy G-1

Kenneth Kipnis

University of Hawaii at Manoa

Reflections on the Organizational Locus of the Office for Protection from Research Risks

Charles R. McCarthy

H-1

Protectionism in Research Involving Human Subjects I-1

Jonathan D. Moreno

University of Virginia

Federal Agency Survey on Policies and Procedures for the Protection of Human Subjects in Research

National Bioethics Advisory Commission

J-1

Local Institutional Review Boards K-1

Steven Peckman

University of California-Los Angeles

Institutional Review Board Assessment of Risks and Benefits Associated with Research

Ernest D. Prentice and Bruce G. Gordon

University of Nebraska Medical Center

L-1

Oversight of Human Subject Research: The Role of the States M-1

Jack Schwartz

Office of the Maryland Attorney General

v

Privacy and Confidentiality: As Related to Human Research in Social and Behavioral Science

Joan E. Sieber

California State University, Hayward

Unfulfilled Promise: How the Belmont Report Can Amend the Code of Federal Regulations Title 45 Part 46—Protection of Human Subjects

Harold Y. Vanderpool

University of Texas Medical Branch, Galveston

The Ethical Analysis of Risks and Potential Benefits in Human Subjects Research: History, Theory, and Implications for U.S. Regulation

Charles Weijer

Dalhousie University

Charles Weijer of Dalhousie University, Halifax, Nova Scotia, Canada, prepared a paper for NBAC on the topic of protecting communities in research. That paper was published in 1999 in the journal Cambridge Quarterly of Healthcare Ethics. The reader can find the article at the following citation:

Weijer C. 1999. Protecting Communities in Research: Philosophical and Pragmatic Challenges. Cambridge Quarterly of Healthcare Ethics 8:501–513.

The papers included in this volume were edited to conform to minimal stylistic consistency. The content and accuracy of the papers are the responsibility of the authors, not the National Bioethics Advisory Commission.

N-1

O-1

P-1

vi

RESEARCH ETHICS IN AUSTRALIA

Commissioned Paper Donald Chalmers University of Tasmania

A-1

Preface

Australia has had a comparatively creditable record of ethical research involving humans. The litany of criticism about shoddy medical research documented in the epochal article by Professor Beecher (Beecher 1966, 1968; Levine 1986) has not occurred in this country. Comparatively fine as the Australian record may be, that record is not unblemished. A report commissioned by the Commonwealth Government in 1994 by Professor Margaret Allars into unsatisfactory aspects of the collection, manufacture, and injection of human growth hormone (Allars 1994) recommended that aspects of the research structure had to be reassessed. In particular, the Allars Report recommended a review of the National Health and Medical Research Council (NHMRC) Statement on Human Experimentation and the Supplementary Note on Reproductive Technology Procedures. Similarly, the Commonwealth Minister for Health (now called the Commonwealth Minister for Health and Aged Care) referred ethical concerns about two postwar procedures and one multi-center clinical trial in the 1990s to the Australian Health Ethics Committee (AHEC). The two postwar procedures involved first, the inclusion of orphans and State wards in vaccine trials conducted in the postwar years and, second the experimental use of estrogen to reduce the height of “tall girls” in the 1950s. The multicenter trial involved the so-called “morning after pill” (RU486).

     Research and experimentation has been a major issue, at least for the research community, in the last two decades in Australia. This “age of skepticism” (pace Eric Hobsbawn) has seen continuing demands for open government and greater public accountability, demands for expanded civil liberties, and demands for privacy protection rights. This wide debate has translated into debate about the protection of subjects in medical research (Laufer 1990; Darvall 1993), its major focus being the maintenance and improvement of ethical standards. This focus of concern is reflected in much of the work of the peak national health ethics body, the AHEC. In particular, the AHEC has conducted two series of National Workshops for Institutional Ethics Committees, a major review of the ethics review system in Australia (Chalmers 1996), and a major revision of the guidelines on research ethics published as the National Statement on Ethical Conduct in Research Involving Humans in mid 1999 (National Statement 1999). Ethical standards in human research and experimentation have not been static. The Australian research ethics community conducted a debate on improving and professionalizing the ethics review system during the late 1980s and 1990s. Researchers, institutions, trial sponsors, academic and professional critics, and changing attitudes to accountability have all contributed to an improvement in the practices and culture of research involving humans in this country.

     The AHEC has come far since the Finn Report amalgamated the National Bioethics Consultative Committee (NBCC) and the Medical Research Advisory Committee to form the AHEC. Professor Finn stated in his report that “until the HEC (AHEC) concept is more fully developed and particularized, until the Council addresses more directly the burden of the ethics function...one cannot surmise with any confidence as to the extent to which those differences between the two bodies in their areas of mutual interest are likely to recede or be perpetuated” (Finn 1990 at 14). Considerable advances were made in the first three triennia toward this “evolutionary” change.

     The Australian research ethics review system continues to evolve. The system could be described as a hybrid or intermediate system in contradistinction to entirely legislatively regulated systems or voluntary self-regulated models. There is no Australian equivalent of the National Research Act 1974. However, there is greater regulation of the system since the pre-1982 Australian voluntary system. Human Research Ethics Committees (HRECs), which conduct ethics review are not established by specific Commonwealth legislation, but they are recognized within the NHMRC Act 1992. In this major respect, research ethics review in Australia is not a voluntary system; it is better classified now as a regulated system.

A-3

     Comparisons between HRECs in Australia and Ethics Committees in the United States are misleading. Some HRECs in Australia may perform some of the functions of Ethics Committees, but the comparable institution in the United States is an Institutional Review Board (IRB). As well as the infamous Tuskegee Study (Furrow et al 1995 at 548–550), a number of questionable human experiments were disclosed before the U.S. Congress in the early 1970s. Disclosures were made particularly about dubious research conducted in prisons and mental hospitals and on human fetuses. Following these events, the National Research Act 1974 was introduced which required each institution conducting federally supported research involving human subjects to establish an IRB. These IRBs are required to review the ethical aspects of all research protocols within the institution. The general standards for the composition, operation, and responsibility of IRBs are contained in federal regulations (Code of Federal Regulations 1992).

     In order to fulfill the requirements of the federal regulations, each IRB is required to follow written procedures for the conduct of initial and continuing review of research and for reporting findings and actions to the investigator and the institution. An IRB determines which projects require review more often than annually and which projects need verification from sources other than the investigator. Changes in approved research may not be initiated without IRB review and approval, except where there are apparent immediate hazards to the human subjects. In addition to reporting to the IRB, there are other safeguards in the system. Both institutional officials and the Food and Drug Administration (FDA) must be told of any unanticipated problems involving risks to human subjects or others. Similarly, any instance of serious or continuing noncompliance with federal regulations or the decisions of the IRB (or any suspension or termination of IRB approval) must be reported to the institution or FDA. There are IRB procedural requirements aimed at ensuring proper consideration of the research. Except when an expedited review procedure is used, a research proposal must be reviewed by a majority of the members of the IRB. On review, at least one of the IRB members must be primarily concerned with nonscientific areas, and the proposal must receive the approval of a majority of those members present at the meeting.

     American Ethics Committees continue to evolve and are not settled in their functions (Annas 1984; In Re Quinlan 1976; President’s Commission 1983). Ethics Committees in the USA include the following roles:

• Advising doctors and family on decisions about withdrawing life support treatment;
  
• Providing advice on withholding treatment from newborn infants with birth defects;
  
• Making policy through drafting guidelines for hospital personnel on controversial areas of medical practice;
  
• Providing education through the organization of seminars on areas of controversy; and
  
• Providing advice on specific ethical dilemmas in the treatment of specific patients.
  

In effect, American Ethics Committees are patient care committees and are often referred to by this title. Some Australian hospital HRECs may perform some of the same functions as American Ethics Committees.

     Comparisons are also sometimes made with Research Ethics Committees in the United Kingdom, but, again, their functions do not compare precisely with those of Australian HRECs. The United Kingdom Research Ethics Committees are diverse in their functions and do not directly relate to Australian HRECs in that they operate within the National Health Service. A United Kingdom Department of Health circular of 1989 (HSC (IS) 153) requires that each district health authority appoint a “...properly constituted Local Research Ethics Committee (LREC), which meets regularly, to register, review and approve (or not approve) the research conducted by its staff, or using its premises or facilities, including access to personal health information held by the authority (and research undertaken by general practitioners within its boundaries).” Research Ethics Committees in the United Kingdom are locally established and formally constituted as subcommittees within the health authority system. It has been noted that an “Ethics Committee acts for and on behalf of the Authority” (Brazier 1990).

A-4

The growth of ethics committees has followed diverse paths, and a number of other ethics committees have been established beyond the terms of the Department of Health Circular Guidelines (Rawbone 2000). Brazier particularly notes that a number of fertility units have established advisory committees to assist practitioners in making decisions about the admission of individual patients to the program (Brazier 1990).

     This report presents background information on the ethics review system in this country, defines the current ethical system, and provides some background information on the new National Statement on Ethical Conduct in Research Involving Humans. This paper considers the current operation of the AHEC and the system of ethical review of research involving humans by HRECs in Australia. The paper also addresses some specific questions posed by the National Bioethics Advisory Commission (NBAC), namely the following:

1.1 Three Tiers: Researcher Ethics Committee and National Body

A three-tier system of ethics review operates within Australia:

• The researcher
  
• The HREC
  
• The AHEC
  

At the first level, the researcher continues to carry ethical responsibilities toward research participants. The National Statement begins with a reference to the researcher and states that the “…guiding value for researchers is integrity…” (National Statement 1999, Principle 1.1 at 11). The National Statement continues that “the guiding ethical principle for researchers is respect for persons…” (Principle 1.2) and that “… the ethical principle of beneficence is expressed in researchers’ responsibility to minimize risks of harm or discomfort to participants in research projects” (Principle 1.3). Researchers are also required to design their protocols to ensure respect for the dignity and well-being of the participants (Principle 1.4). Researchers should not discriminate in the distribution of benefits and burdens of participation in research or in the selection of research participants (Principle 1.5). Researchers have great responsibility in ensuring participant consent is obtained (Principles 1.7–1.12). Researchers must conduct research that has merit and balance the risks and likely benefits to be gained. Only people with the required experience, qualifications, and competence should conduct the research (Principles 1.13–1.15). These General Principles are bolstered throughout the National Statement with specific contextual duties of researchers to research participants in relation to the project. For example, in a clinical trial the researcher must declare any conflicts of interest through involvement in business or other similar association (Principle 12.5 at 36). It was a deliberate policy in drafting the National Statement to recognize and reinforce the ethical responsibilities of researchers.

     HRECs, which, until 1999 were referred to as Institutional Ethics Committees (IECs), conduct the second level of ethical review. The Australia HRECs compare closely with the U.S. IRBs established under federal regulations. Some HRECs were already operating before the system was formally established in 1982 by amendments to the Statement on Human Experimentation. The NHMRC issued the Statement on Human Experimentation, which was the predecessor to the current National Statement on Ethical Conduct in Research Involving Humans,

A-5

promulgated in 1999. The NHMRC was a nonstatutory body until 1992. In that year the NHMRC became a statutory authority when the Commonwealth Parliament passed the National Health and Medical Research Council Act, 1992 (Cth.). Although HRECs are not statutory bodies, institutions cannot receive research funding from public bodies unless consideration had been given to the research proposal by a properly constituted HREC. Originally, HRECs only considered medical and health research projects. Later, the Australian Research Council (ARC) (the major funding agency for nonmedical research) introduced a similar requirement that, in effect, expanded the jurisdiction of HRECs to all research involving humans.

     The third level in the system is the AHEC. This body is established under § 35 and § 36 of the National Health and Medical Research Council Act 1992 (Cth.). The AHEC is required to oversee the operation of the HREC system and receives annual Compliance Reports from every registered HREC (National Statement 1999 Principles 2.46–2.48). In addition, the AHEC has the sole authority to publish medical research guidelines. In so doing, the AHEC is required to follow § 11–14 of the National Health and Medical Research Council Act 1992, which provides a unique procedure of two stages of public consultation before such guidelines may be issued.

1.2 The National Statement: Changes in the Research Environment

The National Statement reflects a number of significant changes in the ethics of human research. First, the National Statement includes a wider and more comprehensive view about research involving humans, going beyond medical experimentation and extending to all research involving humans. The first Australian guidelines in relation to research, the Statement on Human Experimentation, followed the Declaration of Helsinki and applied ethical standards to medical research involving human subjects. Gradually, the Statement on Human Experimentation was applied not only to medical research but other research involving humans particularly in the social and behavioral sciences. The new National Statement recognizes this evolution. Second, the National Statement recognizes the evolution of community and research community acceptance that now “…all kinds of research involving or impacting upon humans should conform to the highest standards academic integrity and ethical practice” (National Statement 1999 at 2).

     Third, legislation is now more common place in the once self-regulated area of research ethics. Increasingly, Commonwealth and State legislation is impacting on and becoming more relevant to any consideration of research ethics. The regulation of Australian research is no longer a voluntary regulatory system of protection for research participants. Many Commonwealth and State Acts apply directly or indirectly to research. In particular, the NHMRC was brought under a statutory framework with the enactment of the National Health and Medical Research Council Act by the Commonwealth Parliament in 1992. Fourth, in a number of countries there have been efforts to identify a better definitional understanding of what is meant by research. The National Statement notes that:

There are many definitions of research. These include a systematic investigation to establish facts, principles or knowledge a study of some matter with the objective of obtaining and confirming knowledge. A defining feature of research is the validity of its results….

An alternative approach to finding a definition of research is to list examples for what constitutes research, such as:

• systematic prospective collection of information to test an hypothesis;
  
• a planned study of existing practices with a view to changing/improving practice in light of the studies by findings/or to increase understanding;
  

or

A-6

     It is accepted that it is difficult to find an agreed-upon definition of research. The National Statement accepts that problems may arise from “…including activity that would not normally be included, like quality assurance activities or audits and excluding activity that probably should be included, such as research conducted as part of a course of education…[and]…omitting newly emerged genres of research, of which various kinds of multi-disciplinary research are examples” (National Statement 1999 at 6). The definitional problem of research has been considered seriously in Australia. The issue of the appropriate boundary between research and innovative therapy in practice arose in the inquiry conducted by Professor Margaret Allars in relation to innovative hormone treatment (Allars 1994; Giesen 1995).

     Fifth, debates about the protection of subjects in research have expanded from concerns about physical protection to modern concerns about personal information privacy. Public concern about individual privacy is a major emerging challenge. Moves to store medical records on computer (rather than hard copy) have increased fears that privacy will be threatened. In respect of privacy, the federal Privacy Act 1988 (Cth.) was a watershed. The Privacy Act, particularly § 95 dealing with privacy in public research and the Information Privacy Principles (NHMRC 2000) has had a significant impact on public health (Cth.). The Privacy Commissioner has also extended the protections available to individuals in relation to their personal information held in the public sector under the Privacy Act 1988 (Cth.) to the private sector with amendments to this Act.

     Sixth, peer review and declining funding to research generally and medical research in particular cannot be discounted as an influence on changing research culture. It is far more difficult to obtain research funding. For example, the NHMRC funds only 20 percent approximately of research applications. Finally, moves to encourage private industry to contribute more funds to national research efforts, particularly in the area of genetics, has introduced increasing commercial considerations into the research environment.

     All of these developments are leading to a more regulatory environment in Australia but still without specific legislation for the HRECs. Legislation, in the form of the National Health and Medical Research Council Act 1992 (Cth.), establishes a national supervisory committee (the AHEC) and recognizes the HREC system. All public research-funding bodies require ethics approval before research can be undertaken. The Commonwealth statutory authority, the Therapeutic Goods Administration (TGA), regulates clinical trials of drugs and devices in the same fashion as the FDA in the United States. Finally, although private institutions and organizations are not obliged to follow NHMRC guidelines, there is a high degree of voluntary compliance on the part of private research organizations.

2. A Brief Background to the Development of Ethical Review in Australia

A brief background is presented of the developments leading to the current system of ethical review in Australia. The primary purpose for the introduction of both codes of research practice and committees to review research has been and remains the protection of the welfare and rights of participants in research. It is axiomatic that the foundation of any system of ethical protection for the welfare and rights of participants depends on the integrity of the researchers themselves. The new Australian National Statement recognizes the centrality of the researcher as the first level of review. The National Statement states that:

A-7

Ethics review committees conduct the second level of review. These were gradually introduced during the 1970s and formally so in the 1980s. HRECs grant ethical approval to researchers for their research and, in so doing, aim to protect the welfare and rights of research participants. However, they are not funded to or capable of acting as a policing agency for the work of researchers (Chalmers and Pettit 1998). Finally, in the early 1990s Australia introduced a third level, with the establishment of a national bioethics committee, the AHEC.

2.1 Toward National Ethical Standards in Research: The First Period—1973–1982

Until 1965, the prime responsibility for ethical standards in human experimentation rested with the integrity of the individual researcher subject to the oversight of that researcher’s institution and colleagues. Australia ratified the Declaration of Helsinki in 1965. This was an important symbolic act that was later realized by the introduction of committees to review the ethical aspects of research experiments on humans. During the same decade, there was awareness of the concerns for ethical standards in the United States, but it is not clear how far this awareness influenced developments toward the establishment of ethics committees to review research (Editorial 1976). Some institutions in Australia already operated ethics committees in the 1960s, and these influenced the development of the ethics review system. These early ethics committees in Australia predated American developments and may account for differences in the ways in which the Australian system has developed. Australia was essentially proactive in developing standards for ethical conduct in research rather than reactive to revelations or incidents of research impropriety.

     A major response to the Declaration of Helsinki was the drafting of Australia’s first guidelines on human experimentation, which were prepared by an ad hoc committee of the Medical Research Advisory Committee and adopted by the NHMRC. This first NHMRC Statement on Human Experimentation was amended in 1973 and again in 1976. This latter amendment was important as it provided that applications to the NHMRC for research grants were required to be submitted to a medical ethics review committee for ethical approval, and that medical ethics research committees were required to be established by institutions conducting medical research and experimentation (Jonas 1969; Fletcher 1973; Gillespie 1988 at 3). Funding was therefore made conditional upon ethical approval. The intention was to ensure peer review. There was only one minimal stipulation in relation to the composition of these committees, namely that one person not connected with the institution was to be appointed.

     This marked the first major step toward developing a systematic structure of ethical review by IECs, which in 1999 became known as HRECs in Australia. In an important sense this marked the end of the era of the self-regulation “closed shop.” This development was contemporaneous with demands for open government and greater public accountability, demands for expanded civil liberties, and demands for consumer rights. It was also in the mid-1970s that the public was beginning to hear reports of recombinant DNA research, genetic engineering, and the possibilities of IVF.

2.2 Toward IECs and the Medical Research Ethics Committee of the NHMRC: The Second Period—1982–1989

The next significant steps in the development of ethical review were the revisions to the NHMRC Statement on Human Experimentation in 1982 and the establishment of the Medical Research Ethics Committee (MREC) in 1983.

     IECs were established formally in 1982. There were already many ethics committees in operation, particularly in the teaching hospitals before 1982. The NHMRC issued a new and substantially revised Statement on Human Experimentation that included four Supplementary Notes (these Supplementary Notes dealt in detail

A-8

with the following specific topics: IECs; research on children, the mentally ill, those in dependent relationships (including unconscious patients); clinical trials; and IVF and embryo transfer). Supplementary Note 1 provided an expanded statement of the membership and functions of IECs, which were to be composed of men and women reflecting different age groups and including a person not associated with the institution. The minimum composition was a minister of religion; a lawyer; a medical graduate with research experience; and a lay woman and a lay man (NHMRC 1993b; McNeill 1993).

     In broad terms, IECs were concerned with the approval of research activities. In this respect a primary concern was ensuring effective consent on the part of subjects in research projects. The IEC reviewed copies of relevant consent forms, the research protocol, relevant past research, the selection criteria for research participants, the scientific method to be employed, the risks and benefits to subjects in the research program, and the perceived benefits of the research. The Supplementary Note established the functions of the IECs that were, in summary, to:

a) Consider ethical considerations of all proposed research projects; b) Maintain surveillance of approved research; c) Maintain a register of projects; and d) Establish and maintain communication with the MREC.

In carrying out the functions defined in Supplementary Note 1, IECs were required to

• Ensure the rights of the subjects of research take precedence over the expected benefits to human knowledge;
  
• Ensure that the free and informed consent of the subjects will be obtained;
  
• Ensure that no member of the HREC adjudicates on projects in which they may be personally involved;
  
• Ensure that research projects take into consideration local cultural and social attitudes;
  
• Give their own consideration to projects that involve research in more than one institution;
  
• Require the principal investigator to disclose any previous decisions regarding the project made by another IEC and whether the protocol is presently before another IEC; and
  
• Determine the method of monitoring appropriate to each project, with monitoring of research to continue until projects are completed (this monitoring requirement was not introduced until 1992 by amendment to the Statement on Human Experimentation).
  

The MREC, which replaced the Medical Research Advisory Council, was established as one of the standing advisory committees to the NHMRC. It was commissioned to keep under review and make recommendations to the council on ethical principles in relation to human experimentation. In addition, the MREC was required to keep under review the work of IECs. The MREC thus created a third level of ethical consideration, and it was directly related to the systematic development of IECs in Australia.

     In 1984 it was decided that the MREC should review the operation of IECs throughout Australia and, in particular, consider the performance and effectiveness of the Supplementary Note on IECs in relation to their composition and function. During 1984 and 1985 a series of workshops were held in the major State capitals dealing with the constitution and functions of IECs (NHMRC 1985). A further round of workshops was held in the late 1980s.

A-9

2.3 Toward a National Ethics Committee: The Third Period—1988 to the Present

2.3.1 MREC

The MREC of the NHMRC was a major step in the evolution toward a national ethics body. The original remit of the committee was to make recommendations to the council on ethical principles in relation to human experimentation, and this the committee did with distinction during the 1980s. For example, the MREC updated the Statement on Human Experimentation in 1982 and included notes on IECs, research in children, the mentally ill, and those in dependant relationships or comparable situations; therapeutic trials; and IVF and embryo transfer (ET). In 1983 the NHMRC produced Ethics in Medical Research Involving the Human Fetus and Human Fetal Tissue which became Supplementary Note 5 to the Statement of Human Experimentation, and, in 1985 the NHMRC produced the Report on Ethics and Epidemiological Research, which was added as a new

Supplementary Note 6.

     At the same time as the revisions to the NHMRC Statement on Human Experimentation in 1982 and the establishment of the MREC, the controversial area of reproductive technology was considered by the NHMRC.

Supplementary Note 4 – In-vitro Fertilisation and Embryo Transfer, adopted by the NHMRC at its 94th session in October 1982, was the “first official, Government-approved regulatory code for the practice of in-vitro fertilisation in this country (or, for that matter, anywhere)...” (Scott 1984 at 3). This Note described IVF as a “justifiable means of treating infertility” (NHMRC 1992 at 14). The note went on to say, however, that “…much research remains to be done and the NHMRC Statement on Human Experimentation and Supplementary Notes should continue to apply to all work in this field.” Accordingly, any institution offering IVF was required to have all aspects of its program approved by an IEC with a register being kept detailing parentage, treatment cycles, and records of success. The programs were to “normally involve” the ova and sperm of married partners (NHMRC 1992 at 14). Research remained “... inseparable from the development of safe and effective IVF and ET” and so embryonic development “...beyond the stage at which implantation would normally occur is not acceptable” (NHMRC: 1992 at 15). Finally, with some prescience, cloning experiments were declared ethically unacceptable (NHMRC 1984).

2.3.2 The Short-Lived National Bioethics Committee

An avalanche of Australian government reports followed this NHMRC Supplementary Note on IVF and embryo transfer (Waller 1982–1984; Demack 1984; Chalmers 1985; Cornwall 1984; Michael 1986; NSW Law Reform Commission 1980–1989; Family Law Council 1985; Senate Select Committee 1986). Reports on artificial conception from some States recommended State regulatory bodies; other States recommended that voluntary adherence to NHMRC guidelines was adequate without the need to introduce further regulatory schemes.

     There were essentially inconsistent recommendations in relation to regulation of embryo experimentation. Then the Commonwealth Senate set up a Select Committee that presented a report on Human Embryo Experimentation in Australia in 1985 (Senate Select Committee 1986). The report made recommendations on the regulation of embryo experimentation. The committee recommended that voluntary adherence to nationally promulgated guidelines monitored by IECs was not adequate (Senate Select Committee 1986, Chapter 4, para. 4.17). Instead, the Select Committee envisaged a national body, issuing research protocols and research licenses that should be required before experimentation of any kind was undertaken on human embryos. The license was to be for a limited time and subject to conditions (Senate Select Committee 1986, Chapter 4, para. 4.25). The committee recommended that a Commonwealth Statute, preferably in company with the States and the Northern Territory, should set down a broad declaration of the principle banning nontherapeutic embryo experimentation that frustrated the development of the embryo and should establish a licensing scheme.

     Importantly, in relation to the development of a national ethics committee, the report recommended the national body be controllable through administrative proceedings, where licenses may be issued outside its

A-10

powers or where the body acted in any way outside its charter. This national body would report to Parliament (Senate Select Committee 1986, Chapter 4, para 4.42), consult with the public (Senate Select Committee 1986, Chapter 4, para 4.43), and

Formulate guidelines, consider research protocols, and monitor research procedures...and initiate prosecution or injunction against those carrying out prohibited experimenting. Such a body would supersede the NHMRC with its MREC (Senate Select Committee 1986, Chapter 4, para 4.46).

     The report by the Family Law Council (a statutory council set up under the Commonwealth Family Law Act 1975 to advise on the development of federal family law) also recommended establishing a National Body (Family Law Council 1985). This report recommended a National Council on Reproductive Technology, which was to take a national approach to research and practice in reproductive technology in Australia (Family Law Council 1985, recommendations 30, 31).

     Both the report of the Senate Select Committee and the Report of the Family Law Council echoed the call in 1982 by Justice Michael Kirby, who had promoted some form of institution to tackle questions of ethics and experimentation, particularly in the area of IVF:

Otherwise, it will be the judgment of history that the scientists of our generation brought forth most remarkable development of human ingenuity—but the lawyers, philosophers, theologians and law-makers proved incompetent to keep pace (Kirby 1983 at 12).

Following the publication of the Senate’s Select Committee Report, the federal government decided to establish the NBCC. In 1988 the Federal Minister for Health in conjunction with the other Australian State Health Ministers announced that, in view of rapid advances in biotechnology creating bioethical issues, a new body would be established. The NBCC was established by the Health Ministers of Australia (with approval of the States’ Attorneys-General), but it was not invested with executive functions and only had advisory powers. The NBCC was limited to issues of artificial conception and was requested to consider and made recommendations in the area of human embryo experimentation.

     The committee was multidisciplinary, with representatives in areas of philosophy, moral theology, social science, women’s health, law, medical research, nursing, and gynecology. It was effectively and ably led by Ms. Robyn Layton QC of the South Australian Bar. The aim of the NBCC was to search for a

more coordinated, national approach to this issue [reproductive technology]...and the National Bioethics Consultative Committee will play an important part in formulating such an approach“ (Senate Select Committee 1986).

The NBCC met for the first time in August 1988. During its brief and at times turbulent period, the NBCC produced a number of major reports including the following:

• Donor Gametes, Record Keeping and Access to Information, June 1988;
  
• Access to Information: An Analogy Between Adoption and the Use of Gamete Donation, December 1988;
  
• Surrogacy Report No. 1, April 1990;
  
• Discussion Paper on Surrogacy 2 – Implementation, October 1990;
  
• Human Embryo Experimentation: Background Paper and Select Bibliography, November 1990; and
  
• Reproductive Technology Counselling, Final Report, March 1991.
  

By mid-1990 the NBCC was gearing down as proposals were being considered to incorporate it into the NHMRC structure (Finn 1990).

A-11

2.3.3 The AHEC Established

Before the introduction of the National Health and Medical Research Council Act, 1992 (Cth.), in 1991 formal discussions began between the Chair of the NBCC, Robyn Layton QC of the South Australian Bar, and the Chair of the NHMRC, Dr. Di Horvath, with a view to amalgamating the MREC and the NBCC. The then Minister for Community Services and Health, The Hon. Mr. Brian Howe MHR, had commissioned a report on the advisability of concentrating advice to government on health ethics matters within a principal committee of the NHMRC (Finn 1990). The NBCC was established to handle specific references from the Australian Health Ministers Advisory Committee (AHMAC). As such, the NBCC could never have been a permanent standing committee. By the time of the publication of its Report on Surrogacy (NBCC 1990), the NBCC had completed the review of the key issues in reproductive technology. In a similar vein, the MREC was not the sole repository of ethical advice within the NHMRC.

     The Minister for Community Services and Health decided to establish a new committee within the NHMRC to advise on health ethics. The new committee was to take up many of the responsibilities of the NBCC and the MREC as well as the ethical advice, which could flow, from the other principal committees of the NHMRC. In early 1991 it was decided that the new committee would be a principal committee of the NHMRC and was to be tentatively called the Health Ethics Committee (HEC). At early meetings, the broad terms of reference and focus of the new amalgamated HEC were established. These were:

The issue of the continued independence of the proposed HEC was the subject in some of these earlier discussions. It should be noted that the early Terms of Reference specified that the HEC was neither to have the role of providing an ad hoc ethics advisory service to the NHMRC nor to be used as a clearinghouse for reports from other principal committees of the NHMRC. Early discussions conceived of a committee of ten people covering many disciplines, with a national representation and balanced gender mix. It was agreed that the expertise of the NBCC could be broadened with the possible inclusion of a further clinician, health economist, and epidemiologist. Most importantly the expertise of the NBCC had to be supplemented with expertise from the MREC, particularly in relation to the operation of IECs. The success of these negotiations were quickly realized with the presentation of a work program to the June 1991 Council Meeting of the NHMRC.

     The processes of the new HEC were discussed in some detail. The new principal committee was to enjoy a fair degree of independence within the structure of the NHMRC with power to set its own priorities. Matters could be referred by the NHMRC, other principal committees of the NHMRC, or from Commonwealth and State ministers. In addition, the new committee:

• Did not expect the NHMRC to edit or change the contents of its reports, but merely to have the power to refer back for further consideration.
  
• Was to carry on work previously undertaken by the MREC.
  
• Was to have flexibility in framing its approaches to the pursuit of particular priorities, for example, organizing workshops, expert panels, community consultation, or the employment of consultants. (This latter practice of using paid consultations was not widespread within the NHMRC.)
  

A-12

• Was to consider its relationship with State governments and other related organizations.
  
• Was to have parity with all other principal committees with its level of NBCC budget maintained.
  

Finally, it was felt that the NBCC had achieved a high international profile and a style and quality of consultation that was important to maintain. For this reason the title “Australian” was to be added to the original suggested title of HEC to form the new AHEC.

3. The Commonwealth Review of Ethics Committees 1995–1996

3.1 Background to the Ministerial Review

Under the National Health and Medical Research Council Act 1992 (Cth.), the AHEC was made responsible for the administration of the national system of HRECs. While the system was generally recognized as working well during the 1990s, a number of areas of improvement were frequently mentioned in correspondence to AHEC, in the Medical Journal of Australia, and at public seminars, particularly the AHEC sponsored workshops in 1993 and 1995. Some of those included:

• Managing the increasing workload pressure on HRECs;
  
• Lack of scientific expertise in some areas;
  
• Absence of formal training programs;
  
• Legal liability and indemnity issues;
  
• Problems in relation to noncommercial or nonpharmaceutical company-sponsored research;
  
• Duplication of effort among the various layers;
  
• Need for a clinical trials register;
  
• Benefits of expedited review; and
  
• Concerns regarding multicenter trials and monitoring of research.
  

In 1995, the Commonwealth Minister for Health, the Hon. Dr. Carmen Lawrence MHR, announced an inquiry into the ethics review system. The review was requested in the context of two events. First, there was the controversy surrounding Family Planning Australia trials of the abortifacient RU486 in 1994. Second, in the same year, the Report of the Inquiry into the Use of Pituitary Derived Hormones in Australia and Creutzfeldt-Jakob Disease by Professor Margaret Allars (hereafter referred to as the Allars Report) (Allars 1994) was released. The Ministerial Review Committee was to inquire into the operation of HRECs with particular reference to the problems which have been identified following the Allars Report (Allars 1994) and the RU486 trials. RU486 was the so-called Morning After Pill which was counter-trialed in both Sydney and Melbourne. These trials formed part of an international multicenter study to determine the effectiveness of various doses of the drug and were sponsored by the World Health Organization (WHO). Although much of the controversy surrounding the trials related to ideological differences and concerns as to the appropriateness of the drug importation procedures, issues regarding the adequacy of the ethics committee review process were also raised. A separate and independent review on the RU486 trials (chaired by Professor John Funder) was conducted. That committee reported that ethics committee review had been adequate and recommended, following some modifications to the consent forms, that the trials recommence.

     The 1995 Ministerial Review was not required to address the science or ethics of the RU486 trials but was requested to comment on issues relating to consent and the adequacy of HREC operation and review

A-13

procedures (including issues of membership and decisionmaking). The Allars Report (Allars 1994) also raised fundamental issues relevant to the Ministerial Review relating to monitoring of ongoing research, the distinction between treatment and research, and the importance of consent by, and the duty to warn, research participants. The pituitary hormones program, which was the subject of the Allars Report, had been initiated at a time before the establishment of the ethics review system. In addition, the use of these hormones was considered to be treatment that had already been tested and adopted overseas. Many of the issues raised in the Allars Report concerned poor practice in relation to the collection and use of damaged pituitaries and were beyond the scope of the Ministerial Review. The Review’s Terms of Reference required that it have “special regard to issues of concern to women particularly in trials relating to reproductive technology” and to “examine and report on recommendation 10 of the Allars Report” which stated:

3.2 Matters Addressed by the Ministerial Review

A number of issues, summarized below, were addressed in the Ministerial Review and presented in the Report of the Review on the Role and Functions of Institutional Ethics Committees (Report on IECs) (Chalmers 1996). These issues provide a background to the consultation and led to the publication of the revised National Statement on Ethical Conduct in Research Involving Humans. A list of the actual recommendations is included in Schedule 1. The Report on IECs noted the heavy and increasing workload of IECs, their lack of resources, their limited expertise in dealing with some types of research, difficulties with monitoring and with multicenter trials, and the dominance of scientists on the committees. The following are some of the main areas addressed.

     Multicenter Research. There was no system of formal regional or national ethics review. Each IEC gave approval to research conducted in the institution. The practice had developed for individual IECs to communicate and exchange views with other IECs, particularly in relation to research projects carried out at different centers. The AHEC received numerous requests urging the establishment of a single national research ethics committee to consider multicenter trials involving humans. Researchers raised difficulties experienced in conducting multicenter trials where ethics approval must be obtained from a number of different IECs which may reach different conclusions in relation to the ethical acceptability of the trial. Different procedures, different meeting times, and different IEC membership often resulted in considerable delay in mounting a trial.

     The Report on IECs proposed that it was appropriate for one Australian IEC to accept the scientific assessment or reasons for ethical approval of another IEC. There was no reason in principle why this other committee need be Australian based; it could be an approved overseas committee.

A-14

     Multicenter Clinical Trials. Until 1991 all pharmaceutical and device trials were conducted under the auspices of the centralized Commonwealth TGA. Following the Baume Report (Baume 1991) a deregulated Clinical Trials Notification Scheme (CTN) was introduced which allowed IRCs to participate in organized clinical trials of pharmaceutical drugs and devices by notification only to the TGA (AHEC 1992). As a result of the CTN scheme, only a self-selecting group of IECs (now known as HRECs), with appropriate infrastructure support, mainly based in major teaching hospitals, participates in this scheme. This issue is dealt with in Section 6 of this report.

     Adequacy of Compensation and Insurance Arrangements. The AHEC considered the issues of compensation, indemnity, and insurance in relation to the introduction of the deregulated CTN scheme for clinical trials of drugs and devices. The concerns of IECs were twofold. First, IECs were concerned that the individual members of the committee might have attracted legal liability from the decisions giving ethical approval to a CTN application (Capron 1985). Second, there were concerns that the institutional arrangements for insurance cover for participants in a clinical trial might not have been clear in relation to existing institutional insurance arrangements.

     In relation to the first concern, a number of legal decisions were widely discussed causing concern in the Australian research ethics community. The High Court of Australia decision in Rogers v Whitaker established that a medical practitioner has not only a duty to exercise reasonable care in the diagnosis and treatment of a patient’s condition, but also a duty to disclose material risks inherent in any proposed treatment. A risk is material if in the circumstances a reasonable person is likely to attach significance to it, and the medical practitioner knows or should know that the particular patient is likely to attach significance if warned of the risk (this is consistent with U.S. and Canadian case law Canterbury v Spence and Reibl v Hughes). In this respect there is a higher duty of disclosure in the case of research projects: Halushka v University of Saskatchewan. There is further direct authority on the liability for nondisclosure of risks to research participants in the Canadian decision in Weiss v Solomon. This case also excited much critical comment (Freedman and Glass 1990). A number of other American cases have established the liability of hospitals in relation to decisions by Ethics Committees (see, for example, Davis v Rodman; Bouvia v Glenchur; Merritt 1987 at 1250–1252).

     In relation to the concerns some institutions questioned the compensation limits, which were included in the documentation supporting some protocols for multicenter clinical trials. The AHEC reviewed a number of research compensation arrangements, which included limits on the amount of any claim for compensation by a research subject in a trial. These limits were clearly inadequate in comparison with Australian insurance payouts for injuries. The AHEC had addressed these concerns earlier in a report that required institutions to review their compensation indemnity and insurance arrangements with their insurer and to put in place appropriate compensation cover for research participants (NHMRC 1994). A major national insurer introduced a specific no-fault liability cover for clinical trials, which was taken up by a number of institutions participating in multicenter clinical trials.

     Workload and Resource Support for IECs. This issue was clearly identified through the 1993 Survey of IECs and the Workshops for IECs (AHEC 1993). There was an expansion in workload because of a failure to sufficiently define the distinction between clinical practice and human experimentation. The result was that additional projects were referred to IECs, which would be more properly described as clinical practice and not experimentation. The other major growth in workload arose from referrals of health related and social science research projects to IECs.

     Monitoring of Projects. Under the NHMRC Guidelines (NHMRC 1992), IECs were required to monitor research. A variety of methods were reported by IECs, mainly taking the form of reports by the investigator. Very few IECs reported systematic methods for monitoring, and only a handful reported the use of “site” visits.

A-15

     Composition. There were concerns that the decisionmaking process was influenced too heavily by those with research interests. The original idea of an IEC was that it should have a majority of outside members. Surveys confirmed that clinicians and medical researchers dominated most IECs in Australia. The NHMRC Statement on Human Experimentation provided a minimum membership (NHMRC 1992). In fact, the majority of IECs were in the range of 10 to 15 members (16 or more members – 5 percent; 10 to 15 – 55 percent; 10 or fewer – 40 percent) with the majority represented by researchers. Paul McNeill has been a strident critic of this (McNeill 1993). Much of this diversity was due not only to the purpose of the institution and the nature of the research, but particularly to the authority, power, and responsibility given to, or accepted by, or assumed by IECs. In some institutions, the IECs had a broader function providing an advisory, policy and educational role relating to matters of clinical practice and management. Such committees may only rarely consider research proposals.

     Procedures. Many of the IECs reported that they were not well resourced. This had the consequence, in some cases, of inadequate official record keeping. IECs make decisions that can have a direct effect on the reputation or standing of the researcher, the rights of the research subject, and the interests of the institution. The question which arises is whether these decisions ought to conform with the accepted standards of good administrative practice requiring that decisions are recorded and that reasons should generally be given. There is some authority for the proposition that an IEC’s decisions are reviewable (R v Ethical Committee of St Mary’s Hospital ex-parte Harriott), and it is probable that professional members in an IEC are answerable to the disciplinary authorities of their profession.

3.3 Comment

The Report on IECs (Chalmers 1996) was accepted by the Council of the NHMRC during 1996, and its various recommendations were steadily introduced culminating in the introduction of the National Statement on Ethical Conduct in Research Involving Humans in 1999. The report recommended that the original NHMRC Statement on Human Experimentation (NHMRC 1992) required a thorough revision taking into account parliamentary references to the AHEC, issues of public interest, and new ethical questions raised by technological advances.

     It is interesting to note the similarities between this Australian Report and a review in the United States by the Office of the Inspector General of the Department of Health and Human Services. This review noted concerns that the IRBs in the United States have generally been doing “too much, too quickly with too little expertise.” The steady move toward more formal, regulated, and professional processes of ethics review of research is, no doubt, a common theme in most countries.

4. The Current System of Ethical Review in Australia

4.1 The National Health and Medical Research Council of Australia

Since its creation in 1937, the National Health and Medical Research Council has been the peak Australian funding body for health and medical research. One of the original aims of the NHMRC was to promote consistency in the health and public health policies of the individual State governments within the federal system. The NHMRC, having been established by Order-in-Council in 1937, was placed under a new statutory framework with the passage of the National Health and Medical Research Council Act 1992. The NHMRC remains the principal independent advisory body on health under the Act. Importantly, it is the principal national body for the provision of advice on matters of health ethics. Under the National Health and Medical Research Council Act, the council is charged with a number of functions including inquiring and issuing guidelines on the improvement of health; the prevention, diagnosis, and treatment of disease; the provision of health care; public health research and medical research; and ethical issues relating to health.

A-16

The Act confers four obligations on the NHMRC:

• To raise the standard of individual and public health throughout Australia;
  
• To foster the development of consistent health standards between the various States and Territories;
  
• To foster medical research and training and public health research training throughout Australia; and
  
• To foster consideration of ethical issues relating to health.
  

4.2 The AHEC Function and Relationship with the Commonwealth Parliament

The ethics advisory function is carried out by the AHEC, a principal committee of the NHMRC.

     The AHEC was established under the National Health and Medical Research Council Act 1992 (Cth.) (see particularly § 35 and § 36). It is a multidisciplinary committee which, under the Act has the following Terms of Reference:

The Minister made such a determination at the time of the Act and conferred further functions on the AHEC as follows:

3.1 To develop and give the Council guidelines for ethical conduct in the health field, additional to those required for function 2 above, and for the purposes of the Privacy Act 1988;

3.2 To promote community debate and consult with individuals, community organizations, health professions and governments, on health and ethical issues;

3.3 To monitor and advise on the workings of institutional ethics committees (now HRECs);

3.4 To monitor international developments in relation to health ethical issues and files with relevant international organizations and individuals.

The NHMRC had some initial challenges in becoming fully acquainted with the expectations of the Senate-initiated AHEC that replaced the MREC (Commonwealth Parliamentary Debates: 1991 at 1089–1092). A short time after the passage of the National Health and Medical Research Council Act, it was decided that there should be an external review of the NHMRC. A Canadian academic was commissioned, and a report was presented in December 1993 (Bienenstock 1993). This report recommended that the NHMRC improve its planning processes for developing and setting priorities and strategies; improving the advisory processes of the NHMRC Committees; improving and simplifying the research funding allocation processes; and, finally, recommending substantial changes to the administrative support of the NHMRC.

AHEC was the subject of specific comment in the Bienenstock Report, which is worth quoting at length:

AHEC is the most recently established of the Principal Committees of the NHMRC, having been in operation for two and a half years at the time of this review. It evolved from the former Medical Research Ethics Committee of NHMRC and the National Bioethics Consultative Committee (NBCC) of the Australian Health Ministers’ Conference.

It has continued the work of monitoring and supporting around 150 institutional ethics committees through activities such as workshops, introducing a newsletter and providing

A-17

advice and speakers on request. AHEC has also developed the broader ethics role, conducting some preliminary work into the ethics of health resource allocation, guidelines to promote ethical conduct in the health field, and issued various discussion papers on health ethics issues....

It is apparent that AHEC has had some difficulty in coming to grips with its role and function in what is undoubtedly a complex and extraordinarily wide ranging area. It has attracted considerable criticism from some quarters for failing to provide concrete advice on practical issues relating to research, particularly those relating to the operations of Institutional Ethics Committees (IECs), though some progress appears to have occurred in this area at the most recent Council meeting. It is seen by some people as being dominated by the members of the former NBCC, which was concerned with broader ethical, social and legal aspects of health care, and as having insufficient expertise and involvement by practicing researchers to deal with concrete ethical problems relating to research. On the other hand, some members of AHEC have felt that the Committee has been too occupied with the agendas of subcommittees, particularly the IEC Subcommittee, to be able to define its broader role and activities.

Consideration of the legal and ethical aspects of health will grow in importance in the future. The NHMRC will play a vital part in this development. A balanced approach to this issue must involve recognition by health practitioners that ethical considerations are crucial in their work, and by the NHMRC that health practitioners and researchers must be an integral part of the development of appropriate guidelines. To separate ethical considerations from the practice of health and research is to invite irrelevance rather than independence” (Bienenstock 1993 at 23–24).

Professor Bienenstock recommended that AHEC should integrate its activities and priorities with those of the NHMRC as a whole, focus its energies on issues of highest practical and immediate priority, and be accountable to Council for its work. In so doing AHEC was to be restructured to more fully integrated activities with the principal committees of NHMRC (Bienenstock 1993, Recommendation 11). AHEC was to operate as any other principal committee of the NHMRC, but with the unique guideline development function under § 8 of the Act.

4.3 The AHEC Composition and Role

Only two of the principal committees of the NHMRC, namely the Research Committee and the AHEC, were specifically mentioned within the terms of the National Health and Medical Research Council Act 1992. By § 35 of the Act, the Minister must establish principal committees called the Medical Research Committee (now the Research Committee) and the AHEC. During the parliamentary debate and particularly those in the Senate, the composition and independent role of the AHEC was established.

n § 36 of the National Health and Medical Research Council Act 1992 provides that AHEC is to have the following membership:

• the Chairperson;
  
• a person with knowledge of the ethics of medical research;
  
• a person who has expertise in law;
  
• a person who has expertise in philosophy;
  
• a person who has expertise in religion;
  

A-18

• a person who has experience in medical research;
  
• a person who has experience in public health research;
  
• a person who has experience in social science research;
  
• a person who has experience in clinical medical practice;
  
• a person who has experience in nursing or allied health practices;
  
• a person with knowledge of the regulation of the medical profession;
  
• a person with understanding of health consumer issues;
  
• a person with understanding of the concerns of people with a disability; and
  
• no more than two other persons with expertise relevant to the functions of the Committee.
  
• The Act specifies a nomination system that must take place from among peak bodies in relation to these areas of expertise. In an apparent effort to limit the power of the Minister to his/her own appointees, the Act includes a requirement that for most categories peak professional bodies must be consulted. For example, the person with expertise in law should be appointed from persons nominated by the State and Territory Law Societies or the Commonwealth Law Council. Similarly, the senior representative bodies of the officially recognized religions nominate the person with expertise in religion.
  
• AHEC must not have more than one member of the Research Committee of the NHMRC and its Chair must be a person who is not a member of the Research Committee (§ 35(6) of the Act).
  
• Matters could be referred by the NHMRC, other principal committees of the NHMRC or from Commonwealth and State ministers. For example, the reference to the AHEC to prepare a Report on the Scientific, Ethical, and Legal Considerations Relevant to Human Cloning was a reference from the Commonwealth Minister for Health and Aged Care.
  
• The NHMRC cannot edit or change (§ 8(2) of the Act) the contents of AHEC reports, but may refer the guidelines back for further consideration.
  
• Community consultation is a requirement under § 11–14 of the Act. A two-stage public consultation process is specified.
  

The organizational and structural changes recommended by the Bienenstock Report (Bienenstock 1993) were put into place during the first half of the 1990s. By the second triennium of the AHEC (1993–1996) the Council of the NHMRC had a clear appreciation of the role and function of the AHEC. In particular, the Council recognized that the guideline development function of the AHEC was neither an advisory role nor a role which could be interfered with by the Council.

4.4 Guidelines of AHEC and Consultation

The AHEC, in its role as one of the principal committees of the NHMRC, is responsible for developing guidelines for the conduct of medical research involving humans, other advice relating to health, and for providing assistance to HRECs.

     The guideline development function of AHEC is critical. Under § 8 of the National Health and Medical Research Council Act 1992 (Cth.), the NHMRC issues guidelines for the conduct of medical research involving humans. However, the guidelines for the conduct of medical research are developed by the AHEC and must be issued by the NHMRC precisely as developed by the AHEC (§ 8(2)). It should be noted that guidelines promulgated by the NHMRC do not have the same legal effect as legislation. However, the NHMRC is a creature of

A-19

statute (National Health and Medical Research Council Act 1992) (Cth.), and the Act provides that the NHMRC may promulgate guidelines. NHMRC guidelines relating to ethics are laid before Parliament before they come into force. It is therefore not accurate to describe the guidelines as voluntary. Guidelines have two specific legal aspects. First, they establish standards of reasonable practice. HRECs must follow these guidelines and in so doing act with fairness. Rules of administrative law deal with the standards of fairness required of committees. In this way HRECs are probably subject to administrative review which looks to standards of natural justice and procedural fairness. Second, and more importantly, the guidelines could be used and admitted as evidence in court proceedings to demonstrate that the deliberations and actions of a HREC are reasonable and fair and provided that the guidelines themselves are reasonable and that the HREC acted within their scope.

     This rather unusual guideline-making function was inserted by the Commonwealth Parliament. It appears from the Senate Debates in relation to the Act (Senate Debates 1992, at 1089–1092) that this was inserted to ensure that the guidelines were a product of the public consultation process rather than the individual, and possibly medically biased, views of the Council of the NHMRC itself. In this respect the AHEC is a part of the NHMRC but is independent in the development of national guidelines in relation to medical research.

     A complex consultation procedure was established under § 11–14 of the Act. Concerns that guidelines were “in-house” rather than public products resulted in the introduction of a unique two-stage consultation system. At the first stage, there is an advertisement of the intention to consider and develop guidelines in a particular area. In most cases, the AHEC circulated an information package or Issues Paper on the topic proposed for the guidelines. At the second stage the draft guidelines themselves were circulated for further advice and comment. Through these means it was intended that ex cathedra opinions by AHEC were to be avoided. Later, a decision by the Federal Court of Australia placed additional responsibilities on the NHMRC in relation to public consultation. In the case of Tobacco Institute of Australia Ltd v National Health and Medical Research Council and Others,

Justice Finn considered the specific terms of section 12 of the National Health and Medical Research Council Act. This section requires that the NHMRC have “regard” to the submissions presented to consultation and give “genuine consideration to the material.” The appellant, Tobacco Institute, had presented copious material to a consultation in relation to a draft Report on the Effects of Passive Smoking and Health (The report contained guidelines and was therefore subject to the two stage consultation requirements of the Act). The working party on the report decided to divide this material among the various members for reading and comment. Accordingly, each member read only part of the material. Justice Finn concluded that the obligation to have regard to the submissions required the NHMRC in its working parties preparing any report to give “positive consideration” to the contents of the submissions as this was a fundamental element of decisionmaking. As a result of this decision, the AHEC introduced lengthy minute taking of all consideration of submissions. AHEC developed a system of recording the acceptance or rejection (with reasons) of particular points raised. The minutes of AHEC in relation to public consultation were always treated as public documents available under the Freedom of Information Act 1982 (Cth.).

     The AHEC is also required to promote community debate and consults with individuals, community organizations, health professionals, and governments on health and ethical issues.

4.5 Accountability of AHEC

The AHEC is subject to the normal organizational accountability procedures. The AHEC is required to present a work plan to the Council of the NHMRC. In addition, the AHEC is subject to financial and internal audits, presents reports (through the Chair) to meetings of the full Council and prepares a final report that is included in the publicly available Annual Report of the NHMRC (an example is included in Schedule 2).

     Public accountability is perhaps best achieved by the public consultation provisions of the National Health and Medical Research Council Act. As described above, the AHEC is required to conduct public consultation,

A-20

and the guidelines which issue must have proper “regard” and pay positive consideration, to the contents and views expressed in the submissions. As a national organization, it is also subject to professional comment and criticism in the press and academic literature.

     The AHEC is also answerable through the political processes. First, the relevant Commonwealth Minister may refer matters for consideration by the AHEC. For example, in late 1997 the Commonwealth Minister for Health and Aged Care referred the issue of human cloning to the Committee for advice (AHEC 1998). Importantly, the Commonwealth Parliament of Australia Senate was modeled on the United States Senate and enjoys the strong investigator committee system of the United States (the Lower House of Representatives reflects the Westminster Parliamentary system, and the Upper House Senate reflects the American Senate; as such the Parliamentary system is often referred to as a “Washminster” Parliamentary system). The Senate Estimates Committee has regularly interrogated the Executive Secretary of the AHEC on its works and finances. This was a deliberate consequence of placing the NHMRC under a Commonwealth statutory framework.

4.6 Australia’s System of Ethics Committee Review

Number of Committees. HRECs are the foundation of the ethical review system in Australia. (Breen 1997; Bennett 1997; Skene 1998; Freckelton and Petersen 1999). There are some 217 HRECs operating in Australia and registered with the AHEC. HRECs rely on the voluntary contribution of members, a degree of self-regulation, and modest financial support. The HRECs are responsible for the protection of research participants and ensure that research protocols are considered in conjunction with NHMRC and other applicable guidelines, with support and advice from AHEC.

     At the time of this writing there are now 217 registered HRECs in Australia with the following approximate proportional distribution:

• Hospitals – 45 percent
  
• Universities – 22 percent
  
• Health Departments/Government Agencies – 20 percent
  
• Research Institutions – 9 percent
  
• Professional Associations/ Organizations – 4 percent
  

There continues to be variation among the HRECs. There are several aspects to this variation, which can be identified. There are a number of different types of institutions within which HRECs operate, ranging from large teaching hospitals to small regional universities, and from research institutes to small, special purpose organizations. Health institutions for example, range from the large teaching hospitals associated with the major medical schools to small rural base hospitals. There are also repatriation (for ex-defense force personnel) hospitals, area health services (in NSW and Queensland), specialist organizations such as the Red Cross and the Bone Marrow Donor Registry, as well as the specialist medical colleges. A third level of variation among HRECs, which can be identified, is the regional differences that arise from the variation in State legislation. For instance, HRECs in different States face different issues when considering a specific type of research (such as embryo experimentation) when State legislation is inconsistent. Therefore, it should be borne in mind that the HRECs in Australia are not entirely homogeneous, though much standardization is under way.

     Review by and Role of HRECs. The Preamble to the National Statement clarifies its purpose as a whole and the role of HRECs in particular as the protection of the welfare and rights of participants involved in research. Some submissions to the public consultation in relation to the new National Statement expressed the view that Research Ethics Committees should “facilitate” research. While it is to be hoped that the HREC is not deliberately obstructive, the National Statement clearly places the protectory role on HRECs. Members of a HREC do

A-21

not have many representative responsibilities to the constituency from which they are appointed. The members do not in any sense represent the constituency. The National Statement again clarifies that the HREC members’ responsibility is to decide independently whether conduct of the research proposal involves the proper protection of the welfare and rights of research participants (see, for example, Bennetts v Board of Fire Commissioners of New South Wales). Importantly, HRECs consider all research involving humans and are not confined to the consideration of medical research only. HRECs are required to consider a large number of protocols ranging from drug trials and gene therapy to behavioral or social science research. All research involving clinical trials, regardless of the funding source, are assessed. To date, the review system has managed to cope adequately with the increasing number of clinical trials and research projects. In 1997 around 1,400 clinical trials were approved under the CTN, not to mention those trials under way and being monitored.

     Membership of the HREC. The National Statement has increased the core membership of HRECs with a view to ensuring that the HREC responds to its protectory role rather than the institutional interests in promoting research. The membership now consists of:

• A Chairperson;
  
• Two lay people, a man and a woman;
  
• A person with knowledge of and current experience in research, the type of which is regularly considered by the HREC on which the person serves;
  
• A person with knowledge of and current experience in professional care, counseling or treatment;
  
• A person who is a Minister of Religion or served a similar role in their community; and
  
• A person who is a lawyer.
  

If, at any stage, further members are added to the HREC, the institution is required to retain the balance and diversity of the institutional/noninstitutional members.

     Procedures. The National Statement has introduced a number of new requirements to ensure proper discussion, contributions from members, and recording of decisions (this is discussed more extensively in Section 5 of this report).

4.7 Accountability of HRECs

Annual Compliance Requirements to AHEC. Under the previous Statement on Human Experimentation, IECs were required to present a minimal report confirming compliance with the guidelines at the end of the calendar year. There was no formal system of certification or accrediting of the committees. Under Principles 2.46–2.48 of the new National Statement on Ethical Conduct and Research Involving Humans, the compliance reporting requirements have increased considerably. The AHEC audits the activities of the HRECs to ensure compliance through a detailed Annual Report that seeks responses on issues of membership, meetings, agendas, approvals, rejections of projects, difficulties, and complaints. A failure to present an acceptable compliance report may, after investigation, lead to a removal of external funding from the institution. In this respect, HRECs are required to register with the AHEC as a precondition to being able to submit research projects for funding to the major public bodies.

Complaints Mechanisms. Before the National Statement, many of the long-standing Research Ethics

Committees had established complaints mechanisms. The National Statement now requires that any institution that establishes a HREC must also establish an independent complaint mechanism to handle complaints from research disciplines. In the first instance, it is expected that a research protocol should include a reference to a person nominated by the HREC to receive complaints. If this initial procedure cannot resolve the complaint

A-22

from the research participant, the HREC must formally refer the complaint to the institution’s complaint handling processes. The HREC is also required to ensure that information about pursuing complaints is made known to the research participants at the time of consenting to entering the research protocol.

     Independent of these National Statement complaint mechanisms, all States and Territories have established administrative procedures for making complaints about the health system. The Health Complaints Commissioners in the States and Territories receive complaints about medical practitioners and the delivery of medical services. Where these complaints relate to research by a medical practitioner or medical research carried out in the health system, these complaints may be referred to the Health Complaints Commissioner. Very few complaints concerning research have been referred to the Health Complaints Commissioners among the many thousands of general complaints. This may indicate an absence of complaints about the research system or, alternatively, problems in the making and reporting of complaints.

4.8 The Work of the AHEC: 1991–2000

A brief outline of the references, work, and guidelines produced by the AHEC is presented. This illustrates the manner in which the AHEC has established functions both within the NHMRC and nationally within the research ethics committee system.

     AHEC met for the first time at the end of August 1991. During its first two triennia (1991–1996), AHEC undertook work on a case study of the legal and ethical implications of HTLV-I; information papers on the legal liability of institutional ethics committees, ethical considerations relating to health care resource allocation decisions, nature of qualitative research, human gene therapy, workshops for institutional ethics committee members; monitoring and supporting the HRECs through workshops, newsletters and advice, and, guidelines relating to IVF and embryo transfer, privacy in medical research, and the use of patient tissue samples for research.

The third triennium of the AHEC was marked by a substantial revision on the Statement of Human

Experimentation and a formal reference of work on human genetics by the Commonwealth Minister for Health and Aged Care. The work was as follows:

n The National Statement on Ethical Conduct in Research Involving Humans

The Statement is discussed below at Section 5 of this report.

n The Genetics Program

The ethics of human genetic research was the major focus of the work of the AHEC during this period. A specific Working Party was convened, and developed and finalized two sets of guidelines are as follows:

Guidelines for Genetic Registers and Associated Genetic Materials and Guidelines for Ethical Review of Research Proposals for Human Somatic Cell Gene Therapy and Related Therapies. The former gave guidance on all aspects of the operation of genetic registers on the collection, use, and access to this material. The guidelines also deal with aspects of recruitment and storage of genetic material. The latter is intended to give guidance to the select HRECs that deal with gene therapy applications. In addition to the two sets of guidelines, the AHEC has published an Information Paper addressing issues of equity, resource allocation, commercialization, and counseling and testing of children in a document entitled Ethical Aspects of Human Genetic Testing: An Information Paper.

Finally, for the first time, the National Statement included a specific set of principles of human genetic research (National Statement 1999, Principles 16.1–16.21).

A-23

n HREC Operating Manual

A HREC Operating Manual is in preparation, which will be in the form of annotations to the Statement providing explanation and procedural information to HREC members. It is important to note that the use of the operating manual will not be mandatory and will not prevent HRECs from developing their own operating manuals or varying any published national standard operating manual. It is anticipated, though, that an operating manual at the national level will assist the decisionmaking processes of HRECs, contributing to consistency and predictability in the operation of HRECs in Australia. The manual will be developed in consultation with HRECs and other key stakeholders and is based in part on the Kings College Manual in the United Kingdom.

n 1999 HREC Workshops

The AHEC held workshops for HRECs in 1993 and in 1995. There were many calls for another series of workshops as a means of imparting information, discussing issues, and networking for the HRECs. The fifth series of National Workshops were held in 1999 to launch the National Statement on Ethical Conduct in Research Involving Humans.

n Guidelines for the Protection of Privacy in Medical Research (1995)

The Guidelines for the Protection of Privacy in Medical Research were revised and issued under § 95 of the Commonwealth Privacy Act 1988 and provide a framework for the protection of privacy in medical research involving personal information obtained from Commonwealth agencies. The purpose of the guidelines is to ensure that such personal information is protected against unauthorized collection or disclosure.

The AHEC was invited to develop the ethics program for the HUGO Human Genome Meeting (HGM 1999) held in Brisbane, Australia in March 1999.

n Cloning of Human Beings

In January 1998, the Commonwealth Minister asked AHEC to provide advice on the ethical issues and the need for further pronouncement or possible legislation regarding the cloning of human beings.

This advice was published in a report to the Minister entitled Scientific, Ethical and Regulatory Consideration Relevant to Cloning of Human Beings (AHEC 1998).

n Xenotransplantation

Given the national and international interest in the possibility of xenotransplantation, the AHEC was asked to consider issuing ethical guidelines on the subject. In view of the risk of rejection and possibility of transmission of unknown infectious agents from animals through immuno-compromised hosts into the general community, the AHEC sought scientific advice from the Research Committee of the NHMRC to clarify the potential risks and benefits before considering necessary action.

5. The National Statement on Ethical Conduct in Research Involving Humans

5.1 Background to the National Statement

The report on IECs (Chalmers 1996) recommended that the AHEC should redraft the Statement on Human Experimentation and “…change its title so that all health investigation involving humans (including non-biomedical research and innovative practice) was encompassed” (Recommendation 5.3.1).

A-24

The review process incorporated not only the advice in the submissions made but also a number of developments, documents, and practices that may be briefly summarized as follows:

• The NHMRC Statement on Human Experimentation was increasingly applied to research funded by bodies, other than the NHMRC.
  
• NHMRC guidelines were more suited to health and medical research, and refinements were required for their application to research such as social science research involving humans.
  
• Additional NHMRC guidelines, published since 1992, had implications for researchers and ethics committees
  (these included General Guidelines for Medical Practitioners on Providing Information to Patients; Report on Compensation, Insurance and Indemnity Arrangements for Institutional Ethics Committees; and Aspects of Privacy in Medical Research).
  
• There was a need to recognize developments in research practices and culture:
  
• a recognition that groups as well as individuals are involved in research;
  
• following from this, a recognition that some groups are not merely geographical, social, or religious entities but are bound together by traditions, beliefs, and customary practices. It has been useful to adopt the Canadian terminology of a “collectivity” to recognize the special characteristics of these groups in our society;
  
• increasing focus on the ethics of providing innovative treatments and interventions;
  
• an acceptance that harm could include breaches of privacy and confidentiality;
  
• the increasing number of multicenter trials and the need to facilitate their ethical approval;
  
• the increasing use and acceptance of qualitative methodologies in disciplines additional to the social sciences; and
  
• the increasing acceptance that research information should be disseminated especially, where appropriate, to research participants.
  
• The role of IECs had become more complex and demanding, and more formal administrative procedures were required.
  
• There had been developments in the law with implications for researchers and IECs (including the High Court decision in Rogers v Whitaker, guardianship law, privacy guidelines, and clinical trials regulations).
  
• There were requirements to implement specific recommendations contained in the report of the Review of the Role and Functioning of Institutional Ethics Committees (Chalmers 1996) which was accepted by the Council of the NHMRC.
  
• There was an obligation to respond to certain specific matters referred by the Commonwealth Minister for Health and Family Services, including the Report of the Inquiry into the Use of Pituitary Derived Hormones in Australia and Creutzfelt-Jakob Disease (Allars 1994), and ethical concerns raised by the inclusion of orphans and State wards in vaccine trials conducted in the post war years, and informed consent for experimental use of estrogen to reduce attainable height in “tall girls” in the 1950s.
  
• There were concerns in relation to research involving persons with a mental illness or intellectual impairment and the inclusion of indigenous peoples in the section on collectivities and human genetic research.
  

There was a perceived need to take into account international considerations in introducing the new National Statement. Submissions received by AHEC during the public consultation processes included increasing references by researchers, organizations, and community groups to overseas research guidelines, international conventions

A-25

and treaties, and international practices. The Australian Government, with the consequent implementation obligations had signed some of these Conventions and Treaties. The most notable of these international developments were as follows:

• The recognition of standards contained in Conventions, Declarations, and Treaties to which Australia is a party and others which are respected international standards (e.g., World Medical Association Declaration of Helsinki; the Council of Europe Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine 1996 (the Bioethics Convention); the Universal Declaration of the Human Genome and Human Rights 1997);
  
• The increasing internationalization of research and the consequent need to move toward international consistency in Codes of Practice. For example, in clinical trials, the International Conference on Harmonization Guidelines for Good Clinical Practice (CPMP/ICH 1995) are a recognized standard;
  
• The Council for International Organizations of Medical Sciences Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS 1993);
  
• The codes of ethical research practice which have developed in other countries, e.g., the influential United States Federal Code of Research Practice. The AHEC referred particularly to the revisions in ethical codes recently completed in a number of other countries including Canada (Canadian Code 1997; NCBHR 1995), United Kingdom (Royal College of Physicians 1996), and New Zealand (Health Research Council of New Zealand 1997), and was familiar with the relevant American guidelines (Furrow 1995);
  
• Increasing collaboration between research funding bodies with the development of common code, for example the new Canadian Code of Ethical Conduct for Research Involving Humans which is a tri-partite effort by the Medical Research Council, Natural Sciences and Engineering Research Council, and the Social Sciences and Humanities Research Council of Canada.
  
• To the usefulness of adopting the Canadian terminology of a “collectivity” to recognize the special characteristics of these groups in our society.
  

5.2 The National Statement and Its Nationwide Application

In 1999 the NHMRC concluded its public consultation on a new National Statement for Ethical Conduct in Research Involving Humans (National Statement 1999). The report on IECs had recommended that “The NHMRC in conjunction with other peak bodies responsible for research and clinical practice (Australian Research Council, Australian Vice-Chancellors’ Committee, Australian Medical Council) should promulgate guidelines representing a national statement for the ethical conduct of research” (Recommendation 5.2.2.). This was achieved during late 1998 and the first half of 1999, and the Statement was also endorsed by all the national funding agencies, universities, and the learned academies. This is the first time that all research funding agencies, universities, and learned academies have subscribed to a single national code of conduct for the ethical conduct of research involving humans. Importantly, this statement has continued to include a section on clinical trials, which was the subject of considerable comment by researchers, the Australian Pharmaceutical Manufacturers Association, institutions, and consumer organizations. The predecessor Statement on Human Experimentation 1992 contained a Supplementary Note 4 that dealt summarily with key elements of clinical trials.

     The National Statement applies universally to all disciplines of research involving humans. The guidelines includes new sections on human genetics research, use of human tissue samples, emergency care research, and some additional guidance in relation to multicenter trials and modified composition of HRECs. This is a significant step in promoting a uniformly high ethical standard for all research involving humans.

A-26

5.3 The Contents of the National Statement

Comments are made in this section in relation to parts of the National Statement to provide some background rationale for the Principles.

     Purpose of the Statement. The Preamble to the National Statement notes that the purpose of the Statement is to provide a national reference point for ethic consideration relevant to all research involving humans. All major bodies involved with human research have endorsed the National Statement. Not only symbolically, but also actually, the National Statement will serve the major national reference point in the future development of research ethics involving humans in this country. If this goal is achieved, it is hoped that not only will there be simplification in place of many differing codes but also improvement in the quality of ethical consideration through uniform standard setting.

     The Principles to be Applied. The National Statement includes a more detailed summary of the Principles of ethical conduct than the former Statement of Human Experimentation (Brody 1981; Engelhardt 1986; Beauchamp and Childress 1994; Pellegrino and Thomasa 1996). It is intended that the General Principles (Principles 1.1–1.21) will assist in the interpretation of the other parts of the National Statement. Integrity of the researcher is placed at the forefront of these principles. Respect for persons and beneficence are expressed in traditional forms, but the well-being of the participants takes precedence over expected benefits to knowledge, and researchers have a responsibility to minimize risks of harm or discomfort to research participants. For the first time, the principle of justice is included and requires fair distribution of benefits and burdens of participation in research; avoidance of unfair burden by participation; fair recruitment of research participants; and avoidance of discrimination in the selection of participants. The Operating Manual when published will explain the intention of these important principles, which are intended to address concerns about over-researching of particular groups, questionable recruitment practices for participants, and applying selection criteria for the participants which may, in effect, discriminate. The focus, in this respect was on the process of research rather than the results of the research. The National Statement focuses on the dissemination of such findings but does not oblige researchers, sponsors, or others to actually distribute research benefits among the participants.

     HRECs (Principles 2.1–2.5). The National Statement attempts to achieve further development of the established ethics review system. A clear responsibility is established for institutions to establish and properly resource HRECs. Institutions are now required to set clear Terms of Reference for the HREC. If, for example, the HREC is to undertake policy or educational tasks as well as the primary research review function, these additional functions must be provided for in the Terms of Reference. In addition, the institution is required to accept expressly the legal responsibility for the members of the HREC while they are acting within the scope of their approved functions. Where researchers are not affiliated with a particular institution, institutions are encouraged to accept these projects for consideration by the HREC. The aim of this provision is to try to ensure that all research conducted in this country is under the umbrella of the protectory research ethics review system.

     Membership of the Committees (Principle 2.6–2.9). No longer are medical graduates required to form the core membership of a HREC. There is now provision to appoint a person with knowledge of and current experience in the research that is regularly considered by the HREC. Thus, if the research considered by the HREC is social science, then the person appointed should be knowledgeable and experienced in social science research. Second, the core membership has been expanded by the inclusion of a person with knowledge of or current experience in professional care, counseling, or treatment. This person was seen as offering additional insights into the way in which research participants may view a research project and the way in which it impacts upon them. This does not have to be a doctor, but can extend to a psychologist, nurse, social worker, or the like depending on the type of research considered by the HREC.

A-27

     From time to time suggestions have been made that some members of a HREC should be appointed solely for the purpose of representing the research participants (McNeill 1993). This view is misconceived in the sense that all members of a HREC are required to protect the welfare and rights of the research participants.

     In addition, the National Statement includes a requirement that institutions should be mindful of institutional and noninstitutional balance in the membership of their HRECs. The National Statement requires that any increase in the core membership of the HREC should retain this balance. This provision was included to address difficulties that have arisen under the old IEC system. Many of the old IECs had, in addition to the five core members, a membership of between 12 to 15 members (See Section 3.2 of this report). Many of these additional members were appointed for research expertise resulting in lay members being in the minority. Institutions must, if membership is increased, maintain the balance of core membership to new members. For example, if another researcher was to be appointed the institution may very well wish to appoint a further lay person.

     HREC Meetings (Principles 2.15–2.24). A number of new provisions are included in relation to meetings for HRECs. The HREC may now invite a researcher to attend to provide advice to the HREC. This formalizes the procedure, which had developed in some IECs. Importantly, a HREC must proceed to deliberate without any conflict of interest by any member. It is the responsibility of HREC members to announce any conflict of interest, which may affect the independence of their decisionmaking. HRECs may seek expert scientific advice on a research protocol. This procedure was introduced to address concerns by many researchers that HRECs were spending too much time deliberating on the scientific rather than ethical aspects of research protocol. As there is no neat division between scientific aspects and ethical aspects of research, the National Statement directs the HRECs’ attention to their ethical function but recognizes from time to time that research protocol may require explanation to illuminate the ethical issues involved. Researchers are now required to disclose any funding or any financial interest, which they may have which may be related to the project. A HREC must then decide whether its disclosure in any way affects any relevant ethical considerations in the protocol.

     Monitoring (Principles 2.33–2.38). The previous Statement on Human Experimentation was amended in 1992 to recognize the responsibility of ethics committees or monitoring research. The new National Statement includes Principles requiring the HREC to monitor research. The Principles also recognize that the primary responsibility rests with the institution. In addition, the frequency and type of monitoring which is carried out in relation to research protocol should reflect the relative degree of risk to the participants. In this way, HRECs are encouraged to concentrate on riskier protocols. HRECs are required to receive reports of anything that might warrant review of the original ethical approval or anything which may result in the early discontinuance of the research.

     These Principles were intended to address growing concerns among members of ethics review committees that they have neither the expertise nor the resources to conduct effective and timely monitoring of research. Many institutions and ethics committees had, during the 1990s, developed “tailored” monitoring mechanisms, which, as a matter of fact, reflected the degree of risk involved. The National Statement reflects this development and requires HRECs to implement appropriate monitoring mechanisms dependent on the risk involved in their research protocol.

     Expedited Review and Multicenter Research (Principles 3.3–3.7). For the first time the National Statement has formalized expedited review for minimal risk research. Recognizing the growing burden on HRECs, the National Statement permits a HREC to nominate classes of research, which may be reviewed in an expedited fashion by the Chairperson and later ratified by the full Committee. However, the National Statement does not permit risky or ethically controversial research to be subjected to expedited review.

     The National Statement for the first time sets up two procedures for handling multicenter research. First, HRECs are now permitted to communicate with other HRECs; to accept scientific assessments of other HRECs;

A-28

to adopt the reasons and ethical decisions of other HRECs; to adopt any procedures of another HREC with a view to avoiding duplication; and to agree on common monitoring responsibilities. Second, there is now a formal procedure, which allows HRECs and institutions to agree before the start of a multicenter research project to nominate the “primary, ethical and scientific assessment process subject to the approval of the other participating institutions and HRECs.” These informal and formal multicenter research procedures are intended to address complaints by researchers about delays and inefficiencies in ethical review. Frequently, researchers complained that HRECs were more engaged in difficulties about procedure or documentation rather than points of ethical substance. These procedures are intended to facilitate multicenter research without in any way compromising proper ethical safeguards. In both New South Wales and Victoria efforts are now in progress to develop common application forms and systems to allow multicenter research procedures to be implemented (Kelly and Boyages 1999).

     Special Categories for Protection (Principles 4–7). The National Statement includes specific Principles intended to protect participants who are either vulnerable or at greater risk. In the case of children and young people, research should only be permitted where their participation is indispensable and the physical, emotional, and pathological safety of the children and young people are ensured. As with other like categories, a HREC should not approve the research where it is contrary to the child or young person’s best interests. Similar provisions apply to research projects that involve participants with an intellectual or mental impairment.

     The National Statement recognizes that those in highly dependent medical care situations (emergency, intensive, neo-natal intensive and terminal care) may be unconscious or otherwise impaired in their capacity to communicate. In such cases, it may not be possible for the researcher to obtain consent to the research. However, in these circumstances there may be greater risk of coercion and undue burdens from involvement in research. HRECs, in these cases, may allow the research to be conducted provided it is generally not contrary to the patient’s interests; the research is therapeutic; the risks are no greater than those involved in accepted treatment; and there is a reasonable possibility of benefit over standard care. In addition, the patient, guardian, or family is informed as soon as possible of the option to withdraw.

     Recognizing the pressures that can be brought to bear in the workplace, education, or in institutions, the National Statement recommends that HRECs should exercise extra care when considering research where there are dependent or unequal relationships. In these cases, the HRECs should be satisfied that the consent is, in fact, voluntary and that no discrimination should follow where a person refuses.

     Research on Collectivities (Principle 8). The National Statement includes principles to cover research involving collectivities. Collectivities are defined to include those with common cultural, customary, social organization but not extending to clubs or associations. The term was proposed by the Canadian Tri-Council Code and was considered a helpful contribution to understanding research among the multicultural communities of Australian society. In essence, research in collectivities requires, as well as individual consent, consent by the collectivities recognized legally. In addition, researchers must satisfy a HREC that the customs and beliefs of that collectivity will be respected.

     Aboriginal and Torres Strait Islander (Research Principle 9). Interim Guidelines were introduced by the NHMRC in 1991 before the establishment of the AHEC. During the public consultation, differences were expressed in this area. Some submissions expressed satisfaction with the existing Interim Guidelines, others suggested new Guidelines and others suggested that the proposed principles on research involving collectivities were sufficient to include Aboriginal and Torres Strait Islander people. The Interim Guidelines have been continued in force, and the Interim Guidelines will be reviewed in the future.

Clinical Trials (Principles 12.1–12.13). This topic is discussed in greater detail in Section 6 of this report.

A-29

     Innovative Therapy. Innovation is a major part of good clinical practice. The medical practitioner is given freedom to vary standard treatments to find the best and most appropriate treatment regime for his/her patient. The integrity and professional responsibility of the medical practitioner define the limits to the use of this clinical freedom. The Ministerial Review recommended that a guideline be introduced to regularize practice in this area (Chalmers 1996). The National Statement includes a principle that any systematic investigation or innovation to determine efficacy should be considered as clinical research and referred to a HREC for approval. The purpose of this guideline is to permit and encourage clinicians to seek HREC advice and approval where researcher innovation is in fact, being conducted (see Section 3 of this report).

     Epidemiological Research (Principles 14.1–4.13). The National Statement includes a number of new principles to facilitate epidemiological research while maintaining proper protections for research participants particularly in relation to privacy. First, the National Statement distinguishes epidemiological research from conventional public health surveillance of public health records by authorized public servants. This definition was included to address concerns by State and Territory government departments in increasing requests for access to records under their control.

Second, the National Statement includes 3 categories of data:

• Identified
  
• Potentially identifiable
  
• De-identified
  

Confusion has arisen in recent years in Australia with access to “coded” information. On the one hand, researchers complained that HRECs set unrealistic and impractical consent requirements in relation to their projects. On the other hand, HRECs are reflecting growing community concerns about privacy and access to personal records. This schema of identified, potentially identifiable, and de-identified data aims to assist HRECs to focus on projects that involve identified or potentially identifiable information. The first category is straightforward. “Potentially identifiable information” refers to information that is coded and may easily be translated into identified information. In addition, the term “potentially identifiable” refers to small population groups (by region or by disease indications) which may be identified by reference to other sources, e.g., post code.

     Third, where potentially identifiable data is used by a HREC, the HREC should generally require that once the linkage has been established, the information should be coded and placed in secure storage.

     Fourth, these principles permit a HREC to approve access to data without consent when the consent process is likely to cause unnecessary anxiety or prejudice to scientific value and there is no disadvantage to participants. The HREC may also grant access without consent where it is impossible in practice to gain consent because of the numbers involved or accessibility to them. In either of these cases the HREC must again be satisfied that the research interest outweighs to a substantial degree interest in privacy. This expression is used in the Commonwealth Privacy Guidelines in relation to research conducted using Commonwealth data. The expression is also to be used in the new public sector guidelines produced by the Commonwealth Privacy Commissioner. It is used in these Guidelines to develop a consistent approach to personal privacy and research.

     The privacy principles were included to address directly researchers’ concerns about HRECs setting unrealistic consent requirements in relation to large data sets. The principles also require any new use of the data for a new research project to be resubmitted to a HREC for a new approval. In addition, if clinical knowledge is disclosed to researchers during the research project that information should be made available to health authorities and where possible to participants or their medical practitioner.

     Finally, the general principle that research results be disseminated is qualified by further requirement that the results should not identify the participants and should respect cultural sensitivities.

A-30

     Human Tissue (Principles 15.1–15.9). For the first time the National Statement includes principles for the use of human tissue in research. The use of human tissue samples in medical research raises compliance issues with both ethical and legal standards (Magnusson 2000). Samples are defined to include diagnostic, statutory (e.g., Coroner’s Inquiry), and research samples not including fetal, reproductive, or autopsy tissue. Institutions are requested to develop policies for research on tissues related to the source, nature, cultural sensitivity, and reason for collection in the purpose for the research. Generally, consent is required for the use of a person’s tissue. Where there is follow-up research, the new research should be presented for new approval by a HREC. Consistent with the principles in epidemiological research and genetic research, a HREC may waive consent having regard to the following considerations:

• Whether a previous consent which permitted further use;
  
• Whether the researcher presents an acceptable justification for not seeking consent;
  
• Whether there is proper protection of privacy and the de-identification of information;
  
• Whether the de-identification requirements pose no risk to the privacy of the person;
  
• Whether there is any intention to commercially exploit the results of the research; and
  
• Whether any relevant Commonwealth State or Territory law must be complied with.
  

These principles are expressed in relatively general terms. They represent the first step in setting a direction for the more regulated use of human tissue and research. This is a sensitive area where there are public concerns about coronial powers to dispose of human tissue, commercial access to samples, and retention of samples without an individual’s knowledge or consent.

     Genetic Research (Principles 16.1–16.16). A special Working Party was convened to prepare these principles which were developed in close consultation with community groups, professionals, and the Human Genetics Society of Australia. After outlining the special aspects of genetic information and its capacity to stigmatize, HRECs are requested not to approve research with contestable or dubious scientific merit. HRECs are reminded that much genetic research at this stage will be more likely to contribute to knowledge rather than products and treatment. For this reason research proposals must be balanced against the potential for risk to individuals. Research results are to be carefully stored to ensure privacy, and researchers are required to state whether the information will be kept in an identified, identifiable, or de-identified form. Generally, the consent of participants will be required and researchers are required to inform them:

• That they can refuse to participate;
  
• How privacy will be protected;
  
• Whether the data will be returned in an identified, identifiable, or de-identified form;
  
• How the information will be passed on;
  
• How information and results from the research project will be disseminated;
  
• Whether and how family members will be contacted and that if they are to be contacted, it will only be with the consent of the participant;
  
• What is to happen if nonpaternity information is uncovered;
  
• Whether any commercial or further use is to be made of the genetic information; and
  
• Where a collectivity is involved, whether and how that consent is to be obtained from the traditional leaders.
  

A-31

Consistent with the principles on epidemiological research and human tissue, a HREC may waive consent having considered a number of matters (essentially the same considerations as above under Human Tissue). There are also requirements that the institution conducting research has access to current genetic counselling services for the benefit of the participant.

     Deception (Principles 17.1–17.2). The National Statement recognizes that some research; for example, psychological research involves deception pursuant to purpose or covert observation of individuals. HRECs should approve such research only as an exception where the research cannot be conducted without deception. In these cases a HREC may approve if it is satisfied that:

• Full information may compromise the scientific validity of the project;
  
• The extent and detail of the deception is explained in the research protocol;
  
• There are no suitable alternatives to the deception;
  
• There is no increased risk to the participants;
  
• There will be disclosure as soon as possible after participation;
  
• The participants are free to withdraw their data; and
  
• The activity will not affect the relationship between researchers and research in general with the community at large.
  

Privacy (Principles 18.1–18.5). The Commonwealth Privacy Act 1998 includes a number of Information Privacy Principles defining the proper collection, detection, use, access, challenge, and amendment of privacy information. This Commonwealth Act only refers to information held by a Commonwealth Department or its agency. However, for the last ten years many HRECs have used the Information Privacy Principles as standards for privacy protection for research involving information held by agencies other than the Commonwealth. In this respect the highly unsatisfactory patchwork of Australian law in this area has been remedied to a degree by the practice of some HRECs. The National Statement sets very general Guidelines for the protection of privacy. This is clearly an area, which will require further legislative and guideline development in the future. The privacy of personal information is to be protected using the Information Privacy Principles as a standard.

     There is a specific Section 95 in this Act that requires Commonwealth agencies to report to AHEC where the HREC has released information without the consent of the individuals concerned (and in breach of any Information Privacy Principle) but is satisfied that the public interest in the research outweighs, to a substantial degree, the public interest in the protection of privacy (NHMRC 2000).

6. Some Matters for the Future and the New National Statements

Ethical review in this country remains, as elsewhere in the world, in a revolutionary stage. Ethical standards in the review of research were never envisaged as constant. For example, in the introduction to the Declaration of Helsinki it was stated that the guidelines should “…be kept under review in the future.” The Declaration was adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1965 and amended in Tokyo 1975, Venice 1983, Hong Kong 1989, and the Republic of South Africa 1996. The Declaration is currently under review (Bulletin of Medical Ethics 1996) The Australian research guidelines have been regularly reviewed. This section briefly outlines a number of matters, which are likely to command attention in the near future. These matters are clinical trials, the development of a clinical trial register, multicenter research, expedited review, and monitoring of research.

A-32

6.1 Clinical Trials

Clinical trials are likely to command greater international public attention. In recent years there has begun a steady stream of media and academic revelations about certain trials.

• The failed Pennsylvanian Gene Therapy Trial in which a teenager (named Gelsinger) without his father’s knowledge or consent had been given a heavy dose of gene-altered viruses directly into his blood stream to treat his disease which had caused his liver to fail and his blood to thicken like jelly (OTC-ornithine transcarbamylase deficiency—a disease which leaves the liver unable to break down ammonia). There were also disturbing reports of some $37 million paid by Biogen Inc., to Genovo for the right to market these gene therapies (Nelson and Weiss 1999).
  
• The striking off the medical register of a leading United Kingdom asthma researcher who was found guilty of serious professional misconduct and falsification of laboratory tests (Bulletin of Medical Ethics 1999a).
  
• Randomized trials of a well-known antidepressant which was suspected of a significant link to suicide by the users where there had been a failure in many cases and unsatisfactory reporting of the serious adverse events (Healy 1999).
  
• The controversy over the use of placebos in trial to study drugs for rheumatoid arthritis where there was evidence of irreversible damage when the usual treatment was delayed for a period of months (The Lancet 1999).
  
• Criticism that Research Ethics Committees, which approved the clinical trials, are not sufficiently resourced to adequately monitor trials (Chalmers 1996).
  
• The controversy surrounding the placebo-controlled trials of short-course zidovudine to HIV-infected pregnant women to prevent perinatal HIV transmission. Long-term courses of zidovudine have been trialed in both the United States and France and proved to be effective. However, trials in Africa were conducted against a backdrop of a placebo arm where a best-proven therapeutic method had been established, and it was also unlikely that the country could ever afford the zidovudine treatment.
  

Clinical Trials in Australia: Some Background. Before examining the new clinical trial guidelines, some background may be useful (AHEC 1992). Until 1983, sponsors of all clinical trials involving imported products were required to obtain Federal approval prior to the initiation of the trial. Pharmaceutical chemistry, preclinical, and clinical data were required in the same detail as that required to support applications to market a new chemical entity. In February 1983, review times were changed to 45 working days for early phase trials (Phase I and IIa) and 80 working days for later phase trials. In addition, a degree of deregulation was introduced in that sponsors were permitted to undertake additional trials without Federal review of the subsequent protocols, provided that the trial was within the approved dosage range and duration of treatment. Each trial required approval by the IEC of the host institution, and sponsors were required to notify the Federal agency at the time of approval by a HREC.

     The TGA is a Commonwealth organization responsible for the registration of therapeutic goods including drugs and devices. The TGA conducts monitoring of licensed manufacturers who must comply with the Code of Good Manufacturing Practice; in addition, the TGA tests drugs and devices, reports and acts on problems, and ensures fair and truthful advertising (Therapeutic Goods Act). The scheduling of drugs is usually conducted under the various drug legislation of the States and Territories. In August 1987, revised procedures for review of clinical trials were introduced incorporating the concepts of a Clinical Trial Exemption (CTX) scheme under which the trial was permitted to proceed if no objection was raised by the TGA within a given time frame.

A-33

Under these arrangements, consideration of the essential safety aspects of a product proposed for use in a clinical trial remained a Federal responsibility, and consideration of the inter-related protocol was the responsibility of the HREC at the institution(s) at which the trial was to be conducted. The scientific validity of the study and the ability of the researcher and institution to effectively carry out the particular study were to be included in the HREC’s consideration of ethical aspects of the trial.

     The CTN Scheme. In the early 1990s following the publication of the Baume Report the centralized system of approval for drug trials was replaced with a devolved approval system. HRECs were given the option of approving drug trials under the CTN. At first, there were considerable concerns about the implementation of this new scheme particularly in relation to potential legal liability (Day 1993). However, the implementation of the scheme has been realized through a process of self-selection under which only HRECs in large hospitals are now undertaking significant involvement in the CTN process. In the early 1990s it was recognized that there had been a major increase in the workload of those IECs that had undertaken this type of work (Chalmers 1996). In May 1991, links between clinical trials in Australia and marketing applications were severed. This allows clinical trials to be conducted while an application for registration for marketing is under review and vice versa.

     The introduction of the CTN Scheme at the same time allows for drugs to be released for clinical trial purposes, provided authorities are notified of the trial beforehand and the trial is approved by the ethics committee of the hospital or university where it is to be conducted. Only HRECs complying with the National Statement (National Statement 1999), particularly Principles 2.1–2.48 on HRECs, are able to participate in these arrangements.

     The main impact of the deregulation of clinical trials, from the point of view of HRECs, has been an expansion of their tasks and responsibilities to include the assessment of toxicological and safety data for trials submitted under the CTN Scheme. This was the subject of a specific review of the introduction of the CTN Scheme which was completed in 1993 (Day 1993). HRECs expressed particular concern over possible legal liability in administering these schemes and the need for appropriate indemnity. Of particular concern was the fact that some HRECs did not have the expertise to assess pharmacology or toxicology data. The responsibility of HRECs was reflected in the Therapeutic Goods Regulations as amended by the Therapeutic Goods Act. This provides that the institution which is responsible for conducting the trial must take advice from the IEC (now HREC) on the conduct of the trial, give approval to the trial (the institution may be responsible for more than one site), set terms of approval for the trial which are no less restrictive that the ethics committee’s advice, and withdraw approval for the trial if the ethics committee advises that continuation of the trial is not appropriate.

     The move to using the CTN Scheme has been steadily increasing. By mid-1999, the TGA reported that some 1,500 were proceeding under CTN and only 10 under the CTX (information provided by Manager of TGA to AHEC, July 1999). In essence the CTN is a deregulated system where all responsibility for the trial rests with the institution, and notification only is given to the TGA about the conduct of the trial. On the other hand, under the CTX Scheme the TGA remains responsible for the safety aspects of the product and charges fees for this service.

     The National Statement Principles. The new Australian National Statement (National Statement 1999) is a comprehensive and uniform set of guidelines which includes general principles and sections (Principles) on many aspects of research (e.g., epidemiological research, genetic research, use of human tissue, psychological research, and multicenter research). The National Statement includes more detailed guidelines of the establishment, composition, operation, functions, and duties of HRECs.

     The National Statement includes a section dealing with clinical trials, which are defined to apply to natural therapies and other interventions. The previous Statement on Human Experimentation included a supplementary note on clinical trials but in considerably less detail than the National Statement. The introduction to Principles 1212.1–12.13 states:

A-34

A clinical trial is a study involving humans to find out whether an intervention, including treatments or diagnostic procedures, which it is believed may improve a person’s health, actually does so. A clinical trial can involve testing a drug, a surgical or other therapeutic or preventive procedure, or a therapeutic, preventive or diagnostic device or service. Any intervention, including so-called ‘natural’ therapies and other forms of complementary medicine, can be tested in this way. Other related disciplines also conduct research, which involves similar ethical considerations to those raised in clinical trials.

In pharmaceutical and medical device trials there are established codes of good clinical research practice which define clearly what is meant by a clinical trial for those purposes.

12. Clinical Trials has principal application in the context of biomedical clinical trials but should also apply to any other intervention claiming therapeutic benefit, wherever provided or conducted (emphasis added).

The trial must be properly designed and conducted and be approved by a HREC. The HREC that considers the clinical trial is not required to judge the actual science involved. Rather the HREC must ensure that it is “…sufficiently informed on all aspects of a research protocol, including its scientific and statistical validity” (National Statement 1999, Principle 2.8). Principle 12.1 goes on to state:

The aims of every trial must be precisely stated in a protocol presented to and approved by a Human Research Ethics Committee (HREC) and every trial must be conducted by researchers with suitable experience, qualifications and competence and, where applicable, adequate training in relevant procedures including the use of any device being trialed.

See also Principle 12.2, which gives details on scientific hypothesis and methodology.

     A HREC, before granting approval to a clinical trial, must be satisfied that the protocol conforms to a number of international obligations in addition to the National Statement as well as relevant Australian laws. The Code of Good Manufacturing Practice issued by the TGA is broadly similar to many equivalent documents in other countries (TGA 1991). In addition, it is recognized that Australian researchers may be involved in multi-center international trials. Indeed, in the case of American trials, Australian researchers are required to comply with American regulations promulgated by the FDA. There was a quite deliberate intention in the revision of the National Statement to ensure consistency with established international guidelines. In this regard, Principle 12.3 of the National Statement provides:

An HREC, before granting approval to a clinical trial, must be satisfied that the protocol conforms to:

Principles 12.12 and 12.13 also refer to relevant standards.

     The National Statement also includes a specific guideline on the acceptable uses of placebos in clinical trials and, essentially, outlaws their use where there is an effective treatment available (National Statement 1999, Principle 12.4). There was considerable discussion in relation to this particular guideline. In the end the AHEC, in publishing the guideline, preferred the view that it is difficult to create a research project (testing a

A-35

hypothesis when there is a treatment available which has been clearly shown to be effective). To ignore a proven effective treatment breaches the medical practitioner’s duty to provide best available treatment to the patient.

12.4

The use of a placebo alone or the incorporation of a non-treatment control group is ethically unacceptable in a controlled trial where:

If there is genuine uncertainty about the net clinical benefit of treatment, a placebo controlled trial or a trial with a no-treatment arm may be considered.

Apart from general guidelines against conflict of interest, (National Statement 1999, Principles 1.1 and 2.20) researchers are required to declare financial or business interests in relation to the clinical trial presented for approval before the HREC (National Statement: 1999, Principles 12.5 and 12.6). A researcher is not required to disclose every interest to research participants; rather, a HREC is required to examine the budget of the clinical trial and consider aspects of the budget that raise ethical issues. The HREC then decides whether any information in relation to the financial aspects of the trials should be declared to participants.

12.5

A researcher must inform an HREC of any business or other similar association which may exist between a researcher and the supplier of a drug or surgical or other device to be used in the trial.

An HREC must examine those aspects of the budgets of clinical trials which raise ethical issues, including capitation fees, payments to researchers, institutions or organisations involved in the research, current and consequential institutional or organisational costs and costs which may be incurred by participants. It should be satisfied that:

12.6

Since the early 1990s the NHMRC has published guidelines requiring HRECs to review the compensation arrangements for the trial (NHMRC 1994). Principle 12.7 of the National Statement provides that compensation arrangements must be in place for participants who may be injured in the trial.

12.7

An HREC must be satisfied, before approving a clinical trial, that arrangements exist to ensure adequate compensation to participants for any injury suffered as a result of participation in the trial.

There are, finally, guidelines about the reporting of all serious or unexpected adverse events, review of the trial, suppression of the trial, and privacy of findings (National Statement 1999, Principles 12.8–12.11).

     The new Principles have deliberately aimed to put greater responsibility on the HREC that approves a trial, the reality being that the preponderance of Australian clinical trials of drugs and devices are performed under

A-36

the terms of the CTN Scheme. In summary, the HREC must be satisfied that the trial is properly designed (including methods of recruitment and statistical significance). The HREC must also decide whether the trial conforms with the international standards where relevant (CPMP/ICH 1995). Placebos should not be used where they are already proven effective available treatment. In addition, conflicts of interest must be declared, funding arrangements reviewed; compensation arrangements put in place; all serious or unexpected adverse events reported by the researcher; the trial monitored and reviewed; and information on the trials kept in a durable form to protect privacy. The monitoring of trials and research generally has been a continuing difficulty in Australia (Chalmers 1996).

     Again, the new Principles are only a start and further questions remain for consideration for the further development for ethical clinical trials. For example, should the same rules apply where the trial involves an entirely new procedure, e.g., malaria vaccine, where new knowledge is being developed and the risks attaching to long-term effects are quite unknown or unpredictable at this early stage? Should there be different rules for autologous immuno-therapies and certain types of oncological gene therapies where the patients are usually suffering from terminal illnesses? Should there be a separation of drug trials conducted in the public institutions as opposed to those conducted in private institutions? Should special rules apply to trials conducted by the doctors in general practice whose primary duties to the patient may conflict with any research protocol in which the doctor is involved? Should different rules apply where the trial involves blood or tissues on which genetic information is to be gathered? This is not a comprehensive list but illustrative only (Mant 1999)

6.2 Other Matters

Development of a Clinical Trial Register. The report of the Review of the Role and Functioning of Institutional Ethics Committees supported the implementation of a clinical trial register in Australia. The report stated that a national register of statistics and data would enable the effectiveness of particular interventions to be monitored over time and would facilitate the effective monitoring of clinical trial operations. This database will be a useful information resource for HRECs and will reduce duplication of efforts. The proposal has appeared from time to time in the pages of the Medical Journal of Australia and was part of the official submission of the AHEC to the Wills Review (Wills 1999). A central Clinical Trial Register would track the results of all trials, not simply the results that are later published in official journals. In this way the poor as well as the best results would be recorded and a proper assessment of the level of clinical trials could be maintained.

     The NHMRC Clinical Trials Centre is an NHMRC funded center at Sydney University, with Professor John Zynes as director. At present it has a voluntary system of registration for cancer research only. The benefits of expanding this role to include all clinical trials would significantly add to community confidence and support for research. Data from these clinical trials would significantly assist the long-term follow-up of participants of clinical trials.

     Training. Training and continuing education are key elements in the effort to increase the responsiveness of the ethical review system. The continuing professionalising of HRECs requires the introduction of formal accredited courses. For a number of years the Monash Bioethics Centre ran annual residential seminars for HREC members. In recent years other course providers have advertised in their programs. The AHEC has not begun to formally accredit these courses.

     HRECs are becoming increasingly concerned about legal aspects of protocols. Often protocols cross legislative boundaries and HRECs must be sufficiently versed in areas such as privacy, guardianship, and other matters addressed in Commonwealth and State legislation. The AHEC workshops, conducted in 1993, 1995, and 1999 provided a forum for networking and information sharing but should not be seen as substitutes for certified, professionally conducted training programs.

A-37

     A major contract was tendered by AHEC for the preparation of a HREC Operating Manual that will consist of explanatory, textual and reference annotations to the National Statement on Ethical Conduct in Research Involving Humans. The HREC Operating Manual is intended as a resource and reference for all members of HRECs, especially new members.

     Centralized System of Scientific and Ethical Review for Streamlining Clearance of Multicenter Clinical Trials. There has been an ongoing debate in a range of forums that the scientific assessment of clinical trials be undertaken centrally to streamline the process of review and to assist HRECs in focusing their deliberations on the “ethical” issues of the protocol (Cohen 1998; Clarke 1998; Henman et al. 1998; O’Brien et al. 1998; Gandevia et al. 1998). In effect, the TGA undertakes this “centralized” scientific assessment under the CTX Scheme. This debate has also raised the problem of accreditation of ethics committees. The NHMRC does not currently have authority over State institutions to allow a system of HREC accreditation unless there was the necessary referral of power from the States and Territories to the Commonwealth Parliament.

     There have been many debates about a form of centralized approval for research; particularly multicenter research is desirable. Suggestions have ranged from the establishment of a “peak” national HREC to the establishment of regional HRECs akin to the United Kingdom LRECs or the New Zealand Regional Ethics Committees. As a matter of practice, there has been considerable and developing cooperation and collaboration between existing HRECs. The process of ethical review of multicenter trials can become complex and protracted, particularly when a number of centers are involved.

     The National Statement proposes two options to streamline the ethical review process for multicenter trials (National Statement 1999, Principles 3.1–3.8). First, when a project is under way, HRECs are permitted to communicate with each other; accept the scientific assessment of another body; adopt the ethical reasoning for another body; or adopt any other procedure from that body to avoid unnecessary duplication (National Statement 1999, Principle 3.4). Second, there is for the first time in Australia a formal system for initially setting up multicenter research. Under this system institutions may agree before the start of the research that “…the primary ethical and scientific assessment be made by one agreed institution or organisation…” (National Statement 1999, Principle 3.5). There have already been some efforts in some regions of Australia to streamline the scientific and ethical review of protocols (Kelly and Boyages 1999).

     Any system for centralized HREC decisionmaking must preserve local HRECs. Ethical considerations concerning the safety and scientific validity of a proposal may not differ substantially from one HREC to another; however, there may be important local issues. For example, certain institutions may be involved in research with subjects from a particular ethnic, social, or minority group, which might involve special consideration of local cultural, moral, religious, and/or ethical values. In addition, the particular institutional mission will need to be observed. This consideration would apply, for example, for hospitals of religious affiliation.

     Expedited Review and Efficiency. The recommendations elsewhere in this report to introduce expedited review will assist the HRECs in concentrating on approval and monitoring of research projects involving higher risk. Under these procedures a HREC can determine classes of research which may be subject to expedited review and confer authority on the Chair of the HREC to approve the research subject to later ratification by the HREC (National Statement 1999, Principles 2.27–2.29). Expedited review is not suitable for research projects with the potential for harm or where there may be some departure from ethical standards in the Statement. In these cases the full Committee must consider the project.

     The Report of the National Council on Bioethics and Human Research in Canada (Canada 1995) encourages Research Ethics Committees considering fewer than 50 research protocols to amalgamate with another or other Research Ethics Committees. In Australia there has been a substantial increase in HREC numbers. There have been suspicions expressed in some submissions that some HRECs may have been established with the researcher interests rather than the subjects in mind. The Canadian approach of amalgamation where a

A-38

Research Ethics Committees considers less than 50 protocols was not included in the final draft of the National Statement. The Second Consultation Draft included a section inviting small HRECs to amalgamate. This was dropped from the final National Statement in the light of submissions received. Provided a HREC was properly and independently constituted, there were good reasons for the continuation of certain specialized HRECs. For example, the National Red Cross HREC considers few protocols but most are complex requiring considerable discussion by the Committee.

     Monitoring of Research. Monitoring responsibilities are constrained by resources. Recognizing this, the National Statement has recommended a strategic approach to monitoring where “the frequency and type of monitoring determined by a HREC should reflect the degree of risk to participants in the research project” (National Statement 1999, Principle 2.33). The National Statement includes minimum reporting and proposes that the HREC adopt “…any additional appropriate mechanism for monitoring…” provided that researchers immediately report any “…serious or unexpected adverse effects on participants; changes to the protocol; and unfit foreseen events” (National Statement 1999, Principles 2.36 and 2.37). The National Statement followed the recommendations of the Ministerial Review Committee and the submissions at the Second Stage Consultation. The National Statement did not introduce a system of public monitor-officials as recommended in the United Kingdom (Neuberger 1992) or as operates in the United States with the Office of the Inspector General of the Department of Health and Human Services.

     Monitoring by a HREC is only one aspect of the overall strategy for the protection of the interests of research participants. Peer review, institutional supervision, ethical integrity of researchers, and effective information and complaints mechanisms should all be promoted to facilitate the earliest possible detection of potential harm in the course of research projects.

7 The Questions of the National Bioethics Advisory Council

7.1 What Are the Strengths and Weaknesses of Nonregulatory Systems of Protection?

The philosophical debates in bioethics rarely operate in a legislative or legal vacuum (Englehardt 1981; Pellegrino and Thomasma 1996). In most areas debated by bioethicists, governments have played a role either in the form of policy development or legal regulation (Breen 1997; Bennett 1997; Skene 1998; Freckelton and Petersen 1999). As examples, mental institutions have been governed by legislation for over a century; marriage laws have to an extent established rules about reproduction; hospitals are legally regulated and within them research is conducted and resources allocated; euthanasia has remained under the fiat of the criminal law; mass screening was a cornerstone of the public health movement and population genetics and the discredited eugenics movement have, at different times influenced governments. There is established case law in relation to doctrines of informed consent and the duty to warn in the doctor/patient relationship. Where children, the aged, the disabled, or the mentally impaired are treated the rules of consent are varied in the circumstances, the courts have a protective jurisdiction. Specific guardianship legislation may apply also in these circumstances. Finally, debates about artificial conception have led to the introduction of specific status of children legislation and restrictions on experimentation either in the form of legislation or guidelines.

     Australia has moved gradually from a self-regulatory system of research ethics review to a more regulated system. HRECs in Australia are not directly established by statute but rather, AHEC was given the responsibility for monitoring and advising on the workings of HRECs (see Section 4.2 of this report). The Australian ethical review system has the following regulatory features:

A-39

• The AHEC is the peak health and medical research ethics body responsible for the promulgation of research guidelines. The AHEC is responsible for monitoring all HRECs in this country. (See section 4.2–4.5 of this report.)
  
• The AHEC requires Annual Compliance Reports from all HRECs (National Statement 1999, Principles 2.46–2.48).
  
• These HREC Annual Compliance Reports are included in the Annual NHMRC Report to the Commonwealth Parliament.
  
• Institutions are required to establish and properly resource a HREC as a condition for application for public funding from research funding organizations such as the NHMRC, the ARC, and others (National Statement 1999, Principle 2.1).
  
• Institutions are required to set out Terms of Reference, responsibilities, accountability, and mechanisms of reporting for HRECs (National Statement 1999, Principle 2.2).
  
• Institutions must accept legal responsibility for their HREC members and indemnify them (National Statement 1999, Principle 2.3).
  
• The NHMRC and other funding bodies can remove public funding to institutions, which fail to observe the procedures in the National Statement (National Statement 1999, Principles 2.1–2.48).
  
• Researchers for a duty of care law to research participants and have legal and ethical duties to provide information on risks involved in research.
  
• The Commonwealth TGA and relevant State authorities supervise trials of drugs and devices. Legislation includes the Federal Therapeutic Goods Act 1993; the relevant Poisons Acts in the States and Territories (ACT 1933; WA 1964; Tas 1971; NSW 1966); the Victorian Drugs Poisons and Controlled Substances Act 1991; the Queensland Health Act 1937; the Northern Territory Poisons and Dangerous Drugs Act 1983; and the New South Wales Therapeutic Goods and Cosmetics Act 1972. Clinical trials are also regulated by
  Codes of Good Manufacturing Practice (TGA 1990) and NHMRC guidelines (National Statement 1999, Principles 12.1–12.13).
  

The Australian ethics review system has the following strengths and weaknesses.

7.1.1 Strengths

(a) A National System of Review of Research Ethics. Since the formal decision to establish research ethics committees in 1982, there has been a steady development toward an integrated national system of research ethics review (see Section 2 of this report). HRECs are established within institutions under the oversight and guidance of the AHEC. AHEC is the statutory national apex to the research ethics review system. The Report on IECs (Chalmers 1996) (Schedule 3 of this report provides a summary of recommendations from that report) did not recommend that specific legislation be enacted to regulate HRECs. The report considered that the HREC system was operating satisfactorily under the legislative supervision of AHEC. The report further accepted that the AHEC and the HRECs could adapt to meet future demands on the system.

     The development of the national research ethics system was particularly prominent during the 1990s (see Sections 1.2, 2 and 3 of this report). A number of events contributed to the accelerated development of the national research ethics system during this decade. Included in these events were the enactment of the National Health and Medical Research Council Act 1992 (Commonwealth), the establishment of the AHEC under this Act, the Commonwealth Ministerial determination to confer responsibility on AHEC for monitoring and advising on

A-40

HRECs (see Section 4.2 of this report), three rounds of national workshops to consider the operation of HRECs, and the decisions by funding bodies, other than the NHMRC, to require ethics approval for human research projects (see Sections 1.1 and 4.6).

(b) Ownership. The ethics review system was not imposed but rather recognized by government. The system was introduced through the NHMRC and evolved over a number of years, the members of the HRECs and the institutions themselves have developed a sense of ownership and responsibility for the system. The accelerated development toward an integrated national system of ethics review in Australia was driven largely by those involved in the system. The National Health and Medical Research Council Act 1992 (Cth.) gave detailed prescriptions about the composition and operation of the AHEC but left the “…monitoring and advising on HRECs” to be developed by the AHEC in consultation with the HRECs. This sense of ownership was built up during the 1990s in the following ways:

• National Workshops. During this period the AHEC organized three rounds of National Workshops. Each round had a distinctive character and were milestones in the development of the system. “In May 1993, AHEC conducted a survey of IECs to gather information on the establishment and current operation of IECs”
  (NHMRC Annual Report 1998 at 23). The Workshops which followed in July and August were principally for members of IECs but also provided opportunities for “…researchers and consumers to contribute their views on the workings of IECs and AHEC” (NHMRC Annual Report 1998 at 23). Importantly, these workshops were of considerable importance “…in the clarification of AHEC’s role in the IEC system, and in the identification of priority areas for attention by AHEC in the coming year” (NHMRC Annual Report 1998 at 23). A further series of workshops were held in 1995. These Workshops “…provided valuable feedback to AHEC on issues of concern to IECs that need to be addressed.” In particular, the workshops were able to provide direct input into the Commonwealth Review of the Role and Functioning of Institutional Ethics Committees (see Section 3 of this report) (NHMRC Annual Report 1996 at 18). The 1997 Annual Report was able to state that the work of the AHEC for the 1997–2000 triennium would be substantially directed by the recommendation to the independent Ministerial Review, the IEC Report (NHMRC Annual Report 1997 at 20). The third series of workshops moved far beyond investigation of role and function or input into a review of examining the new National Statement. In August 1999 a series of workshops were conducted to facilitate the use and understanding of the new National Statement. Well over 1,000 attended the workshops, which were conducted in all State and Territory capitals and regional centers. These Workshops were attended by members of HRECs but also substantial numbers of researchers, academics, administers from public and private institutions and research centers. “The 1999 workshops provided valuable opportunities for detailed and comprehensive discussion of all aspects of the National Statement” (NHMRC Annual Report 1999 at 69–70).
  
• Guideline Development. A sense of ownership has arisen from the input by researchers, members of HRECs, and organizations to the guidelines that they administer. A major example is the National Statement. The Annual Report for 1998 (NHMRC Annual Report 1998) recognized that the development of the National Statement has proved to be a massive undertaking in view of the numbers of submissions received and the “scale, quality and thoughtfulness of those submissions” (NHMRC Annual Report 1998 at 68) which prompted a rethink of a lot of what was said in the first stage draft. The Annual Report for the following year stated that “in response to the extraordinary number of submissions received from researchers, HRECs and members of the public, the National Statement significantly altered many aspects of research involving humans” (NHMRC Annual Report 1999 at 70).
  
• Institutional Responsibility. The National Health and Medical Research Council Act 1992 (Cth.) did not alter the fundamental arrangements for the establishment and operation of HRECs. Institutions establish HRECs and were responsible for their decisions. The Report on Compensation, Insurance and Indemnity Arrangements for
  

A-41

Institutional Ethics Committees (AHEC 1993) confirmed that institutions had the responsibility to ensure that proper compensation arrangements were in place for research participants and that HREC members were indemnified for decisions made in the course of their work.

requirement (see Section 4.4 of this report). The first-stage consultation operates in the same manner of any other public consultation, namely advertisements are placed seeking submissions on the subject under consideration by the AHEC. The second-stage consultation is conducted in relation to the draft guidelines prepared by AHEC in response to the submissions received at the first-stage consultation. This second stage has the following advantages:

• First, those presenting submissions in the first round can assess whether their points have been included in the actual wording of the draft guidelines. On the other hand if there is an omission of their particular point they can request that the AHEC provide an explanation for the decision not to include the point.
  
• Second, the second stage consultation frequently attracts new submissions which suggest actual amendments or additions to the text of the draft guidelines. Often these take the form of points not considered or overlooked by the AHEC. “Mini-consultations” can be arranged on particularly complex areas within the draft guidelines. For example, the principles in relation to clinical trials (National Statement: 1999, Principle 12.1–12.13) involved detailed discussions between representatives of the Commonwealth TGA and the association representing the drug companies, The Australian Pharmaceutical Manufacturers Association. Both organizations carried out some further background work in relation to their submissions and represented revised submissions in relation to the draft guidelines.
  

A-42

This second stage has added invariably to the quality of the published guidelines. The National Statement is a very good example of quality improvement. The Working Group at First Stage Consultation was persuaded that it should build on the former Statement on Human Experimentation rather than copying or adopting an available international Code. The draft circulated at the second stage was substantially rewritten in response to the extraordinary number of submissions received. Importantly, the National Statement “…significantly altered many aspects of research involving humans. These changes ranged from research involving deception through to the membership and operating requirements for HRECs” (NHMRC Annual Report 1999 at 70).

     Accountability. Although neither Commonwealth nor State legislation create HRECs, there are a number of ways in which the system is publicly accountable (see Section 4.5 of this report).

(d) Accountability. Researchers are at the first tier of ethical review. Researchers must present all publicly funded research for ethics approval. In addition, a substantial amount of privately funded research (e.g., within private hospitals) is also subject to the ethics review system. Almost all funding bodies now require annual progress reports including reports on any difficulty with the ethical conduct of the project. Importantly, the National Statement clarifies the various circumstances in which it is the responsibility of the researcher to report adverse events during the course of the project or to discontinue the research (National Statement 1999, Principles 1.4, 1.15, 1.17, 1.21, 2.35, 2.44, 245 and 12.8). In addition, researchers must avoid conflicts of interest and, in the case of clinical trials, are required to declare any conflict of interest to the HREC as a condition for approval. (National Statement 1999, Principle 12.5) (see Section 1.1 of this report).

     HRECs conduct the second level of ethical review and are also accountable in a number of ways within the system. HRECs are advisory and are accountable within the structures of the institution in which they are established (National Statement 1999, Principle 2.2). The HRECs are also required to report annually to the NHMRC (National Statement 1999, Principle 2.48). These HREC reports are consolidated by the AHEC, which then presents a report to the Council, which is later included in the NHMRC Annual Report presented to Parliament (see Section 4.7). The institutions which establish HRECs carry considerable responsibilities under the National Statement. The institution is required to properly resource the HREC (National Statement 1999, Principle 2.1) and must set out the HREC Terms of Reference including the scope of its responsibilities (National Statement 1999, Principle 2.2). The institution must accept legal responsibility for decisions and advice received from the HREC and indemnify its members (National Statement 1999, Principle 2.3). The institution should ensure that adequate compensation arrangements are in place for research conducted under its supervision. The institution is also required to set up proper complaints handling mechanisms for receiving and promptly dealing with complaints and concerns about the conduct of an approved research project (National Statement 1999, Principles 2.39–2.43).

     The AHEC constitutes the third tier in the review system. It was the express intention of the Commonwealth Parliament, particularly the Senate, to ensure that the NHMRC was an open and accountable public institution. The openness and transparency of the AHEC processes to public scrutiny arise from the following:

A-43

Act 1992 (Cth.), the AHEC has sole responsibility for the development of guidelines for the ethical conduct of medical research. This authority combined with the two-stage consultation process has resulted in the production of the series of guidelines with national application. In a federal system, it is difficult to achieve uniformity in legislation and policy in some areas within State and Territory authority. Similarly, uniformity in guidelines is more difficult and elusive in a largely self-regulatory medical research environment. During the early period of efforts by the NHMRC, through the Medical Research Ethics Committee, to establish a national ethics system, many organizations produced guidelines. The NHMRC had an influential but not exclusive function in producing guidelines for health and medical research. Guidelines were frequently published by a variety of funding authorities, medical colleges, and associations. It is difficult to gainsay the importance of the work by the NHMRC in moving toward national uniform guidelines. This process was finally realized and consolidated by the National Health and Medical Research Council Act. Two examples may assist in illustrating the strengths of having a central national committee with authority to publish national guidelines:

A-44

technology debate in Australia as elsewhere raised fundamental social, ethical, and legal questions about the very essence of personhood and humanness; the debate saw the clash of science and religion. There was considerable uniformity in the various Commonwealth, State, and Territory reports with respect to Status of Children (Status of Children Act 1978 (Qld)); Access to Programmes; Keeping of, and Access to, Information and Records; Counselling; Use of Donor Gametes; and Surrogate Motherhood.

In two major areas, there were substantial differences in the conclusions in the reports. These were Research and Experimentation on Embryos and Control and Regulation. Three States in Australia introduced committees to deal with decisions in the area of reproductive technology. These States were in order, Victoria, South Australia, and Western Australia. The Victorian Parliament passed the Infertility Treatment Act 1995 (successor to the Infertility [Medical Procedures] Act 1984), but the Act was not proclaimed for some years afterwards. The relevant legislation in South Australia is the Reproductive Technology Act 1988 and in Western Australia, the Artificial Conception Act 1985.

When the AHEC was set up in 1992, a reference was reserved by the Commonwealth Senate that required the AHEC to consider the publication of guidelines in the area of reproductive technology. The NHMRC published specific guidelines entitled the Ethical Guidelines on Assisted Reproductive Technology 1996 (AHEC 1996). These Guidelines applied uniformly and were later accepted by the Reproductive Technology Accreditation Committee (RTAC). The RTAC is a voluntary organization funded by the Fertility Society of Australia, which accredits centers offering such services. Once the RTAC accepted the AHEC Ethical Guidelines on Assisted Reproductive Technology, they formed part of its Code of Practice for centers using IVF and related reproductive technologies.

In effect, therefore, the nonlegislation States were practically and uniformly covered by the AHEC

Guidelines.The Reproductive Technology Councils in South Australia and Western Australia also approved the AHEC Ethical Guidelines on Assisted Reproductive Technology, thus achieving new uniformity in approach to research in the area.

in overseas forums. Following the initial invitation of NBAC, the Summit of National Bioethics Commissions was convened in San Francisco in 1996 and again in Tokyo in 1998. Many countries have appointed national bioethics commissions, although there is far from being comparability in jurisdiction, terms of reference, resourcing, status, and guidelines. The meeting in Tokyo agreed that there were matters of common interest between the various commissions. In particular, it was noted that clinical trials (discussed elsewhere in this report) were an area likely to command public international attention. Developments in the last two years have proved this view to be prophetic. The issue of clinical trials has commanded further public attention with the debates within the World Medical Association to revise the current wording of the Declaration of Helsinki. The amendments proposed by the American Medical Association would include a new Article 18, Access to Health Care, in the following terms:

A-45

In any biomedical research protocol, every patient-subject, including those of a control group, if any, should be assured that he or she will not be denied access to the best programme, diagnostic, prophylactic therapeutic method which would otherwise be available to him or her. This principle does not exclude the use of a placebo on non-treatment control groups with such a justified or scientifically and ethically sound research protocol.

Arguably, the proposed changes to wording may lead to “ethical export” where developing countries may be used for the conduct of clinical trials where lesser ethical standards are applied than in developed countries (Nuffield Council on Bioethics 1999; Healy 1999; Bulletin of Medical Ethics 1999b). This would not replace but complement the work which is currently under way with the development of international standards represented in the CPNC/ICH Note for Guidance on Good Clinical Practice (135–95).

     The AHEC has, on behalf of the NHMRC, sent comments to the World Medical Association consultation. Equally, national bioethics commissions are in the position to liaise with other national bodies to provide information to contribute to the development of improved ethical trials.

7.1.2 Weaknesses

A number of weaknesses can be identified within the current ethical review system in Australia as follows:

(a) Enforcement. § 8(1)(ii) of the National Health and Medical Research Council Act authorizes the AHEC to develop medical research guidelines and for the Council to issue those guidelines in the form developed by the AHEC. Infringement of any Principle in the National Guidelines does not constitute a prosecutable legal offence. The sanctions for infringement of the Principles involve the loss of access to or withdrawal of research funds. In practice, this has been threatened on a number of occasions and is treated most seriously by institutions. For example one major metropolitan hospital was noncompliant for part of a year of report. Senior officers from the hospital were granted time to reconsider and ratify noncompliant decisions by the HREC. This particular incident resulted in the review of the sanction procedures of the NHMRC. In particular, a “show cause” opportunity was introduced into the procedures. In another example a major national research institute is required to reconvene with a compliant HREC and reconsider de novo decisions dealing with a noncompliant period. With the statutory requirement for the NHMRC to report annually to Parliament, the NHMRC could name guideline infringers in the report tabled before the Parliament (this has never been done to date).

     At one time there was a deal of criticism of the NHMRC for being “in-house” and lacking any “teeth” to prosecute. In defence of the NHMRC, this view confuses police-style prosecutions for anti-social criminal behaviour with the promotion and maintenance of ethical standards in an otherwise orderly research community. It is the difference between as police person patrolling on the assumption that crime is breaking out as opposed to the fire service, which attends when the unexpected fire breaks out (Chalmers and Petit 1998). It is the latter analogy that is more applicable to health and medical research. Nevertheless, the enforceability question is raised frequently by the medical and in the public forum.

(b) Uniformity and Complimentarity. In some areas the AHEC has produced national guidelines with national remit. In other areas, the guidelines have not applied uniformly. For example, as noted above the Ethical Guidelines on Assisted Reproductive Technology form a de facto national code in all States except Victoria, where the Infertility Treatment Act 1999 (Vic) overrides the Ethical Guidelines. However, the legislation in the three States (Victoria, Western Australia, and South Australia) have different provisions in relation to human cloning. This will be a barrier to uniform legislation or AHEC guidelines.

     In late 1997 and with the benefit of the substantial work done by NBAC (NBAC 1997), the Commonwealth Minister for Health and Aged Care requested a report on cloning from the AHEC. The issue of human cloning was not confined to ethical questions; the issue overlapped substantially with existing regulations in three

A-46

States. The report from the AHEC (AHEC 1998) has now been referred on for consideration by the

Commonwealth House of Representatives Standing Committee on Constitutional and Legal Affairs with a view to introducing uniform or complementary regulation. This lengthy and complex process may be seen as a weakness in the AHEC structure and authority with respect to guidelines. On the other hand the AHEC is essentially advisory only when requested to give a report to a Commonwealth Minister. Admittedly, guidelines would suffer the same lack of force in three States with legislation. In recognition of this, the AHEC produced a recommendation that the Parliament consider legislation. An extract from Chapter 4 of the AHEC Report is included in Schedule 3 to illustrate this jurisdiction limitation in relation to legislation and guidelines relevant to cloning in Australia at the relevant period.

(c) Private Institutions. As a matter of law the provisions of the National Health and Medical Research Council Act 1992 (Cth.) do not apply directly to privately funded research (see also comments in Section 7.3 below). So far Australian private institutions have generally complied with NHMRC and other public standards. Some of these institutions informed the AHEC (in the consultation process for the National Statement) that compliance was observed because NHMRC guidelines represented best practice; private institutions were conscious of avoiding possible negligence claims, and all universities, the AVCC, the ARC, and all the Learned Academies had endorsed the National Statement.

     Nevertheless, the AHEC recognized in its Report on Cloning (AHEC 1998) that commercial pressures are increasing in this country, and there is no guarantee that the current regulatory and part self-regulatory system of self-restraint will continue. Certainly, in the case of human cloning, it was considered for ethical and commercial reasons that uniform national legislation was required to bolster existing guidelines.

(d) Second-Stage Consultation. The second-stage consultation process has proved to be a lengthy and costly exercise. The AHEC has profited from the quality and depth of input at the second stage consultation. However, other principal committees of the NHMRC, especially the Health Advisory Committee (HAC), have questioned the value of the process. Many of the reports prepared by the HAC are developed in draft by other major specialist health organizations, and the second-stage consultation is of less value as the specialist input has already been given. For example, the HAC received a report from the Victorian Anti-Cancer Council on Familial Cancers. This report had been prepared over a period of three years and involved the Australian Cancer Network. One stage of consultation was arguably sufficient to inform the public and seek their views on a complex and technical area. In fact, two stages had to be conducted under the terms of the NHMRC Act. In fact very few submissions were received at the second stage.

     The NHMRC decided in 1999 to propose amendments to its Act to allow the possibility of one-stage public consultation in most cases rather than exceptional cases. One-stage consultation was previously permitted in exceptional cases under the NHMRC Act 1992 (Cth.). The amendments to the Act were passed by the Commonwealth Parliament in 1999 (NHMRC Annual Report 1999 at 9). The AHEC is most likely to continue to apply the full two stages of public consultation.

7.2 What Features of These Systems, If Any, Should Be Incorporated in the U.S. System?

At a general level, there is much commonality between the research community in basic ethical principles. There would be little dispute that among the essential values for research is the integrity of the researchers. The Australian National Statement did not invoke any autochthonous principles but referred to the classic U.S. Belmont Report for a statement of the three basic ethical principles for the ethical evaluation of human action (Belmont 1979). These are respect for the person, beneficence, and justice (Beauchamp and Childress 1994; National Statement 1999 at 4). On the other hand, institutions are not so easily transplanted. Committee structure, which operates successfully with refinements, subtleties, and technicalities, may not be suited to

A-47

the conditions of another country. Adaptation and pruning will always be required (Nyali Ltd. v the Attorney-General per Lord Denning at 16–17).

     With the cautionary remark about ethical institutional transplants, the following features of the Australian system may be worthy of some consideration by the members of NBAC.

(a) A National Committee/Commission. It may seem inconceivable to the international ethics community that the engine-room of modern biomedical research does not have a permanent standing committee considering ethical issues. The reports of the present NBAC, like the Belmont Report (Belmont 1979), remain profound reference points and rich sources for ethical discussion. NBAC contributed significantly to the global debate with its report on Cloning of Human Beings.

     There is a lacuna if the NBAC or some other appropriate nationally based ethics body is not operating to organize and encourage the development of international collaboration between national bioethics commissions. NBAC has already fulfilled this role with distinction at the inaugural meeting in San Francisco and the second meeting two years later in Tokyo in 1998. Obviously, NBAC or an equivalent body would be concerned principally with the preparation of national guidelines, reports, or advice on specific matters.

     Nevertheless, relations with other national bioethics commissions can be a smaller but highly important roles for a national body. The AHEC has devoted a small but not insignificant percentage of its time dealing with other nations’ bioethics commissions. In fact, many of these dealings have involved the collection of reports of documents or seeking advice on specific regulations, guidelines, or procedures from a national bioethics commission.

(b) Reporting to Parliament. Under the terms of the National Health and Medical Research Council Act 1992 (Cth.) the NHMRC is required to prepare a plan of work which is presented to the Parliament. In each subsequent year the NHMRC including the AHEC present a report to Parliament. This not only provides an essential and important line of accountability; it requires the NHMRC and AHEC in particular to establish work programs to complete reports in a timely and orderly fashion. As both the Strategic Plans and Annual Reports are presented to Parliament they form public documents which are accessible to the public and interested bodies. The process of reporting to Parliament is recognition of the status of the NHMRC and AHEC.

(c) Public Consultation. The two-stage public consultation has been a complex and weildly process. Nevertheless, it has provided an authentic and transparent opportunity for public comment and for that comment to be integrated into the body of the report and guidelines. As noted earlier in this report the second-stage consultation where the draft guidelines are presented for comment has proved to be successful. At this stage, detailed comments on the specific draft guidelines have invariably led to improvement in the content as well as the wording of the final guidelines. Some 200 submissions were received at each of the stages of consultation for the National Statement on Ethical Conduct in Research Involving Humans. In a small population of 20 million this number may be magnified so much in the more populous United States as to present very considerable challenges to the management of the information presented.

(d) Aspects of the National Statement. NBAC may wish to consider the current principles in the National Statement in relation to epidemiological research, human tissue, and genetic research, which are noted in Section 5.3 of this report. These particular Principles are internally consistent and may offer a modest contribution in these difficult areas.

A-48

7.3 What Are the Strengths and Weaknesses of Models That Are Comprehensive, Those That Encompass Private and Government Sectors, and Nonbiomedical and Biomedical Research?

Fears of High Medical Dominance by Nonbiomedical Researchers. During the period of the Ministerial Review (the IEC Report) and also during the consultation for the National Statement, comments were made and submissions received expressing concerns that some forms of social science research were not appropriate for consideration by HRECs. In essence, many of these concerns centered on the composition of the pre-National Statement HRECs. Until recently, the former Statement on Human Experimentation required a medical graduate as one of the core members. Under the terms of the new National Statement a HREC should be composed of a person with experience in the research considered by the Committee. This has removed some of the concerns. Nevertheless, there has been in Australia for a number of years some tension between the nonbiomedical and biomedical researchers. It is too early to tell whether the comprehensive revisions in the new National Statement will assuage these concerns.

     Creating a Universal Research Culture. The consensus of opinion supported the move to establish a single National Statement as a means to achieving the goal of a universal research culture in this country. Universities in submissions to the public consultation particularly promoted this universal view for the new National Statement. In particular, these submissions stressed the continuing blurring of distinctions between private and publicly funded research and growing of distinctions between medical, health, health-related, and social science research. Many submissions noted that Australia, in line with other countries, was developing research policies to encourage private investment in research. For this and other reasons, it was more appropriate to consider a single research code. Similarly, a researcher has a number of common obligations and ethical duties to the research participant, which are common to research generally.

     That Research Can No Longer Be Assumed to Be of Value to the Community. There is an assumption expressed in the new National Statement that the development of the recognition of human rights and the ethical standards of respect of persons preclude conducting research without the knowledge and voluntary consent of the participant. In this respect, an assumption can no longer be made validly that research is automatically a value to the community. Research, whether privately or publicly funded and whether nonbiomedical or biomedical, must be disclosed to the research participants. The National Statement requires disclosure, information, and voluntary consent. More critically, the Preamble recognizes that the researcher is required to justify the research and that the community expects that research will be conducted in an equitable, professional, and ethical fashion.

     Risk Minimization. The idea of expanded human rights protections in the late 20th century extends far beyond the protection of the physical body of the individual. The doctrines of human rights extend to rights to the protections of law, rights of freedom of speech, rights to nondiscrimination, and equitable treatment as examples. In this sense, the ethical and legal requirements for the respect for persons extends to respecting the privacy of the individual as well as the bodily protection. The National Statement throughout places responsibilities on researchers and HRECs to ensure that risk is minimized and that if risk exists there is a careful balancing of those risks against the potential benefits to be gained within the research project.

     International Research. Australia conducts research outside of its national borders. The National Statement places responsibilities on researchers to conform not only to the standards within the National Statement but to also conform to any local ethical standards in the country in which the research is conducted. With more research being conducted as part of international multicenter trials, the National Statement recognizes that there are national responsibilities to regulate and supervise research conducted outside Australian borders in overseas countries. The existence of a comprehensive National Statement conveys clearly to all researchers be they non-biomedical or biomedical that the high standards of research integrity expected of researchers conducting research in Australia applies equally to overseas research. There is a responsibility on national governments in

A-49

their international relations to maintain appropriates standards. In this respect the recognition that trade and commerce standards probably extend to aspects of international research.

     Private Institutions. There are no compulsory or mandatory powers in the National Health and Medical Research Council Act or in the AHEC to make private institutions comply with the standards of ethical review. The Australian research review system is essentially compulsory in the public arena. Major public institutions including universities and hospitals and research centers have endorsed the National Statement. These bodies recognize that funding from the major public funding organizations (NHMRC and ARC) require approval by a HREC. On the other hand, private companies are essentially complying voluntarily. If they wish to access public funds they are required to comply. In addition, many private companies comply because they are conducting the research in public institutions. Finally, many private companies comply because approval by a registered HREC is considered a prudent step in reducing risks of complaints or possible litigation. As there is an approved national standard for ethical approval from a registered HREC many private companies use the HREC system to ensure that in the event of misadventure a failure to receive ethics clearance would not be seen as a negligent act.

The National Statement applies to de facto private institutions for the following reasons:

• The National Statement has also been accepted by government authorities such as the TGA which therefore requires clinical trials, publicly or privately funded, to comply with the CTN and National Statement Guidelines.
  
• Most clinical trials (see section 6 of this report) in this country are conducted within a select group of institutions. Consequently, only the HRECs within this select group of institutions are called upon to approve clinical trials in accordance with the requirements of the National Statement. While there have been some concerns that a deregulated system would result in deregulated and risky trials, experience to date has not followed this path. Access to participants, quality of researchers, and legal liability and indemnity considerations have directed much of the clinical trial work in Australia into these self-selected and leading hospital ethics committees.
  
• Some private institutions may receive public funding. In these cases, the National Health and Medical Research Council Act rules clearly apply to all research funded by the NHMRC. Similarly, all research funded by the ARC must follow national guidelines. The ARC has adopted the NHMRC National Statement.
  

As stated, in practice, many private institutions follow the principles of the National Statement. It is not clear at this early stage whether this voluntary compliance will continue. It is equally unclear whether the increasing movement toward greater private funding of research will affect this process of voluntary compliance. For example, will private funders expect ethics clearance as part of the “service” provided by the research organization? If the HREC refuses clearance will the private funder simply go to the “market” and seek approval elsewhere? In practice, privately funded clinical research under the national CTN scheme has not followed this path. In practice, the institution conducting the research has required clearance from its own HREC. No “market” in ethics approval has arisen.

A-50

Schedule 1

Report of the Review of the Role and Functioning of Institutional Ethics Committees AGPS Canberra (1996) Summary of Recommendations

1. To National Health and Medical Research Council

The NHMRC in conjunction with other peak bodies responsible for research and clinical practice (Australian Research Council, Australian Vice-Chancellors’ Committee, Australian Medical Council) should promulgate guidelines representing a national statement for the ethical conduct of research. Recommendation 5.2.2 The Review Committee endorses the moves by the NHMRC to implement a clinical trials register in Australia. Recommendation 5.6.1

2. To Australian Health Ethics Committee

AHEC should redraft the Statement on Human Experimentation and change its title so that all health investigation involving humans (including nonbiomedical research and innovative practice) is encompassed.

Recommendation 5.3.1

     AHEC should re-draft the Statement on Human Experimentation to include reference to research on distinct cultural groups to the effect that these groups have specific needs that must be addressed. In particular, the guidelines should address the need for an IEC to:

• take additional care in ensuring that consent is voluntary and that the research project is clearly understood;
  
• ensure that special regard is being paid to participant confidentiality and privacy and that specialist advice on the participant group has been obtained;
  
• ensure that proper consultation has been conducted amongst the research subjects and group which could involve participants as members of an IEC where this is practical. Recommendation 5.4.1
  

AHEC should re-draft the Statement on Human Experimentation to:

• specifically address privacy issues with particular reference to confidentiality of the data both at the time of collection and future storage.
  
• take account of good practice codes (e.g., Australian Vice Chancellors Committee, Therapeutic Goods Administration) and the current Commonwealth Privacy Principles. Recommendation 5.8.1
  

The redrafted Statement should cover all research on humans and not be restricted to NHMRC-funded research. Recommendation 6.1.3 To improve communication and networking between IECs generally and in particular in relation to multi-center trials, AHEC should prepare an IEC directory which includes the names and contact addresses for the Chairs and Secretaries of all Australian IECs. Recommendation 5.5.4 The annual IEC compliance report to AHEC should require details of monitoring arrangements for high risk projects. Recommendation 5.7.3 A checklist for researchers detailing the requirements for the collection and storage of research data and results should be developed by AHEC, and IECs should be made responsible for monitoring compliance with the checklist on privacy guidelines. Recommendation 5.8.2 AHEC should coordinate the preparation of a national standard form of Application for Approval of a research project before an IEC. Recommendation 6.4.1

A-51

     AHEC should supervise the preparation of a Manual of Procedures for IECs following the completion of the re-drafting of the Statement on Human Experimentation and Supplementary Notes, and AHEC should be allocated adequate resources to fund this project. Recommendation 6.5 AHEC should maintain a clearinghouse function, and be responsible for coordinating, collecting, and disseminating information as well as monitoring IECs in line with its statutory requirements. As well, education of IECs researchers and institutions should form a part of the role of AHEC. Recommendation 7.3.1 AHEC should be funded for the appointment of an IEC officer. This officer is required as a matter of priority to coordinate the development of a resource kit (educational package) for ethics committees. Following the development of the kit this officer should remain responsible for ongoing duties relating to the administration and education of IECs. Recommendation 7.3.2 AHEC through its Research Ethics Working Committee should identify appropriate stakeholders in the ethics committee system and consider appropriate means to facilitate their contribution to the system.

Recommendation 8.2

     AHEC should examine the issue of appropriate levels of administration fees for IEC approval. Recommendation 8.5

     AHEC should revise its current compliance information form to include the following information from IECs:

Institutional Ethics Committees which do not consider more than 50 research protocols should consider amalgamating their IEC with another IEC or IECs. Recommendation 5.5.1 The Review Committee does not recommend the establishment of regional Institutional Ethics Committees. Recommendation 5.5.2 Institutional Ethics Committees should consider procedures for improving the consideration of multi centre research protocols such as communication between chairs of IECs and the acceptance of another IECs scientific assessment of a project where appropriate. Recommendation 5.5.3 An IEC has the responsibility when approving a research protocol to ensure that appropriate and adequate monitoring arrangements are in place consistent with the level of risk involved in the project to research subjects. Recommendation 5.7.1

A-52

     An IEC must ensure that appropriate and adequate procedures for monitoring are in place prior to the commencement of the project. Recommendation 5.7.2 An IEC should put in place good administrative and record keeping practices. Recommendation 6.1.1 Where an IEC has grounds for concern about a research protocol, the IEC should initiate consultation with the researcher, and where a protocol is rejected by an IEC, reasons for the rejection should be recorded and made available to the researcher. Where a researcher is unhappy with the decision the complaint should be referred to the institution. Recommendation 6.1.2 An IEC should consider the introduction of a system of expedited of review allowing IECs to grant approval to research projects not involving significant risk to the research subjects. Such expedited review have the following features:

• All research proposals should be assessed according to the level of potential harm with minimal risk studies referred to a person/subcommittee/chair faculty for consideration;
  
• Full IEC review is still required for research involving significant actual or potential risks to participants;
  
• IEC has power to delegate consideration of low risk proposals to nominated persons or sub-committees;
  
• Sub-committees need not consist of IEC members (e.g., faculty sub-committee for consideration of student proposals) and may consist of the Chair alone;
  
• Delegated sub-committees are responsible for approving the protocols before them however, all decisions will be reported to the IEC for information. Recommendation 6.2.1
  

     Institutional Ethics Committees should not approve a research project unless they are satisfied that an acceptable Consent Form will be administered to the subjects of the research project. Recommendation 6.4.3 An IEC should have in place appropriate grievance/complaints procedures for participants and these procedures should be included as part of an information sheet provided prior to involvement in the research. This information should include both internal and external contact names and numbers of available participant advisors. Recommendation 6.6 IECs should produce an annual report or contribute to the annual report of their institution. This report should include the compliance information forwarded to AHEC and a listing of all research approved by the committee. Recommendation 9.1.1

4. To Institutions Which Have an Established IEC

An institution should appoint members to the IEC with attention to the following:

A-53

An institution should maintain its IEC with the following minimum required membership:

Members of an IEC should be reimbursed for expenses incurred in the conduct of their duty (e.g., parking, additional child care expenses) but should not ordinarily receive a fee for service. In exceptional circumstances a fee for service may be appropriate; however, care should be taken to ensure that this does not result in an apparent or actual conflict of interest for the member(s) concerned. Recommendation 7.2 An institution should make available sufficient (ongoing) funding to enable its IEC members to avail of opportunities leading to improved performance of the IEC (e.g., attendance at seminars/conferences; support for IEC network meetings). Recommendation 7.3.3

A-54

     Each institution is responsible for ensuring that adequate resources are made available to its IEC for the assessment and ongoing monitoring of approved research protocols. Recommendation 8.1 An institution should not establish an IEC unless the institution can assure AHEC that there are adequate means for resourcing the committee. Recommendation 8.3

5. To Researchers

The UK, MRC distinction between innovative therapy/treatment and research should be adopted by AHEC and the Statement on Human Experimentation modified to reflect that the systematic use of an innovative treatment or therapy be considered as research and consequently be subject to assessment by an IEC.

Researchers should endeavour to simplify all Consent Forms for research subjects and should aim to achieve a form of words which is understandable by a student with Grade 8 schooling. Recommendation 6.4.2

6. Further Recommendations

Funded positions should be created in each State for an “area liaison” officer whose duties will involve coordination of liaison between AHEC and IECs and fostering communication/networking between IECs. Recommendation 8.4

Schedule 2

AHEC Chair’s Report for the NHMRC Annual Report 1999

I am pleased to report that 1999 has been a very productive year for the Australian Health Ethics Committee (AHEC). Some significant documents have been finalised by AHEC namely the National Statement on Ethical Conduct in Research Involving Humans, Guidelines for Genetic Registers and Associated Genetic Material, and Guidelines for Ethical Review of Research Proposals for Human Somatic Cell Gene Therapy. A number of other documents are close to being completed. One of the highlights for AHEC in 1999 was its organisation of the Ethical, Legal and Social Implications program of the prestigious Human Genome Organisation meeting held in Brisbane.

     Objective IV of the NHMRC Strategic Plan 1997–2000. ‘To continue to provide high quality ethical advice with respect to health research and health care’ concerns the Australian Health Ethics Committee. The documents produced by AHEC in 1999 will allow Council to continue to provide high quality advice about health from an ethics perspective.

Research Standards/Protection of Research Participants

To support a strong and well-managed research sector, the Australian Health Ethics Committee completed its revision of guidelines relating to the ethical conduct of research. The National Statement on Ethical Conduct in Research Involving Humans was presented to NHMRC in June 1999, following an intensive period of development.

     The National Statement was developed by the Australian Health Ethics Committee and endorsed by the Australian Vice-Chancellors’ Committee, the Australian Research Council, the Australian Academy of the Humanities, the Australian Academy of Science and the Academy of the Social Sciences in Australia. The

A-55

Academy of Technological Sciences and Engineering also gave the National Statement its support, as did the Ministers for Health and Aged Care, Industry, Science and Resources, and Education and Youth Affairs.

     The significance of this level of support for the National Statement should not be underestimated, as it will ensure a very high standard of protection for participants in all areas of research. All research involving human participants conducted in Australian universities, funded by NHMRC or the Australian Research Council, or involving the learned academies, will now have to be conducted in accordance with these guidelines.

National Workshops

In August 1999, the National Statement was the focus of a series of workshops convened in the capital cities of each State and Territory, and including Alice Springs. These workshops were designed to facilitate the use and understanding of the National Statement by those directly responsible for the maintenance of ethical standards of research in Australia. They were attended collectively by approximately 1,000 representatives of Human Research Ethics Committees from around the country.

Human Genetics

A further major achievement for AHEC has been the finalisation of two guidelines in the field of genetics: Guidelines for Genetic Registers and Associated Genetic Material and Guidelines for Ethical Review of Research Proposals for Human Somatic Cell Gene Therapy and Related Therapies.

     Guidelines for Genetic Registers and Associated Genetic Material covers all aspects of register operation and provides guidelines in such difficult areas as gathering, using and releasing register data and associated genetic material; recruiting people to genetic registers and obtaining their consent; and security and storage of genetic material. The revised document has a wider focus than the original guidelines.

     Human somatic cell gene therapy remains experimental. Guidelines for Ethical Review of Research Proposals for Human Somatic Cell Gene Therapy and Related Therapies provides guidance to Human Research Ethics Committees that are asked to review and approve research proposals involving somatic cell gene therapy, and assists researchers to prepare their submissions for ethical review. The document identifies bodies other than Human Research Ethics Committees from which approval may need to be obtained. An information paper on human somatic cell gene therapy, that provides background information to the Guidelines, is included with the Guidelines.

     A third genetics document is expected to be finalised early in 2000. Ethical Aspects of Human Genetic Testing—an information paper addresses issues of equity, access and resource allocation; commercialisation; geneticisation; counselling; and genetic testing of children. Although not formal guidelines, this information paper has been the subject of wide consultation—a feature which has strengthened the document.

     Genetics is an ever-changing field of research and the guidance and guidelines developed by AHEC will play a crucial role in protecting individuals whilst encouraging a high standard of research.

Human Research Ethics Committees

Compliance by Human Research Ethics Committees with NHMRC ethics guidelines is reported annually to the Research Committee and NHMRC. This process ensures consistent application of the guidelines as well as providing an auditing mechanism to support quality research.

     In 1999, AHEC continued to provide support to Human Research Ethics Committees by acting as a focal point for queries and concerns as well as preparing guidelines on issues that are likely to be raised during the conduct of research. A major thrust to this end was the 1999 Workshop series which introduced the new National Statement and gave representatives from the research, academic and HREC sectors an opportunity to discuss issues of concern.

     AHEC is developing an operating manual for Human Research Ethics Committees, which is expected to be finalised in 2000. When completed, the manual will form a “how to” guide addressing common questions and

A-56

providing procedural advice on the application of the National Statement on Ethical Conduct in Research Involving Humans.

Section 95 Privacy Guidelines

Stage two of the public consultation process for the privacy guidelines was conducted in 1999. The Privacy Act 1988 (Commonwealth) authorises the NHMRC to issue guidelines for the protection of privacy in the conduct of medical research. The Federal Privacy Commissioner is also involved in this process. The existing guidelines, Aspects of Privacy in Medical Research, were issued in 1995.

     The revision of these guidelines is a result of a number of changes in the environment in which the guidelines operate, namely the introduction of the NHMRC Act 1992 and the National Statement on Ethical Conduct in Research Involving Humans, and developments in privacy regulation.

     The guidelines provide a framework in which medical research involving personal information obtained from Commonwealth agencies should be conducted, to ensure that such information is protected against unauthorised collection or disclosure.

     The revised Guidelines under Section 95 of the Privacy Act were developed in collaboration with the Federal Privacy Commissioner. Two stages of public consultation were conducted as required by the NHMRC Act, and AHEC endorsed the revised guidelines at its November 1999 meeting. They will be tabled at Council and in the Federal Parliament in early 2000.

Aboriginal and Torres Strait Islander Guidelines

AHEC has reaffirmed its commitment to the protection of Indigenous Australians participating in research by planning a revision of the ‘Interim guidelines for ethical matters in Aboriginal and Torres Strait Islander health research.’ Recognising that the revision must be a transparent and inclusive process, AHEC is committed to full consultation.

Ethical, Legal and Social Implications Program

AHEC organised the Ethical, Legal and Social Implications (ELSI) program of the Human Genome Organisation’s 1999 meeting. The meeting was a vehicle by which AHEC was able to showcase its own work, as well as contribute to the national and international debate on ethical issues.

     The ELSI program included a debate, chaired by the Hon. Justice Michael Kirby, that “Too much is expected of human genetics research and the human genome project.” It was judged a great success by participants.

     Three workshops were chaired by AHEC members and were part of the ELSI program. These were: ‘Commercialisation and benefit-sharing’; ‘Religious and cultural perspectives in contemporary genetics’; and ‘Genetic susceptibility testing.’ The financial and intellectual contributions made by the Australian Health Ethics Committee were duly acknowledged. The ELSI program was highly praised by participants and the President of HUGO, and was considered to be one of the best prepared and attended.

Conclusion

This is the third year of the triennium and, in doing my report, I would like to pay tribute to the dedicated and hard-working members of AHEC who have given unstintingly of their time. The Committee’s success is due to the combined efforts of members.

     It has been my pleasure to chair this Committee for a second triennium. The challenges for AHEC in the future are increasing, especially as a result of the increased use of technology and the improvements in health care testing and information collection.

Professor Donald Chalmers

Chairman

A-57

Schedule 3

Recommendations to the Commonwealth Minister for Health and Aged Care

Recommendation 1

The Commonwealth Government, through the Minister for Health and Aged Care, should reaffirm its support for the UNESCO Declaration on the Human Genome and Human Rights, in particular Article 11, which states that:

Practices which are contrary to human dignity, such as reproductive cloning of human beings, shall not be permitted. States and competent international organisations are invited to cooperate in identifying such practices and in determining, nationally or internationally, appropriate measures to be taken to ensure that the principles set out in this Declaration are respected.

Recommendation 2

Noting that Victoria, South Australia and Western Australia have legislation regulating embryo research and prohibiting the cloning of human beings, the Minister for Health and Aged Care should urge the other States and Territories to introduce legislation to limit research on human embryos according to the principles set out in Sections 6 and 11 of the NHMRC Ethical Guidelines on Assisted Reproductive Technology.

Recommendation 3

Noting that there are statutory authorities established in Victoria, South Australia and Western Australia which consider and may approve human embryo research under strict conditions, the Minister for Health and Aged Care should urge the remaining States and Territories to establish similar statutory authorities with power to regulate research on human embryos according to the principles set out in Sections 6 and 11 of the NHMRC Ethical Guidelines on Assisted Reproductive Technology.

Recommendation 4

The Minister for Health and Aged Care should encourage and promote informed community discussion on the potential therapeutic benefits and possible risks of the development of cloning techniques.

Resolutions of the Australian Health Ethics Committee Pending State and Territory Legislation

Resolution 1

The AHEC proposes that, until legislation is introduced in the remaining States and Territories, the AHEC will collect information from institutional ethics committees (IECs) in these States and Territories on IEC research approvals of projects involving the application of current cloning techniques to human embryos. This information will be obtained in the course of the IEC annual compliance reporting system that is currently in place.

Resolution 2

The AHEC proposes that, until legislation is introduced in the remaining States and Territories, the NHMRC should consider the establishment of an expert advisory committee to assist IECs which seek advice on the scientific aspects of research projects involving the application of current cloning techniques to human embryos.

A-58

Chapter 4 - Australian Legislation and Guidelines Relevant to Cloning in Existence at November 1998

Introduction

4.1

This chapter discusses current State legislation and NHMRC ethical guidelines governing research which deal directly or indirectly with human cloning. The Reproductive Technology Accreditation Committee (RTAC) of the Fertility Society of Australia also issues a Code of Practice for accreditation of all IVF clinics.

The chapter evaluates the adequacy and effectiveness of the current legislation and research guidelines to deal with current and likely future technological processes with human cloning projects.

The definition of cloning in the three States which have relevant legislation is not consistent. The importance of clearly defining this term will be of great importance in ensuring adequate regulation of this expanding area of science.

4.2

4.3

Embryo Experimentation

4.4

4.5

Some of the work in cloning research may involve human embryos. In this case, the current legislation and ethical guidelines on human embryo experimentation will apply directly to such research proposals.

State and Territory governments established Committees of Inquiry which produced a succession of Australian reports on IVF during the 1980s. These reports also dealt with the difficult and controversial issue of embryo experimentation. There continues to be a tension between views that the embryo is, if not a human being, certainly deserving of respect, and that some experimentation ought to be allowed to uncover information relevant for the purposes of: (a) improving IVF techniques; (b) understanding male infertility; (c) understanding chromosomal abnormalities; (d) understanding gene defects; and (e) improving contraception.

Most reports recommended that no experimentation could be carried out either on embryos produced specifically for research or on embryos excess to IVF requirements.

4.6

Victoria

4.7

4.8

Victoria was the first state and the first jurisdiction in the world to introduce legislation to regulate infertility treatment. Legislation was later introduced in both Western Australia and South Australia.

The Victorian Infertility Treatment Act 1995 explicitly prohibits certain research which involves the “formation or use of a zygote if the research proposed that the zygote continue to develop to syngamy” amongst other prohibited practices is altering the genetic constitution of a gamete intended for use in a fertilisation procedure.

Western Australia

4.9

The Western Australian Human Reproductive Technology Act 1991 contains a list of offences which include conducting unapproved research or diagnostic procedures with an egg in the process of fertilisation or an embryo, and maintaining an embryo outside the body of a woman after fourteen days from the time of mixing of the gametes.

Ministerial Directions under the Human Reproductive Technology Act 1991 (WA) include regulations which would apply if research involving human cloning were to be carried out. Where approval is sought for any research or diagnostic procedure to be carried out involving an embryo, the intention must be that the procedure will be therapeutic and unlikely to have any detrimental effects.

4.10

A-59

South Australia

4.11 The Reproductive Technology Act 1988, together with the Reproductive Technology (Code of Ethical Clinical Practice) Regulations and the Reproductive Technology (Code of Ethical Research Practice) Regulations, prohibit, except in accordance with a licence, experimenting with “human reproductive material” (meaning a human embryo, human semen or a human ovum).

New South Wales

4.12 In October, 1997, the New South Wales Government issued a discussion paper titled “Review of the Human Tissue Act 1983.” In the Foreword to this paper, the New South Wales Minister for Health, the Hon. Dr Andrew Refshauge stated that

In response to community concern the Government has decided to introduce a law to ensure that two procedures do not develop in New South Wales. The Government has announced the banning of human cloning and trans-species fertilisation involving human gametes or embryos.

NHMRC Ethical Guidelines on Assisted Reproductive Technology (ART)

4.13 The NHMRC has published specific guidelines dealing with ART which include reference to cloning of human beings. The Ethical Guidelines were tabled in Parliament prior to their release in 1996. These guidelines were accompanied by a recommendation that they form a basis for complementary legislation in the States and Territories which had not yet introduced legislation.

4.14 The NHMRC Act authorises the Council to issue guidelines for the conduct of health research and of other purposes related to health. Although infringement of their provisions is not a legal offence, sanctions for infringement usually involve loss of access to research funds from the fund managed and administered by the Council or publication of the names of infringers in Parliament. The guidelines are regarded as national standards of acceptable practice.

4.15 The NHMRC Ethical Guidelines include a number of guidelines relating to embryo experimentation. A practical requirement of note is that “the recognition that any experimentation and research involved in these technologies should be limited in ways which reflect the human nature of the embryo, acknowledging that there is a diversity of views on what constitutes the moral status of a human embryo, particularly in its early stages of development.”

4.16 The NHMRC Ethical Guidelines contain restrictions on research relevant and specifically prohibit certain practices.

Comment

4.17 In Australia, substantial limits are placed on research involving embryos. Statutory approval for embryo experimentation is required in three States. The effect of the NHMRC Statement on Human Experimentation and the specific NHMRC Ethical Guidelines which deal with embryo experimentation allow research in this area only in exceptional circumstances. In the other States and Territories an institutional ethics committee (IEC) is required to grant approval for such research in accordance with the NHMRC Ethical Guidelines on Assisted Reproductive Technology.

Assisting in Reproductive Technology Programs

4.18 Cloning techniques of nuclear transfer or embryo splitting could have applications in assisted reproductive programs. One commentator has noted that the nuclear transfer process may have applications in assisted reproductive programs to overcome male infertility problems. An infertile husband could benefit from the asexual nuclear transfer process by contributing his genetic material to the enucleated cell of his

A-60

wife. Applications of cloning techniques could be used to assist in ART by the splitting of embryos, so increasing the number of embryos for later transfer, facilitating fertilisation in women over 40 (by cloning of the mitochondrial or gene set (cytoplasm replacement)), or replacing defective mitochondrial genes that cause disease.

4.19 If any of these procedures were to be undertaken in ART programs, statutory and/or ethical committee clearance would be required. Assisted reproductive technology is regulated by specific legislation in three States. There is a system of self-regulation and accreditation comprising the RTAC and its Code of Practice for units using IVF and related reproductive technologies, with RTAC setting professional and laboratory standards for clinical practice under this system of accreditation.

Status Of Children Legislation

4.20 The status of any child born in an ART program is addressed in State and Territory legislation. This legislation was introduced so that any person donating gametes to another person in an assisted reproductive process was not the parent at law of that child. In essence this legislation established the principle that the recipient social parent, rather than the biological parent, assumed all responsibilities at law for that child. In addition, the legislation also established that the person contributing the gametes did not assume any parenting responsibilities at law under such an arrangement.

4.21

This legislation rests on the donation of gametes rather than the contribution of genetic material. In a scenario where an infertile husband contributes his own genetic material by way of nuclear transfer, the genetic as well as legal relationship is to the husband. On the other hand, were the genetic material to be contributed by a person other than the husband, current legislation may not apply.

Replacing Human Tissue and Organs

4.22 In Chapter 2 there was discussion about early stage research into the development of cell lines from embryonic stem cells. This research may illuminate understanding of the programming and reprogramming of cell lines. Understanding of the process of differentiation and dedifferentiation could be the key to provide an unlimited source of therapeutic cells from which transplantable tissue and organs might result.

Human Tissue Legislation

4.23 All Australian States have enacted legislation regulating the donation and transplantation of human tissue. The definition of “tissue” is not identical, but in NSW includes “an organ, or part, of a human body and a substance extracted from, or from a part of, a human body.” In essence, this legislation requires the consent of the parties involved for the donation and for the acceptance of the human tissue in a transplantation procedure.

4.24 Current human tissue legislation may apply to some aspects of proposed cloning techniques. Where a cloning technique uses material from one body for transplantation to another or for research or other purposes, the consent provisions of the human tissue legislation would apply.

Cloning an Individual Human Being—Prohibitions in Australia

State Legislation

Victoria

4.25 The Victorian Infertility Treatment Act 1995 deals specifically with cloning and defines it as the formation “outside the human body” of “a human embryo that is genetically identical to another human embryo or person.” The Act prohibits a person from carrying out or attempting to carry out cloning. The Victorian Act contains prohibitions on destructive research on embryos. There are several clauses with a very direct bearing upon cloning.

A-61

Western Australia

4.26 In Western Australia, the Human Reproductive Technology Act 1991 establishes a regulatory structure and Code or Practice. The Act itself contains a list of offences including any procedure directed at human cloning or producing a chimaera.

South Australia

4.27 The South Australian Code of Ethical Research Practice also contains a list of prohibitions which include: cloning altering the genetic structure of a cell while that cell forms part of an embryo or an ovum in the process of fertilisation; replacing the nucleus of a cell of an embryo or of an ovum in the process of fertilisation with any other nucleus; and placing reproductive material in the body of an animal.

4.28 The procedure of nuclear transfer which does not involve human semen may not be regulated by the Act or the South Australian Code of Ethical Clinical Practice. The Code of Ethical Clinical Practice does not contain a definition of the term “cloning.”

NHMRC Ethical Guidelines on Assisted Reproductive Technology

4.29 The NHMRC Ethical Guidelines list a number of practices which are considered to be ethically unacceptable and to be prohibited. These include experimentation with the intent to produce two or more genetically identical individuals, including development of human embryonic stem cell lines with the aim of producing a clone of individuals.

4.30

Supplementary Note 7 to the NHMRC Statement on Human Experimentation clearly states that the introduction of pieces of DNA or RNA into germ (reproductive) cells or fertilised ova is not acceptable, because there is insufficient knowledge about the potential consequences, hazards, and effects on future generations.

4.31 Specific accreditation standards have been formulated by the RTAC and the Fertility Society of Australia has included in its Code of Practice a specific prohibition on nuclear transfer.

Comment

4.32 Embryo splitting and nuclear transfer for the specific purpose of cloning an identical human being is either prohibited or against the intention of the regulatory framework established in Victoria, Western Australia, South Australia and the NHMRC Ethical Guidelines. Production of embryonic stem cell (ES cell) lines is contravened by the Victorian and Western Australian Acts and NHMRC Ethical Guidelines.

Common Law

4.33 There is a general principle that contracts whose formation or performance is contrary to public policy are not enforceable in a court. In determining whether contracts are contrary to public policy, courts can have regard to relevant legislation. Thus, where statutes prohibit cloning, there would be grounds for concluding that a contract to provide tissue for the purpose of cloning an individual human being was contrary to public policy and thus unenforceable. Unenforceability alone does not, of course, provide a ground for prohibition of such contracts and does not mean that the parties by their contract have acted illegally.

Privately Funded Institutions

4.34 A concern at this stage is whether a private, rather than publicly funded, organisation in a State or Territory other than Victoria, Western Australia or South Australia might consider a venture in cloning of human being or cloning of human parts without the approval of an IEC under NHMRC guidelines.

Currently, the NHMRC guidelines are only enforceable against institutions receiving NHMRC funding. The possibility exists that a private institution could decide to undertake such work. Without legislation the NHMRC cannot stop private institutions conducting such work.

A-62

References

International Reports

President’s Commission Report. (1983) The Study of Ethical Problems in Medicine and Biomedical and Behavioural Research: Deciding to Forego Life Sustaining Treatment Washington.

The Belmont Report. (1979) Ethical Principles and Guidelines for the Protection of Human Subjects of Research The National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research, Department of Health, Education and Welfare, pub. No. (OS) 78-0012 U.S. Government Printing Office Washington.

Council of Europe. (1996) Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine Strasbourg (164).

CPMP/ICH. (1995) Code of Good Pharmaceutical Practice/ International Conference on Harmonisation Note for Guidance on Good Clinical Practice–135/95. See also ISO 14155 Clinical Investigation of Medical Devices.

CIOMS. (1993) Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO), International Ethical Guidelines for Biomedical Research Involving Human Subjects Geneva Switzerland.

Canadian Code. (1997) Code of Ethical Conduct for Research Involving Humans, which is a tri-partite effort by the Medical Research Council, Natural Sciences and Engineering Research Council and the Social Sciences and Humanities Research Council of Canada.

Royal College of Physicians. (1996) Guidelines on the Practice of Ethics Committees in Medical Research Involving Humans London.

Health Research Council of New Zealand. (1997) Ministry of Health Review of the Ethical Review Structure in New Zealand Health Department New Zealand.

Nuffield Council on Bioethics. (1999) The Ethics of Clinical Research in Developing Countries United Kingdom.

National Bioethics Advisory Commission. (1997) Cloning Human Beings: Report and Recommendations of the National Bioethics Advisory Commission Washington.

Legislation

Poisons Act. 1966 New South Wales (see also the Poisons Act in ACT 1933; WA 1964; Tas 1971 and Vic Drugs Poisons and Controlled Substances Act 1991; Qld Health Act 1937; NT Poisons and Dangerous Drugs Act 1983).

Status of Children Act. 1978. (Qld) (and Artificial Conception Act 1984 (NSW); Status of Children Act 1974 (Vic); Family Relationships Act 1975 (SA); Status of Children Act 1974 (Tas); Artificial Conception Act 1985 (WA); Artificial Conception Act 1985 (ACT); Status of Children Act 1978 (NT); Family Law Act 1975 (Cth.).

Freedom of Information Act. 1982 Commonwealth Parliament Australia.

Human Tissue Act. 1983 ss. 6–9 NSW (see also Transplantation and Anatomy Act 1978 ss. 6–10 ACT; Human Tissue Transplant Act, ss. 6–10 NT; Transplantation and Anatomy Act 1979 ss. 8–12 Qld.; Transplantation and Anatomy Act 1983 s.7–10, SA; Human Tissue Act 1985 ss. 5–9 Tas; Human Tissue Act 1982 ss. 5–12 Vic.; Human Tissue and Transplantation Act 1982 ss. 6–9 WA).

Reproductive Technology Act. 1988 No 10 Parliament South Australia.

National Health and Medical Research Council Act. 1992 No 225 of 1992 Commonwealth Parliament Australia.

Code of Federal Regulations. (1992) 21 Food and Drugs Part 56.

Therapeutic Goods Act. 1993 Commonwealth Parliament Australia.

Infertility Treatment Act. 1995 Victoria Parliament Australia.

Human Reproductive Technology Act. 1993 Parliament Western Australian.

A-63

Books and Articles

Annas G. (1984) Ethics Committees in Neo-Natal: Substantive Protection of Procedural Diversion? Am J Pub Health 74; 843.

Beauchamp T. and Childress J. (1994) The Principles of Biomedical Ethics (4ed ) Oxford UP.

Beecher H. (1966) Ethics and Clinical Research New Eng J of Med 274:1354.

Beecher H (1968) Ethical Problems Created by the Hopelessly Unconscious Patient New Eng J of Med 278:1425.

Bennett B. (1997) Law and Medicine, LBC.

Brazier M. (1990) Liability of Ethics Committees and their Members Professional Negligence 186.

Breen K. (1997) Ethics Laws and Medical Practice Allen and Unwin Melbourne.

Brody H. (1981) Ethical Decisions in Medicine 2d ed Little, Brown and Co.

Bulletin of Medical Ethics. (1999a) Medical Research has its Downsides Bulletin of Medical Ethics, November 152: 7 (citing reports in The Times, 2 October 1999; The Guardian 8 November 1999; and 1999 Brit Med J 319274).

Bulletin of Medical Ethics. (1999b) Helsinki Declaration Revising Continues Bulletin of Medical Ethics 146:3.

Capron M.A. (1985) Legal Perspectives on Institutional Ethics Committees Journal of College and University Law 11:7.

Chalmers D. and Pettit P. (1998) Towards a Consensual Culture in the Ethical Review of Research Med J of Aust 168:79.

Clarke C. (1998) Should There Be an Accredited Ethics Committee System of Centralised Review of Multi-Centre Clinical Research Med J of Aust 169:283 (and Henman M. et al. Med J of Aust 169:283–4; E. O’Brien E. (1998) et al. Med J of Aust 169: 284–5; S. Gandevia S. et al. Med J of Aust 169:285.

Cohen M.(1998) Should There Be an Accredited Ethics Committee System for Centralised Review of Multi-Centre Clinical Research? Med J. of Aust 168:528.

Darvall L. (1993) Autonomy and Protectionism: Striking a Balance in Human Subject Research Policy and Regulation Law in Context 11:82.

Editorial. (1976) 7 Med J of Aust 7:179–80.

Engelhardt H. T. (1986) The Foundations of Bioethics Oxford UP.

Fletcher J. (1973) Realities of Patient Consent to Medical Research Hastings Center Studies 1:1.

Freckelton I. and Petersen K. (1999) Controversies in Health Law Federation Press Sydney.

Freedman B. and Glass K. (1990) Weiss v Solomon: A Case Study in Institutional Responsibility for Clinical Research Law, Medicine and Health Care 18:395.

Furrow B. et al. (1995) Health Law West Law Publishing.

Giesen D. (1995) Civil Liability of Physicians for New Methods of Treatment and Experimentation: A Comparative Examination

Med LR 3:22.

Gillespie R. (1988) Research and Human Subjects: an Historical Overview Conference Proceedings: Can Ethics Be Done by Committee? Monash University Centre for Bioethics Australia.

Healy D. (1999) Clinical Trials and Legal Jeopardy Bulletin of Medical Ethics 153:13–18.

Jonas H. (1969) Philosophical Reflections on Experimenting with Human Subjects (1969) Daedalus 98.

Kelly F. and Boyages S. (1999) Pilot Programme to Reform the Ethics Committee System in NSW Med J of Aust 171:52.

Kirby M. (1983) IVF - The Scope and Limitation of Law Conference on Bio-ethics and the Law of Human Conception IVF 29–30 September London UK.

The Lancet. (1999) 353:400–3 (Cited in Bulletin of Medical Ethics 148:5).

Laufer S. (1990) The Regulation of Medical/Scientific Research Practices Involving Experimentation on Human Beings Law in Context 8:78.

Levine R. (1986) Ethics and Regulation of Clinical Research Urban and Schwarzenburg Baltimore.

Mant D. (1999) Can Randomised Trials Inform Clinical Decisions About Individual Patients? The Lancet 353:743–746.

A-64

McNeill P. (1993) The Ethics and Politics of Human Experimentation Cambridge UP.

Magnusson R. (2000) The Use of Human Tissue in Medical Research: Legal Issues for Human Research Ethics Committees J of Law and Medicine 7:390.

Merritt A. (1987) The Tort Liability of Hospital Ethics Committees Southern Cal LR 60:1239.

NCBHR. (1995) Protecting and Promoting the Human Research Subject: A Review of the Function of Research Ethics Boards in Canadian Faculties of Medicine NCBHR Communiqué 6:1–33.

Nelson D. and Weiss R. (1999)Hasty Decisions in the Race to a Cure? Washington Post Sunday Nov 21 p A1.

Neuberger J. (1992) Ethics and Health Care: The Role of Research Ethics in the UK Kings Fund Institute Research Report 13 London.

Pellegrino E. and Thomasa D. (1996) Christian Virtues in Medical Practice Georgetown UP.

Rawbone R. (2000) Observation from Six Years Experience of a Health and Safety Research Ethics Committee Bulletin of Medical Ethics 155:13.

Scott R. (1984) Experimenting with Life: Must Law-Makers Experiment Too? 5th International Conference on Forensic Science, Sydney Australia.

Skene L. (1998) Law and Medical Practice Butterworths Melbourne.

Parliament Debate

Commonwealth of Australia Parliamentary Debates: Senate Volume S154 36th Parliament, 1st Session 5th period 1991.

National Health and Medical Research Council and AHEC Reports

NHMRC. (1984) Supplementary Note on Embryo Flushing AGPS Canberra Australia.

NHMRC. (1985) Report on Workshops on the Constitution and Functions of Institutional Ethics Committees in Australia 1984–85 NHMRC. AGPS Canberra Australia.

Statement on Human Experimentation. (1992) NHMRC Canberra Australia.

AHEC. (1992) CTN Guidelines for Institutional Ethics Committees Canberra Australia (see also Clinical Trials of Drugs in Australia DEB 1 The Clinical Trial Notification (CTN) Scheme; Guidelines for Good Clinical Research Practice Therapeutic Goods Administration; Australian Guidelines: Clinical Trials Exemption (CTX) Scheme for Drugs DBE 5).

AHEC. (1993a) Report of the 1993 Workshops for Institutional Ethics Committees: Consultation with Researchers and Forum on HRECs

NHMRC Canberra Australia.

NHMRC. (1993b) Report of the 1993 Survey of Institutional Ethic Committees NHMRC AGPS Canberra Australia.

NHMRC. (1994) Annual Report 1993 AGPS Canberra.

Bienenstock J. (1993) Report of an External Review of the National Health and Medical Research Council AGPS Canberra Australia.

NHMRC. (1994) Report on Compensation, Insurance and Indemnity Arrangements for Institutional Ethics Committees, AGPS Canberra Australia.

AHEC. (1996) Ethical Guidelines on Assisted Reproductive Technology AGPS Canberra Australia.

NHMRC. (1997) Annual Report 1996 AGPS Canberra.

NHMRC. (1998) Annual Report 1997 AGPS Canberra.

AHEC. (1998) Report on the Scientific, Ethical and Legal Considerations Relevant to Human Cloning Commonwealth Minister for Health and Aged Care NHMRC Canberra Australia.

NHMRC. (1999) Annual Report 1998 AGPS Canberra.

NHMRC. (2000) Annual Report 1999 AGPS Canberra.

NHMRC. (2000) Guidelines under Section 95 of the Privacy Act 1998 Canberra Australia.

National Statement on Ethical Conduct in Research Involving Humans. (1999) Commonwealth of Australia AGPS Canberra (www/nhmrc.gov.au/ethics/statemen.htm).

A-65

Australian Reports

Allars M. (1994) Report of the Inquiry into the Use of Pituitary Derived Hormones in Australia and Creutzfeldt-Jakob Disease (CJD) Commonwealth of Australia AGPS Canberra Australia.

Baume P. (1991) A Question of Balance: Report on the Future of Drug Evaluation in Australia Report to the Commonwealth Minister for Aged, Family and Health Services AGPS Canberra Australia.

Chalmers D. (1985) Interim and Final Report of the Committee to Investigate Artificial Conception and Related Matters Government Printer Tasmania Australia.

Chalmers D. (1996) Report of the Review of the Role and Functioning of Institutional Ethics Committees Report to the Commonwealth Minister for Health and Family Services AGPS Canberra Australia.

Cornwall J. (1984) Report of the Working Party on IVF and AID (and 1987 Select Committee of the SA Legislative Council, Report on Artificial Insemination by Donor, In Vitro Fertilisation and Embryo Transfer Procedures and Related Matters in South Australia)

Government Printer South Australia Australia.

Day R. (1993) Review of the Clinical Trials Notification (CTN) Scheme: Report to the National Manager of the Therapeutic Goods Administration, Therapeutic Goods Administration Canberra Australia.

Demack J. (1984) Report of the Special Committee Appointed by the Queensland Government to Enquire into the Laws Relating to AID, IVF and Related Matters Government Printer Queensland Australia.

Family Law Council of Australia. (1985) Creating Children: A Uniform Approach to the Law and Practice of Reproductive Technology in Australia Family Law Council AGPS Canberra Australia.

Finn P. (1990) Health Ethics: The NHMRC and the NBCC Report to the Federal Minister for Health Canberra 29 October 1990.

Michael C. (1984) Interim Report of the IVF Ethics Committee of W.A. and a final report in 1986; Report of the Committee Appointed by the Western Australian Government to Enquire into the Social, Legal and Ethical Issues Relating to In Vitro Fertilisation and Supervision

Government Printer Western Australia Australia.

Privacy Commissioner. (1996) The Privacy Implications of Genetic Testing AGPS Canberra Australia.

Senate Select Committee. (1986) Human Embryo Experimentation in Australia Commonwealth Parliament Australia.

TGA. (1990) Australian Code of Good Manufacturing Practice for Medicinal Products AGPS Canberra.

Waller L. (1982–1984) Interim Report of the Committee to Consider the Social Ethical and Legal Issues Arising from IVF; Report on Donor Gametes in IVF; Report on Disposition on Embryos Produced by IVF Government Printer Victoria Australia.

Wills P. (1999) Virtuous Cycle Report to Commonwealth Government AGPS Canberra July 1999 which reviewed the structure and financing of medical research in Australia.

Court Decisions

Bennetts v Board of Fire Commissioners of New South Wales (1967) 87 WN (NSW) 307.

Bouvia v Glenchur (1986) No C 583828 Cal. S Ct. Los Angeles County 7 10.

Canterbury v Spence (1992) 464 F2d 772.

Davis v Rodman (1921) 146 Ark. 385, 227 SW 612.

Halushka v University of Saskatchewan (1965) 53 DLR(2d) 436.

In Re Quinlan (1976) 70 NJ 10; 355 A 2d 647 Certificate denied, 429 US 922.

Nyali Ltd. v the Attorney-General (1956) 1 QB at 16–17.

R v Ethical Committee of St Marys Hospital ex-parte Harriott (1988) 1 FLR 512.

Reibl v Hughes (1980) 114 DLR (3d)1.

Rogers v Whitaker (1992) 67 ALJR 47; (1992) 175 CLR 479.

Tobacco Institute of Australia Ltd v National Health and Medical Research Council and Others (1996) 142 ALR 1.

Weiss v Solomon (1989) 48 CCLT 280.

A-66

LOCATION OF THE

OFFICE FOR PROTECTION FROM RESEARCH RISKS WITHIN THE NATIONAL INSTITUTES OF HEALTH: PROBLEMS OF STATUS AND INDEPENDENT AUTHORITY

Commissioned Paper John C. Fletcher University of Virginia

B-1

I. Introduction

Task and Methods. The task is to examine the location of the Office for Protection from Research Risks (OPRR) within the National Institutes of Health (NIH) and its effects on the mission of the Office. Recommendations will accompany the findings.

     The issue of location is conceptually related to OPRR’s mandate, the institutional histories of OPRR and the NIH with regard to human subjects research (HSR), and the general performance of the U.S. system for protection of human subjects of research (HSoR).¹ These themes will be addressed in the report, although the discussion will mainly address the location issue.

     In addition to literature on the strengths and weaknesses of other federal regulatory agencies, the author reviewed the history and present mandate of two federal bodies with similar missions and past problems of conflicts of institutional interests: 1) the Office of Government Ethics (OGE) and 2) the Nuclear Regulatory Commission (NRC).

Interviews

B-3

Executive Summary and Major Findings

A. On the Location of OPRR in Government

1) OPRR’s location within the NIH is a structural conflict of missions and incompatibility of functions. This structural conflict gives rise to several troubling and persistent problems—including conflicts of interest—for the professional staff of OPRR and the NIH officials who administer OPRR.

The report’s arguments are based on these points and findings:

1) Federal legal protections exist only for HSR that is a) conducted or supported by any of 17 Federal Departments or Agencies that adhere to the Common Rule or b) regulated by the Food and Drug Administration (FDA). A substantial volume of HSR occurs beyond the perimeter of those protections;

2) Sanctions are inadequate for violations of federal regulations to protect HSoR;

3) No permanent national forum exists for informed debate, continuing interpretation, and application of ethical principles and rules for HSR, consideration of problematic cases, or formulation of policies to meet new needs;

4) OPRR, the federal office for oversight of human subject Assurances representing approximately 5,000 domestic and foreign institutions and for consultation with 17 Federal Departments or Agencies that conduct or sponsor HSR, is now severely undersized and compromised in effectiveness, given the magnitude of its oversight of HSR activities within its current authority. If there were universal protection of HsoR, the current OPRR would be totally inadequate to the task.

B-4

Recommended Remedies:

For A.1, B.3, and 4: Elevated status, independent location, and adequate funding for a successor to OPRR: the National Office of Human Subjects Research (NOHSR) along with a National Advisory Committee for Human Subjects Research (NACHSR).

     For B.1 and 2: Federal legislation that confers the protections of informed consent and Institutional Review Board (IRB) review for all HSoR, with appropriate sanctions for violators.

II. Moral and Political Reflection on the U.S. System to Protect

Human Subjects

Answers to this question depend on ethical perspectives on the status of research. Given society’s major goals and interests, is there a defensible moral imperative to conduct biomedical research and human experimentation? Is there a moral obligation—arising from the needs of society and the social contract with its members—for biomedical scientists to conduct research and for persons who are sick or well to participate in it? Does society have “rights” in human experimentation that it should claim to procure knowledge to save lives and reduce the incidence of disease? McDermott argued for a strong version of such a position in the 1960s.³ If his argument prevails, then the reasons for society to protect HSoR are weaker than reasons that flow from a different moral argument.

     Jonas saw no moral duty to conduct research and especially HSR. Contrary to McDermott and other scientists who argued for the moral priority of society’s need for knowledge to struggle against death and sickness, Jonas defended the dignity of the individual over the advance of knowledge. He wrote that social progress through medical progress is an “optional goal, not an unconditional commitment….”⁴ His words capture the moral sense that, in my view, deserves the stronger loyalty in this debate. Jonas wrote: “Let us also remember that a slower progress in the conquest of disease would not threaten society, grievous as it is to those who have to deplore that their particular disease be not yet conquered, but that society would indeed be threatened by the erosion of those moral values whose loss, possibly caused by too ruthless a pursuit of scientific progress, would make its most dazzling triumphs not worth having.”⁵ Higher loyalty to the dignity and welfare of HSoR ought (almost always) to prevail over loyalty to the cause of science and the needs of society for knowledge, relief of suffering, and cure and prevention of disease. The origin of this loyalty is respect for persons and their capacity for expressions of altruism and sacrifice—the ideal (although rarely the actual) moral source of participation in research. As Jonas pointed out, society has no special claim or command over the altruism and sacrificial gifts of subjects of research, especially those who are sick. Conscription for research is unethical in any society. The “yes” to participate in research is one that only the individual or a legally authorized representative has the authentic moral capacity to give, despite all of the other real influences on subjects’ motivation, including financial inducements and physicians’ recommendations.

     The caveat of “almost always” above recognizes those periods in social life when morally justified wars and national emergencies can lead to troubling degrees of relaxation of normal moral boundaries for the sake of survival. Even on these extraordinary occasions, however, there should be no involuntary experimentation on members of the armed services, prisoners of war, or otherwise incarcerated research subjects. At such times, some degree of secrecy about specific research projects may be required to protect the national interest. Even in this special context, all HSR in secret or protected projects should still have the twin protections of prior review and informed consent.

B-5

     U.S. law and regulations on HSR fall far short of the moral ideal, in that legal protections are extended only to subjects who participate in certain federally funded or regulated projects. Universalizing the scope of legal protection, as has now been done by the 21 member countries of the Council of Europe,⁶ is now a moral imperative for the U.S. Congress. A large and unknown number of human subjects are at risk in research projects funded through the private sector. The nations belonging to the Council of Europe have implemented the first truly international legal protection of all human subjects.

     Higher loyalty to the welfare of HSoR does not mean that no loyalty at all is owed to science’s quest for truth or to the needs of society to reduce and prevent disease. There is an important right of scientists to seek knowledge that can be infringed rarely and with a compelling public interest as the test. This right is constitutionally grounded in the right of “free speech.”⁷ There is at least a nonbinding civic obligation (but not a stringent moral duty) for members of modern and democratic societies to support scientific investigation and to participate if able in research conducted within prevailing ethical and legal norms. This civic duty arises from the value of science to democracy and from a shared commitment to resolve significant social and scientific disputes by evidence rather than ideology.

     Rather than a sharp “either-or” division of loyalty that places all moral weight on protection of HSoR and none on any other related cause or claim, it is practical to recognize a hierarchy of loyalties in research activities. Loyalties are owed, in this order, to 1) protection of HSoR, 2) protection of scientific and academic freedom, 3) commitment to meeting society’s needs for biomedical knowledge, and 4) concern for the welfare of particular research institutions and investigators. Such a hierarchy of loyalties underlies the author’s views and recommendations of this report. The societal obligation to protect HSoR is higher than the other three, but it is also morally justifiable to be loyal to the other claimants when doing so does not override and unjustifiably infringe loyalty to protecting HSoR.

     The guiding moral premise of this report is that Congress originally created the mandate that was delegated to OPRR out of fidelity to higher loyalty to the protection of HSoR. However belated this recognition by Congress in 1974, it is the moral core of OPRR’s mission. Further reasons to protect human subjects arise from three realities of HSR: 1) HSR is mainly for the benefit of society and the medical sciences, 2) HSoR are vulnerable—they frequently volunteer with motives driven by a “therapeutic misconception”⁸ that research will benefit them as well as trust in their physicians who refer or recruit them, and 3) the motivation of physicians who are also investigators studying their own patients is extremely complex and vulnerable to internal and external influences that can run counter to the welfare of the subjects—e.g., competition for scarce funding, career advancement, and financial inducements to enter patients into studies.⁹

Congress amended the Public Health Service Act (July 12, 1974) with Public Law 93-438, the National Research Act. This law directed the Secretary, DHEW, to 1) promulgate regulations regarding IRB review and institutional Assurances, 2) establish a program of ethical guidance, and 3) establish a process for responding to violations of the rights of HSoR. The second item was handled by OPRR’s predecessor, the NIH Institutional Relations Branch, and was formally delegated by the Secretary to OPRR. OPRR is thus the DHHS-wide authoritative voice on clarification and guidance on ethical issues. The first and third items have always been done exclusively by OPRR.

2. The U.S. System of Protection of HSoR

Turning attention to the U.S. system of protection of HSoR and to OPRR’s place within it, a very mixed picture of strengths and weaknesses emerges. Justified pride is due in that the United States was the first nation to extend

B-6

legal protection for HSoR in federally funded research. A vast and very diverse network of IRBs, estimated at between 3,000 and 5,000, has evolved. These IRBs serve as the nation’s primary resource for the protection of HSoR by examining the ethical aspects of a project before it begins. A morally valid process of informed consent to the particular research project is the second major resource to protect HSoR.

     IRBs and their authority have gradually been accepted by clinical investigators with rare exceptions. However, the nation’s IRBs have well-known problems, such as poor relationships to their local communities, inadequate education and training for members, inadequate scientific expertise, misallocation of effort to assure scrutiny of studies carrying greatest risk, poor quality control of reviewer performance, poor performance in continuing review, and little first-hand exposure to the context of clinical investigation and specific studies.¹⁰ These problems need attention within cooperative efforts between the local and federal partners in the enterprise. In my view, significant improvements will not occur without a national strategy, adequate funding incentives, and a strengthened successor to the OPRR, which is charged by Congress with the role of education and IRB welfare. Small staff and other pressures greatly limit OPRR’s role and effectiveness in IRB education and oversight as compared to its role with Assurances and compliance.

     Nishimi’s testimony¹¹ captures the history of the U.S. system of protection of HSoR. She explains that the approach that the federal government employs to protect HSoR is intentionally decentralized and diffused. The structure of the current system has changed very little from the approach set out by the 1966 Public Health Service (PHS) guidelines. Local review has been the centerpiece of protection, based on the belief that a local group of relatively disinterested individuals is most desirable because they are in the best position to know the prevailing values and ethics of the community and proposed subject population. At the NIH from 1966–1969, the author witnessed the earliest stage of the PHS regulation of HSR. The NIH leadership believed that local review coupled with a very modest NIH-based oversight mechanism would suffice. In 1982, the author interviewed Dr. James Shannon, former Director, NIH, and other NIH and PHS officials about the main features of the Surgeon General’s policy and their memories of the need for it.¹² Dr. Shannon stated, “None of us wanted a bureau of ethics in Bethesda. Local prior group review was the linchpin of the policy.” Despite the wish of Dr. Shannon and others, the OPRR, if not a bureau of ethics, is the sole official voice and continuing presence within government with a priority of protecting HSoR. The OPRR is inadequate, for several reasons, to do this task within its current mandate. Problems arising from location contribute to this condition. The NIH exercises a dual role to promote and regulate HSR. Although the NIH’s problem is far less dangerous, there is a historical analogy in the Atomic Energy Commission’s (AECs) failure from 1951–1973 to hold together both the promotion of nuclear energy and regulation of its uses. DHHS and Congress should face and resolve a persistent conflict of missions and interests between the NIH and OPRR.

III. Location of OPRR: Impact on its Mission

A. Historical Background on HSR and the NIH

The argument in this report is that structural conflicts of mission between OPRR and the NIH engender conflicts of interest for OPRR’s staff and NIH officials. How does this report use the term “conflicts of interest?” In his discussion of this topic in the context of health care, Erde first describes an “artificially narrow account” of a conflict of interest, i.e., “conflicts of interest occur when and only [when] a [physician] strays or is tempted to stray from...role mandated duties for the sake of...economic benefit.”¹³ Erde goes on to discuss a much broader range of causes (e.g., motives, situations, and structures) that may or may not influence conflicts of interests. This report seeks an understanding of conflicts of interest informed by Erde’s broader discussion, e.g., in this situation—for regulators (at OPRR) and for funders and sponsors of HSR (at the NIH)—conflicts of interests are either “motives that …[regulators or funders/sponsors] have and/or situations in which we could reasonably

B-7

think...[their] responsibilities to observe, judge, and act according to the moral requirements of their role are or will be compromised to an unacceptable degree.”¹⁴ The next several parts of the report provide historical background and data to support the argument.

1. Historical Background

A brief historical background should preface a discussion of OPRR’s location. The history of NIH’s role in the protection of HSoR can be evaluated from different standpoints. Viewed from within the NIH, there is much in which to take pride. From 1953, a form of prior group review at the Clinical Center, NIH, was an early predecessor of IRBs. The NIH leadership responded in the early to mid-1960s to social and media criticism of a lack of protection of HSoR and to the legal risks to clinical researchers.¹⁵ As described below, the NIH’s intramural leaders continued to improve a very effective research review system from 1966 to the present. The NIH also helped to staff and support the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1974–78), whose work developed consensus and a foundation for a systematic ethical perspective and body of ethical guidance on HSR. The work of the Commission, especially on research with children, had immediate effects within the intramural program. The NIH also funded and housed the OPRR to the present time.

     From outside the NIH and the PHS, critical questions can be raised about the HSR record of the nation’s major funder and sponsor of biomedical research. One finds at different periods examples of “institutional blindness” to HSR issues,¹⁶ to congruence of public accountability between the NIH’s intramural and extramural programs, and to the OPRR’s legitimate authority. The first two examples are preludes to a condition of institutional blindness to the conflict of interests issue embedded in OPRR’s location within the NIH.

a. Early History of NIH-PHS and HSR: How Could the Tuskegee Study Have Endured So Long?

The founders of the NIH’s intramural program, which began when the Clinical Center opened in 1953, were very conscious of their moral responsibilities in HSR. Accordingly, they created and continued to improve forms of prior group review suited to the requirements of the intramural program. These efforts from 1953–1977 are described below. In this period, there was a greater degree of protection for normal volunteers and patients in research carrying higher risk than for patients in research with lower risks or who were being followed and studied in experimental conditions. The ethos of these years was also grounded in deep commitments to scientific freedom and flexibility for researchers to follow the implications of their discoveries with particular patients. It is important to remember that, in this period, there was no systematic body of ethical principles and guidance for HSR. As in the wider research community,¹⁷ the norms of the NIH culture permitted wide latitude with regard to informed consent and did not require prior group review of each research project with patients or of a single experiment involving one or a few patients.

     In the 1950s and 1960s, the NIH was a relatively new agency where streams from two research cultures and one research bureaucracy met, but with apparently little creative or critical interaction. The first was an older pre-WWII research culture marked by a few general moral norms and an overriding degree of ethical relativism. It was this culture that created and supported the PHS-Centers for Disease Control (CDC) Tuskegee syphilis study from 1932–1972. The second was a post-WWII and post-Nuremberg research culture. It was marked by high commitment to the best science, to informed consent (tinctured heavily with flexibility and the therapeutic privilege), and to new forms of prior peer review of proposed research. The founders of the intramural program were largely members of this second culture. A third stream, a research bureaucracy with written ethical requirements on HSR, grew up around the NIH’s extramural grants and contracts program in the 1960s. The 1966 and 1971 PHS-NIH policies requiring local IRBs and prior group review were required of grantees and contractors in this program.

     A question deserving of more historical research arises as to whether the principals in these three arenas seriously discussed ethical issues among themselves. If they did so, it was without much perspective on the

B-8

implications that strong commitments to post-Nuremberg research ethics within the intramural program had for the extramural program or for earlier research (e.g., Tuskegee syphilis study) being conducted by PHS and CDC physicians. If one hypothesizes great social distance between these three arenas, and such could be demonstrated, it would help greatly to explain subsequent events.

     How else could the most dramatic example of institutional blindness to HSR issues in the history of the PHS-CDC be explained? Jones¹⁸ describes the mid-1960s confrontation of PHS and CDC officials about the Tuskegee study by Peter Buxton, a PHS venereal disease interviewer and investigator. These officials¹⁹ could find no ethical reasons to criticize or halt a longstanding (1932–1972) Tuskegee study of untreated syphilis, even after the discovery of penicillin. The depth of blindness and resistance to Buxton’s moral claims can also be measured by two factors. First, awareness of the civil rights movement should have focused PHS’s concern on the fact that all the subjects were black and totally uninformed.²⁰ Second, it is also striking that the officials’ resistance to Buxton’s criticisms occurred at exactly the same time that the PHS-NIH was requiring prior group review of HSR in response to other famous cases, scandals, and Dr. Henry Beecher’s historic article.²¹ In fact, the PHS-NIH requirement of local prior review grew directly out of a decade of experience in the NIH intramural program. Did the right hand (PHS-CDC) know what the left hand (NIH-extramural/intramural) was doing? More historical research is needed to answer this question and to explain the reasons for such profound silence about the implications of post-Nuremberg ethics, as practiced at the intramural NIH, for evaluation of the Tuskegee study.

b. Applying Federal HSR Regulations to NIH’s Intramural Program

A second but less dramatic example of institutional blindness is a ten-year (1971–1981) period in which federal regulations incongruently applied to extramural grantees and contractors but not to the intramural research program. In government generally prior to this period, there was institutional blindness and a slow learning process as to the need for reforms in HSR ethics.²² The learning process within the PHS and the NIH was provoked by crises that sparked reforms and resulted in more NIH commitment to bioethics.

     In 1966, PHS promulgated a Surgeon General’s policy requiring local prior group review of all grant applications to PHS to involve human subjects.²³ The 1966 policy was revised in 1971 (“the Yellow Book”) to require IRBs to have outside members who were nonscientists. However, this policy did not apply to the NIH’s intramural research at the Clinical Center. The policy was translated into federal regulations in 1974. Notably, the 1974 federal regulations requiring IRBs²⁴ stated:

46.1 Applicability

The regulations did not apply to NIH’s intramural program until the 1981 revised regulations²⁵ were published, but with a loophole to provide flexibility:

46.101 To what do these regulations apply?

(1)This includes research conducted by Department employees, except each Principal Operating

Component head may adopt such nonsubstantive, procedural modifications as may be appropriate from an administrative standpoint.

     In 1991, Subpart A of the regulations was extended by the Common Rule to apply to all HSR conducted, supported, or otherwise subject to regulation by any Federal Department or Agency.²⁶

B-9

     In 1993, Congress finally closed the gap by specifically requiring all research conducted by the NIH be subject to IRB review:²⁷

Section 492A (a) Review as Precondition to Research

A) … [requirement of prior IRB review of all applications to the Secretary for financial assistance to conduct research…]

B) In the case of research that is subject to review under procedures established by the Secretary for the protection of human subjects in clinical research conducted by the National Institutes of Health, the Secretary may not authorize the conduct of the research, unless the research has, pursuant to such procedures, been recommended for approval.

     What explains this long period of incongruence and differences of public accountability to federal regulation? Three factors influenced this delay. The first factor was that the source of leadership for reform of research ethics in the mid-1960s as well as the substance of that reform arose from within the NIH and was promulgated outward for grantees and contractors. NIH officials, especially Dr. James Shannon, led the response to widespread evidence of abuses of HSoR and fashioned the requirement of local prior group review as U.S. public policy.²⁸ Dr. Shannon and the Surgeon General, Dr. Luther Terry, presented the arguments for this policy to the National Advisory Health Council in September 1965.²⁹ It did not occur to them to require prior group review intramurally because it was already being done. Later, directors of the NIH and leaders of the intramural program in the period 1971–1981 probably did not believe that the regulations should apply to them because they were already highly self-regulated and believed that they were doing what the regulations required. In truth, a great deal had been done.³⁰

1) Protection of HSoR Within the NIH Intramural Program

When the Clinical Center opened in 1953, a document had been prepared, based on extensive discussion, requiring “group consideration” of clinical research procedures that “deviated from acceptable medical practice or involved unusual hazard.”³¹ A Clinical Research Committee (CRC) was organized as a subcommittee of the Medical Board of the Clinical Center. The CRC was designed as an “expert body” to deliberate scientific and ethical questions in research proposals that were referred to it. Between 1953 and 1966 three types of research were required to be referred to the CRC: research with patients involving unusual hazard (1953), research with normal volunteers (1954), and purely investigational (nontherapeutic) research with patients (1961). The director of the NIH exercised second-level review of normal volunteer studies. Also, from 1953, internal Clinical Center staff who volunteered for research had to meet written consent requirements.

     Prior to 1966, NIH intramural leaders changed policy and procedures to ensure more protection of HSoR. In 1964, an ad hoc committee was appointed by Dr. Jack Masur, Director of the Clinical Center. The group was charged with the evaluation of practices in group review and informed consent since the 1953 document. Led by Dr. Nathaniel Berlin, the National Cancer Institute (NCI), the committee did a major study of the existing system and interviewed each clinical director and many senior investigators. Its recommendations were adopted in July 1966, and prevailed until further revisions were made in 1976 and 1977.

     The specific change was to require review bodies (CRCs) within each institute. These bodies were charged to review patient research that fell outside the boundaries of accepted practice. The institute CRC or clinical director could refer a controversial project to the medical board’s CRC. Written informed consent was required only of normal volunteers. Patient consent could be given verbally with a note in the chart by the responsible physician. All normal volunteer studies remained under the aegis of the medical board’s CRC.

     Federal regulations of 1974 led to a response from the intramural program and more changes in 1975–1977. All patient and normal volunteer studies were centralized in a two-level system of review.³² The official review bodies in each institute were renamed Institute Review Subpanels,³³ and their membership enlarged to include

B-10

a richer mix of scientists and nonscientists from outside government. The author served as an outside member on a Subpanel at the NCI from 1975–1977. After 1977, I was responsible for helping NIH intramural officials to complete the process of shaping the Subpanels.

     The drafters of the 1974 regulations were NIH officials whose attention was aimed at reducing research risks in the extramural program.³⁴ Under congressional pressure, the 1974 regulations were hurriedly constructed. Little attention was devoted to bringing the intramural research programs under the regulations, because intramural research was not covered in the 1971 policy that served as a model for the regulations. These officials were also confident that the intramural program was reasonably well regulated.

     Pressure for congruence of applicability of the regulations began to mount in the mid-1970s due to OPRR’s mandate and influences of the work of the National Commission on the intramural program. The revised 1981 regulations created congruence (with a loophole), and the intramural program’s Assurance was negotiated and approved by OPRR in 1981.

2) Protection of the NIH Intramural Program

A second factor influencing a degree of institutional blindness to the incongruence was the prominent and protected environment of the NIH intramural program in this period. One must assume efforts by NIH’s directors to protect scientific freedom and flexibility in the intramural program, as well as their belief that its internal practices of peer review were sound. Flexibility and freedom from restrictions on research were prized values. Many research ideas were born by experimentation and observation in a single patient. Regimentation of almost any kind was considered an anathema.

     The first three years of the author’s service in the intramural program (1977–1987) were marked by challenges to a long tradition of freedom from external oversight and treasured flexibility in research practices.³⁵ The areas of sharpest conflict were over a) complaints from patients and family members about lack of informed consent, b) the obligation to seek informed assent of children to research or major medical procedures, c) disclosure of psychologically sensitive information to patients, d) changing protocol strategy in midcourse without Subpanel permission, e) conflicts of interest in Subpanel review of protocols of Scientific and Clinical Directors of the Institutes, f) testing normal volunteers for psychopathology, and g) complaints of pressure on normal volunteers to complete studies.

     At this time, there were internal struggles between advocates of NIH’s past and advocates for change. Many intramural officials felt strong pulls from both sides. The former argued for a type of “ethics exceptionalism” allied with the strong research culture. NIH scientists and officials with careers spanning the 1960s and 1970s tended to view their roles and mission as exceptional. They also viewed subjects’ participation in clinical research largely as beneficent, in part due to the quality of medical care received. Also contributing to this view was the fact that the costs of research and patient care were borne by the federal government, including patient and family travel costs and housing. Advocates for change appealed to the larger claims of social movements, of values that informed legal issues in medicine, and of bioethics as a discipline. The work of the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (1980–1983) made a strong case for these claims bearing on the practice of medicine. The work of the President’s Commission had effects in the intramural program. The same officials who wrote the 1974 regulations had been strongly influenced by the work of the National Commission and the President’s Commission. They saw the imperative for congruence of public accountability between the two programs and effected it in 1981.

3) Social Distance Between Extramural and Intramural

A third factor was the social distance between intramural and extramural programs described above. Each program had different leadership who rarely talked with one another. Neither wanted to be governed by the other. Failure of intramural leaders to communicate with extramural leaders was a significant reason, among others, why the protection of HSoR was not extended to the intramural program.³⁶

B-11

OPRR’s authority to require Assurances derives from the 1974 Act, which formalized the practice of obtaining written Assurances from DHHS-funded research institutions of their commitment to the ethical conduct of research. Before the 1974 Act, NIH had already developed such Assurance documents with many research universities, which were reviewed by OPRR. Even today, approval of an Assurance does not involve a site visit but reviews of paperwork and telephone discussions.

     OPRR’s Assurances are of several types. MPAs pledge compliance for all federally funded projects as well as a voluntary pledge regarding compliance in the context of privately funded research. Renewals are for a five-year period. OPRR currently has 448 MPAs with 756 entities. At non-MPA institutions, a Single-Project Assurance agreement must be negotiated with OPRR for each individual study. OPRR must negotiate each of these agreements as well as approve the consent document. OPRR today is holding approximately 3,000 active Single-Project Assurances. There are also cooperative project Assurances for large multiple site studies. Today, OPRR has more than 1,500 active cooperative project Assurances.

     The NIH is an MPA holder with the OPRR. OPRR is the authority for assessing the NIH’s compliance with federal regulations to protect human subjects. There have been longstanding concerns about the independence of OPRR and its ability to oversee the NIH itself, especially the NIH’s intramural program. The GAO report to Senator Glenn cited above pointed to “a potential weakness…because NIH is both the regulator of human subjects protection issues as well as an institution conducting its own human subjects research. The Director of NIH, therefore, has responsibility for both the success of NIH’