Special Section -- Research Ethics

Institute Establishes Houston Journal of Health Law & Policy

Mark Coffin accepts award from Mark Rothstein
On April 6, 2000, the Health Law & Policy Institute held a reception in celebration of the founding of the Houston Journal of Health Law & Policy.  The journal will debut in June 2001.

Mark A. Rothstein, director of the Institute, presented awards to individuals and firms who have given financial support to the journal.  Professor Rothstein presented awards to: Mark Coffin; Adams and Reese; J.D. Epstein; Vinson & Elkins; Fulbright & Jaworski; and Wood, Lucksinger & Epstein.

Mark Coffin of Adams and Reese is serving as chairman of the journal's development committee.

Profesor Rothstein announced the newly appointed, inaugural editorial board of the journal. The new editorial board consists of:

Editor-in-Chief -- Heather Morlang
Managing Editor -- Laurel Thorpe
Chief Articles Editor -- Alex Hecht
Senior Articles Editor -- Marilyn Larsen
Publications Editor -- Chris Lewis
Business Development -- Gail Rodgers
Articles Editors -- Tiffany Kithkart, Lois Miller, and Debra Wilkinson
Chief Notes and Comments Editor -- Jessica Strickel
Notes and Comments Editor -- Jessica Siff and Lucia Romano
Associate Editor -- Debbie Housel

Founding students were honored for their efforts in getting the journal started.  The founding students are: Rujul Desai, Melanie Dolgoff, Amy McGuire, and Jennifer Jasper.

Melanie Dolgoff, Jennifer Jasper, Rujul Desai, Amy McGuire, and Mark Rothstein

Enron, Texas Medical Center Win Institute's Texas Employer Innovation in Healthcare Award

Enron and the Texas Medical Center have been awarded the Health Law & Policy Institute's first annual award to Texas employers that have implemented innovative solutions to provide better healthcare to employees. The awards will be presented in June.

Enron, winner in the large employer category, has created a comprehensive healthcare plan with several positive elements . The program increases access to care by expanding benefits for part-time employees, including establishment of a new employment status of "reduced work hours" as well as part-time. Enron makes health and welfare benefits available to domestic partners. Access to health care is very convenient for Enron employees through an on-site primary care physician’s office at its headquarters. The company also delivers prescription drugs to employees at their work site. Enron’s plan focuses on the health needs of children by providing discounted sick child day care through St. Joseph’s "Kids on the Mend" program and summer camp opportunities for children.

The Texas Medical Center, winner in the mid-size employer category, instituted a study and program whereby its employees have unlimited access to a nurse practitioner in the employ of the Texas Medical Center. The nurse practitioner either helps address employees' healthcare needs or helps direct employees as to how best access healthcare under their healthcare plan. Improved access to primary care through the nurse practitioner may reduce unnecessary trips to an emergency room and could improve prenatal care, including reducing the incidence of low birth weight babies. The Texas Medical Center also has a program that utilizes the incentive of a free car seat as an award to pregnant mothers who make every prenatal appointment.

Wang Joins Research Faculty

Joseph J. Wang has joined the Health Law & Policy Institute as a Research Professor. Mr. Wang will be serving as a co-investigator on a two-year NIH grant to research pharmacogenomics and minority populations. His other responsibilities include work on a variety of projects for the Texas Legislature and for other research grants. Before joining the Institute, Mr. Wang worked as a policy analyst in the area of public human services.

Mr. Wang received his B.A. in 1995 from the University of Pennsylvania. In 1999, he received his M.P.H. from Johns Hopkins University and his J.D. from Georgetown University.

Texas Tobacco Pilot Study

Dr. Phyllis Gingiss, Professor of Public Health Education is coordinating a UH team responsible for establishing a comprehensive implementation tracking and support system for the Texas Department of Health Tobacco Programs. The pilot for the statewide program is focused in urban and rural communities in East Texas. Focus in ears 2000 and 2001 will be to identify baseline information about "what’s happening" in youth prevention programs schools and communities; adult cessation; enforcement; and community aspects of the project at the time of initial availability of Tobacco Settlement Fund expenditures. Additionally, site capacity analyses and historical/policy analyses will be conducted to diagnose factors at the school, worksite and community levels which influence likelihood of successful implementation of new programs or the strengthening of existing ones. This information and the tracking system to be developed will provide the foundation for on-going analysis of state and community progress in Tobacco Control.

In addition, a report will be prepared by the UH team for the Texas Legislature. This report will provide information about the status of state-level policies and practices in comparison to other states. Partners at UH include the Health Law & Policy Institute, Center for Public Policy, and the Graduate School of Social Work, with coordination through the Department of Health and Human Performance, where Phyllis Gingiss, Dr.P.H. is Principal Investigator.

The Health Law & Policy Institute will be involved in three issues:

• The Institute will assist in a workplace smoking policy survey (with Richard Murray, Center for Public Policy of UH) to see how Texas employers in the target area compare with employers outside the target area and outside Texas on issues such as cessation programs and motivational/incentive programs. The Institute will also look at laws regulating workplace smoking in both the public and private sectors.
• The Institute will review and analyze the legal structure of tobacco regulation in Texas and nationally, including local ordinances in the target areas.
• Finally, the Institute will review what smoking cessation programs are offered by HMOs and health insurance companies, and whether any such programs are "mandated" by other states’ laws.

Chet Brooks Honored with Distinguished Service Award

Mark Rothstein and Chet Brooks
On April 6, 2000, Chet E. Brooks, legislative consultant and former state senator, was awarded the Health Law & Policy Institute's Distinguished Service Award. Senator Brooks has been a member of the Institute's Advisory Board for many years.  Without his support in the early 1990s, the Institute might not exist today.

Cathy Rupf Honored for Many Years of Service

Mark Rothstein and Cathy Rupf
Cathy Rupf, Associate Director of the Health Law & Policy Institute was honored on April 6, 2000 for her 12 years of service at the Institute. She has worked at the University of Houston for 20 years.

Comprehensive Medical Ethics Compendium Published

Medical Ethics: Codes, Opinions, and Statements was recently published by BNA Books. It is the only collection of authoritative medical specialty documents addressing a wealth of current and controversial medical ethics issues from all the major medical organizations and specialty colleges in the United States. Medical Ethics includes:

• all key ethics standards from the 26 major medical societies and specialty colleges, presented colleague to colleague by the practitioners themselves;
• guidance on an astonishing variety of medical ethics topics, from confidentiality to research on human subjects, facing today's health centers, laboratories, regulators, and litigators;
• extensive cross-indexing that enables you to compare multiple perspectives on crucial topics across medical specialties.

A companion volume will be published later this year that will address relevant texts and laws and court decisions. Medial Ethics: Analysis of the Issues Raised by the Codes, Opinions, and Statements will supply citations and analysis for study and practical application of emerging standards on key issues.

Institute Hosts Texas State Bar Committee on Disability Issues Meeting

The Texas State Bar Committee on Disability Issues meeting was hosted by the Health Law & Policy Institute on May 6, 2000. The Committee was formed in 1993 to recommend policies and programs to promote full and equal participation in the legal profession and legal system for persons with disabilities.

Among the recent activities of the committee are the Disability Pledge program and the development of a Guide to Accessible CLE Programs. Through the Disability Pledge program more than forty major law firms, corporations, and agencies have pledged to uphold the principles underlying the ADA in their employment practices. The Guide to Accessible CLE Programs is a resource to help CLE planners to maximize the accessibility of CLE sites for all members of the State Bar of Texas and other attendees. Copies of the Guide are available through Texas Lawyer's Care at the State Bar offices, 1-800-204-222 (ext. 2155) or tlcmail@texasbar.com.

Another past project was the surveying and reporting on bar members and disability issues. See Texas Bar Journal at 690 (July 1997) for a review of that survey.

The Committee is currently working to produce an educational video for law students, recent law graduates, and practicing attorneys about lawyers with disabilities in employment situations. The focus will include both accessibility issues and the hiring and retention aspects of law office employment.

The Committee is chaired by Brian Shannon, Professor of Law at Texas Tech Law School. Its 35 members include Texas Supreme Court Justice Gregory Abbott and Laura Rothstein, Professor of Law at the University of Houston Law Center. More information about the Committee is available from Cynthia Riley at 800-204-222 ext. 2155 or tlcmail@texasbar.com.

BOOK REVIEW

Genome: The Autobiography of a Species In 23 Chapters
By Matt Ridley
Harper Collins (1999)
$26.00

Reviewed by Phyllis Griffin Epps
Research Professor
Health Law & Policy Institute

Life is governed by change and conflict. Competition is the force that drives not only the best of political economies but also the best of genetically-expressed traits in all living organisms. Each day in the continuing pursuit to comprehend the human genome, or the complete set of human genes, brings greater insight into the history and nature of humans and life itself. With greater knowledge comes greater evidence that all beings are constantly changing as a function of conflict, not among species but between genes and the proteins that ensue. So goes Genome: The Autobiography of a Species In 23 Chapters, Matt Ridley’s highly accessible introduction to the exploding field of genetic research. From Dolly the sheep to mad cow disease, from eugenics to assisted reproductive technology, from resistance to malaria to vulnerability to sickle-cell anemia, Ridley tells a story that informs and excites the lay reader about the extent to which knowledge of the human genome will change our lives.

The strength of the book lies in the author’s approach to his subject. Each chapter is "named," or numbered for a chromosome. In each chapter, Ridley discusses an episode or theme important to understanding the constant development of the human genome by highlighting a gene that appears on that chromosome. The sixth chapter is titled thusly, "Chromosome 6: Intelligence," and details the debate over the heredity of intelligence by reference to the gene called IGF₂R, which is located on the long arm of chromosome 6. The eighth chapter is named for the sex chromosomes X and Y, which are not labeled by number. Chromosome 21, an extra copy of which results in Down syndrome, opens a discussion on the history of eugenics. In this fashion, Ridley attempts two tasks simultaneously. First, he leads the reader through a tour of the twenty-three pairs of chromosomes that are the human genome. Second, Ridley places the human species in the continuum of time and space and, well, life. Ridley succeeds in both tasks with aplomb. Well served by his background as a journalist and editor for the Economist magazine, Ridley writes in simple but clever prose with humor, documentation, and examples that serve his points well.

Ridley’s success in communicating the rudiments of genetic composition, including the four-letter alphabet that spells out the billion or so three-letter words that make up the human genome, is attributable in part to his use of digital and word-processing methodologies. Gene replication immediately takes shape in the reader’s mind when likened to binary code and electronic mail. The use of a computer virus to explain selfish DNA and harmful mutation is particularly effective. In fact, references to computers and computer processing are so effective that a cynic will doubt the accuracy of the metaphor. If the fit is indeed true, then one must accept the invitation to search for parallels elsewhere in the human condition. Has binary code imitated life, or vice versa? Which came first, the chicken or the egg (a question Ridley answers, by the way)?

Ridley accepts his own invitation to draw connections between the phenomena of gene replication and social relationships. Several times he draws parallels between competition among genes and the triumph of capitalism over centralized market systems. A theme to which Ridley returns repeatedly is the role of competition, conflict and self-interest in the evolution of humans. Evolutionary biologists still subscribe to Darwin’s theory of natural selection, but with a twist. Natural selection is not about competition between species, between groups, or even between individuals; natural selection is about "competition between genes using individuals and occasionally societies as their temporary vehicles." The chapter on sex chromosomes is notable for its explanation of gender determination as the final result of a lopsided war between conflicting genes. He extends the theme to describe conflict in behavior between the sexes. The selection of sexual partners, he explains, is "an expression of sexual antagonism between genes for seduction and genes for resistance." Competition and conflict dictate the selection of sexual partners, the gender and perhaps the sexual orientation of fetus.

Ridley struggles most with the tension between biological determinism and social determinism, or the concept of free will given the evidence of genetic influences. The paradox is this: "To the extent that you act in character you are responsible for your actions; yet acting in character is merely expressing the many determinisms [such as genetics, nutrition, relationships] that caused your character." The explanation, Ridley says, is chaos theory. Developed by physicists and mathematicians, chaos theory holds that knowledge of all the determining factors in a system does not enable one to predict its course because of the many ways in which different causes can interact. In response to arguments that one’s behavior may be predicted (or excused) by reference to one’s genetic composition, Ridley counters that "the interaction of genetic and external influences makes my behavior unpredictable, but not undetermined. In the gap between those words lies freedom."

In addition to an inadequate index, the book stumbles most when the author fails to acknowledge the advantage of his expertise and fails to respect the squeamishness with which the public greets the possibilities of advances in genetic research. In recounting the outbreak of mad cow disease in Great Britain, Ridley uses examples of how little scientists understand about prions and prion diseases like mad cow disease even today. Yet, even as he describes the mystery that still surrounds the circumstances that caused cows to become infected, he faults the public for overreacting on what he describes as misinformation and the government for yielding to public pressure by banning the sale of beef across Europe. One wonders how Ridley would have the public and government act when faced with a mysterious and potentially deadly disease.

Nevertheless, through sports metaphors and Harvey Keitel, Ridley demonstrates a flair for generating images that help non-scientists grasp complex biological processes. The result is a well documented but fun read suitable for the mainstream. The book may never see the inside of a public school in Kansas, but the curious will enjoy the book for its insight into the substance behind the headlines touting successes in research and what our genes tell us about our personalities, longevity, and the world in which we live.

FOCUS ON ADJUNCT PROFESSOR

Judge Caroline E. Baker

Caroline E. Baker is Judge for the 151^st Civil District Court, Houston, Harris County, Texas. She began teaching Medical Malpractice Litigation at the University of Houston Law Center in the spring of 1998.

From 1988 to 1996, Judge Baker served as an attorney for McFall, Sherwood & Sheehy, P.C., in Houston, where she specialized in medical malpractice defense of physicians, hospitals, and nurses. She is Board Certified in Personal Injury Trial Law. She has served as Instructor for the National Institute of Trial Advocacy, member of the Peer Committee of the Texas Center for the Judiciary, and Chairman of the Rules Committee of the Board of District Judges.

Judge Baker graduated from Princeton in 1984 with an A.B. in History and European Cultural Studies. She received a J.D. from The University of Texas School of Law in 1988.

From the Web

The following articles were added to Health Law Perspectives, which can be found on the Health Law & Policy Institute's Web site at http://www.law.uh.edu/healthlawperspectives, between February 1 and May 1, 2000:

Have Prescription, Must Travel: A Look at the Link Between a Pharmacy’s Inventory and the Racial Composition of Its Customer Base

Massachusetts Court Diminishes Role for Contract in Reproductive Decisions

FDA Issues Proposed Guidance: Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research

e-Health Ethics Initiative

Filming in the ER: Invasion of Privacy or Public Service?

Incorporating Cost Criteria in Health Policymaking: The Case of Vaccination

Medicating Kids with Behavioral Problems: Solution or Problem?

School Choice Would Leave Needy Further Behind

Texas Board of Medical Examiners Adopts Internet Prescribing Policy

Supreme Court Holds F.D.A. Cannot Regulate Tobacco: Tobacco Industry Dodges Another Bullet

Houston’s Immunization Rates Lag Behind Other Cities

Fifth Circuit Joins Seventh in Rejecting ADA Attacks on AIDS Benefit Caps

Former Attorney General Thornburgh Reflects on the Americans with Disabilities Act's Tenth Anniversary

Is Compulsory Vaccination Compatible with Informed Consent?

Should Insurers Pay for Bone Marrow Transplants to Treat Breast Cancer?

Electronic Surveillance in the Service of Health

Amanda Snowden, HLO President,
Madge Bush of the MLK Center,
Tiffany Frost, HLO 1st Vice President,
and Lois Miller, HLO Treasurer

HLO culminated a year of fundraising efforts by presenting a check for $500 to the MLK Center.

On April 5, 2000, the University of Houston Law Center's Health Law Organization (HLO) hosted a presentation by Connie Wallace, Assistant Vice President of the Methodist Healthcare System Business Practices Office. Ms. Wallace presented "So You Want to be a Healthcare System Lawyer."

On April 6, 2000 the HLO members attended the reception celebrating the kickoff of the Houston Journal of Health Law & Policy. HLO members elected officers for 2000-2001 on April 11, 2000. HLO's new officers are:

President -- Susan Valka
1^st Vice President -- Diane Miller
2^nd Vice President -- Adria Conklin
Secretary -- Carol Chaffin
Treasurer -- Andrew Gratz

PUBLICATIONS

Mary R. Anderlik

Medicolegal and Ethical Issues in Genetic Cancer Syndromes, Seminars in Surgical Oncology 2000; 18:339-346 (with Elaine A. Lisko)

Laura F. Rothstein

DISABILITY LAW: CASES & MATERIALS (2d edition) (Lexis - 2000 Supp.)

DISABILITIES AND THE LAW (WestGroup - Summer 2000 Cum. Supp.)

"Don't Roll in My Parade: Sports and Entertainment Cases and the ADA," published by the U. Tex. Rev. of Litigation symposium issue

"Reflections on Disability Discrimination Policy: 25 Years," 22 U. Ark. L. Rev. 147 (2000)

"The Implications of Bragdon v. Abbott on Genetic Discrimination," for the National Action Plan on Breast Cancer and the National Human Genome Research Institute (to be published by University of Maryland Health Law Journal)

"School Choice Would Leave Needy Further Behind," Outlook Section of the Houston Chronicle, 23A (March 27, 2000)

Ronald Turner

Employment Discrimination, Labor and Employment Arbitration, and the Case Against Union Waiver of the Individual Worker's Statutory Right to a Judicial Forum, Emory L.J. (2000);

The Unenvisaged Case, Interpretive Progression, and the Justiciability of Title VII Same-Sex Sexual Harassment Claims, Duke J. Gender L. & Pol'y (2000).

HIV/AIDS, the Workplace, and Federal Appeals Courts’ Construction of the ADA will be published in a forthcoming issue of the AIDS & Public Policy Journal.

William J. Winslade

A brush with off-road rage on the Gulf Freeway, Houston Chronicle, May 1, 2000, p. 21A

PRESENTATIONS

Laura F. Rothstein

"Current Issues for Disabled Persons on College and University Campuses," University of Alabama Conference on the ADA, Tuscaloosa, Alabama, March 3, 2000

"Legal Issues Regarding Public School Students with Disabilities," Presentation to University of Houston Graduate Students, College of Education, Houston, Texas, April 5, 2000

"Legal Issues Regarding Public School Students with Disabilities," Texas Southern University Graduate Students, College of Education, Houston, Texas, April 12, 2000

Mark A. Rothstein

"The Social Challenges of Behavioral Genetic Research," University of Houston Research Day, Houston, Texas, April 7, 2000

"The Genetic Revolution Meets Health Law, " Houston Bar Association Health Law Section, Houston, Texas, May 12, 2000

"Legal and Ethical Issues in Genetic Medicine," Baptist Health Care System, San Antonio, Texas, May 13, 2000

"Ethical Guidelines for Medical Research on Workers," American College of Occupational and Environmental Medicine, Philadelphia, Pennsylvania, May 17, 2000

"Who Cares About Genetic Privacy?" Dartmouth College, Hanover, New Hampshire, June 29, 2000

William J. Winslade

Concepts of Fairness & Justice, Lenten Lecture Series: Faith & Healing, Continuing Medical Education Program Program, University Presbyterian Church in Conjunction with The Institute for the Medical Humanities, University of Texas Medical Branch, Austin, Texas, April 9, 2000

Law and Ethics in Radiology, Continuing Medical Education Program, Texas Radiological Society's 87^th Annual Meeting, Austin, Texas, April 29, 2000

AWARDS

Laura Rothstein

• Was named Professor of the Year for 2000 by the Black Law Students Association.

• Received the Asian Law Students Association Appreciation Award for 2000.

Mark Rothstein

• Has been appointed to the Steering Committee of the Pharmacogenetics Research Network of the National Institute of General Medical Sciences of the National Institutes of Health.

• Has been promoted to full professor Ron Turner.

• Has been selected to serve as the chair for the 2000 Southeast/Southwest Scholars of Color Conference that will be held at the University of Arkansas, Fayetteville.

Introduction to Research Ethics

Joseph J. Wang, J.D., M.P.H.
Research Professor
Health Law & Policy Institute
University of Houston Law Center

Advances in biomedicine, increased funding for biomedical research, and the partnership of biotechnology and information technology are driving larger and more frequent clinical trials, more complex research protocols, and higher expectations. This level of scientific inquiry will demand an ever-increasing number of human participants. In this issue of Health Law News, experts in law and bioethics explore various aspects of research involving human subjects and consider many of the leading ethical issues in research.

Although the use of humans as research subjects is an integral and indispensable part of biomedical investigation, the implications of such use extend well beyond the scientific.

Whether research promises to provide therapeutic value to patient-subjects or is undertaken solely to yield knowledge, it may pose various risks to participants as individuals or as a group. Physical harm is cited most often as a risk in experimentation. Risk goes beyond the physical, however. Mark A. Rothstein considers how genetic research may have a negative impact on individuals, families, and entire ethnic groups. Jeffrey M. Cohen identifies human subjects issues arising in the age of the Internet.

Research with human participants should be conducted in a manner that reflects respect for persons and acknowledges personal autonomy. Researchers should not treat a person merely as a passive thing to be acted upon, use that person as a means to an end, or disregard the will of that person for the sake of gaining knowledge. These considerations guide Baruch Brody's examination of the ethical quandaries surrounding the use of placebos in research.

Another ethical issue raised by research involving human subjects involves who should bear the burdens of research and who should share in the fruits of its success. The issue is one of distributive justice. Historically, the poor, the sick, the uneducated, and other vulnerable classes have been used more often as research subjects, particularly in non-therapeutic trials. The allocation of risks and benefits is ethically significant and must be assessed to prevent the unjust recruitment of human subjects. Sharon Cooper looks at both the intuitive and counterintuitive ethical issues that arise in the study of migrant farmworkers.

The ethical principles of beneficence, respect for persons, and justice must be honored in any study involving humans. The Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research summarizes these basic ethical principles in connection with research on human subjects. Failure to honor these principles in the past resulted in dire consequences as exemplified by the atrocities committed by the Nazis and Japanese, and the incidents of wrongdoing by the United States in the name of science. As the demand grows for human participants in research, studies become more complex, and the risk of harms increases, the need for regulatory safeguards to protect the interests of human subjects becomes more important. The establishment of ethical standards should not be left to the discretion of researchers because the pursuit of knowledge may cloud their judgment. The two primary forms of human subject protection are informed consent and oversight by institutional review boards (IRBs).

Both the Nuremburg Code and the Declaration of Helsinki firmly established the need for scientists and physicians to obtain the informed consent of participants or patients before conducting any experimentation on them. Although getting the informed consent of a person requires only that the person be informed, be free to consent, and have the capacity to consent, many questions arise as to what the various elements require. The issue is more complicated when dealing with special populations such as children, prisoners, mentally infirm persons, terminally ill patients, and other groups either with diminished capacity or under great duress because of their increased vulnerability to manipulation and harm. Sharona Hoffman looks at the problems of informed consent and confidentiality in biomedical research involving prisoners.

IRB review, approval, and oversight of research involving human subjects is required under the "Common Rule." The Common Rule, embodied in regulations promulgated by various federal agencies, governs all federally funded research and research to support applications to the Food and Drug Administration. IRBs are usually appointed and commissioned by the institution seeking federal funds for research. Although IRBs function as a first and last defense against ethically dubious research, they are plagued by an increased workload and a constriction of resources, both of which adversely affect the adequacy of review and oversight.

In April 2000, the Department of Health and Human Services Office of Inspector General (OIG) released a report on the status of its June 1998 recommendations to the National Institutes of Health and the Food and Drug Administration on protection of human subjects in research. The 1998 recommendations focused on six categories of IRB reform: flexibility and accountability, oversight and protections, education, conflicts of interest, workload, and federal oversight. The OIG concluded that, although enforcement of federal human subject protections has increased substantially, few of its recommendations have been implemented. J. Thomas Puglisi presents the view from the Office for Protection from Research Risk on the issue of federal oversight.

Efforts to educate researchers about ethical issues should complement external enforcement of human subject protections. In the end, researchers must obtain the proper informed consent from research participants. They must weigh the potential benefits of their proposed research against the possible risks and they must minimize risks to subjects. They must consider the possible ethical, legal, and social consequences of their studies.

Research on human subjects is much more than the pursuit of empirical knowledge. Research is a social act and how it is conducted has consequences reaching farther than any knowledge that may come from it. In the final analysis, our very humanity rests on how we treat each other, including our most vulnerable individuals.

Placebos in Clinical Trials: New Forms of an Old Issue

Baruch A. Brody, Ph.D.
Director, Center for Medical Ethics and Health Policy
Baylor College of Medicine

Clinical trials are the gold standard for evaluating medical and surgical therapeutic interventions. In these trials, a treatment group receives the intervention to be tested while a control group does not receive that intervention. Subjects in the trial are randomly assigned to one of the groups, and the outcomes of the two groups are compared to see whether the intervention being tested produces a favorable outcome. Two features are essential to the scientific validity of a clinical trial. There must be a control group as well as an intervention group so that the results of the intervention can be compared with the results in a group not receiving the intervention, and subjects must be randomly assigned to the two groups to ensure that there is no selection bias leading to a more favorable outcome in one group because of the selection of subjects assigned to it.

A long standing issue in research ethics is the treatment to be provided to the subjects in the control group. If there exists no already established treatment for the condition in question, then the control group can simply receive no active intervention. To avoid biases in the assessment of outcomes and in the provision of other therapies, it is customary, where possible, to provide the subjects in the control group with a sham treatment that is indistinguishable from the active treatment. This is called blinding the subjects and the researchers to the assignment of the subjects to the group to which they are assigned; in drug trials, this is accomplished by giving the subjects in the control group a placebo pill which resembles and tastes like the drug being tested. The situation is more complicated when there exists an already established treatment and the goal of the clinical trial is to test a new (and perhaps better) intervention. From an ethical perspective, it seems better to provide the subjects in the control group with the established treatment and to compare the results in the intervention group receiving the new treatment with the results in the control group receiving the established treatment. Such clinical trials are called active controlled trials and seem mandated by the Declaration of Helsinki, which says:

On the other hand, from a scientific perspective, it is easier to conduct and to interpret the results of clinical trials when a placebo control group is used, and risks can be lessened by limiting the time in which the control group receives only a placebo and by providing for rescue treatments if subjects in the control group get into trouble. While the FDA regulations allow for the use of both types of control groups, they clearly prefer the use of placebo control groups unless the condition being treated is life threatening. 21 C.F.R. 314.126 (1999). There is a considerable literature assessing the ethical validity of this stance. This is the traditional version of the placebo-in-clinical-trial issue. Two new versions of this issue have emerged in recent years and have attracted considerable attention. One relates to placebo controlled trials in third world countries and the other relates to blinded placebo controlled surgical trials which require a sham surgery component.

ACTG 076 was an NIH sponsored placebo controlled trial which showed that the extensive use of AZT in HIV positive pregnant women and their newborn children could drastically reduce the extent of transmission of HIV from the pregnant women to their children. This regimen of AZT has become the standard of care in developed countries, except when an even more intense cocktail of drugs is used. But the cost of these drugs is very high, making them unaffordable in many poorer countries that are today the major locations of the HIV epidemic. Several clinical trials have been run to assess the value of less intense less expensive therapeutic regimens. Some of these have been successful, although not necessarily as good as the 076 regimen; others have not. An excellent summary of the trials is found in E. Marshall, "Controversial Trial Offers Hopeful Result" 279 Science 1299 (1998) and "Cheap Treatment Cuts HIV Transmission" 283 Science 916 (1999). All of these trials have been run as placebo controlled trials, since this makes them easiest to run and validly interpret. But was it ethical to deny any intervention to the control group? The critics said that it was unethical and cited as support the above-quoted standard of the Declaration of Helsinki. The defenders argued that it was not unethical because the subjects in the control group would not have received any intervention outside of the trial so they were not being unjustly deprived of an intervention they would otherwise have received. "Science, Ethics, and the Future of Research into Maternal Fetal Transmission of HIV-1" 353 The Lancet 832-5 (1999). All of this has led to an attempt to revise the Declaration of Helsinki. See the debate between Brennan and Levine in 341 New Eng. J. Med. 527-34 (1999).

For many years, there was a ban on the federal funding of research using fetal tissue. This was repealed by the NIH Reauthorization Act of 1993. 42 U.S.C. 498A. One of the first protocols funded by the NIH was a study of the transplantation of fetal tissue to patients with Parkinson's Disease. The intervention group received this surgical intervention while the control group did not. But how could the subjects and the investigators be blinded to the treatment assignment to avoid biases in the assessment of outcomes and in the provision of other treatments? The investigators chose to perform sham surgery on the subjects in the control group, exposing them to the risks of general anesthesia and of the boring of burr holes in the skull. Critics objected to this trial, not because of the use of a placebo control group but because of the risks imposed in the blinding process. Defenders argued for the scientific necessity of the sham surgery and defended it ethically on the grounds that the risks were reasonable and the subjects had consented. See the debate between Freeman and Macklin in 341 New Eng. J. Med. 988-996 (1999).

The classical ethical issues about placebo controlled clinical trials are still present. But this crucial form of scientific research has now given rise to new issues.

Human Subjects Issues in Internet Research

Jeffrey M. Cohen, Ph.D.
Associate Director for Education
Division of Human Subjects Protection
Office for Protection from Research Risks

It is clear that the Internet will be used increasingly in conducting human subjects research. Research on the Internet presents new concerns to the traditional human subjects issues: risk/benefit, informed consent, participation by minors, and confidentiality. Investigators are going to have to provide technical information on how they will deal with these issues and IRBs are going to have to have sufficient expertise to ask the right questions and evaluate the information provided. An IRB that reviews a protocol involving Internet research without sufficient expertise is not in compliance with the regulations.

Human Subjects Issues

Risk. There are two sources of potential harm to subjects from research: harm resulting from participation in the research (e.g., acute emotional reactions to certain questions), and harm resulting from breach of confidentiality. Since there is generally no direct contact with subjects participating in research over the Internet, it may be difficult or impossible to deal with individual subject reactions. As a result, some sensitive research may not be appropriate for the Internet. Breach of confidentiality is the primary source of harm in most Internet research and is dealt with below.

Benefit. Conducting research on the Internet raises concerns about the reliability and validity of the data. This can be the result of skewed subject populations due to differences in access to computers, the ease with which subjects can mislead investigators, or difficulty in preventing multiple submissions. Research which results in unreliable or invalid data can have no benefit and, as such, is inappropriate if the research involves any risk to subjects.

Consent. Not all research needs documentation of informed consent; IRBs can waive the requirement for consent where appropriate. Innocuous research on non-sensitive subjects conducted over the Internet may not need documentation of consent. [Note - only the IRB can make that decision.] When a signed consent form is not required, investigators can use a "portal"; i.e., where subjects must click on a consent page to get to the rest of the research. Since it is currently not possible to get a signed consent form over the Internet (although the technology for electronic signatures is not far off), where that is required, investigators can have subjects submit a signed consent form and send them a password to gain access to the research pages. In any event, investigators must indicate to the IRB how they plan to get consent from subjects.

Participation by Minors. The IRB has the authority to waive the requirement for parental permission and, where the research qualifies for such a waiver, no additional safeguards for minors are required. Either minors can participate without permission or a simple statement in the consent that the participant is over 18 is sufficient. Where parental permission is required, investigators can use passwords as above. To screen out minors completely from the research, investigators can take advantage of Internet Monitoring software (SafeSurf and RSACi ratings) or use Adult Check systems. Since no system can guarantee that minors are not participating, some research may not be appropriate for the Internet.

Confidentiality. Since it is impossible to guarantee absolute data security over the Internet, some extremely sensitive research may not be appropriate for the Internet. Investigators need to address how they intend to assure confidentiality, keeping in mind that the degree of concern over confidentiality is directly related to the sensitivity of the data. Data transmitted via e-mail cannot be anonymous without the use of additional steps. Almost all forms of e-mail contain the sender's e-mail address. In order to maintain anonymity the research must use an "anonymizer" - a third party site that strips off the sender's e-mail address. Data submitted over the Web can only be anonymous if software is used to store the information directly in a database without identifiers; otherwise identifiers are attached to the data. Web servers automatically store a great deal of personal information about visitors to a web site and that information can be accessed by others.

Types of Research on the Internet.

There are three types of research conducted on the Internet:

• Recruiting Subjects over the Internet
• Observation of Internet Activity
• Collecting Data Over the Internet

Observation of Internet Activity. Observation of Internet activity usually involves such activities as gathering information about the use of the Internet, recording user information or users’ comments. Examples include: participant observation of an on-line discussion group, using "cookies" to track web sites visited, or asking visitors to a web site to provide demographic information. The human subjects issues involved in this type of research generally involve consent/disclosure issues. Investigators need to indicate to the IRB how they intend to obtain the subjects' consent to use this information for research. As with other types of participant observation, investigators generally must disclose their role as researchers to the group participants.

Gathering data over the Internet. This type of research generally involves having subjects submit data, e.g., survey data, over the Internet and presents the most serious human subjects concerns. As in the other types of Internet research, the investigator needs to indicate how subjects' consent will be obtained and their confidentiality protected. Of particular concern with this type of research is the participation by minors and investigators must address this issue in their IRB protocols.

Ethical Issues in Migrant Farmworker Studies

Sharon Cooper, Ph.D.
Associate Professor of Epidemiology
Assistant Dean for Academic Affairs
The University of Texas-Houston School of Public Health

Agriculture is still one of the most hazardous industries in the U.S. and in Texas, although little is known about the magnitude of injuries and illnesses in migrant farmworker populations consisting of both adults and children. Despite the importance of these workers to the agricultural economy and food production in this country, their work does not provide them financial security, the conditions are conducive to injury and hazardous exposures, the wages are low, and their life-span is shortened. The farmworker population in the U.S. is becoming increasingly foreign-born and unauthorized. Further, the median annual income of farmworkers is less than $7,500, and on average, farmworkers complete six years of education (U.S. Department of Labor, 2000). By whatever definition is used to describe vulnerable populations, migrant farmworker families fit into this designation.

The permanent residence for many migrant farmworkers in the U.S. is Texas. Approximately three-quarters of the estimated 500,000 migrant and seasonal farmworkers and their dependents in Texas reside along the Texas/Mexico border. Starr County is one of these border counties, where the population is 97% Hispanic (primarily Mexican American), many of the residents are migrant farmworkers, and a majority of the county is strikingly economically disadvantaged (The University of Texas System Texas-Mexico Border Health Coordination Office, 1998). A series of four feasibility studies, funded by the National Cancer Institute, was conducted in Starr County, and nearby Hidalgo County by investigators at The University of Texas-Houston School of Public Health. Many ethical issues related to research with this population arose, some expected, but many unexpected.

In the first study, the objective was to follow-up a cohort of approximately 200 migrant farmworkers, self-identified in diabetes/gallbladder studies conducted 10 years earlier, with no interim contact for the majority of this group. We were able to trace 91% of this cohort, ten years later, and administer a short questionnaire to 100% of those we traced who were living. This is astonishing in epidemiologic research, and the study team learned that we needed to be extremely cautious about what we asked, since the response was extraordinary. It was clear we needed to be especially respectful of their willingness to participate. The second study was a pretest among older farmworkers of a questionnaire to assess a lifetime work history. This questionnaire took from 1-3 hours to complete, depending on the farmworker’s age and work history, and was administered in the homes of the farmworkers during the hot summer months in south Texas (without air-conditioning). This raised the issue of administering a perhaps excessively long questionnaire to participants in extremely hot weather conditions. A third feasibility study involved three focus groups (one each with farmworker mothers, and their sons and daughters) to assess job tasks and activities, which could involve pesticide exposure to children. The importance of cross-cultural research, children’s participation in research, and qualitative data, become evident. And finally, the last feasibility study was conducted among nine pregnant farmworker women to obtain biologic measures of pesticide exposure based on maternal urine, umbilical cord blood, and placenta samples. Contrary to our expectations, The University of Texas Committee for the Protection of Human Subjects would not allow us to share individual study results with our participants or with the treating health care providers. The rationale for this was that we could not adequately interpret the results in terms of health effects, and if there were evidence of very high pesticide levels or acute pesticide poisoning, then exceptions would be made for medical referral. The results of our study, did, in fact, support the wisdom of this approach, since many of the contaminants were measurable, but not interpretable in terms of health effects. Individual knowledge of these results would have done harm without any compensating benefits.

In summary, the investigators identified a number of ethical issues that arose from these feasibility studies, some of which were intuitive, but some very unexpected. Issues of language, compensation, and the ethical principles which guide epidemiologic and other types of research, such as beneficence, nonmaleficence, autonomy, and justice (Coughlin and Beauchamp, 1996), are complex, but intuitive issues in research with migrant farmworkers. However, we also learned, with the guidance of our institutional review board, that academics do not have automatic rights to obtain scientific knowledge, that the inclusion of children in research is important, that the scope of human subject considerations in research is large, and although initially counterintuitive, there are times when it is not appropriate to share results of research with individual study participants. We also learned the importance of community involvement in research, a partnership that we credit for the success of these studies.

The need for intensive manual labor performed by migrant farmworkers and their children is expected to increase in the U.S. (General Accounting Office, 1998), suggesting a continuation and proliferation of health risks to migrant farmworker families. The need for more research is clear; this pursuit includes the careful consideration of complex ethical issues.

Prisoner Participation in Biomedical Research

Sharona Hoffman, J.D., LL.M.
Assistant Professor of Law
Case Western Reserve University School of Law

Prisoners constitute a growing segment of society. In 1999, over 1.8 million people were in jail at any given time in the United States, generating an imprisonment rate of 672 inmates per 100,000 residents in this country.

A disproportionately large number of prisoners are sick. A 1992 study revealed that while HIV had an incidence rate of 18 cases per 100,000 in the general population, the rate among prisoners was 362 per 100,000 that year. In 1992-93 there were more than 11,500 AIDS cases and almost 3,500 AIDS-related deaths among prisoners in state, federal, county, and large city correctional facilities. The New Jersey Department of Health has estimated that almost 9 percent of adult male prisoners and more than 14 percent of adult female inmates are infected with HIV, and among prisoners with a history of illegal drug use, 40 percent of the men and 42.6 percent of the women are HIV positive.

There is also a significant tuberculosis problem in prisons. In 1992 tuberculosis had an incidence rate of 189 per 100,000 among New York state prisoners. Prisoners have many other serious ailments as well, including cancer, heart disease, and liver problems.

Prisoners are generally not included in biomedical research studies, even when conventional treatments have failed and experimental therapies might provide them with their only hope of survival. The reluctance to include prisoners in clinical trials is rooted largely in history. Up until the latter part of the twentieth century prisoners were widely used in biomedical experimentation and were often severely abused in the process.

The most notorious example of experimentation conducted with prisoners is the "research" that took place in the Nazi death camps. Many prisoners were involuntarily infected with yellow fever, smallpox, typhus, cholera, malaria, and diphtheria germs. Others were subjected to experimentation involving high altitudes, freezing, mustard gas, bone transplantation, amputation, sea water, sterilization, burning, and incendiary bombs. The vast majority of those human subjects died after suffering unimaginable torments and physical pain.

During WWII Japanese researchers also conducted barbarous experiments on prisoners in Manchuria. Unlike the Nazi doctors, however, the Japanese investigators were never prosecuted. In exchange for silence, the Japanese agreed to share the results of their experiments regarding biological warfare with the American government.

In this country we were also far from innocent. Until the 1970s prisoners were used in biomedical experimentation involving malaria, hepatitis, cancer, radiation, rubella, dioxin, and many other substances and diseases. By 1969, 85% of new drugs were tested on incarcerated persons in 42 prisons, and many of the prisoners suffered long-term ill effects. A powerful expose of this research is found in a book by Allen Hornblum, entitled Acres of Skin, which focuses on studies that were conducted in one facility, Philadelphia’s Holmesburg Prison, from the early 1950s to the early 1970s.

As a result of the abuses that were discovered, the Department of Health, Education and Welfare, now the Department of Health and Human Services, implemented regulations designed to protect prisoners participating in clinical trials. Prisoners can participate in only four types of studies: (1) studies of the possible causes, effects, and processes of imprisonment and criminal behavior that involve no more than minimal risk to the subjects; (2) studies of prisons as institutional entities or of inmates as incarcerated individuals, so long as there is no more than minimal risk to the subjects; (3) research on particular conditions affecting prisoners as a class, so long as the research is approved by the Secretary of Health and Human Services or an authorized DHHS employee ("Secretary"); and (4) research involving a treatment likely to benefit the prisoner himself or herself. If a prisoner might be assigned to a placebo control arm, the study can proceed only with approval by the Secretary. Among the other applicable regulations is a requirement that each IRB that reviews a protocol involving prisoners include at least one prisoner or prisoner advocate.

In order to ensure that prisoners are not abused in biomedical research and to avoid the burden of meeting regulatory requirements for such research, many states have implemented regulations that preclude prisoner access to clinical studies. Only a few medical facilities have provided inmates with access to clinical trials, including research institutions located in Colorado, Connecticut, Maryland, New York, Virginia, and UTMB in Galveston, Texas.

Abuse of prisoner subjects in biomedical research or failure to obtain meaningful informed consent from inmates can lead to violations of their constitutional rights established by the Fourth, Eighth, and Fourteenth Amendments. However, prohibiting seriously ill prisoners from participating voluntarily in clinical research may constitute an equivalent contravention of their constitutional rights under the Eighth Amendment and Due Process and Equal Protection Clauses.

Prisoners have a constitutional right to receive medical care while they are incarcerated. Treatments for HIV and AIDS, which affect a large number of prisoners, are often experimental. Many cancer treatments are also investigational therapies. When seriously ill prisoners are denied access to potentially life-saving experimental treatments developed through clinical trials, they may be deprived of the only medical care that could be of benefit to them.

In addition, prisons provide a uniquely diverse population with a high concentration of minorities. Diversity in clinical research is important because various minorities may be affected differently by particular diseases and may react differently to therapy. Approximately half of the prison population is African American, and 15% is Hispanic. As of 1998, Blacks accounted for 49% of all AIDS deaths, and 18% of AIDS deaths were among Hispanics. Black men also have a higher risk of cancer and cirrhosis of the liver than non-African American men, and Hispanics report higher rates of heart disease and chronic liver disease than do non-Hispanics. Traditionally, however, African Americans, Hispanics, IV drug users, and women have been underrepresented in clinical trials. For example, two important studies in which AZT was tested were conducted with a population that was more than 92% white and male.

Researchers have found that members of different genders and races at times respond to treatments in different ways. Whites and blacks, for example, respond differently to hypertensive therapy. Some ethnic groups have different attitudes about health care and medical intervention. Women at times react to drugs differently from men because of variations in size, body fat, and hormonal levels. The efficacy of drugs may also be significantly affected by other drugs, including illegal substances taken by the patient. Exclusion of minority subjects from clinical studies is "bad science." The inclusion of prisoners in studies would therefore benefit not only the inmate patients themselves, but also future patients and medical science.

Admittedly, allowing prisoners to participate in clinical studies can generate some logistical difficulties associated with transportation of prisoners to medical facilities, communication with investigators, and confidentiality. For purposes of this article, I will focus only on the confidentiality issues.

Prisoners enrolled in clinical trials risk disclosure of their medical status either because it is obvious that they are receiving frequent and specialized medical care or because of the prison’s record-keeping policies. It is not clear that prisoners have a right to confidentiality regarding medical records in the prison setting since the courts have issued inconsistent decisions with respect to this question. Nevertheless, disclosure of an individual’s medical history in the prison setting may be particularly dangerous, especially for HIV patients, and thus should be avoided. Inmates with HIV might be subjected to violence and abuse by other prisoners or correctional officers because of both disdain and fear of transmission.

Several mechanisms should be implemented to safeguard the prisoners’ privacy. Investigators should publicize the research through newsletters or postings that are seen by all inmates so that particular prisoners do not have to identify themselves and ask for information. If the research institution provides routine medical care to prisoners, enrollment should occur during a regular medical visit by the institution’s staff or on a day when other prisoners will be transported to the medical facility for treatment rather than at a time specifically designated for discussion of the clinical study.

Another concern is the storage of the inmates’ medical records. The prisoners’ medical files should be maintained in secured areas that can be accessed only by medical personnel directly responsible for the inmates’ treatment. Correctional officers and other inmates should not have access to sensitive health records even if they are assigned to work in the prison’s medical department.

Prisoners should also have confidential access to investigators in the event they suffer adverse side effects or have questions about their treatment. Inmates involved in clinical trials should be able to place collect calls to designated medical personnel or to an answering service 24-hours-a-day. Where telephone usage by prisoners is restricted, inmates may be limited to contacting research staff only with permission of prison officials, and thus may be forced to disclose confidential information to correctional officers. However, inmates should be instructed to approach designated individuals who are aware of the clinical trials and have received training related to privacy and confidentiality concerns.

The hurdles associated with the inclusion of prisoners in biomedical research are not insurmountable, as evidenced by the fact that several research institutions have successfully worked with inmates for many years. Under the contemporary regulatory scheme, multiple safeguards exist to protect prisoners from abuse in medical studies. Clinical trials that comply with these regulations and are open to prisoners will not only enhance treatment opportunities for seriously ill inmates, but also will provide medical investigators with access to a diverse subject population that can enrich research results.

Protecting Human Research Subjects: Ten Common Problems

Tom Puglisi, Ph.D.
Director, Human Subject Protections
Office for Protection from Research Risks
Department of Health and Human Services

Last year marked the 25th anniversary of the Department of Health and Human Services (HHS) regulations for Protection of Human Subjects in research (Title 45, Code of Federal Regulations, Part 46; May 30, 1974). At their core (Subpart A), the HHS regulations contain requirements for research institutions to assure protections for subjects; for obtaining and documenting informed consent of subjects; and for review of research by Institutional Review Boards (IRBs). The HHS regulations also contain additional protections for pregnant women (Subpart B), prisoners (Subpart C), and children (Subpart D).

In 1991, Subpart A of the HHS regulations was adopted as the Federal Policy (Common Rule) for the Protection of Human Subjects. Today, the Federal Policy is shared by 17 Departments and Agencies, covering most, but not all, federally supported human-subject research, including the following: Agency for International Development; Central Intelligence Agency; Consumer Product Safety Commission; Department of Agriculture; Department of Commerce; Department of Defense; Department of Education; Department of Energy; Department of Health and Human Services; Department of Housing and Urban Development; Department of Justice; Social Security Administration; Department of Transportation; Department of Veterans Affairs; Environmental Protection Agency; National Aeronautics and Space Administration; and National Science Foundation.

In addition, Food and Drug Administration (FDA) regulations at 21 CFR Parts 50 and 56 confer protections on human subjects when a drug, device, biologic, food additive, color additive, electronic product, or other test article subject to FDA regulation is involved. FDA regulations and the provisions of the Federal Policy are largely congruent, although there are some differences.

The Federal Policy [45 CFR 46.102(d)] defines "research" as "a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge." Activities which meet this definition constitute research, whether or not they are considered research for other purposes.

The Federal Policy [§46.102(f)] defines "human subject" as "a living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information." Some investigators fail to understand that accessing identifiable private information about an individual constitutes human-subject research.

OPRR oversees implementation of the human-subject regulations in all research conducted or supported by HHS. Each institution conducting such research sets forth the procedures it will use to protect human subjects in a written policy statement called an "Assurance" of Compliance. Under the Federal Policy, OPRR has the authority to approve assurances for federal-wide use. Where noncompliance has occurred, OPRR has the authority to require corrective actions under the assurance or to withdraw its approval of the assurance, thus halting the institution's federally-supported human-subject research.

Common Problems in Protecting Human Subjects

Over the years, OPRR has identified a number of common deficiencies in institutional human-subject protection programs. OPRR strongly encourages responsible officials to take proactive steps to prevent the following problems from developing at their institutions:

(1) Inadequate IRB Resources. Lack of resources is the most common root cause of deficiencies in human-subject protection programs nationwide. HHS regulations [45 CFR §46.103(b)(2)] require that institutions provide sufficient staff to support the IRB's duties.

(2) Lack of Understanding about Regulatory Requirements. OPRR often finds that IRB chairpersons, IRB members, and research investigators lack a sufficient understanding of human-subject protection requirements. Substantive initial and continuing education about these requirements is needed on an ongoing basis. Benchmark institutions are now requiring such training as a mandatory prerequisite for the privilege of conducting human-subject research.

(3) Conducting Research without IRB Approval. All research involving human subjects must be prospectively reviewed and fully approved by the IRB before it is initiated [§46.109(a)]. Strong institutional mechanisms are needed to ensure that investigators never initiate human-subject research without IRB approval.

(4) Changing Research Procedures without IRB Approval. The IRB must review and approve all proposed changes to human-subject research prior to implementation of those changes [§46.103(b)(4)]. Institutional mechanisms are needed to ensure that all investigators understand and comply with this requirement.

(5) Inadequate Initial IRB Review. IRBs must determine that eight specific regulatory criteria are satisfied in order to approve research [§46.111]. OPRR often finds that IRBs receive insufficient information from investigators to make the required determinations.

(6) Inadequate Continuing IRB Review. Continuing IRB review of research must be substantive and meaningful, and must occur at least annually [§46.109(e)]. In conducting continuing review, all IRB members should at least receive and review a protocol summary, a detailed status report on the progress of the research, and a copy of the current informed consent document. The regulations make no provision for any grace period extending the conduct of research beyond one year after the last date of IRB approval.

(7) Failure to Report Unanticipated Problems to the IRB. Investigators must report promptly to the IRB any unanticipated problems involving risks to subjects or others [§46.103(b)(4)]. Many investigators do not fully understand this requirement, and many IRBs do not provide sufficient guidance to explain this requirement to investigators.

(8) Deficient Informed Consent Documents. Legally effective informed consent must be consistent with State law and must incorporate eight specific elements delineated in the regulations [§46.116]. OPRR often finds instances where (i) required elements are omitted, or (ii) there are discrepancies between the protocol application and the informed consent document regarding the purpose, risks, and benefits of the research.

(9) Inadequate Informed Consent for Non-English Speakers. Informed consent information must be presented "in language understandable to the subject" and, in most situations, must be documented in writing [§46.116 and §46.117]. Subjects who do not speak English should be presented with a consent document written in a language understandable to them.

(10) Inadequate IRB Membership. An IRB must include the diversity (including consideration of race, gender, and cultural backgrounds and sensitivity to such issues as community attitudes) to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects [§ 46.107(a)]. OPRR often finds that IRBs lack this required diversity of membership.

OPRR's Education Mandate

As the above list suggests, many deficiencies in human-subject protection can be prevented through proactive education. OPRR takes very seriously its statutory mandate under Section 491 of the Public Health Service Act to provide "clarification and guidance" on ethical issues related to research involving human subjects. To this end, OPRR conducts a number of regional workshops each year, participates in many professional meetings, visits research institutions for educational activities, and provides a variety of guidance documents and materials. Information about all of these is available on OPRR's website (http://grants.nih.gov/grants/oprr/oprr.htm).

Family and Community in Genetic Research

Mark A. Rothstein, J.D.
Cullen Distinguished Professor of Law
Director, Health Law & Policy Institute
University of Houston

With the completion of the Human Genome Project's first draft sequence of the human genome expected later this year, it is quite likely that the pace of genetic research involving human subjects will accelerate. This new stage of genetic research will raise a variety of human subjects issues -- some in a different context from other forms of biomedical research. Perhaps the most unique aspect of genetic research is its effect on families and communities.

With the exception of somatic mutations, genetic disorders are, by definition, heritable. Therefore, the information generated by genetic testing is family information. This fact raises important issues for researchers at every stage, including study design, recruitment of participants, the informed consent process, and the sharing of research findings with study participants and others.

There are at least four main areas of special concerns in genetic research. The issues come into sharper focus using specific examples, and I will discuss the issues in the context of research on genetic predisposition to breast-ovarian cancer.

1. Undermining of family relationships.

Two sisters are in a high-risk family, where their mother and some aunts and cousins had breast or ovarian cancer. The threat that one or both of them might also be affected at some point creates a special bond between them. The advent of genetic testing for BRCA1 and BRCA2 mutations in research protocols now gives them the opportunity to determine their risk. What happens if one sister tests positive and the other sister tests negative? Will this cause "survivor guilt" in the unaffected sister and "genetic resentment" in the affected sister? The special bond that has allowed the sisters to cope with this "sword of Damocles" may well be undermined.

The starting point for the cost-benefit analysis of testing for any individual or group of individuals is the predictive value of the test. There is some uncertainty in the literature about the lifetime risk for a woman who tests positive for one of the breast-ovarian cancer mutations, with recent studies suggesting about a 50 percent lifetime risk of breast cancer. The lifetime risk of a woman with a negative test is not zero, but is the population risk of approximately 10-12 percent. With the lack of effective prevention strategies for someone who tests positive, is it worth it to the sisters as a social matter to have the testing?

This illustration makes it imperative that in pretest genetic counseling, it is made clear to each potential participant that a negative test result is not necessarily an unmitigated good and a positive test result is not necessarily an unmitigated harm. Other social issues raised by genetic testing in research include discovering misattributed paternity and the potential psychological dilemma of whether research participants should warn at-risk family members.

2. Concerns raised by clinical genetic research.

The line between research and clinical practice has become increasingly blurred. In genetics (as in other fields such as oncology), much of the testing is now performed in the context of clinical research, in which the patient's treating physician is also the researcher or is working with the principal investigator in recruitment of subjects, analysis of the data, or other aspects of the research. The dual role of clinician-researcher often raises ethical concerns.

In investigational genetic research (i.e., nonclinical research), the investigators must determine whether any individual's test result has sufficient clinical utility that the study participants are offered a choice as to whether they want to be informed about their results. Where the study is preliminary, the design may use anonymous or de-identified samples. The study participants may not learn any findings, the results may not be transferred to the participants' clinical files, and a certificate of confidentiality may be obtained to ensure that research files need not be disclosed pursuant to legal process. By contrast, in clinical research, the genetic testing may be a part of the diagnostic and treatment process.

In an example from David H. Smith and his colleagues (Early Warning: Cases and Ethical Guidance for Presymptomatic Testing in Genetic Diseases (1998)), a woman is recruited by her physician into a research study on breast-ovarian cancer, which is present in her extended family. At the time of enrollment, she made it clear that she did not want to be informed of the results. Her test comes back negative. Through one of her sisters, also a patient of the researcher, it is learned that the first sister is so certain that she will get breast or ovarian cancer that she is contemplating a prophylactic bilateral mastectomy and oophorectomy. This raises the difficult question of whether it is ethical to violate the express wishes of the patient (to not be informed of test results) to prevent a serious harm to the patient.

3. Economic risks to research participants.

For clinical research, the results will generally be included in clinical records for use in medical treatment decisions. Because it is a part of the patient's medical record, its release will follow the same rules as the release of any medical information. Thus, as a lawful condition of employment, insurance, or other transactions, the patient may be compelled to execute a broad medical release disclosing to the third-party all of the medical information in his or her medical files. This is the less-discussed but more common problem surrounding medical record confidentiality: the compelled disclosure of medical information.

For investigational research, even if it is de-identified or anonymous, individuals may still not escape the negative economic consequences of participating in genetic research. For example, in applying for an insurance policy, individuals may be asked whether they have ever been a participant in genetic research and, if so, why and what kind of study. Thus, without anyone knowing the results of the test, mere participation in research could have negative economic consequences.

4. Group risks in genetic research.

The Common Rule (the federal rules applicable to government-sponsored research on human subjects) is primarily concerned with individual risks. Yet, there are undeniable group risks associated with many forms of genetic research. For example, the early studies of BRCA1 involved the reanalysis of blood samples used in Tay Sachs screening programs. The results, demonstrating a nine-fold risk of breast-ovarian cancer among Ashkenazic Jewish women, came at a time when the lifetime risk of having such a mutation was in the preliminary stages of calculation. Yet, the potential for stigma and anxiety does not wait for more precise research findings.

Research involving behavioral genetics raises particular concerns. Even without individual identifiers there is a substantial potential for harm if research were published finding that a particular ethnic group is genetically predisposed to addictive behavior, violence, or mental illness.

Conclusion

Genetic research often poses special challenges to investigators attempting to uphold the three core values of ethical research: respect for persons, beneficence, and justice. Researchers, members of Institutional Review Boards, and genetic counselors need to think beyond the possible physical risks to the individual research participant to consider a wide range of possible risks to individuals, families, and communities.