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Human Subjects Research Regulation

Human Subjects Research Regulation: Perspectives on the Future

I. Glenn Cohen
Holly Fernandez Lynch
Series: Basic Bioethics
Copyright Date: 2014
Published by: MIT Press
Pages: 392
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  • Book Info
    Human Subjects Research Regulation
    Book Description:

    The current framework for the regulation of human subjects research emerged largely in reaction to the horrors of Nazi human experimentation, revealed at the Nuremburg trials, and the Tuskegee syphilis study, conducted by U.S. government researchers from 1932 to 1972. This framework, combining elements of paternalism with efforts to preserve individual autonomy, has remained fundamentally unchanged for decades. Yet, as this book documents, it has significant flaws -- including its potential to burden important research, overprotect some subjects and inadequately protect others, generate inconsistent results, and lag behind developments in how research is conducted. Invigorated by the U.S. government's first steps toward change in over twenty years,Human Subjects Research Regulationbrings together the leading thinkers in this field from ethics, law, medicine, and public policy to discuss how to make the system better. The result is a collection of novel ideas -- some incremental, some radical -- for the future of research oversight and human subject protection.After reviewing the history of U.S. research regulations, the contributors consider such topics as risk-based regulation; research involving vulnerable populations (including military personnel, children, and prisoners); the relationships among subjects, investigators, sponsors, and institutional review boards; privacy, especially regarding biospecimens and tissue banking; and the possibility of fundamental paradigm shifts.ContributorsAdam Braddock, Alexander Morgan Capron, Ellen Wright Clayton, I. Glenn Cohen, Susan Cox, Amy L. Davis, Hilary Eckert, Barbara J. Evans, Nir Eyal, Heidi Li Feldman, Benjamin Fombonne, Elisa A. Hurley, Ana S. Iltis, Gail H. Javitt, Greg Koski, Nicole Lockhart, Holly Fernandez Lynch, Michael McDonald, Michelle N. Meyer, Osagie K. Obasogie, Efthimios Parasidis, Govind Persad, Rosamond Rhodes, Suzanne M. Rivera, Zachary M. Schrag, Seema K. Shah, Jeffrey Skopek, Laura Stark, Patrick Taylor, Anne Townsend, Carol Weil, Brett A. Williams, Leslie E. Wolf

    eISBN: 978-0-262-32082-5
    Subjects: Law

Table of Contents

  1. Front Matter
    (pp. i-vi)
  2. Table of Contents
    (pp. vii-x)
  3. Series Foreword
    (pp. xi-xii)
    Arthur Caplan

    I am pleased to present the forty-third book in the Basic Bioethics series. The series makes innovative works in bioethics available to a broad audience and introduces seminal scholarly manuscripts, state-of-the-art reference works, and textbooks. Topics engaged include the philosophy of medicine, advancing genetics and biotechnology, end-of-life care, health and social policy, and the empirical study of biomedical life. Interdisciplinary work is encouraged....

  4. Acknowledgments
    (pp. xiii-xiv)
  5. Introduction
    (pp. 1-8)
    I. Glenn Cohen and Holly Fernandez Lynch

    Tens of billions of dollars are spent each year on clinical research of investigational treatments in the United States and around the world (Getz 2010 ), but clinical trials represent only the tip of the iceberg when it comes to human subjects research. From the scientists involved in multimillion dollar clinical trials of potential HIV vaccines, to the university anthropologist who wants to conduct interviews in Chile of shamans in the Mapuche tribe (or nation as they prefer to be called) to understand the ways in which they attach mystical significance to legal texts, to the psychology graduate student studying...

  6. 1 Setting the Stage: The Past and Present of Human Subjects Research Regulations
    (pp. 9-24)
    Amy L. Davis and Elisa A. Hurley

    On July 26, 2011, the Department of Health and Human Services (DHHS) and the Office of Science and Technology Policy (OSTP) issued an Advanced Notice of Proposed Rulemaking (ANPRM) titled, “Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators.” The ANPRM requested public comment on how the current regulations for protecting human research subjects might be modernized and revised to improve efficiency and enhance protections.

    The ANPRM represents the first potential revision of the regulations governing federally funded human subjects research in over twenty years; it is no surprise, then, that its...

  7. I Regulation of Risk

    • Introduction to Part I—Regulation of Risk
      (pp. 27-30)
      Nir Eyal

      Participation in some studies is medically far safer than in the studies that defined research ethics and inspired its regulatory framework. Consider post-approval drug follow-up; observational studies that use publicly available data; many surveys; secondary studies of stored tissue. These studies do not test unapproved biomedical substances on any person. Do they require the protections suitable for paradigm clinical studies? Or can their regulation be lighter?

      On the face of it, Rosamond Rhodes’s and Ana Iltis’s contributions to this volume present opposing approaches to this question. Rhodes laments the red tape of so much research review, and proposes a new...

    • 2 De minimis Risk: A Suggestion for a New Category of Research Risk
      (pp. 31-44)
      Rosamond Rhodes

      A sign posted on the New Jersey Turnpike declares: “Inspired. Absolute. Infallible.” Those declarations refer to the Bible, but it struck me that a number of people who work with research regulation and oversight have a similar attitude toward the Common Rule. I see this and other twentieth-century statements of research ethics as impressive first tries at formulating groundbreaking and complex rules for governing human subjects research. But I also find it hard to imagine that the authors of such could, on their first try, have adequately foreseen the future developments of technology and advances in scientific approaches to understanding...

    • 3 Risk Level, Research Oversight, and Decrements in Participant Protections
      (pp. 45-58)
      Ana S. Iltis

      Momentum has been building to revisit the federal regulations governing human research since the National Bioethics Advisory Commission’s 2001 report on research oversight (NBAC 2001). The Department of Health and Human Services’ 2011 ANPRM (Advance Notice of Proposed Rule-making) is a step in this process of revising the regulations. Several sections of the ANPRM focus on measuring and minimizing research risks and calibrating the scope of oversight to studies’ risk levels. This chapter focuses on one risk-related proposal, the proposal to eliminate continuing review of minimal risk research that has undergone expedited review. It examines the goals of the ANPRM,...

  8. II Protection of Vulnerable Populations

    • Introduction to Part II—Protection of Vulnerable Populations
      (pp. 61-64)
      Patrick Taylor

      The future of research on so-called vulnerable populations depends on what makes them distinct and also on vulnerabilities shared with all other research participants. Like all research participants, members of vulnerable populations are personally vulnerable to misunderstanding and mistakenly assessing procedures, risks, and benefits; deception; being over-influenced by financial incentives, therapeutic hope, pressure, and the desire to please; and, in an interventional study, the interplay among their current health, their nonresearch clinical care, and the intervention. Regulations respond by generally requiring consent—although to a very broad range of risks—and relying on IRB review to police the clarity, comprehensiveness,...

    • 4 Classifying Military Personnel as a Vulnerable Population
      (pp. 65-78)
      Efthimios Parasidis

      One of the primary goals of the Common Rule is to ensure that protocols governing human subjects research provide adequate protections for vulnerable populations. The 2011 ANPRM underscores the importance of adopting additional safeguards for vulnerable populations, yet does not include military personnel in its definition of “vulnerable.” This omission fails to account for decades of unethical research on service members and the coercive nature of the relationship between senior and subordinate in the military. DHHS should amend the Common Rule to explicitly classify military personnel as a vulnerable population.

      The Common Rule grants additional safeguards to populations that are...

    • 5 Children as Research Partners in Community Pediatrics
      (pp. 79-92)
      Adam Braddock

      A major goal of community pediatrics as a field of medicine is to identify and reduce the social, economic, and other environmental causes of poor child health (AAP 2005 ). Research in community pediatrics has blossomed in the wake of the discovery of social determinants of health (Greenberg 2003 ). Obesity, asthma, and environmental exposure to lead and other toxins are examples of child health problems that are impacted by social and economic disparities, and approaches to their evaluation and treatment may benefit from community-focused research. As community pediatrics research has gained prominence, community consultation and participation have been emphasized...

    • 6 Back to the Future? Examining the Institute of Medicine’s Recommendations to Loosen Restrictions on Using Prisoners as Human Subjects
      (pp. 93-106)
      Osagie K. Obasogie

      The chapters in this volume generally use the 2011 Advance Notice of Proposed Rulemaking (ANPRM) as a starting point to discuss the changing landscape of human subjects research regulation. This chapter, however, discusses an issue that is not explored in depth in the ANPRM yet is part of bioethicists’ broader conversations about rethinking existing rules: human subjects research with prisoners. A key example of this effort can be seen in the Institute of Medicine’s (IOM) 2006 recommendations to DHHS to loosen federal restrictions (45 CFR 46.300 et seq.) regarding the use of prisoners as human subjects in biomedical, epidemiological, and...

  9. III Redefining the Participant–Researcher Relationship and the Role of IRBs

    • Introduction to Part III Redefining the Participant–Researcher Relationship and the Role of IRBs
      (pp. 109-112)
      I. Glenn Cohen

      Does the existing US regulatory framework applicable to human subjects research work? If it didn’t, how would we know? Even if it has its flaws, how would we determine if there is a better path forward, lest the perfect becomes the enemy of the good?

      Consider the case of the QWERTY keyboard. The story goes (though there has been contestation of the history, to be sure) that in the case of typewriters, the QWERTY key layout was less efficient than the Dvorak Simplified Keyboard (DSK). QWERTY beat out the DSK and other systems because “the mechanical arms tend[ed] to jam...

    • 7 Toward Human Research Protection That Is Evidence Based and Participant Centered
      (pp. 113-126)
      Michael McDonald, Susan Cox and Anne Townsend

      The 2011 ANPRM (DHHS 2011) offered an outstanding vantage point to consider the potential effectiveness of the changes proposed to the Common Rule, as well as the fundamental effectiveness of the human research protection (HRP) systems that have developed in the United States and countries with parallel systems.

      The US regime for HRP affects directly or indirectly provisions in other countries.The Belmont Report(National Commission 1979) was widely influential in the establishment of HRP governance structures around the world (Brody 1998 ; McDonald 2009 ). Thus, in Canada, significant research funding comes from US agencies subject to the Common...

    • 8 Outsourcing Ethical Obligations: Should the Revised Common Rule Address the Responsibilities of Investigators and Sponsors?
      (pp. 127-142)
      Seema K. Shah

      In a study evaluating the prevention of HIV transmission from mother to child, HIV-infected pregnant women receive antiretroviral treatment (ART) to prevent transmission during childbirth. Each mother’s involvement in this study ends with the birth of her child, when her access to the study drugs also ceases. The investigator plans to refer participants who continue to need treatment to the national program for HIV/AIDS treatment and care after delivery. Assuming that the institutional review board (IRB) raises no objections to the investigator’s plan, should she consider her ethical obligations to those participants fulfilled? If the investigator were to consult the...

    • 9 Subjects, Participants, and Partners: What Are the Implications for Research as the Role of Informed Consent Evolves?
      (pp. 143-156)
      Alexander Morgan Capron

      Informed consent has been described as the “ethical cornerstone” (Morin 1998, 185; Pelias and Markward 2000, 837; Malinowski 2003, 169), and a “central tenet of biomedical research” (Rothstein 2005, 91). Indeed it seems safe to say that most researchers, bioethicists, and institutional review board (IRB) members in the United States—and probably around the world—believe that the answer to the question “What makes research involving human subjects ethical?” is “informed consent” (Emanuel, Wendler, and Grady 2000, 2701). In this chapter, I set out to show that a large gap has opened between informed consent as an object of veneration...

    • 10 Democratic Deliberation and the Ethical Review of Human Subjects Research
      (pp. 157-172)
      Govind Persad

      The Presidential Commission for the Study of Bioethical Issues (PCSBI) recently introduced “[t] he principle of democratic deliberation” (2010; 2012) as part of its reports on the ethics of synthetic biology and of human subjects research. The PCSBI noted that democratic deliberation is “a less familiar principle in bioethics than the principles of beneficence and justice” (2010, 30); indeed no other prominent list of bioethical principles lists anything similar (Veatch 2007 ). Though new to lists of bioethical principles, democratic deliberation has been employed elsewhere in practical ethics (Gutmann and Thompson 2004, 18–19, 31, 33).

      This chapter explains democratic...

    • 11 IRBs and the Problem of “Local Precedents”
      (pp. 173-186)
      Laura Stark

      In the 2011 ANPRM, OHRP outlined several high-priority problems in the design of human subjects regulations. One of those problems was the lack of a streamlined system for regulating studies that require review at multiple research sites. Here is how OHRP described the problem of multisite research:

      In many cases, a local IRB for each institution does independently review the research protocol, informed consent documents and other materials, sometimes resulting in hundreds of reviews for one study. When any one of these IRBs requires changes to the research protocol that are adopted for the entire study, investigators must resubmit the...

  10. IV Specimens, Data, and Privacy

    • Introduction to Part IV—Specimens, Data, and Privacy
      (pp. 189-192)
      Jeffrey Skopek

      Biospecimens and associated data from the vast majority of Americans are currently being stored in biobanks and used in medical genomics research, often without the sources’ knowledge or consent; for although consent of the source is generally required for human subjects research by federal regulations, researchers can extinguish this requirement for biospecimens and data by de-identifying them. In this way a sample that was donated for use in one type of research may be used in research that breaches the express terms of the donor’s consent, and a sample that was extracted in the context of a medical procedure may...

    • 12 Biospecimen Exceptionalism in the ANPRM
      (pp. 193-206)
      Ellen Wright Clayton

      In its ANPRM, OHRP deemed biospecimens to be identifiable per se (DHHS 2011 ). This conclusion was based on unfounded notions of genetic exceptionalism (Gostin and Hodge 1999 ) and perceptions of risk that OHRP should explicitly and strongly reject.¹ The realistic likelihood of re-identification is quite small and the risk that harm would ensue in the event of re-identification is smaller still, but OHRP’s message that biospecimens are dangerous is clear.

      That OHRP perceives biospecimens and genetic information to be particularly risky is inconsistent with its proposal that biospecimens can be used for research without institutional oversight so long...

    • 13 Biobanking, Consent, and Certificates of Confidentiality: Does the ANPRM Muddy the Water?
      (pp. 207-220)
      Brett A. Williams and Leslie E. Wolf

      As Davis and Hurley detail in their chapter, the ANPRM proposes substantial changes to human subjects research regulations, including major proposed changes concerning the use of biospecimens in research. Under the current regulations, much biospecimen research may be conducted without consent. The ANPRM would require written consent for most of this research (DHHS 2011, 44519).

      This ANPRM proposal responds to criticisms that the current regulations do not account for scientific advances that present risks in biospecimens research not contemplated when the Common Rule was last amended (McGuire 2008; Wolf 2010 ). Because the DNA in biospecimens makes them inherently identifiable,...

    • 14 Mandating Consent for Future Research with Biospecimens: A Call for Enhanced Community Engagement
      (pp. 221-236)
      Carol Weil, Hilary Shutak, Benjamin Fombonne and Nicole Lockhart

      The use of human biological samples, or biospecimens, in medical research has the potential to transform our understanding of health and disease in the age of the genome. Human biological samples are small amounts of human material (e.g., skin, tissue, or blood) that may be removed for clinical reasons (e.g., a diagnostic biopsy or surgery to excise a tumor) or for research purposes. When samples are removed for clinical reasons, remaining tissue that is not needed for diagnosis or any other medical purpose can be donated and stored in biorepositories for future medical research, including genomic studies.

      The mapping of...

    • 15 Take Another Little Piece of My Heart: Regulating the Research Use of Human Biospecimens
      (pp. 237-250)
      Gail H. Javitt

      Access to human biospecimens is essential to the progress of personalized medicine, as it enables researchers to study the influence of genetic variation on human health and disease. Nearly half a billion biospecimens are currently stored in “biobanks” worldwide.

      The legal status of and ethical obligations owed to biospecimen contributors is unsettled. The current approach increases barriers to research access but fails adequately to consider the preferences and expectations of contributors.

      The ANPRM fails to resolve the legal and ethical challenges associated with research use of biospecimens, and a contemporaneously issued draft guidance from the Food and Drug Administration would...

    • 16 Reconsidering Privacy Protections for Human Research
      (pp. 251-264)
      Suzanne M. Rivera

      The ANPRM shines a spotlight on privacy concerns related to human research by suggesting that new, additional protections are warranted to govern the use of existing data and specimens—even when individual identifiers have been removed. This focus on secondary uses of information and biological materials represents a departure from the current regulatory convention of treating de-identified data and specimens as posing little or no risk, on the premise that even highly stigmatizing information would need to be linked (or reasonably linkable) to the original subject in order to result in material harm.

      At a time when billions of people...

    • 17 In Search of Sound Policy on Nonconsensual Uses of Identifiable Health Data
      (pp. 265-278)
      Barbara J. Evans

      Health data and biospecimens are crucial resources for twenty-first century biomedical discovery and health care system improvement (Institute of Medicine 2007, 128–30; Hakimian and Korn 2004, 2500; Institute of Medicine 2010, 1). Health care providers and payers hold large datasets that are potentially valuable as a scientific resource. An estimated 300 million biospecimens were stored in the United States as of 1999, and this inventory was thought to be growing at about 20 million per year (Eiseman and Haga 1999, xvii–xviii). Testing these stored specimens could yield a wealth of additional health-related data including genetic information.

      Studies of...

  11. V Paradigm Shifts in Research Ethics

    • Introduction to Part V—Paradigm Shifts in Research Ethics
      (pp. 281-284)
      I. Glenn Cohen

      In his novel,G, John Berger writes, in what might be thought of as the mantra of our current era, that “never again will a single story be told as though it’s the only one” (Berger 1972, 129). In a similar vein, in this part focused on paradigm shifts, each of the chapters seeks to radically reconfigure and reconceive of the US regulatory framework applicable to human subjects research, or in one case, to resist just such a move. Echoing the attitudes of many writing in this section of the book, Greg Koski throws down the gauntlet: “Reform is no...

    • 18 What Is This Thing Called Research?
      (pp. 285-298)
      Zachary M. Schrag

      Few people believe that IRBs should review every activity conceivably regarded as human subjects research. Some forms of investigation are so unlikely to harm participants that reviewing them is a waste of time and money that could be better spent scrutinizing riskier activities. And, many argue, review boards should not intrude on relationships that our society holds sacred, such as doctor – patient, teacher – student, reader – book, and citizen – government.

      Agreeing that not all interactions and investigations should require advance approval is easier than agreeing on where to draw the line. In 1978 Albert Jonsen — a member of the National Commission...

    • 19 What’s Right about the “Medical Model” in Human Subjects Research Regulation
      (pp. 299-312)
      Heidi Li Feldman

      Bioethics experts Paul Weindling and Volker Roelcke suggest that current bioethical thinking may use an incomplete picture of the historical context of the Nuremberg code. Volker Roelcke writes: “rather than being the result of a coercive state, Nazi medicine illustrates how medical researchers and their representative bodies co-operated with and even manipulated a totalitarian state and political system relying on expert opinion, in order to gain resources for the conduct of research without any moral and legal regulation.” He states that Nazi doctors “followed the intrinsic logic of their scientific disciplines and used the legally and ethically unrestricted access to...

    • 20 Three Challenges for Risk-Based (Research) Regulation: Heterogeneity among Regulated Activities, Regulator Bias, and Stakeholder Heterogeneity
      (pp. 313-326)
      Michelle N. Meyer

      As Davis and Hurley explain in their chapter, the ANPRM outlined seven areas of “concern” about, and proposed changes to, the Common Rule. A brief commentary by the ANPRM’s architects suggests, however, that most criticisms of the Common Rule can be reduced to two broad categories. On the one hand are “complaints that the regulations impose a variety of burdensome bureaucratic procedures that seem to do little to protect research participants, yet consume substantial resources.” Such criticisms, Emanuel and Menikoff note, are especially frequent in the context of “studies that pose few physical or psychological risks” to participants. On the...

    • 21 Protecting Human Research Subjects as Human Research Workers
      (pp. 327-340)
      Holly Fernandez Lynch

      The changes proposed to the Common Rule in the ANPRM were primarily intended to enhance protections for human subjects while reducing burden on researchers. However, due to a continued view of human subjects research as an exceptional endeavor that ought to be governed by exceptional rules (Sachs 2010 ; Miller and Wertheimer 2010; Wilson and Hunter 2010), the government and interested stakeholders have failed to take this once-in-two-decade opportunity to consider some enhanced protections that could be appropriately imported from a potentially unexpected but analogous setting—the workplace.

      In this chapter I flesh out the analogy between human subjects in...

    • 22 Getting Past Protectionism: Is It Time to Take off the Training Wheels?
      (pp. 341-348)
      Greg Koski

      That human subjects research is a regulated activity in the United States and other countries is an interesting phenomenon. After all, how many areas of scientific inquiry are subject to governmental regulation? Peer review of research is common in virtually all fields of science, generally as part of the funding process and, of course, for publication, but prospective review and approval of research involving human or animal subjects is different—it is required by law.

      In the second half on the twentieth century, public and governmental concern generated by media accounts of irresponsible conduct and unethical research conducted by legitimate...

  12. Appendix: Regulatory Changes in the ANPRM: Comparison of Existing Rules with Some of the Changes Being Considered
    (pp. 349-358)
  13. Contributors
    (pp. 359-362)
  14. Index
    (pp. 363-374)
  15. Back Matter
    (pp. 375-378)