Specimen Science: Ethics and Policy Implications

Basic Bioethics

Arthur Caplan, editor

A list of the books in the series appears at the back of the book.

Specimen Science

Ethics and Policy Implications

edited by Holly Fernandez Lynch, Barbara E. Bierer, I. Glenn Cohen, and Suzanne M. Rivera

The MIT Press

Cambridge, Massachusetts

London, England

© 2017 Massachusetts Institute of Technology

All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means (including photocopying, recording, or information storage and retrieval) without permission in writing from the publisher.

Set in ITC Stone Sans Std and ITC Stone Serif Std by Toppan Best-set Premedia Limited. Printed and bound in the United States of America.

Library of Congress Cataloging-in-Publication Data

Names: Lynch, Holly Fernandez, editor. | Bierer, Barbara E., editor. | Cohen,

  I. Glenn, editor. | Rivera, Suzanne Marie, 1969- editor.

Title: Specimen science : ethics and policy implications / edited by Holly

  Fernandez Lynch, Barbara E. Bierer, I. Glenn Cohen, and Suzanne

  Rivera.

Description: Cambridge, MA : The MIT Press, [2017] | Series: Basic bioethics

  | Includes bibliographical references and index.

Identifiers: LCCN 2016041471 | ISBN 9780262036108 (hardcover : alk. paper)

eISBN 9780262339704

Subjects: LCSH: Biological specimens--Moral and ethical aspects. |

  Bioethics--Legal issues.

Classification: LCC QH231 .S64 2017 | DDC 174.2--dc23

LC record available at https://lccn.loc.gov/2016041471

ePub Version 1.0

d_r0

To Dr. Leona Cuttler (1951–2013), pediatrics research pioneer, and to all those whose contributions of biospecimens have helped to improve the diagnosis and treatment of disease, ameliorate suffering, and advance human health.

Table of Contents

Series page

Title page

Copyright page

Dedication

Series Foreword

Acknowledgments

Introduction

I Background and Foundations

Introduction

1 Legal and Regulatory Issues in Biospecimen Research: National and International Perspectives

2 Property Rights and the Control of Human Biospecimens

3 Research with Biospecimens: Tensions, Tradeoffs, and Trust

II Roots of the Debate: Autonomy, Justice, and Privacy

Introduction

4 Research on Human Tissue Samples: Balancing Autonomy vs. Justice

5 Biospecimens, Commercial Research, and the Elusive Public Benefit Standard

6 What Specimen Donors Want (and Considerations That May Sometimes Matter More)

7 Assessing Risks to Privacy in Biospecimen Research

III Consent and Its Implications

Introduction

8 Broad Consent for Research on Biospecimens¹

9 Evolving Consent: Insights from Researchers and Participants in the Age of Broad Consent and Data Sharing

10 The Ethics of the Biospecimen Package Deal: Coercive? Undue? Just Wrong? Or Maybe Not?

IV Special Populations and Contexts

Introduction

11 Biorepositories and Precision Medicine: Implications for Underserved and Vulnerable Populations

12 The Ethical Management of Residual Newborn Screening Bloodspots

13 Informed Consent for Genetic Research on Rare Diseases: Insights from Empirical Research

14 Considerations for the Use of Biospecimens in Induced Pluripotent Stem (iPS) Cell Research

V Governance, Accountability, and Operational Considerations

Introduction

15 Governance Issues for Biorepositories and Biospecimen Research

16 The Rise of Patient-Driven Research on Biospecimens and Data: The Second Revolution

17 Informing the Public and Including It in Discussions about Biospecimens

18 Investigator’s Commitment during the Consent Process for Biospecimen Research

19 Biospecimen Repositories in the Era of Precision Medicine: Perspectives from a Biobanker in the Trenches

20 Operationalizing Institutional Research Biospecimen Repositories: A Plan to Address Practical and Legal Considerations

Contributors

Index

Basic Bioethics

List of Tables

Table 13.1 Empirical studies on broad consent in rare disease populations

Table 13.2 Selected quotations from Qualitative Studies on Consent for Rare Genetic Disease Research

Table 18.1 Statements in an investigator oath and mean and median scores

List of Illustrations

Figure 8.1 Approaches to consent for future research with biospecimens.

Figure 12.1 Retention Time for Dried Bloodspots. Data from NewSTEPs, August 2015.

Figure 12.2 Responses to the question How concerned would you be if the Health Department saved the leftover blood samples from babies after the tests are done?

Series Foreword

Glenn McGee and I developed the Basic Bioethics series and collaborated as series co-editors from 1998 to 2008. In fall 2008 and spring 2009 the series was reconstituted, with a new editorial board, under my sole editorship. I am pleased to present the forty-eighth book in the series.

The Basic Bioethics 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.

Arthur Caplan

Basic Bioethics Series Editorial Board

Joseph J. Fins

Rosamond Rhodes

Nadia N. Sawicki

Jan Helge Solbakk

Acknowledgments

This volume was based on a public conference held at Harvard Law School in November 2015, the proceedings of which are available at http://petrieflom.law.harvard.edu/events/details/specimen-science-ethics-and-policy/.

We gratefully acknowledge the support of our various collaborators, including The Center for Child Health and Policy at Case Western Reserve University and University Hospitals Rainbow Babies & Children’s Hospital; the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School; the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard; and Harvard Catalyst | The Harvard Clinical and Translational Science Center. Both the conference and this volume were supported by funding from the National Human Genome Research Institute.

We also wish to thank Cristine Hutchison-Jones and Justin Leahey from the Petrie-Flom Center, and our fantastic research assistants—Ethan Stevenson, Shailin Thomas, and José LaMarque—who helped us line edit and format the entire manuscript.

Last, but certainly not least, we sincerely thank all of our contributors for their tremendous efforts.

Introduction

Suzanne M. Rivera, Barbara E. Bierer, I. Glenn Cohen, and Holly Fernandez Lynch

When a blood specimen is drawn from a vein in your arm, is that specimen still you? Do you own it? Are you entitled to any intellectual property interest in or profit from a product derived from it? What if its value is only understood by pooling information from 10,000 blood specimens? Should you be allowed to direct who may use your left-over blood specimen for research or specify under what circumstances such uses may occur? What about your hair that lands on the barbershop floor? Or a tumor that has been excised to prevent it from killing you? These are real questions at the center of a vigorous ethical and legal debate surrounding the use of human biospecimens for research—and they are questions that affect us all.

Existing case law on the collection, storage and use of biospecimens suggests that people do not own their bodily tissue once it has been removed from them. But there is an emerging line of inquiry that questions whether individuals ought to be asked explicitly at the time of collection for consent to use their blood or tissues for research. How far such an ethical requirement might extend remains a heated topic of debate. Should research use of excess tissues that otherwise would be discarded after a surgical procedure also require explicit informed consent? What if there is no identifying information attached to the tissues because researchers need only 100 lung tumor biopsies and don’t need data about their donors? What about tumor specimens collected years ago, before their research uses became evident—should they be unavailable for research now because the original source cannot be found and asked for consent? And if excess tissues are used for research, and ultimately result in the development of a lucrative medical treatment, should the source of the tissues have a right to share in the profits?

These questions fall into a significantly contested area for the ethical conduct of human subjects research. Humans have been experimenting on one another since the beginning of time, but the voluntary nature of participation in such experiments only developed as an ethical—and eventually legal—requirement over the course of the last century (Presidential Commission for the Study of Bioethical Issues 2011). The most famous articulation of this principle is found in the Nuremberg Code, promulgated by American judges in 1947 at the trial of Nazi doctors for war crimes following their experimentation on concentration camp prisoners during World War II. The Nuremberg Code establishes that [t]he voluntary consent of the human subject is absolutely essential, and subsequent US government policy and regulations adopted the same requirement, although not without exception. The regulations governing human subjects research in the United States demand voluntary consent for research participation in most instances, while allowing consent to be forgone, waived, or modified in others—in particular when the research itself is deemed not to involve human subjects at all, which has been the case for certain uses of biospecimens.

A requirement of voluntary consent is not particularly burdensome in the context of prospective research—namely, when biospecimens are collected in person from living individuals for use in a particular study. In these cases, you simply ask permission of the person standing before you, and they can either agree or decline to provide a research specimen. Indeed, in such cases, consent is both ethically mandatory and required by regulation. It becomes much more challenging, however—both ethically and practically—when one wishes to conduct research on biospecimens that already have been collected in the course of clinical care or earlier research. In these cases, researchers do not have (and may not be able to find) the biospecimen source immediately before them to ask for explicit consent for the research use being contemplated. Should the research be forgone? Is consent really necessary in this context, and what are the limits of acceptable use before consent becomes necessary? These questions have come to the fore in a series of foundational cases—some in courts of law and others in the court of public opinion—over the last 25 years.

In Moore v. Regents of California, a patient underwent a splenectomy for therapeutic reasons and had to travel numerous times by airplane to see the physician who performed the procedure for follow-up treatment (including further collection of specimen samples), only to find out later that his physician had utilized the excised tissue for research. The physician then developed a cell line that he commercialized for substantial revenue. The California Supreme Court determined that the patient may have a legal claim for breach of fiduciary duty by the physician and for lack of informed consent to the research use of the tissues. However, the Court rejected a claim of conversion—civil property theft—by the physician, reasoning that the patient had not sufficiently asserted, nor was there sufficient case law to support, an ongoing property interest in the discarded spleen tissue.

In another famous case, the Havasupai, an American Indian tribe living near the base of the Grand Canyon in Arizona, developed a relationship with researchers at the Arizona State University and agreed to participate in research intended to evaluate whether there was any genetic basis for the tribe’s extremely high incidence of diabetes. The researchers collected blood samples for diabetes research, and subsequently provided aliquots—stripped of identifiers but nonetheless identified as belonging to members of the tribe—to researchers studying schizophrenia and theories about the migratory history of the Havasupai. The results were viewed as stigmatizing and in conflict with ancestral tribal beliefs. After an extended legal battle over the precise nature of the consent that had been provided, the case ended with a financial settlement and the return of collected biospecimens for burial in accordance with tribal traditions.

Finally, as is detailed in Rebecca Skloot’s book The Immortal Life of Henrietta Lacks (Crown, 2010), in 1951, Henrietta Lacks, a poor black woman from Baltimore, sought treatment at Johns Hopkins Hospital for cervical cancer. Before administering radium for the first time, the attending doctor cut two dime-size samples of tissue, one cancerous and one healthy, from Henrietta Lacks’ cervix. As was the custom of the day, no one specifically asked Lacks’ permission for collection of the tissue or informed her that her specimens might be studied. The treating physician gave the tissue to Dr. George Gey, a scientist who had been trying to establish a continuously reproducing, or immortal, human cell line for use in cancer research. According to protocol, a lab assistant scribbled an abbreviation of Lacks’ name, HeLa, on the sample tubes. HeLa cells succeeded where all other human samples had failed, and Gey gave away laboratory-grown cells to interested colleagues. Scientists grew HeLa cells in mass quantities to test the new polio vaccine among other uses, and soon a commercial enterprise was growing batches for large-scale use. More than half a century later, Lacks’ tissue has yielded an estimated 50 million metric tons of HeLa cells, and more than 60,000 scientific and medical studies, and are in continued use today. If the specimens had been truly anonymized, Lacks’ identity would not be known and there probably would have been no story to generate a best-selling book.

These cases and others have generated substantial discussion and disagreement in the bioethics and regulatory communities, and beyond. Did the researchers involved do anything wrong? Do the regulations adequately protect the rights and welfare of specimen sources? What, precisely, are specimen sources entitled to by way of consent, control, and compensation? Such questions form the backbone of the urgent need to evaluate the regulation and conduct of specimen science, particularly as regulatory revisions finalized in January 2017 addressed research with specimens but left open a number of difficult ethical questions. This volume looks backward to these cases as the basis for, and to inform, the next generation of policy development in this area.

This volume was born out of a need to make sense of the shifting landscapes of science, technology, public opinion, and law regarding research with biological specimens. In 2010, Dr. Leona Cuttler, a distinguished physician scientist at Case Western Reserve University, assembled a group of colleagues from across the country to propose for NIH funding a project focused on elucidating the ethical and policy challenges associated with collaborative genetic research. Dr. Cuttler was motivated by a desire to prevent and cure the diseases of childhood she saw in her pediatric endocrinology practice, and she believed that scientists working together could get answers more quickly than they could working in isolation. One researcher with access to only her own patients’ specimens might take ten years to amass enough data to test a hypothesis. But a team of researchers combining their samples could make headway in a fraction of the time.

Of course, working collaboratively on genetic research requires the sharing of biological specimens and their associated data, precisely as was the case with the Havasupai specimens, the HeLa cell line, and in Moore. And this, Dr. Cuttler knew, was a matter of considerable difficulty and controversy. The difficulty is borne out of our complex regulatory landscape and the ways in which research rules are interpreted and enforced at academic medical centers across the country and the world.

In the United States, each project that meets the federal definition of research with human subjects—as will be the case for certain types of research involving specimens and data—and that is not otherwise exempted from regulatory oversight must obtain ethical review and regulatory approval from an institutional review board (IRB) specifically constituted to examine the risks and benefits to the individual of the research proposed. However, Dr. Cuttler knew that there were growing differences of opinion about application of the regulations to research with specimens and data. Were they too strict in some areas, and too permissive in others, especially with regard to promoting socially beneficial research and protecting patient autonomy? How could federal regulations in place and unchanged for nearly three decades appropriately foster cutting edge genetic research of the type Dr. Cuttler’s patients needed in order to cure their diseases? Would harmonizing practices across the nation’s leading research centers streamline approval in appreciable ways?

She set out to ask these questions with her grant team using funding from the NIH’s National Human Genome Research Institute, until her untimely passing in 2013. Dr. Cuttler’s project lived on, however. In the pages that follow, philosophers, ethicists, legal scholars, regulators, patients, and others weigh in on these important questions.

This book is the result of a day-long symposium planned by members of Dr. Cuttler’s study team in collaboration with colleagues from Harvard University. The presenters and participants are thought leaders from the fields of law, medicine, and philosophy, each of whom took a different approach to questions about the appropriateness of our regulatory oversight apparatus and how proposed changes to the regulations might promote or impede the ethical conduct of biospecimen research.

One common theme of the chapters in this volume is that the regulations governing federally funded research with human subjects, including those that govern the research use of human biological materials and data—better known as the Common Rule and untouched from 1991 to 2017—were out of step with current technological and scientific conditions. Advances in genetic research, for example, have far exceeded what could have been contemplated by those tasked with writing the rules nearly three decades ago. Because science has evolved, so too must the regulatory landscape, in order to simultaneously protect the rights and welfare of people who participate in research (as well as those who are studied without their knowledge) and to avoid inappropriate hindrance of medical advancement.

When the Common Rule first was promulgated, it was considered by most a fair assumption that a human biospecimen, free of any identifying information such as a name or a patient identification number, could not reasonably be re-identified by a scientist in a laboratory (or anyone else). In fact, for this reason, the use of existing (left over from clinical care or earlier research) human biospecimens (and associated data) traditionally has been deemed not to be human subjects research under the Common Rule if the identity of the subject may not readily be ascertained by the investigator, and to be exempt from most forms of regulatory oversight if the specimens or data are themselves identifiable but information is recorded by the investigator in a non-identifiable manner. This is because the framers of the Common Rule felt confident that these mechanisms of segregating specimens and data from identifiers were adequate to protect any interests of the individuals from which they were derived. Any risk, such as the remote risk of re-identification, was small in comparison to the promise of scientific and medical advances that depended upon the specimens.

Today, this is a matter of considerable controversy. On one hand, technological advances, such as whole-genome sequencing and increasing access to big data, have made it possible for a scientist with access to both sophisticated equipment and a reference key to take an otherwise unidentified human biospecimen and re-identify it using the unique data gleaned from a person’s DNA. Although such equipment is expensive and not widely available, and there is no universal reference key of everyone’s DNA, the potential for unauthorized re-identification has caused some to argue that there is a pervasive and unavoidable risk of informational harm to specimen sources that requires a tightening of the rules. Those who want more restrictions are concerned about protecting individual liberties and most importantly privacy, and want to maximize the principle of autonomy.

On the other hand are those who advocate for fewer restrictions on and greater sharing of biospecimens and data to maximize their utility in solving important problems. This camp is a mix of scientists, ethicists, and disease-oriented patient advocates, each of whom views the risks of unauthorized re-identification as relatively small and better addressed through penalties for violations rather than tighter restrictions that could impede important scientific progress. People who want fewer restrictions on use of biospecimens typically believe that a more communitarian approach to research will increase beneficence and justice.

Despite the lack of consensus around these issues, millions of human biospecimens are collected and stored each year. Most are obtained during routine clinical encounters with patients for diagnostic and treatment purposes, while a minority are collected with explicit research intent following informed consent by a donor. Regardless of the circumstances, it is not possible to know with certainty at the time of collection all the possible future uses for which a specimen could be of value. Thus, the only way to guarantee full informed consent would be to re-approach donors each time a new use is imagined (which notably is not even possible once a specimen has been de-identified). Science is evolving more quickly than our regulatory procedures can accommodate. A permissive stance would be to allow unforeseen future uses without obtaining new, specific consent unless there is an obvious risk of harm, on the premise that such uses might contribute to important medical discoveries. A conservative approach would be to discard biospecimens immediately following the original use for which they were collected to avoid even the appearance of violating donor’s expectations. The current regulatory approach—maintained following revisions finalized in 2017, described more fully below and in chapter 1 of this book—requires consent from the specimen source only for the active collection of specimens and data for research use, and for the secondary use of only identified specimens and data. In light of technological advancement and changing patient attitudes, however, the challenge is how best to balance the importance of protecting individual interests against the value of promoting the good of the larger human community.

The federal agencies that oversee human subjects research made an attempt to address this challenge by proposing a major revision to the research rules in 2015 via a Notice of Proposed Rule Making (NPRM) to amend the Common Rule (following a 2011 Advance Notice of Proposed Rule Making [ANPRM]). The NPRM proposed an approach on one side of the spectrum of possibilities and generated substantial dialogue regarding the best path forward. Although its most controversial proposals regarding biospecimen research were ultimately not adopted in the final rule issued in January 2017, many of the chapters that follow touch upon the NPRM to illustrate the significance of the debate and options that may become more relevant given questions left open in the final rule, especially regarding identifiability and broad consent.

In particular, the NPRM proposed to expand the definition of the term human subject to include a living individual about whom the investigator obtains, uses, studies, or analyzes biospecimens even when those biospecimens have been stripped of all the traditional pieces of identifying information. The presumption underlying this proposal was that all genetic material can potentially serve as a unique personal identifier—if not now, then in the relatively near future. The proposal also was based on the notion that individuals have greater autonomy interests in controlling their biospecimens than previously had been acknowledged. The consequence of this regulatory redefinition would be that secondary research with de-identified biospecimens would no longer be permissible without some form of consent, a dramatic change from the status quo. Under the NPRM’s proposal, that consent could be broad, applying to future unspecified use, rather than specific for each study, but the conditions for waiver of consent for biospecimen research would have been dramatically tightened, such that waiver would become rare.

Just as there is no consensus about how to best balance autonomy and privacy concerns with the desire to advance scientific frontiers, so too there was great disagreement about the wisdom of the proposed rules. An earlier attempt to solicit feedback from the public on the ANPRM resulted in four years of hand-wringing before a substantially similar set of proposals was released as an NPRM, the last step before issuance of a final rule. This, despite the fact that the government received over 1,100 comments reflecting considerable differences of opinion about the appropriateness of the suggested changes.

Not surprisingly, nearly twice as many public comments were submitted in response to the NPRM (2,186 in total, many of which were from organizations), and they, too, showed a clear lack of consensus. According to a systematic analysis of these comments released in May 2016 led by the Council on Government Relations (COGR), with support from the Association of Public and Land-grant Universities (APLU), there was significant opposition to most major NPRM proposals regarding the regulation of biospecimen research. More specifically, the comments submitted by patients and the research community (e.g., researchers, universities, medical centers, and industry) overwhelmingly opposed the proposed changes involving non-identified biospecimens on the grounds that they would have reduced the availability of specimens for research, negatively impacting medical advances. Influential advisory groups, including the Presidential Commission for the Study of Bioethical Issues and the Department of Health and Human Services Secretary’s Advisory Committee on Human Research Protections (SACHRP) questioned whether the proposal could even satisfy its goals of protecting participant autonomy. Members of the public who did not specifically identify as patients were more divided in their comments, but given that the government’s rationale for many of the proposed changes regarding biospecimen research was ostensibly that public trust demanded them, it is important to note that 55 percent of the general public comments opposed one or more of the major proposed changes (a fact recognized in the preamble to the final rule). Sixty-one percent of the general public comments specifically opposed the expanded definition of human subject to include non-identified biospecimens, and opposition to that particular proposal was even higher among those who self-identified as patients and researchers; the same trend was noted in comments regarding broad consent for storage and secondary research with biospecimens. It is also essential to note that calculations offered by the American Society for Investigative Pathology indicate that the NPRM underestimated the true cost of its proposals to require broad consent for biospecimen research—which it estimated to be $1.2B annually—by a factor of at least ten (COGR and APLU 2016).

In light of these public comments on the NPRM, a final rule was published in January 2017 that did not significantly alter the regulatory approach to biospecimen research—at least for now. As explained more fully in chapter 1, the revised Common Rule will continue to treat research with non-identified specimens as outside the bounds of human subjects research, such that neither IRB review nor consent is required. However, the regulatory agencies, alongside appropriate experts, will periodically revisit the definition of identifiable every few years, such that more types of research with specimens could fall within the regulatory parameters in the future. Moreover, the final rule includes a provision that would allow research with identifiable specimens and data to proceed on the basis of broad, rather than specific, consent. Thus, the themes addressed by our authors, and the debate exemplified in the NPRM between greater control over biospecimens research and facilitating scientific advances for the public good, are enduring.

In view of the tension between the two main goals—patient autonomy and social benefit—any regulatory change will be unsatisfying to some. Increased protection of patient autonomy will necessarily increase burdens on conducting research with specimens and data, and minimizing such barriers will necessarily diminish protection of patient autonomy. That there is no consensus about the best path forward is about the only thing upon which all the authors in this volume can vigorously agree. In the pages that follow, experts from a range of disciplines and backgrounds explore the myriad ethical, social, and legal implications of biospecimen research with a focus on regulation and its consequences. Readers will learn about the prevailing practices for using biospecimens in research and will hear from a variety of viewpoints about the potential advantages and pitfalls of proposed changes. All of the chapters that follow will make reference in some way to the regulatory landscape, but they will also do much more. They will explore an imagined future for biospecimen research in which not only the rules are different, but also the expectations, opinions, and priorities of physicians, scientists, and patients.

The book is divided into five parts. Part I, introduced by Aaron Kesselheim, sets the stage for the rest of the volume by summarizing the legal, ethical, and historical foundations underlying the collection, ownership, control, and future use of biospecimens, and the implications for individual privacy and autonomy. While acknowledging that this volume relies upon and refers to US law, regulations, and customs, the exchange and sharing of biospecimen materials, research, and information are international undertakings. This first part of the book lays the foundation upon which further ethical, social, political, and scientific deliberations considered in the remainder of the volume rest.

In chapter 1, David Peloquin, Mark Barnes, and Barbara E. Bierer survey and analyze laws and regulations governing the research use of biospecimens around the world, with a focus on privacy, control, and return of research results. They begin with US law, exploring how the common law of property (exemplified in several foundational court cases), regulations specifically governing human subjects research (including 2017 revisions), and privacy laws are implicated in biospecimen research and biospecimen repositories. Next, they turn to European law, addressing both individual countries and Council of Europe standards for biospecimen research, and the particular challenge of biospecimens transferred outside of the European Union. They then address nuances of several other representative countries, including China, Brazil, and India, with an analysis of several significant challenges in international biobanking. After addressing a variety of recent regulatory changes, they conclude that the patchwork of national and international law governing biospecimens can hinder research.

In chapter 2, Russell Korobkin reviews many of the same cases referenced in chapter 1, but argues that these cases lay a foundation that counters the conclusion that there are no property rights that remain with the specimen donor. Indeed he argues that the donor may retain the right to their property, and he calls upon the informed consent document (and common law) to define the retained versus transferred property rights of the donor. He also introduces the concept of compensation, not only by consideration of value of the gift of the specimen but potentially by reference to patent law.

In chapter 3, Elisa Hurley, Kimberly Hensle Lowrance, and Avery Avrakotos step back from the legal and technical issues to discuss the role of public trust. They recount the history of several cases that have informed the current debate: those of Henrietta Lacks, the Havasupai, and the Newborn Screening Saves Lives Reauthorization Act of 2014. Each of these cases illustrates in its own way the tensions between the issues of privacy, informed consent, and the advancement of science. Hurley, Lowrance, and Avrakotos call for greater, expanded education and pubic engagement around biospecimen research, a theme that is further discussed later in the volume.

In part II, we are introduced to some of the thorniest and most important ethical challenges facing researchers, regulators, and bioethicists today. Introduced by Steven Joffe, the four chapters in this part explore the tension between three foundational principles of research ethics (respect for persons, beneficence, and justice) as they relate specifically to the use of human biospecimens for research. Chapters 4–6 address donors’ rights and obligations, raising questions about the extent to which an individual’s autonomy may or may not trump other important considerations, such as scientific advancement and public health. Chapter 7 focuses on the risk of privacy and questions assumptions about the true likelihood of harm to individuals whose biospecimens may be used in science.

In chapter 4, David Korn and Rachel Sachs argue that each person who benefits from advances in science and medicine has a duty to participate in the scientific enterprise by allowing his or her biospecimens to be used in research. Focusing on the often neglected principle of justice, Korn and Sachs assert that it is unfair for people who don’t allow their biospecimens to be used to receive treatments developed by using materials derived from others. They conclude that the principle of respect for persons—as expressed by honoring autonomy through the mechanism of informed consent—should be balanced appropriately against the equally important and valid principle of justice.

In chapter 5, Barbara J. Evans and Eric M. Meslin also explore important questions about individuals’ rights and obligations. They note that individuals seem more comfortable donating their biospecimens for science when the work is performed at academic and non-profit institutions than at for-profit entities, but they challenge the wisdom of that preference, noting that in many cases pharmaceutical companies may create significant public good through product development. Evans and Meslin approach these questions from a legal perspective and they promote the idea of a public benefit standard for evaluating research risks. Ultimately, they urge a balancing of individual and public interests for the purpose of mutually advantageous exchange.

In chapter 6, Suzanne M. Rivera and Heide Aungst examine what is known about why people are willing or unwilling to donate biospecimens for research, assess the various challenges (legal, ethical, and practical) associated with honoring donors’ wishes, and evaluate to what extent we ought to be beholden to such wishes in the face of compelling scientific advancements that may be brought about by biospecimen research for the betterment of society. They draw analogies to the various ways in which individuals relinquish information about themselves on a daily basis in return for valuable services, via smartphones, social media, and Web searches, to demonstrate that perhaps biospecimens need not be treated so differently. Ultimately, Rivera and Aungst urge recognition of the social value of biospecimen research, rather than solely claims to individual autonomy, and call for a different ethos, in which all people who could benefit from medical advances willingly contribute biospecimens for research in the context of trust and collaboration with scientists.

In chapter 7, Ellen Wright Clayton and Bradley A. Malin take a different approach. They focus on the question of privacy by examining the risk of material harm to individuals from biospecimen use in research. They conclude, despite growing concerns about privacy risks from research, that the likelihood of potential harm to individuals is quite small and does not justify the proposed increases in oversight and control.

Part III focuses more specifically on the idea of informed consent—what it is meant to do and how it might be altered. Introduced by Pearl O’Rourke, the chapters in this part offer a further exploration of the different types of consent that may be utilized for biospecimen research (if consent is sought at all).

In chapter 8, Christine Grady and her co-authors recognize that various processes exist for obtaining consent for the future research use of biospecimens, and that there is confusion and uncertainty about appropriate and ethically permissible types of consent in this context. They focus on broad consent (as distinguished from both blanket and specific consent), which would permit an unspecified range of future research conditional on a few content or process restrictions and coupled with governance. Noting that various bodies have recently endorsed the broad consent approach, including the revised Common Rule, they endeavor to assess its ethical justifications and potential concerns. Reasons in its favor include respect for biospecimen donors, autonomy, and transparency, as well as some support for the approach in empirical studies to date and recognition that it is less burdensome than other potential approaches. The authors address various objections before concluding that broad consent is ethically appropriate and preferable to the alternatives in either direction. They recommend that broad consent include initial consent, oversight of future research projects, and mechanisms for communicating with donors.

In chapter 9, Nanibaa’ A. Garrison discusses insights from researchers and participants in the age of broad consent and data sharing. In particular, Garrison focuses on the perspectives of several distinct groups, including certain indigenous tribes involved in recent litigation concerning genomics research and others with reservations about the ethical validity of broad consent. She describes the Havasupai controversy in detail and the desire of many indigenous peoples to have greater tribal control over research with their specimens than broad consent would allow. Garrison argues that it is essential to acknowledge that one implication of the trend toward broad consent may be that some communities that have been historically underrepresented in research may also be less willing to participate in research where their data are shared widely, leading to an inability to benefit from such research. She concludes that, for at least some groups, more engagement than is required by the regulations is needed to build respect and trust regarding biospecimen research.

In chapter 10, Ivor Pritchard and Julie Kaneshiro assess whether it is ethical to require subjects to agree to donate their specimens for future studies as a condition for being eligible to participate in a present study that offers the prospect of direct benefit. More specifically, they assess whether such package deals violate the regulatory prohibition on coercion and undue influence. Pritchard and Kaneshiro outline the relevant regulatory enforcement actions in analogous circumstances before concluding that, while some such package deals are ethical and some are not, in general package deals ought to be avoided because they might diminish the voluntariness of informed consent needed for ethical study participation.

Part IV, introduced by Pamela Gavin of the National Organization for Rare Disorders, examines how the general issues raised by specimen science have particular salience for special communities of patients (e.g., newborns, the underserved, those with rare diseases) and special communities of researchers (e.g., stem cell researchers).

In chapter 11, Aaron J. Goldenberg and Suzanne M. Rivera examine the implication of possible changes in the regulation of specimen science for precision medicine—the now-well-funded push to tailor treatment and prevention to subsets of patients on the basis of biological, behavioral, and social determinants of disease. They consider how such research efforts will be stymied if attention is not paid to the role of underserved and vulnerable populations. In particular, they focus on biorepository design and participant recruitment, specimen and data storage and management, and specimen and data research use and translation as obstacles to achieving truly representative national cohorts for biorepositories. They also discuss how to better enable members of these vulnerable and underserved groups to help in development and governance of biorepositories.

In chapter 12, Jeffrey Botkin, Erin Rothwell, Rebecca Anderson, and Aaron Goldenberg focus on a highly valued but controversial set of biospecimens: residual dried bloodspots (DBS) from newborns. They review the history of such programs and the controversies surrounding them, including lawsuits that have been brought in Indiana, in Minnesota, and in Texas. They also report findings from their large national survey (conducted in 2012) of public attitudes regarding the retention and use of DBS. Ultimately, they conclude that in this context a perfunctory consent process such as that used for compliance with the Health Insurance Portability and Accountability Act of 1996 will fail to rebuild the public’s trust in the use of these biospecimens. They suggest that the larger challenge is to develop more sophisticated approaches to information and education that foster a higher level of true understanding about how research is conducted and, potentially, the need to collaborate with communities to support research.

In chapter 13, Sara Chandros Hull takes a data-driven approach to controversies over the appropriate governance frameworks and consent models for biospecimen research. She systematically reviews the empirical literature on public attitudes toward broad consent for biospecimen banking, including controversies over the level of consensus in favor of broad consent. In keeping with the focus of this part of the book, she then reviews the more limited empirical work on attitudes of those with rare diseases and their family members. She finds that the limited data available about the attitudes and preferences of potential participants in research on rare genetic diseases are generally consistent with robust frameworks of broad consent that have been described in recent policy proposals and are being used with increasing frequency. Using the example of researchers organizing a leukodystrophy research database, Hull shows how biospecimen repositories can use surveys and other empirical methods to tailor their governance frameworks and consent models to the needs and preferences of particular patient populations.

In chapter 14, Geoffrey Lomax and Heide Aungst use the experience of the California Institute for Regenerative Medicine (CIRM) as a case study in the challenges faced by some biorepositories. Among the issues CIRM faced were whether to require consent for commercial use of cell lines, the return of results to donors, the parameters and consent for re-contact regarding clinically significant events, and the management of donor withdrawal. Lomax and Aungst also discuss CIRM’s decision making regarding sensitive uses of derived lines, including reprogramming cells to produce gametes, cloning, and somatic cell nuclear transfer. They conclude the chapter by discussing the difficulties of setting policies for deriving pluripotent induced stem cells using previously banked research specimens.

Part V concludes the book with six chapters that explore practical, logistical, and operational aspects of changing norms with regard to biospecimen collection and use. Introduced by Barbara E. Bierer, the chapters in this part outline the current approach to governance and accountability of biospecimen repositories and detail specific operational obligations of creating and running a repository. In addition to institutional and organizational management, the responsibilities of the investigator are specifically elaborated. But the historical approach to governance, one that is reminiscent of institutional paternalism protecting the patients, is evolving: true partnerships with patients and their families, patient-led communities, and patient advocates are emerging and are leading to meaningful engagement.

In chapter 15, Karen Maschke focuses on biospecimen repository governance, summarizes the current approach to biospecimen repository management in the United States, and examines the concept of participatory governance as articulated by the working group for President Barack Obama’s Precision Medicine Initiative (PMI). She also puts these concepts in broader context, explaining how previous attempts as participatory governance of biobanks, such as the attempt made in the United Kingdom, prepared the way for a new model of governance for biospecimen repositories in the United States. She concludes with an assertion that the PMI may increase the public’s expectations about the role that specimen contributors should play in the research enterprise.

In chapter 16, Susan M. Wolf and Isaac S. Kohane argue that genomic science has caused a fundamental shift in the roles of patients and families in the conduct of research. With personal interests in driving research to generate new treatments for their diseases, patients and their families are setting agendas for the collection of data and specimens and are challenging traditional scientific norms that situated scientists at the center of decision making. Wolf and Kohane call this shift a patient and family revolution and explain how new technologies, including social media, have empowered individuals and groups to take a leadership role propelling research agendas. In historical context, Wolf and Kohane characterize today’s level of engagement of patients and families in research as a movement from paternalism to partnership.

In chapter 17, Jane Perlmutter and Heide Aungst approach the aforementioned issues from the perspective of patients and patient advocates. For too long, they argue, patients and their advocates have not been involved in planning, communicating, or providing oversight for clinical research, nor have they been at the table in important policy deliberations. The patient’s perspective is important to consider at all stages of research, beginning when the initial research question is being framed and continuing through dynamic consent and decisional input over the use of specimens. While the availability and the nature of information are changing rapidly, Perlmutter and Aungst argue that timely and comprehensive education is nevertheless important and should occur in advance of approaching any individual to donate rather than at a time of crisis, and that researchers should be sensitive to the health literacy and numeracy needs of the populations they study. Finally, greater understanding of and demonstrable respect for the contributions of the donors should be evident.

In chapter 18, Erin Rothwell and Erin Johnson reimagine the process of informed consent. Considering the literature showing that comprehension of informed consent has been disappointingly low, they explore alternatives to traditional informed consent and report the results of their empirical study to determine whether potential subjects would support new