The blog of the Presidential Commission for the Study of Bioethical Issues

Commission Wraps Up Miami Meeting

For the past year the Presidential Commission for the Study of Bioethical Issues has been conducting a careful and transparent review of the ethical considerations of conducting clinical trials of medical countermeasures (MCM) with children.

The examination raises many challenging and complex issues.  MCM research could carry some risk in order to protect children from high consequence events that have an unknown or unknowable likelihood of occurring.  This is the Commission’s fourth meeting on the topic.  A sampling of comments from the meeting in Miami (January 14-15):

Amy Gutmann, Ph.D., Commission Chair:  “We must keep in mind that we do not have a research protocol before us.  We are not equipped to sit as an IRB or a national review panel under Section 407 and it is outside the purview of our Charter to do so.  The question we must address is whether the U.S. Government could ethically support a pediatric AVA study under any circumstance.  We will not render a final decision as to whether a particular study should move forward.  Nor are we working to justify any particular protocol or outcome.”

Amy Gutmann, Ph.D., Commission Chair:  “[In post-event research] there are still ethical guidelines, but they have a different implication when children stand to directly benefit from research. And then you impose no more than necessary risk.  Risk has to be proportionate to the benefit and you still want the informed consent of parents and if possible of children, but there is a direct benefit to the child and that makes all the difference and we absolutely will make sure we articulate that in the report.”

Dan Sulmasy, M.D., Ph.D., Commission Member:  “What I think we need to be clear about, is that by doing age de-escalation protocols, we turn what would be by definition because of the uncertainty more than minimal risk research into minimal risk.  We have got to be very clear about that.”

Christine Grady, Ph.D, R.N., Commission Member:  “We are more resistant in this case to research than we were in the genome project… I think that the reason we are is because it’s MCM research. I don’t think anybody around this table is saying that research with children in general is not a good thing if it finds ways to treat children who are ill, or prevents illness in children.  The issue here of course… is that these are conditions that may never happen, that we hope never will happen, and so we’re sort of balancing a different kind of need than we would be if it was studying a treatment for a disease that kids have.”

Lonnie Ali, Commission Member:  “We always talk about military personnel feeling coerced, perhaps because their superior office is asking; but children too can have that feeling.  ‘I want to please my mother, the doctor;’ so they assent. I feel having somebody in there who is independent [to review the informed consent process] so the child’s not feeling coerced is extremely important.”

Col. Nelson Michael, M.D., Ph.D., Commission Member:  “There is no body of clinical data on the safety and immunogenicity of AVA in children. What is the optimal AVA regimen for children in terms of dose, schedule, route of administration in terms of the critical research results of safety and immunogenicity? What are the correlates of risk of infection and mechanistic correlates of protection for AVA in animal models and, by extension, in vaccinated adults? These are critical questions to ask.”

“Col. Nelson Michael, M.D., Ph.D., Commission Member:  “Given our Commission’s concern about endorsing greater than minimal risk pre-event research with no current benefit to pediatric research volunteers, it seems logical to me to explore the questions above first in young adults in the 18-20 range. Especially in terms of expanded safety data, the assessment of levels of risk could be made in young adults with increased statistical confidence. This, in turn, would influence possible experimental protocol design of a series of age de-escalating safety and immunogenicity studies, starting with 16-17 year old adolescents, that could possibly be done in a pre-event, non-imminent framework if risks could be assessed to be at minimal level or with a minor increment over minimal risk in an imminent threat framework.”

Tom Beauchamp, Ph.D. to address Commission

Tom Beauchamp, Ph.D., an invited speaker at the 12th meeting of the Presidential Commission for the Study of Bioethical Issues, has been a Senior Research Scholar at the Kennedy Institute of Ethics and a Professor of Philosophy at Georgetown University for more than 30 years.

Beauchamp has earned many accolades in the field of bioethics.  He joins the Commission’s meeting for continued discussion of the issue of pediatric medical countermeasures.

In 1975 he began work as a staff member of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, where he jointly authored the Belmont Report, a formative text in bioethics. The National Commission is generally viewed as the first national bioethics commission.  (For more information about prior bioethics commissions see

Beauchamp’s research interests include the ethics of human subjects research, the place of universal principles and rights in biomedical ethics, methods of bioethics, the philosopher David Hume, and business ethics.

Beauchamp received B.A. and M.A. degrees from Southern Methodist University, a B.D. degree from Yale University, and a Ph.D. in Philosophy from Johns Hopkins University.

His 140 plus scholarly publications include: Frontiers of Biomedical Ethics; The Oxford Handbook of Business Ethics; The Oxford Handbook of Ethics and Animals; Principles of Biomedical Ethics; A History and Theory of Informed Consent; The Human Use of Animals; and Philosophical Ethics. He is also an editor of The Clarendon Hume.

Beauchamp was presented with Georgetown’s Career Recognition Award in 2003 for distinguished research across an entire career and in 2004, he received the Lifetime Achievement Award from the American Society of Bioethics and Humanities.

He currently holds an NIH Challenge Grant for work on the distinction between research and treatment, as well as a National Science Foundation award to continue his work in animal research ethics.

He joins the meeting today via videoconference to discuss how the Belmont principles apply in assessing whether research with individual children as participants is ethically permissible, as well as the ethical permissibility of balancing research risk and direct benefit to the individual child.

Dennis Thompson, Ph.D. to address Commission

As the Presidential Commission for the Study of Bioethical Issues gathers in Miami to continue its discussion of the development of an ethical framework around the issue of pediatric medical countermeasures, Commission members will hear from additional experts in relevant fields.

This afternoon Dennis F. Thompson, Ph.D., the Alfred North Whitehead Professor of Political Philosophy at Harvard University, and the founding director of the Edmond J. Safra Center for Ethics at Harvard, will address the Commission. At issue: the philosophical grounding for the ethical approach that the Commission is considering for the complex issue of pediatric medical countermeasure research.

The Commission is not the first to ask Thompson to advise on a challenging topic.  He has served as a consultant to the Institute of Medicine on the topic of Conflict of Interest in Medical Research, Education, and Practice, and as advisor to the American Medical Association, the Food and Drug Administration, the U.S. Senate Ethics Committee, as well as the Joint Ethics Committee of the South African Parliament.

Thompson’s work focuses on political philosophy, ethics in government and healthcare, and democratic theory. He received a first class honors degree in philosophy, politics, and economics from Oxford and a doctorate in political science from Harvard University, where he has been teaching since 1986.

The Edmond J. Safra Center for Ethics serves as a university-wide academic center for the study of theoretical and practical ethics across a variety of disciplines. The Center hosts faculty fellows, graduate fellows, and a wide variety public events programming. Thompson led the center for two decades.

Dr. Thompson will be a part of the Commission’s discussion regarding the ethical aspects of pre-event testing of an anthrax vaccine with children and, more broadly, the content of deliberations of the ethical considerations that should guide pre- and post-event medical countermeasure research with children.

Federal Regulations Concerning Pediatric Research

“Under what conditions is participation of children in research ethically acceptable?”

This was the question the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research faced in 1974 when it began its deliberations on pediatric research.

Its report, Research Involving Children, ultimately became the foundation for pediatric research regulations adopted in 1983.  These regulations, which were codified in Subpart D of 45 CFR Part 46, are at the heart of the Presidential Commission for the Study of Bioethical Issues’ discussions of pediatric medical countermeasures research at Meeting 12 held in Miami, Florida.

Most provisions of 45 CFR Part 46 provide general protections for human subjects research with adults. In formulating the principles that animate Subpart D, the National Commission maintained the view that children, as a separate class, must be given additional protections in the context of research; unlike adults, children cannot provide informed consent to research and therefore constitute a “vulnerable” population. The National Commission developed standards for pediatric research protections intended to both adequately protect children and allow beneficial or important pediatric research to take place.

The regulations of Subpart D provide four ways to determine whether pediatric research is permissible based on the National Commission’s recommendations in Research Involving Children.  The first, described under 45 CFR § 46.404 (referred to as Section 404), permits research with children that presents no greater than minimal risk, or risk equivalent to that which children encounter in their daily lives, as long as adequate measures are taken to solicit informed parental permission and meaningful child assent, and other research protections, such as independent review, are in place.

The second category, Section 405, provides standards for research that presents greater than minimal risk, but is justified by the expected direct benefit to research participants – a benefit at least as favorable as alternative interventions.

Section 406 permits IRBs to approve research that is greater than minimal risk and does not offer direct benefit to participants if the research is likely to yield knowledge about participants’ condition and meets other ethical and regulatory requirements.

Finally, Section 407 regulates research that cannot be approved under 404, 405, or 406, but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.  Unlike research approved under sections 404, 405, and 406, research reviewed under this provision cannot be approved by a local institutional review board; rather it must be assessed by a national review panel and can only be approved by the Secretary of Health and Human Services.  This type of review is rare.

Each type of review in Subpart D requires researchers to obtain both parental permission, and child assent, where meaningful before children can participate.

A major part of the current Commission’s deliberations today and tomorrow concerns how to best apply the ethical foundations underlying the regulations in Subpart D to pediatric medical countermeasure research in general and to anthrax vaccine research in particular.

Commission in Miami

The Presidential Commission for the Study of Bioethical Issues is meeting today and tomorrow in Miami, Florida (January 14-15, 2013).

At this meeting the Commission is expected to wrap up its exploration of the issues surrounding the ethical issues associated with research that could carry some risk in order to protect children from high consequence events that have an unknown or unknowable likelihood of occurring.

At the request of Health and Human Services Secretary Kathleen Sebelius, the Commission is carefully reviewing the ethical considerations of conducting clinical trials of medical countermeasures for children.

As she opened the first session Commission Chair Amy Gutmann, Ph.D., said, “We must keep in mind that we do not have a research protocol before us.  We are not equipped to sit as an IRB or a national review panel under Section 407 and it is outside the purview of our Charter to do so. The question we must address is whether the U.S. Government could ethically support a pediatric AVA study under any circumstance.  We will not render a final decision as to whether a particular study should move forward.  Nor are we working to justify any particular protocol or outcome.”

The meeting will be mostly devoted to Commission member discussion of this ethically complex issue. Guest speakers Dennis F. Thompson, Ph.D. of the Kennedy School of Government at Harvard University and Tom L. Beauchamp, Ph.D. of the Kennedy Institute of Ethics at Georgetown University will discuss the philosophical grounding the Commission may consider to its ethical approach to this issue.

New HIPAA Guidance on De-Identification

On November 26, 2012, the Office for Civil Rights (OCR) within the Department of Health and Human Services released new Guidance on De-identification of Protected Health Information. The new Guidance provides covered entities—defined as certain health care providers, health care clearinghouses, or health plans—with specific tools and techniques for de-identifying health information using the two methods set forth in the Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule.  The new Guidance addresses key questions and provides examples that help clarify the Privacy Rule’s two de-identification standards.  The Guidance included input from an OCR workshop convened in March 2010 to tackle specific topics related to the two methods of de-identification of data addressed in HIPAA’s Privacy Rule. 

In its report Privacy and Progress in Whole Genome Sequencing, the Presidential Commission for the Study of Bioethical Issues focused on the privacy issues associated with whole genome sequencing. These privacy issues are particularly relevant given more widespread sharing of whole genome sequencing data, both in the clinic and in research.

Several federal laws—including HIPAA—protect identifiable health information that can be linked to an individual person. HIPAA requires that consent be obtained before protected health information—medical information that identifies a particular person—can be shared in certain circumstances. Once health information is de-identified, the information is no longer subject to the Privacy Rule’s restrictions and can be shared without consent. The question remains, however, whether whole genome sequence data can actually be de-identified or should be considered de-identified for purposes of HIPAA’s protections.

The new Guidance provides explanations and clarification about the two ways in which protected health information can be de-identified, as initially set forth in the HIPAA Privacy Rule: the Expert Determination method and the Safe Harbor method. The Expert Determination method requires an expert to apply statistical methods and principles to de-identify the data and determine that the risk that the data could be linked to an individual is “very small.” The Safe Harbor method requires that covered entities remove all identifiers (such as name, date of birth, Social Security Number) that might link an individual to their information. Under the Safe Harbor method, covered entities must also have no actual knowledge that the health information, alone or in combination with other information (e.g., public voter registration records), can link a particular individual to the disclosed health information. In some cases, these methods minimize the risks to individual privacy and allow scientists to have access to large databases for their research.

While this Guidance clarifies some of the questions surrounding the de-identification methods, it remains silent on the de-identification of whole genome sequencing data. Even though the issues surrounding the de-identification of whole genome sequencing data have become more acute over the past two and a half years that OCR has considered this Guidance, it nevertheless remains critical that regulations and guidance respond to the rapid advancement of science, such as whole genome sequencing.

Applying lessons learned in Guatemala to research today: Exploring the PCSBI Study Guide

The Presidential Commission for the Study of Bioethical Issues has consistently noted the marked need for effective ethics education. With this commitment in mind, the Commission recently released a companion study guide to its 2011 historical investigation report, “Ethically Impossible” STD Research in Guatemala from 1946 to 1948,in which the Commission detailed the egregious treatment of vulnerable populations in Guatemala by researchers during the 1940s.  The new companion piece, A Study Guide to “Ethically Impossible” STD Research in Guatemala from 1946 to 1948 serves as a supplement for instruction in existing bioethics courses and seeks to provide resources to instructors teaching responsible conduct of research (RCR) courses.  Given this wide audience, the Study Guide includes discussion questions and suggested readings appropriate to undergraduate and graduate-level coursework, and allows instructors to use the report and related materials to illustrate the ethics topics of their choice.

In the now well-documented Guatemala case, the U.S. Public Health Service approved research that exposed individuals to STDs and then failed to subsequently treat all of them.  Researchers drew from susceptible populations including prisoners and the mentally ill; intentionally deceived some subjects about the nature of the study and what was being done to them; and there is no record of any of the subjects giving consent.

For the purposes of teaching ethics, the challenge facing instructors is to translate this historical event into lessons pertinent to the experience of modern day researchers. The set of case studies provided by the Study Guide is accessible to the average student and promotes guided ethics discussion based on real world examples and historical documents. The Study Guide takes students through difficult questions that arise when it is necessary to make moral assessments about unethical events in the distant past and applies such lessons to the present. The Study Guide covers various topics that can be incorporated into ethics courses as a whole, or independently as individual modules. These topics include: research with vulnerable populations; issues of race, consent and deception; ethical aspects of informed consent; and ethical aspects of methodological design and publication.

For existing bioethics curricula, the Study Guide enables instructors to expose students to a period in U.S. history with resources that lend the case context, including how researchers planned and carried out the Guatemala experiments.  The inclusion of primary sources right in the text of the Study Guide allows students to see an example of an historical investigation and its place within the interdisciplinary practices of bioethicists. Instructors new to teaching ethics will find an array of materials to choose from, starting with a sampling of basic research ethics texts and resources to introduce students to the work of previous presidential bioethics commissions and the ethical foundations of research regulation.  Subsequent sections allow instructors to pick and choose topics that fit with the course design they have in mind.

By extrapolating to ethical issues beyond the individual case and encouraging students to view contemporary research in the same light, students are introduced not only to the ethical errors of the past, but also to the method of casuistry and a particular form of moral reasoning; students reflect on what makes this case immoral and what makes it similar to, or different from, other cases. Recommended readings span a wide range, allowing instructors to engage students on questions that bridge the highly theoretical (e.g., whether our moral concepts are stable enough to allow for retrospective judgment of the past) and the highly practical (e.g., when an individual can give consent on behalf of another).  As a result, the resources included speak to a broad audience within research ethics education, providing a jumping off point for some and a much-needed starting place for others.

This post can also be seen on Ampersand, the blog of Public Responsibility in Medicine and Research (PRIM&R).

Recent Workshop on “Ethically Impossible” Study Guide Hosted by PRIM&R

Paul Lombardo, Ph.D.

Commission Senior Advisor Paul Lombardo, Ph.D., conducted a workshop about the Commission’s newly developed teaching resource, A Study Guide to “Ethically Impossible” STD Research in Guatemala, at the Advancing Ethical Research annual conference hosted by Public Responsibility in Medical Research (PRIM&R).  PRIM&R, a professional group working to advance the ethical conduct of research with humans and animals, held its conference December 4-6.  The Study Guide was a natural fit for PRIM&R’s members, including researchers, hospital and university administrators, participant advocates, industry stakeholders, and institutional review board (IRB) members.

Lombardo provided a brief overview of the now well-documented Guatemala case, in which the U.S. Public Health Service approved research that intentionally deceived some individuals, exposed members of vulnerable populations to STDs and then failed subsequently to treat all of them.  The Study Guide serves as a companion to the Commission’s report on its historical investigation of the Guatemala research. Readers of the Study Guide will find copies of primary source documentation leading up to and regarding implementation of the STD research.  Correspondence between members of the Public Health Service and researchers helps to place the case in its historical context, and to engage readers in thoughtful discussion.

The session was well attended by 50-60 members of the research community.  Some teachers had already used the Commission’s report in the classroom, while others expressed interest in the relevance of the report and Study Guide to IRB and research ethics training.  For these professionals, the Study Guide is structured in segments that allow users to discuss different aspects of the research in short and manageable portions.  Lombardo says this format lends itself to short, periodic educational sessions such as those provided at IRB annual retreats, or monthly meetings.

Discussion also included translating of the unethical research in Guatemala into concrete lessons for contemporary researchers.  For example, one question from the audience addressed the challenges of whistle-blowing, and whether research assistants involved in the Guatemala case, as well as those today, could openly express reservations without facing retaliation.  Lombardo suggested that these insights reveal the importance of “not just thinking of these Guatemala researchers as monsters, but trying to understand what they were thinking and why,” as well as the larger context that influences research conduct.  Lombardo believes that such reflections better enable us to construct more supportive research environments, and to educate ethical researchers.

Considering Opt In vs. Opt Out Consent Procedures in WGS Research

When it comes to whole genome sequencing research, consent procedures can be complex, especially for the patient. Some patients could be unaware that their whole genome sequence data might be used in future research without additional consent. To highlight the issue, consider this hypothetical example:

After a painful gallbladder attack, 27-year-old Cindy allowed surgeons to remove her gallbladder. Before the surgery, Cindy read and signed the necessary lengthy consent forms. During surgery, doctors took a blood sample and placed it in the hospital’s stored collection of biological samples. Her de-identified DNA is now available to researchers who have access to that collection.

To determine the type of research consent Cindy signed, we need to look at how researchers structured the consent: Was Cindy required to opt in – to affirmatively choose to allow her data to be used for future research purposes? Or was she required to opt out – a default in which her data is used for future research unless she specifically declines to participate?

If researchers used opt in, Cindy would have been required to consent explicitly to future research. In opt in consent the default is to prohibit the researcher’s use of the samples without an individual’s active consent. If instead researchers obtained opt out consent, the default would be that researchers could use Cindy’s samples in future research. In this type of consent, at the time researchers collected the samples, Cindy must have specifically refused to participate in future research, or her samples could be used in this manner.

In some contexts, it might be more advantageous to use a consent process that makes it easier for individuals to participate. For example, organ donation policies in Europe, which uses an opt out consent model, have donation rates over 99 percent, as opposed to a 44 percent donation rate in the United States, which uses an opt in model. Although the Commission recognizes the substantial public benefit of widespread participation in whole genome sequencing research, the Commission firmly believes that the most important issue in respecting persons is not the type of consent obtained, but rather that the consent is properly informed and consistent with voluntary choice.

In Privacy and Progress in Whole Genome Sequencing, the Commission recommends the evaluation and adoption of “robust and workable consent processes that allow research participants, patients, and others to understand who has access to their whole genome sequences.” The Commission believes that as long as an individual is fully informed in the consent process, and as long as the process does not overly influence an individual’s ability to make genuine and voluntary choices, there is no ethical imperative to use opt in or opt out consent.

Executive Director Lisa M. Lee Presents “Privacy and Progress” at Personalized Medicine Conference

Presidential Commission for the Study of Bioethical Issues Executive Director Lisa M. Lee, Ph.D., M.S., presented the Commission’s recent report, Privacy and Progress in Whole Genome Sequencing at the 8th Annual Personalized Medicine Conference at the Harvard Medical School in Boston.

The conference, held November 28-29, is organized by Harvard Medical School, Harvard Business School, and Partners HealthCare Center for Personalized Genetic Medicine – a research organization that aims to integrate genetics and genomics into patient care.  Each year, the meeting convenes hundreds of presenters and attendees from government, academia and the private sector to discuss recent developments in personalized medicine and its broader applications in policy and health outcomes. 

Lee discussed the findings and recommendations of the Privacy and Progress report during an ethics session titled Ethical Aspects of Whole Genome Sequencing.  The report, which deals with the ethical considerations of privacy and whole genome sequencing, concludes that while whole genome sequencing serves to advance personalized medicine and public health, ethical guidelines are needed for its use in clinical and research contexts to respect and secure individual interests in privacy. In short, to ensure the kind of progress whole genome sequencing promises, privacy must be protected.

Robert Green, M.D., M.P.H., an Associate Professor of Medicine at Harvard Medical School and Brigham and Women’s Hospital and the Associate Director for Research at Partners HealthCare Center for Personalized Genetic Medicine, also presented during the session.

Both Lee and Green fielded questions that concerned the ownership of whole genome sequence data and the handling of data in medical records.  Lee and Green noted that ethical conversations on these topics may be more concerned with transparency, access and use of data rather than ownership.

Lee also discussed whether genomic data security should be considered a public good that is shared across the biotechnology industry, or if it can be variable across companies in order to maintain a competitive edge.  Lee reiterated the Commission’s view that public trust depends on the maintenance of data security and its view that security best practices be shared across industry to maximize public trust.

“Many of the participants had read the Commission’s Privacy and Progress report,” noted Lee after the conference. “It was heartening to hear the robust ethics discussion at this intensely scientific meeting.”

Commission Member Raju Kucherlapati, Ph.D. chaired the meeting’s organizing committee and delivered opening and closing remarks, as well as a presentation, during the conference.