Members of the Second Wave Initiative, including Berman Institute faculty, have submitted comments on the proposed revisions to the Common Rule.  The Common Rule refers to the Federal Policy for the Protection of Human Subjects. These rules apply to all federally funded human subjects research, and extends to all human subjects research in institutions receiving any US federal funding for research. In the proposed changes, this reach would be extended to include institutions receiving any federal funds, and not just research funding. The Office of Human Research Protections has now closed the 90-day comment period on their proposed revisions.


Each year, hundreds of thousands of pregnant women in the US face significant medical illness during their pregnancies. Diabetes and hypertension complicate 40,000+ pregnancies; psychiatric illness complicates an estimated 500,000; cancer and autoimmune diseases are not uncommon, and yet we have surprisingly little data about how to safely and effectively treat these conditions. The pregnant body can substantially change the ways in which drugs are metabolized; and concerns about the safety of taking medication must be balanced against the medical risks — to woman and fetus alike — of undertreating significant medical disease.


The Second Wave Initiative is a consortium of physicians, scientists, and bioethicists working to advocate for the importance of advancing the evidence base for the treatment of pregnant women facing serious illness.


View comments below or (pdf)


Oct. 26, 2011


Jerry Menikoff, MD, JD

Office for Human Research Protections

1101 Wootton Parkway, Suite 200

Rockville, MD 20852


Re: Docket No. HHS-OPHS-2011-0005



Dear Dr. Menikoff,


On behalf of the Second Wave Initiative, a consortium of physicians, scientists, and bioethicists working to advocate for the importance of advancing the evidence base for the treatment of pregnant women facing serious illness, we are pleased to provide comments on “Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators (Federal Register Thursday, July 26, 2011, 44512–44531; Federal Register Thursday, September 1, 2011, 54408).  We congratulate the hard work and significant progress represented by the proposed changes to regulations governing human participation in research (45 CFR part 46, subpart A; “the Common Rule”).


The ANPRM suggests significant changes to 45CFR46, many of them welcome.   Because this announcement has initiated a process to modernize the regulations that will not likely be undertaken again anytime soon, it is critical that the proposed changes address serious deficiencies in the current regulatory structure.  We note an area of omission in the ANPRM that is of particular concern:  namely, improving guidance on research with pregnant women.


Over 500,000 women in the United States face serious medical illness while pregnant, but we have a paucity of information on how to safely and effectively treat them. Researchers have been understandably skittish about this area; and the current regulations contain both vagaries and constraints that make it difficult for researchers to feel comfortable understanding the parameters of responsible research with pregnant women.


This comes at a substantial cost to the health of both women and their newborns.  First, medications needed to treat significant illnesses are often metabolized by the pregnant body in very different ways than by the non-pregnant body, and evidence-based dosing of medications for pregnant women sorely lacking; second, information specific to safety in use during pregnancy is needed; finally, in the absence of the sort of reassurance that proper research can provide, the lack of evidence base can contribute to a reticence on the part of some pregnant women or their providers to use medication that is in fact critical to support the health of the woman and newborn.


Without better direction from the regulations, researchers will, we fear, continue to sidestep the issue, leaving intact our ignorance about how to safely and effectively treat pregnant women who face serious illness.


We urge in the strongest possible terms the following:


1.  Amend 45CFR46.204 (Subpart B) to add a category of “minor increase over minimal risk” or its equivalent.  Currently, any research that does not carry the potential for direct health benefit to pregnant woman or fetus is disallowed unless it involves “no more than minimal risk.” In practice, this policy has led to an untoward chilling of research.  The concept of minimal risk is challenging; in the context of research in pregnancy, it has been interpreted incredibly conservatively.  To give just one example, we have had experience with government officials who interpret this as ruling out pharmacokinetic studies with pregnant women – an extremely low risk study methodology that is critical to determining dosing of medications in pregnant women.  We strongly urge that the regulations here follow the lead taken in pediatric research (another research arena with special ethical complexities), that of adding and allowing the category of “minor increase over minimal risk” or its equivalent.  In the absence of such a category, interventions with any risk will necessarily continue to be initiated, untested, in clinical contexts, thereby exposing women and fetuses to the possibility of harm without creating generalizable knowledge.


2.  Amend 45CFR46.204e to remove the paternal consent requirements on research.  While endorsing the good intentions behind this regulation, we note that in practice it is worrisome, for the reasons put forward by the Ethics Committee of American College of Obstetrics and Gynecology statement against the requirement for paternal consent.   The claim is not that the interests of both parents in the well-being of their offspring are unimportant, but rather how this claim is instantiated in practice and research rules.  We note that in pediatric research, paternal consent is required only for research in which there is no prospect of direct benefit for the child and the risks are greater than minimal; not only are the pediatric regulations less restrictive, but they also apply to research that does not involve the health of another, namely the pregnant woman.


3.  Amend 45CFR46.107 and §46.111 to remove language labeling pregnant women as a vulnerable population, defined in the document as a population that is at high risk of coercion and undue influence.  Pregnant women are indeed a highly complex population for consideration as research participants: there are specific scientific and ethical challenges that require specific attention.  But it is misleading and unhelpful to describe these complexities as equivalent to being at risk of coercion and undue influence.  Such a formulation unintentionally casts pregnancy as a condition that inherently threatens women’s ability to make rational, informed, and voluntary decisions; it also distracts from the significant and gestation-specific issues that urgently need attention.  Thus, while we concur with the current proposal that for expedited studies, criteria 3 and 8 (which include pregnant women) in 46CFR46.111 should not be required for IRB approval, we strongly urge changing the language from “vulnerable” to “population meriting special regulation.”


4.  Explicitly confirm that the proposed changes with regard to excused and expedited research include research with pregnant women, to avoid inappropriate exceptionalism about pregnancy on the part of researchers and institutional review boards.


5.  Establish and formally charge a working group to propose new model language for the special regulation of clinical research with pregnant women that strikes a more appropriate and more just balance of rights, needs, and interests.  Even if suggestions 1-4 proposed here are adopted, but especially if they are not, the current regulatory structure puts forward serious barriers to the conduct of research on the health needs of pregnant women and the securing of evidence-based direction on how best to treat women who face serious medical illnesses while pregnant.


i. Lyerly AD, Little M, Faden R. Pregnancy and Clinical Research. Hastings Center Report 2008;38(6):53.

ii. Baylis F.  Pregnant Women Deserve Better.  Nature 2010;465(7229):689-90.

iii. Chambers CD, Polifka JE, Friedman JM.  Drug Safety in Pregnant Women and their Babies: Ignorance Not Bliss. Clinical Pharmacology and Therapeutics 2008;83(1):181-3.

iv. Second Wave Initiative at http://secondwaveinitiative.org/


Thank you so much for the opportunity to submit these comments, and congratulations again on the work that has been accomplished.


Sincerely,


Margaret Little, BPhil, PhD

Director, Kennedy Institute of Ethics

Georgetown University

Washington, DC


Ruth Faden, PhD, MPH

Director, Berman Bioethics Institute

Johns Hopkins University

Baltimore, MD


Anne Drapkin Lyerly, MA, MD

Assoc. Director, Center for Bioethics

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina


Co-Signatories

Katherine Wisner, MD

Director, Women’s Behavioral HealthCARE

Kelly Edwards, PhD

Assoc. Prof., Dept. of Bioethics & Humanities, University of Washington School of Medicine

Sharon Maynard, MD

Assoc. Clinical Prof, George Washington University School of Medicine

Richard Beigi, MD, MSc

University of Pittsburgh, Magee-Women’s Hospital

Patricia King, JD

Professor,

Georgetown University Law School

Anna Mastroianni, JD

Professor, University of Washington School of Law and Institute for Public Health Genetics

Debra DeBruin, PhD

Interim Co-Director,

University of Minnesota Center for Bioethics

Françoise Baylis, PhD

Professor, Dalhousie University School of Medicine

Rebecca Kukla, PhD

Sr. Research Scholar, Kennedy Institute of Ethics,

Georgetown University

Anna Rachel Brandon, PhD, ABPP


Clinical Assistant Professor, University of North Carolina at Chapel Hill

Department of Psychiatry

Vanessa Merton, JD

Professor, Pace University School of Law

Toby Schonfeld, PhD

Director, Masters in Bioethics, Associate Professor, Medicine, Emory University School of Medicine

Kimberly Yonkers, MD

Professor of Psychiatry and of Obstetrics, Gynecology, and Reproductive Sciences and Lecturer in Epidemiology (Chronic Diseases); Director, PMS and Perinatal Psychiatric Research Program,

Yale Medical Group

N. Jean Amoura, MD, MSc

Assoc. Professor, Ob-Gyn, University of Nebraska Medical Center

Kate Greenwood, JD

Research Fellow & Lecturer in Law

Center for Health & Pharmaceutical Law & Policy, Seton Hall Law School

Robyn MacQuarrie, MASc, FRCS

Novel Tech Ethics Program, Dalhousie University

Gary Shangold, MD

President, InteguRx Therapeutics LLC

Charles McCarthy, MD

Former Director of the Office for Protection from Research Risks (OPRR), NIH

LeRoy Walters, PhD

Sr. Research Scholar, Emeritus, Kennedy Institute of Ethics, Georgetown University

Steven J. Ralston, MD

Tufts Medical Center

John Sadler, MD

Professor of Medical Ethics, University of Texas Southwestern Medical Center

Simon Lee, PhD, MPH

University of Texas Southwestern Medical Center

Ruth Macklin, PhD

Professor of Bioethics,

Albert Einstein College of Medicine

Joseph Biggio, Jr., MD


Director, Division of Maternal Fetal Medicine | Medical Director, Obstetric Services  Associate Professor | Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Department of Obstetrics and Gynecology

Nancy Kass, ScD


Professor of Bioethics and Public Health, Johns Hopkins Berman Institute of Bioethics &
Bloomberg School of Public Health

Miriam Kuppermann, PhD, MPH



PhD, MPH Professor, Obstetrics, Gynecology and Epidemiology Director, Program in Clinical Perinatal and Comparative Effectiveness Research,

University of California, San Francisco

Tom Beauchamp, PhD

Sr. Research Scholar, Kennedy Institute of Ethics, Georgetown University

Hadar Sheffer, MPH


Elizabeth Mitchell Armstrong, PhD


Associate Professor of Sociology and Public Affairs

Princeton University

Lisa Harris, MD, PhD

Assistant Professor

Department of Obstetrics and Gynecology

Department of Women’s Studies

Program in Sexual Rights and Reproductive Justice

University of Michigan


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