The Second Wave Initiative



OCTOBER 26, 2011

Dear colleagues, friends and allies,

We are writing to thank you all for being co-signatories on the comment to DHHS. We sent the comment, which you can read below, on October 26th.
Many thanks,

Maggie Little
Anne Drapkin Lyerly
Ruth Faden

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 Report2008;38(6):53.
ii. Baylis F. Pregnant Women Deserve Better. Nature2010;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 Therapeutics2008;83(1):181-3.
iv. Second Wave Initiative at

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


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


Katherine Wisner, MD
Director, Women’s Behavioral HealthCARE
University of Pittsburgh
Western Psychiatric Institute and Clinic
3811 O'Hara St
Pittsburgh PA 15213

Kelly Edwards, PhD
Assoc. Prof., Dept. of Bioethics & Humanities, University of Washington School of Medicine
Department of Bioethics and Humanities
University of Washington School of Medicine
Box 357120
Seattle, WA 98195

Sharon Maynard, MD
Assoc. Clinical Prof, George Washington University School of Medicine
Dept. of Medicine
Lehigh Valley Health Center
1250 S. Cedar Crest Blvd
Allentown, PA 18105

Richard Beigi, MD, MSc
University of Pittsburgh, Magee-Women’s Hospital
Magee-Womens Hospital of the University of Pittsburgh Medical Center
Office #2326
300 Halket Street
Pittsburgh, PA 15213

Patricia King, JD
Professor, Georgetown University Law School
Georgetown Law School
600 New Jersey Avenue NW
Washington, DC 20001

Anna Mastroianni, JD
Professor, University of Washington School of Law and Institute for Public Health Genetics
University of Washington School of Law & Institute for Public Health Genetics
420 William H Gates Hall
Box 353020
Seattle, WA 98195

Debra DeBruin, PhD
Interim Co-Director, University of Minnesota Center for Bioethics
University of Minnesota
Suite N504 Boynton
410 Church St SE
Minneapolis, MN 55455

Françoise Baylis, PhD
Professor, Dalhousie University School of Medicine
Dalhousie University School of Medicine Novel Tech Ethics
1379 Seymour Street P.O. Box 15000
Halifax, Nova Scotia Canada B3H 4R2

Rebecca Kukla, PhD
Sr. Research Scholar, Kennedy Institute of Ethics, Georgetown University
415 Healy Hall, Georgetown University, Washington DC 20057

Anna Rachel Brandon, PhD, ABPP
Clinical Assistant Professor, University of North Carolina at Chapel Hill Department of Psychiatry
University of North Carolina at Chapel Hill
Department of Psychiatry
Women's Mood Disorders Center
Campus Box 7160
Chapel Hill, NC 27599-7160

Vanessa Merton, JD
Professor, Pace University School of Law
Pace University School of Law
78 North Broadway
White Plains NY 10603

Toby Schonfeld, PhD
Director, Masters in Bioethics, Associate Professor, Medicine, Emory University School of Medicine
Emory University
1531 Dickey Drive,
1st floor
Atlanta, GA 30322

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
Yale Psychiatry 142 Temple Street New Haven, CT 06510

N. Jean Amoura, MD, MSc
Assoc. Professor, Ob-Gyn, University of Nebraska Medical Center
University of Nebraska Medical Center 983255 Nebraska Medical Center Omaha, NE 68198-3255

Kate Greenwood, JD
Research Fellow & Lecturer in Law Center for Health & Pharmaceutical Law & Policy, Seton Hall Law School
Seton Hall Law School
One Newark Center
Newark, NJ 07102

Robyn MacQuarrie, MASc, FRCS
Novel Tech Ethics Program, Dalhousie University
Dalhousie University Novel Tech Ethics
5248 Morris Street
Halifax, Nova Scotia B3H 4R2

Gary Shangold, MD
President, InteguRx Therapeutics LLC
14 Laurel Mountain Way
Califon, NJ 07830

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
7118 Exfair Road, Bethesda, MD 20814-5503

Steven J. Ralston, MD
Tufts Medical Center
800 Washington St
Boston, MA 02111

John Sadler, MD
Professor of Medical Ethics, University of Texas Southwestern Medical Center
UT Southwestern
5323 Harry Hines Boulevard
Dallas, TX 75390-9070

Simon Lee, PhD, MPH
University of Texas Southwestern Medical Center
UT Southwestern Medical Center, Dept of Clinical Sciences MSC 9066,
5323 Harry Hines Boulevard, Dallas, Texas 75390

Ruth Macklin, PhD
Professor of Bioethics, Albert Einstein College of Medicine
Epidemiology & Population Health
Albert Einstein College of Medicine
1300 Morris Park Ave.
Bronx, NY 10461

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
University of Alabama at Birmingham,
Department of Obstetrics and Gynecology
1702 6th Ave. So, Women and Infants Center STE 10270Q Birmingham, AL 35249-7333

Nancy Kass, ScD
Professor of Bioethics and Public Health, Johns Hopkins Berman Institute of Bioethics & Bloomberg School of Public Health
Johns Hopkins Bloomberg School of Public Health
Deering Hall
1809 Ashland Avenue
Baltimore, MD 21205

Miriam Kuppermann, PhD, MPH
Professor, Obstetrics, Gynecology and Epidemiology; Director, Program in Clinical Perinatal and Comparative Effectiveness Resesarch, University of California, San Francisco
3333 California Street, Suite 335
San Francisco, California 94143-0856

Tom Beauchamp, PhD
Sr. Research Scholar, Kennedy Institute of Ethics, Georgetown University
Healy Hall
Georgetown University
Washington DC 20057

Hadar Sheffer, MPH
1207 W. North Loop Blvd #A
Austin, TX 78756

Elizabeth Mitchell Armstrong, PhD
Associate Professor of Sociology and Public Affairs
Princeton University
Office of Population Research
253 Wallace Hall
Princeton, NJ 08544

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
L4000 Women's Hospital
1500 East Medical Center Drive
Ann Arbor MI 48109

In the absence of information about the safety and efficacy of medications, pregnant women and the clinicians who care for them are left with two unsavory options -- use a drug with unknown safety and efficacy, or leave the woman and her fetus vulnerable to the consequences of the underlying illness. Women and the children they will bear deserve better. Clinical research with pregnant women is morally challenging, but it is a challenge we must confront. For the alternative to responsible research with pregnant women is relegating pregnant women to second-class medical citizens -- something, it turns out, that is good for neither pregnant women nor the fetuses they carry.