Filed under: Children, Research, Women's Health Issues
In an article out in the American Journal of Obstetrics and Gynecology, the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS)—a Gates Foundation-funded initiative of Seattle Children’s Hospital and the University of Washington School of Medicine’s Departments of Global Health and of Obstetrics and Gynecology—reports on its efforts to develop “a research agenda related to pregnancy, childbirth, and early life[.]” In addition to interviewing scientific thought leaders and convening a “technical team of 13 prominent researchers from multiple disciplines in the developed and developing world,” the GAPPS spoke to “18 representatives of funding organizations—including government agencies, global foundations, and other financial partners—to gain a deeper understanding of the current perspectives, attitudes, and commitments of funders toward research on pregnancy, childbirth, and early life.”
The GAPPS’ conversations with funders surfaced a number of challenges to increasing funding, including 1) “a range of understanding of the issues[,]” 2) “varying degrees of interest in the topic[,]” and 3) concern about “the challenges of progress with such a long-term and complex problem.” The authors, to their credit, do not deny that the question (questions, really) of what causes prematurity, stillbirth, and other pregnancy and early life problems are among the “most difficult … in biomedical research today.” The authors note that “[d]ifferent biological pathways are involved in the adverse outcomes of pregnancy, and these can be characterized at different biological levels from the genome to the exposome (the combined effects of environmental influences).”
At the level of the exposome, recently-published research by investigators from New Jersey’s own UMDNJ-Robert Wood Johnson Medical School, brings us incrementally closer to understanding the effects of ambient air pollution on stillbirth, while exemplifying the complexity of the science involved. Ambarina Faiz and colleagues compiled data contained in “New Jersey electronic birth certificate records for live births and fetal death certificates for stillbirths linked to their corresponding hospital delivery discharge records from 1998 to 2004[,]” along with data on air pollutants from 25 New Jersey Department of Environmental Protection monitoring stations. Their analysis of the data revealed that “[i]ncreased concentrations of ambient air pollutants during pregnancy were associated with increased relative odds of stillbirth after adjustment for known risk factors for stillbirth, mean temperature, and a neighborhood level measure of socioeconomic status.” Numerous questions remain, though. The authors call for “molecular studies with specific biomarkers … to define more clearly the roles of specific pollutants and to investigate possible biologic mechanisms that lead to stillbirth.”
Drawing on what it learned from funders, as well as from scientific thought leaders and from the technical team it convened, the GAPPS developed eight recommendations aimed at encouraging such research, with the ultimate goal of “making every pregnancy a healthy pregnancy[.]” The GAPPS calls for 1) determining and publicizing the true cost of prematurity, stillbirth, and other pregnancy and early life problems, 2) establishing alliances among funders, researchers, and other stakeholders, 3) agreeing on research priorities, and 4) promoting research opportunities, particularly opportunities for “new investigators from multiple disciplines.” While these are clearly daunting tasks, the authors report that “[s]everal interviewees observed that the Bill and Melinda Gates Foundation has an unparalleled ability to persuade, convene, and organize important players, both nationally and internationally. In particular, they pointed to the potential for the foundation to move the concept of coordinated funding forward.” The prospect of a new clarity about research priorities, combined with a coordinated approach to funding, is a hopeful one for all of us since “healthy outcomes in pregnancy benefit everyone, directly and indirectly.”
*I thank Catherine Finizio, the Administrator of Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy, for keeping me focused on this important issue. (My prior posts are here, here, and here). Cathy’s grandson, Colin Joseph Mahoney, was stillborn at 39 weeks gestation on November 10, 2008.
- In The Ninth Circle of Hell: An Eighth Amendment Analysis of Imposing Prolonged Supermax Solitary Confinement of Inmates with a Mental Illness (forthcoming in the Denver University Law Review), Thomas Hafemeister and Jeff George provide a fascinating history of prolonged solitary confinement and helpful reviews of the empirical research establishing that such confinement “is virtually guaranteed” to cause significant psychological harm and of the Eighth Amendment jurisprudence addressing the practice. Tragically, the limited extant empirical evidence indicates that our “supermax” facilities and units house not the worst of the worst but rather “a disproportionally large number of inmates suffering from a serious mental illness.” Hafemeister and George conclude that prolonged solitary confinement, without more, is not unconstitutional under the Supreme Court’s current standard. Inmates who are mentally ill or highly vulnerable to becoming so, however, “can readily establish the requisite deliberate indifference on the part of [prison] officials with regard to the impact of prolonged solitary confinement[.]“
- On May 31, 2012, the Center for Constitutional Rights filed an amended complaint in Ruiz v. Brown, a proposed class action lawsuit brought on behalf of prisoners at California’s Pelican Bay State Prison who claim “that prolonged solitary confinement violates Eight Amendment prohibitions against cruel and unusual punishment, and that the absence of meaningful review for [Security Housing Unit ("SHU")] placement violates the prisoners’ right to due process.” In its press release announcing the suit, CCR highlighted the following allegations: “SHU prisoners spent 22 ½ to 24 hours every day in a cramped, concrete, windowless cell. They are denied telephone calls, contact visits, and vocational, recreational or educational programming. Food is often rotten and barely edible, and medical care is frequently withheld. More than 500 Pelican Bay SHU prisoners have been isolated under these conditions for over 10 years, more than 200 of them for over 15 years; and 78 have been isolated in the SHU for more than 20 years. Today’s suit claims that prolonged confinement under these conditions has caused “harmful and predictable psychological deterioration” among SHU prisoners. Solitary confinement for as little as 15 days is now widely recognized to cause lasting psychological damage to human beings and is analyzed under international law as torture.”
- Priscilla Ocen’s article Punishing Pregnancy: Race, Incarceration and the Shackling of Pregnant Prisoners (forthcoming in the California Law Review) is also well worth reading. Ocen contends that because our Eighth Amendment jurisprudence is racially blind, the historical and ideological foundations of the practice of shackling pregnant prisoners during labor, childbirth, and recovery have been obscured. She argues, compellingly, for an “antisubordination” reading of the prohibition on cruel and unusual punishments, one that would take account of “the racial and gender stereotypes of women prisoners that render then vulnerable to shackling practices.”
- I also recommend Lisa Heinzerling’s searing blog post on the cost-benefit analysis which accompanied the Department of Justice’s recently-released final rule implementing the Prison Rape Elimination Act. Heinzerling describes the DOJ’s analysis as “a labored, distasteful, and gratuitous essay on the economics of rape and sexual abuse.” In it, she writes, DOJ finds “itself in the remarkable position of asking how much money the victims of rape would be willing to pay to avoid rape and also asking how much money these victims would be willing to accept in exchange for being raped. … Never mind that rape is a serious crime, not a market transaction. Never mind that framing rape as a market transaction strips it of the coercion that defines it. Never mind that the law under which DOJ was acting is the Prison Rape Elimination Act, not the Prison Rape Optimization Act. In the topsy-turvy world of cost-benefit analysis, DOJ was compelled to treat rape as just another market exchange, coercion as a side note, and the elimination of prison rape as a good idea only if the economic numbers happened to come out that way.”
- Finally, Rick Hills’ response to Heinzerling’s post is also provocative and worth a read. Hills argues that the DOJ’s analysis should have gone further down the road of quantifying the benefits of prison rape regulation, in order to support additional, costly, reforms. Hills writes “that it is better to ‘feel violated’ by facing up to the need to choose between costly reforms and substantial benefits than to refrain from adopting any costly reforms at all in order to avoid the comparison. Put more generally, sometimes it is impossible to induce judges, legislators, and the voters at large to bear big burdens unless one makes explicit the benefits that such burdens will produce.”
Filed under: Drugs & Medical Devices, Research, Women's Health Issues
In 2000, the General Accounting Office (since re-named the Government Accountability Office) reported that more women than ever were being included in clinical trials funded by the National Institutes of Health. In fact, the GAO noted, over 50% of the participants in the trials that NIH funded in fiscal year 1997 were women. At the same time, the NIH had made much less progress implementing the requirement that certain clinical trials it funds be designed to reveal sex-linked differences in a treatment’s safety and efficacy. In 2012, sex-linked differences in responses to treatments are still not being studied in research funded by the government or by the private sector. In a summary released last month of an Institute of Medicine workshop on the problem, Theresa Wizemann reports that “[e]ven when women are included in clinical trials, the results are often not analyzed by sex” despite “growing acknowledgement that men and women have substantial and widespread biologic differences.”
As its title — “Sex-Specific Reporting of Scientific Research” — suggests, a focus of the IOM Workshop was whether medical journals could drive reform in this area by requiring that authors report sex-specific data. Wizemann writes that because “[r]esearchers are eager to have their papers published in high-profile journals[,]” “editorial policies implemented by those journals can be effective in modifying behavior.” But several participants in the IOM Workshop noted that studying population subgroups poses “methodologic and analytic” challenges. In many cases, Wizemann reports, “achieving statistical significance for subgroup analyses would require unattainable or unjustifiable numbers of participants.” Workshop participant Gregory Curfman, who is the Executive Editor of the New England Journal of Medicine, “cautioned against editorial policies that require trials to be designed to reach valid statistical conclusions for males and females separately[,]” because “[s]uch editorial policies would create a ‘steep mountain to climb for investigators and for funding agencies[.]‘”
The participants in the Workshop seemed to be largely in agreement that journals could not, acting alone, re-shape “research culture to embrace consideration of sex differences as part of sound study design.” There are steps that journals could (and should, I think) take short of dictating study design, though, including requiring study authors to tabulate and make available raw sex-specific data to facilitate future studies that draw on data from multiple trials.
Government agencies and other funders have a role to play too. The NIH should more stringently enforce the statutory requirement that certain later-stage trials it funds be designed to evaluate sex-linked differences, and the FDA should take similar action with regard to trials funded by drug and device companies.
A study published last year by Sanket Dhruva, Lisa Bero, and Rita Redberg in the journal Circulation highlighted how little progress the FDA made on the device side over the last decade. In 1994, the FDA issued a directive requiring that every time it makes a decision on an application for approval to market a new device, it issue a Summary of Safety and Effectiveness Data (SSED) that includes, among other things, a “gender bias” statement addressing the following two questions: (1) Did the proportion of men and women in the clinical trial reflect the distribution of the disease? and (2) Were there any sex-linked differences in safety or effectiveness? Dhruva and colleagues reviewed all of the of the SSEDs for all of the cardiovascular premarket approval applications submitted and approved between 2000 to 2007 and found (1) that women were underrepresented in the underlying clinical trials and (2) that less than half (41%) of the SSEDs included the required “gender bias comment or analysis.” Nearly a third (28%) did not even report the percentages of men and women enrolled in the studies supporting the application. And, there was no improvement over time; “[t]here was no change in the presence of gender bias comments or analyses over the 8-year period” studied.
The FDA has been working for several years to address the problem and in December of 2011 it released a draft guidance in which it “strongly recommends” that device companies work closely with the agency to “investigate and report differences in study outcomes of treatment by sex.”
The Guidance provides clear direction for companies regarding (1) increasing the percentage of enrollees in device trials who are women, (2) designing studies to allow for the “consideration of sex and associated covariates” such as body size, (3) analyzing study data for sex-linked differences, and (4) “reporting sex-specific information in summaries and labeling for approved devices.” Whether these strong recommendations translate into strong and consistent agency action remains to be seen, but the Guidance is an excellent start. As Carolyn Clancy, the Director of the Agency for Healthcare Research and Quality, who participated in the IOM Workshop, emphasized, “[b]etter data on women would be better data for everyone,” allowing for more specific clinical practice guidelines and better-tailored care of individual patients.
This month, the thoughts of Christians around the world turn to a laboring mother in “a stable at midnight in Bethlehem in the piercing cold.” It seems an appropriate time to direct your attention to the work of the Second Wave Initiative, “a collaborative academic effort to advocate for, and help find, ethically and scientifically responsible solutions for increasing our knowledge base for the treatment of pregnant women who face medical illness.”
At the end of October, the Initiative submitted comments on the Department of Health and Human Services’ Advance Notice of Proposed Rulemaking (ANPRM) regarding revisions to the regulations governing human participation in federally-funded research, known as the Common Rule. The Initiative’s comments, of which I am a co-signatory, call attention to the fact that the ANPRM fails to address “vagaries and constraints” in the current regulations “that make it difficult for researchers to feel comfortable understanding the parameters of responsible research with pregnant women.”
The Initiative recommends that HHS take the following five steps.
First, amend the Common Rule to allow for research in pregnant women, fetuses, and neonates that creates a minor increase over a minimal risk of harm, as is already permitted in children. The Initiative’s comments explain that the regulations currently provide that “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.’” Some government officials have concluded from this that even pharmacokinetic studies — which involve nothing more risky than drawing blood and which are vital to determining dosing in pregnancy — are ruled out.
Second, eliminate the requirement that, with certain delineated exceptions, fathers must consent to research that “holds out the prospect of direct benefit solely to the fetus.” The current regulations do not require paternal consent where there is a prospect of direct benefit to the pregnant woman or, oddly, where there is no prospect of direct benefit to the pregnant woman or the fetus. The regulations governing pediatric research seem more sensible, requiring that both parents give consent where the research involves greater than minimal risk and holds out no prospect of directly benefitting the child.
Third, amend the regulations so that they no longer label pregnant women as “vulnerable.” As Seton Hall Law’s Carl Coleman has explained, the Common Rule does not define vulnerability and the examples it gives of vulnerable populations are diverse. With regard to pregnant women, “it is not clear why any special issues related to capacity or coercion would necessarily arise.” The Initiative recommends changing the word “vulnerable” to “population meriting special regulation.”
Fourth, confirm that HHS’ proposed changes with regard to research that is excused from ethics review and research that is eligible for expedited review encompass research with pregnant women. The Initiative contends that explicit confirmation is necessary “to avoid inappropriate exceptionalism about pregnancy on the part of researchers and institutional review boards.”
Finally, “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.” As I explained here, “[w]e lack data on the efficacy or safety or both of most drugs when used by pregnant women. … Without denying or dismissing the real moral conundrums that arise in maternal-fetal medicine, the information gap is deeper and wider than that.” To the extent that the Common Rule creates unjustified barriers to desperately-needed, ethically-appropriate research, revisions must be made.
While the ubiquitous pink ribbons (and pink everything else) ensure that everyone knows that October is Breast Cancer Awareness Month, less well known is that it is also Pregnancy and Infant Loss Awareness Month, proclaimed so by President Ronald Reagan in 1988. As I wrote last October, about 1 in every 160 deliveries in this country ends in a stillbirth, and all too frequently no one can say why. Stillbirth is a “largely unstudied … problem in obstetrics.”
Encouragingly, the work of the physicians and scientists participating in the National Institute of Health’s Stillbirth Collaborative Research Network (SCRN) is beginning to bear fruit. The August 2010 issue of the journal Obstetrics & Gynecology included an important article in which the SCRN investigators presented their “standardized method to assign probable and possible causes of death of stillbirths based on information routinely collected during prenatal care and the clinical evaluation of fetal death.” Rigorously defining and more accurately determining causes of fetal death will both facilitate research and have useful clinical implications. As the authors note, “[a]ccurately assigning a cause of fetal death is critically important for counseling grieving families.”
There will be much more to come from the SCRN, which has completed data collection on three distinct studies conducted between March 2006 and December 2009. The first is a surveillance study designed “to assess the completeness of two reports of stillbirths: hospital labor and delivery logs and state vital statistics records. The data from the two sources will be linked statistically to determine incidence of stillbirth, the extent of under- or over-reporting, and factors associated with reporting.” The second study entails a complete evaluation of 500 women and their 512 stillborn babies; the study also includes a control group of 1,932 women with live births. The goal of this study was to develop and apply the method for determining cause of fetal death discussed above, with the ultimate goal of “determin[ing] maternal and fetal risk factors associated with increased risk of stillbirth.” Finally, the SCRN conducted a follow-up study of the participants in the second study who experienced stillbirths, “to determine how many of the women have had subsequent pregnancies and subsequent pregnancy complications; how well women with a loss have resolved their grief and whether grief resolution is associated with the course and care of the pregnancy; and whether life-course stresses and environmental factors are associated with an increased risk of stillbirth.”
Research of the sort conducted by the SCRN is expensive and time consuming. The SCRN investigators collected and are now analyzing 130,000 forms containing information provided by study participants and 120,000 maternal, fetal, and placental samples. Stillbirth is an important public health problem but one that private sector actors lack the incentive or wherewithal or both to tackle. Government support for research into what causes it and what can be done to prevent it is crucial — something for advocates to bear in mind as the struggle unfolds over funding for the National Institutes of Health for Fiscal Year 2011.
Photo Credit: I Should Be Doing Laundry via Flickr.
 I thank Catherine Finizio, the Administrator of Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy, for keeping me focused on this important issue. Cathy’s first and only grandson, Colin Joseph Mahoney, was stillborn at 39 weeks gestation on November 10, 2008.