Galileo's Middle Finger (27 page)

I am about to write and publish an article critical of your use of dexamethasone in the maternal-fetal period without IRB oversight. You have a major grant to study the long-term effects of this experimental treatment, which clearly indicates you understand that there are risks to the children (not to mention the mothers) subject to what you understand to be an experimental treatment, yet apparently you do not have IRB approval for the experiment that is the treatment itself. In the event you have IRB approval for the experimental, off-label use of dexamethasone in pregnant women “at risk” of carrying a child with 21-Hydroxylase Deficiency [CAH], please let me know that within 48 hours. In the event I am wrong, I will correct my work. Thanks.

Two days later, I got a response, not from Dr. New but
from Jeffrey Silverstein
, the director of the Program for the Protection of Human Subjects at Mount Sinai, i.e., the person who would be in charge of overseeing New’s human-subjects research.

Silverstein wrote to say, “While your email was unusual, I am responding in the spirit of academic collegiality. In the time frame given, I am only able to confirm that Dr. New has an IRB-approved protocol for the study of ‘Rare Diseases of Steroid Metabolism,’ that includes treatment with dexamethasone in pregnant women with 21-Hydroxylase Deficiency.”

I knew from searching ClinicalTrials.gov (the government Web site showing who has what federal clinical research funding) and Dr. New’s papers what that probably really meant: Mount Sinai had in all likelihood given permission for the low-risk retrospective follow-up studies on prenatal dex for prevention of sex atypicality, studies conducted years
after
the pregnancies, but not for the high-risk prenatal drug administration itself. If so, there were no ethical protections in place at the important moment—when the woman was offered the drug.

Nevertheless,
I asked Dr. Silverstein to clarify
: “I know Dr. New has IRB approval for the . . . ongoing study of children who were subjected to dexamethasone in the womb. I am asking whether she has IRB approval for the treatment of pregnant women themselves with dexamethasone, a drug use understood to be experimental and off-label.”

He didn’t answer.

I
N A STRICT
LEGAL
SENSE
,
American medical researchers are not obligated to follow the principles laid out in the Nuremberg Code, the code of ethics drafted in 1947 in response to Nazi medical research atrocities. Nor are they legally bound to adhere to the Declaration of Helsinki, the expanded medical research ethics code adopted by the World Medical Association in 1964. But
American medical ethics regulations
do require adherence to the same basic principles advanced in these foundational codes.

What was going on with prenatal dexamethasone for CAH seemed to violate a number of those principles, including the first principle of nearly all research ethics codes: Except in extraordinary circumstances, researchers must obtain the voluntary informed consent of a subject to participate in an experiment. There appeared to be a fundamental failure of informed consent in prenatal dex “treatment.”
New consistently described
the intervention to the CAH families as safe
even while
she was telling the NIH she needed grant money “
to establish that prenatal treatment with dexamethasone is safe
.” Did the families New encouraged to use prenatal dex know they were being used as “
human subjects of research
” for funding purposes? It sure didn’t look like it to me.

Medical research ethics codes also called for animal modeling before use of a drug on humans, yet, in spite of the extreme high risks in intentionally changing fetal development, no animal modeling of intersex prevention had occurred. The codes also required that researchers do the best science possible; if researchers are going to put people in harm’s way as experimental subjects, ethics require that they design the study to produce the best data ascertainable. Unfortunately, the way Dr. New was “studying” this intervention—primarily using retrospective phone surveys of only a portion of the population exposed—was completely inadequate to ascertaining the risks and harms involved. No placebo-controlled trials, no blinded studies, no prospective studies, and inadequate retrospective studies—the science here was so bad that it itself could be viewed as unethical.

What was going on was so out of line with accepted standards that many of the physicians and ethicists I called for advice on what to do simply could not believe what I was describing. It seemed especially shocking to many that someone of Dr. New’s stature would engage in such reckless behavior. Historically, though, it’s researchers of the highest stature who get away with this sort of behavior the longest. They have the reputation and the
resources to weather criticism
. And New had reputation and resources. At Cornell, New had been chair of Pediatrics and the head of the children’s clinical research unit at Cornell; as such, she had been one of the most powerful pediatric researchers in the country. Even after she left Cornell, because the fraud case related to New’s grant had been settled with no admission of wrongdoing and because by then New had found herself a new job at Mount Sinai School of Medicine, to the outsider there appeared to be no blemish on her record. She boasted membership in the National Academy of Sciences, a history of leadership in her field, the adoration of thousands of CAH-affected families, and a remarkable three decades of continuous NIH funding.

One might wonder how a researcher of Maria New’s stature could bring herself to violate the most basic principles of medical research, but if history is any guide, like most American researchers who engage in unethical behavior, Dr. New probably had the attitude shared by many American medical researchers: that the Nuremberg Code was not written for her because it was a
code meant for Nazis
, not for good people. In public Maria New positioned herself as a brave advocate for CAH-affected families, fighting back against the seemingly unreasonable—even uncaring?—calls for extreme caution from groups like the American Academy of Pediatrics, the Pediatric Endocrine Society, and the European Society for Pædiatric Endocrinology.

Why didn’t those groups do more than issue cautions? Medical societies like these cannot discipline individual researchers. The only institutions that can are the researchers’ own medical schools and certain official authorities, including the Office for Human Research Protections (OHRP) and the FDA. For them to act, typically someone would have to make a complaint. No clinician had done so, presumably because they all knew the kinds of backlash they’d get for breaking ranks.

In late January 2010, I started using various networks to collect names of academics in bioethics and allied fields who would be willing to sign a formal “
letter of concern
” about the way prenatal dexamethasone for CAH was being deployed under Maria New’s leadership. Early in the process, Ellen Feder, a tenured professor of philosophy at American University, whom I knew from academic intersex studies, offered to sign, and I asked her if she’d do more—draft the letter and become the corresponding author. She did so, creating a letter that would be as much about alerting Cornell, Mount Sinai, the Office for Human Research Protections, and the FDA as alerting obstetricians, genetic counselors, CAH-affected families, and health reporters.

In our formal letter, we questioned using such a risky intervention for a matter of genital appearance. We indicated serious concern that there had been inadequate institutional review board (ethics committee) oversight for the pregnant women, and that there had been inadequate scientific rigor as well.
We pointed to Dr. New’s misleading promotions of the intervention as safe. We referred to studies that suggested that the use of glucocorticoids in pregnancy could be seriously harmful. The letter ended:

We call for rigorous investigation into possible regulatory violations in this matter. We also believe that women who have been treated without the protection of IRBs should now be advised of the information that may not have been made available to them at the time of treatment, and that they should be given the most recent information from studies indicating long-term risks to women and children. Finally,
we agree with Dr. Miller
, Distinguished Professor of Pediatrics and Chief of Endocrinology at the University of California San Francisco, who has written that “this experimental treatment is not warranted and should not be pursued even in prospective clinical trials.”

I felt certain that the federal investigation we were calling for—an investigation that would be independent of politics, transparent, evidence-based, and rule bound—would finally produce a statement that everyone, including Maria New, would have to heed. The feds would have to recognize that what had happened
was
another DES—and a deeply troubling case of doublespeak by its main promoter-researcher, too.

By early February, Ellen and I had signatures on the letter from thirty-two academics in bioethics and affiliated fields from a total of twenty-seven institutions, enough for us to feel we should go ahead and submit. The sooner the letters reached the people with real power, the sooner the CAH-affected families might have their rights protected. I also calculated that, with thirty-two signatories, we had a big enough group for reporters to notice. Garnering press attention had to constitute a major strategic aim. We needed external eyes and ears if we were going to make it impossible for Maria New to work against all the doctors calling for ethics and science in this case. Besides, government paper pushers were more likely to act if journalists came asking what they were doing about a problem involving pregnant women and experiments on fetuses. And it was just that hook—experimentation on pregnant women and fetuses—that made me sure it was going to be easy to get reporters interested in this story.

But once I tried calling reporters about dex, I began to understand just how much the tradition of investigative journalism had been weakened in the decade since the early intersex rights movement by the economic struggles of magazines and newspapers in the wake of the Internet’s rise. Previously, knowledgeable and engaged investigative health reporters had been plentiful and critically important to the success of our work. Now, a number of reporters I tried to contact from my address book seemed to have left the business. A few of the national health reporters I did reach told me the story was too complex to cover, given the short time frames their editors could allow them nowadays to work up a single story. I also got the sense that some reporters didn’t like the idea of having one particular researcher named—and for that hesitation, knowing what had happened to various researchers vilified for ethical violations and/or bad science when the press rushed to repeat accusations, I would not have been so troubled if I hadn’t had the sense that this hesitation had less to do with fear of smearing someone than a newfound editorial fear of costly fact-checkers and lawyers. The American press, once a large and fearsome institution, now seemed emaciated and timid, jumpy and distracted.

All we could do was push on. Not long after we submitted the letters, staff members from the
OHRP and the FDA had let us know
they would be looking into the matter—a development that made me both hopeful and genuinely sick to my stomach. Strange as this may sound, until I read these replies, I hadn’t really specifically envisioned what my actions might do to Maria New as a person. I certainly didn’t want to ruin her or her reputation; I just wanted the CAH-affected families’ rights protected, and her and all the clinicians involved to fix all the ethical and scientific problems in this situation. Now I found myself imagining the octogenarian New going through the whole descent into blackness that I had charted in so many researchers accused of being unethical. At least this left me feeling less disappointed in the lack of press interest; perhaps it was best that this stay out of the press until an independent group of government investigators confirmed what we and her other critics were seeing. Not that there was any question in my mind that the government would confirm that what New had done was deeply unethical. But there was also no question in my mind that Dr. New had bounded ahead thinking she was doing what was best for these families. That’s exactly why she had been so persuasive: She had all the charisma of the true believer.

As the weeks went by, I found myself having to go for more midday runs than I usually do in the winter. In spite of finding more and more evidence that what had happened had been both unscientific and unethical, I wasn’t happy to be caught up in yet another tangle. If it hadn’t been for my friends calling me in to help with a rights movement that had so long been dear to me, I would have ignored this as I had so many recent invitations to investigate other controversies. To make matters still more uncomfortable, in contrast to our early intersex rights work—when no surgeon would go on record to defend cosmetic genital surgeries on intersex children—the work on dex had quickly started to generate pushback. Answering us at the Hastings Center’s blog site, one
group of Boston clinicians
, specialists in intersex treatment, claimed that we were misrepresenting the problem as a “cosmetic” treatment. They insisted that dex was critically necessary to prevent the urogenital sinus, the condition in which, in some CAH females, the urethra and the vagina join, increasing risk of infections and problems with vaginal intercourse. But as we said
in the response
I rapidly drafted, in the literature on dex, New (like other researchers) didn’t talk about it as primarily being a preventative for urogenital sinus. In fact, when writing about dex, physician-researchers barely talked about the urogenital sinus
at all
. The specialist medical literature made clear that the primary goal of dex was prevention of atypical genitals in genetic females. The goal was to give the parents hope of a “normal” girl. New’s major critic on dex, the pediatric endocrinologist Walter Miller, acknowledged this truth dryly: “It seems to me that the main point of prenatal therapy [for CAH] is to allay parental anxiety. In that construct, one must question the ethics of using the fetus as a reagent to treat the parent, especially
when the risks are non-trivial
.”

Meanwhile, on a major
bioethics e-mail discussion list
, we were being sharply criticized by a bioethicist out of Texas’s Baylor College of Medicine, a fellow named Larry McCullough. According to McCullough, we had utterly misrepresented the question of IRB oversight; Dr. New, he claimed, had had proper oversight. Our letters of concern were full of gas, declared McCullough, a man who had mastered the authoritative medical-expert tone. This had several of my collaborators sweating bullets until I rechecked the papers to which McCullough was referring. Doing so confirmed what I’d seen before: In the 2001 “extensive personal experience”
report on 532 pregnancies
subject to this intervention, Dr. New appeared to have IRB approval only for subsidiary studies, like whether a particular genetic screening technology picked up CAH, or for retrospective phone surveys,
not
approval for the prenatal drug intervention itself. And it was the drug intervention that was the real issue. I wrote an evidence-based response to McCullough, and sent it to the list.

All this angry pushback had me feeling like I was chewing tinfoil for gum. Had I done this wrong? I hadn’t taken the time to do anything like a full-blown historical investigation on this—nothing like the year I had spent on Bailey’s controversy or the year on the Tierney fiasco. Of course, that was in large part because it all seemed pretty clear and very urgent. Moreover, much of what we really needed to know to judge the scene—i.e., what had really happened at Cornell and Mount Sinai in Dr. New’s clinics—could in all likelihood only ever be found out via a formal governmental inquiry.

But maybe I should have done even more research before setting out as I had. I had dragged in so many colleagues who had basically signed on my word. Or more specifically, on my reputation for being meticulous. . . . I kept doing this self-check, to see if the problem was that I had done this because I had wanted to prove something—something that might blind me to the facts. Had I become self-deluded? Even self-righteous? But I was pretty sure self-righteous people didn’t feel this anxious, this unsure of their own actions. Still, at my request, Aron and Ellen kept going over the evidence with me. And I kept reminding myself: The reason those good clinicians had called me was because all the conventional routes had been tried and had failed.