Galileo's Middle Finger (30 page)

So I crawled out of my hole and pulled myself forward. I started by carefully looking into the characters in the drama. I put out a series of feelers to find new leads. I tracked medical conferences and the medical literature to find any new data. I corresponded with strangers who sent me information, among them several mothers who wrote to tell me what they had been through with Maria New. (Such stories were only “anecdotal evidence,” but they gave me leads.) I learned how to use the Freedom of Information Act (FOIA) to get copies of New’s grants and information on the federal investigations we had initiated. When the OHRP FOIA office wouldn’t give me what I asked for and the FDA FOIA office wouldn’t even acknowledge my written requests,
I hired a lawyer and sued
the government. Meanwhile, when I had nothing new on dex on my plate to analyze, I kept up my reputation as a researcher and health and science writer by working on side projects. In private, I distracted myself with pro bono, confidential, medical-history-recovery work for individuals who had been medically traumatized, work that made me think I had some use to the universe, even if it ultimately turned out that I had been all wrong about dex. And day by slow day, week by slow week, I pressed on with investigatory historical research into dex.

After a few years of steady work, I could finally see clearly what had happened with dex. I could finally see where we’d been right, where we’d been wrong, and where we’d perhaps been played.

 • • • 

A
S WE HAD
FEARED
,
prenatal dex did turn out to be a story of how layers upon layers of medical research protection systems can fail—and fail even around the group recognized to be the most vulnerable: human fetuses. As we hadn’t fully understood, prenatal dex also turned out to be a story of what results when you get a perfect storm of beneficent intentions, professional loyalties, gut-level fears of sexual anomalies, unmanaged conflicts of interest, and mindless bureaucratic paper-pushing. To my horror, prenatal dex also turned out to be something of an
ethics canary in the modern medical mine
; whereas I had assumed at the outset of my investigations that prenatal dex would always be a story of exception, over the years I learned that in fact the same story of failed protections—and failure of truly informed consent—may well be playing out in clinics all over the United States.

That’s the short version of what I discovered in those three years of work. Here’s the slightly longer one:

Maria New’s main NIH grant, a grant to study many forms of and treatments for various adrenal disorders, had been consistently funded all the way back to the 1970s. When the idea of using prenatal dexamethasone to prevent virilization in CAH-affected females came along in the mid-1980s, New successfully rolled the intervention into her multiarmed grant renewal applications, thereafter using prenatal dex to give the NIH more reason to fund her work. She started offering prenatal dexamethasone for CAH through her
Cornell clinic in 1986
, and right around that time, presumably because she planned to publish on the intervention, she sought and obtained Cornell research ethics committee (IRB) approval to study what happens when you dose pregnant women and their fetuses with dexamethasone starting very early in pregnancy to try to prevent intersex in the female offspring. These pregnancy
drug trials were not rigorous
, in spite of the fact that the goal was to have the drug cross the placenta and change fetal development, in spite of the fact that seven out of eight of the offspring exposed in the first few weeks of embryonic development could stand no benefit and would assume all the risks. There was no placebo control, and no blinded assessments of results. In the mid-1990s, Maria New’s team published
some results
, comparing girls who had been exposed to prenatal dexamethasone to sisters who had not; they claimed that this showed the intervention worked.

Contrary to what I had thought when we sent our complaints to the feds, New
did
seem to have consistently gotten IRB approval at Cornell for studies of prenatal dexamethasone for intersex prevention. However, New’s IRB applications at Cornell, which I obtained via FOIA, throw up multiple red flags, flags which apparently did not attract the notice of the IRB members. For example, in 1985, in
New’s first Cornell IRB application
to include (among many other endocrinological studies) a plan to study the use of prenatal dexamethasone for CAH starting at two to four weeks of gestation, New did not check the “special populations” boxes on the front page of the form to indicate that her subject population would include pregnant women and fetuses. Checking those important header boxes would normally have set off special layers of review. Checking those boxes would have ensured that absolutely everyone in charge of managing research subject protections knew that, deeper in the packet, there was a plan for fetal experimentation—and yet as New renewed her IRB approvals each year, no one serving on the Cornell IRB seems to have noticed these “special groups” boxes were not being checked. It took
sixteen years
for someone to notice.

The consent forms that the Cornell IRB approved for New’s prenatal dex work also minimized the risks of this experiment in shocking ways. Any woman who did sign them could not legitimately be said to have given informed consent to put herself and her offspring into this experiment. Instead of describing the risks as essentially unknown, the
1985 consent form
approved by Cornell described potential harms of dexamethasone exposure as “
transient and reversible suppression
of the maternal and fetal adrenal gland.” A pregnant woman reading this description would have reasonably assumed any harm from prenatal dex would be—well, transient and reversible, especially given how the form went on to emphasize the relatively low dose and that “pregnant women and fetuses treated to date with this regimen have not experienced complications.” There is no way, given the high risks, the unknowns, and the extremely controversial status of this intervention, Cornell should ever have allowed such a reassuring description as put forth in this form. But problems with the consent forms persisted year after year, including in that they did not contain appropriately
updated information
about findings of possible harm to mothers and children from prenatal dex.
As late as 2004, Cornell’s IRB
was still approving consent forms that reassured pregnant women that prenatal dexamethasone “has been shown to be safe for the fetus” even while the supposed point of the study was to determine “long-term safety of prenatal treatment.”

New repeatedly boasted to the NIH that a strength of her research team was that her clinic had far more CAH-affected and dex-exposed patients to use as research subjects
than any other researcher
. By her own admission, she had this advantage of numbers specifically because offering prenatal diagnosis and dex treatment brought CAH-affected families to her door. In her
2001 grant renewal application
, for example, she told the NIH, “The prenatal diagnosis and treatment program has
provided a new source of patients
with CAH, adding about 15 patients per month. Clearly we are in a position to expand the [clinic’s] database to provide sufficient patients to answer the [medical research] queries relevant to CAH.” That particular NIH application included a table describing human subjects under the research arm called “prenatal dx [i.e., diagnosis] and treatment in families at risk.” The total number of her research subjects for that study aim is stated as 2,144. So prenatal dex wasn’t just a boon in and of itself in terms of clinic and research income; prenatal dex allowed New a big boost in numbers of CAH-affected people who could then be used to obtain research funding for studies beyond prenatal dex.

To get and maintain her NIH funding for experimentation involving exposing fetuses to dexamethasone, New had to show that she had Cornell’s IRB’s approval for such studies. As noted above, it appears that, indeed, she consistently got Cornell’s IRB’s approval for studies that would have involved pregnant women, and that she then reported to the NIH the IRB approvals. Keep in mind she didn’t have to show the NIH signed consent forms from the mothers she was naming as subjects, or even the blank consent forms—just IRB approval to enroll subjects. The NIH would have assumed that the human subjects she was talking about in her grants had been properly enrolled—that they had signed well-vetted forms that meant they had been fully and honestly informed about potential benefits and risks before agreeing to become experimental subjects.

For many years, New’s work chugged along, approved and funded annually.
By 1996, the NIH was specifically
funding New to study whether prenatal dexamethasone for CAH could “succeed” in making CAH-affected females, in effect, more likely to be straight and interested in becoming mothers. No one at the NIH seems to have raised a question about whether this was a reasonable goal of clinical care or medical research.

In August 2001, the young, Greek pediatric endocrinologist
Kyriakie Sarafoglou was hired
to work in the pediatric research program at Cornell’s medical school. Under a new national program designed to provide on-site monitors for big NIH study locations, Sarafoglou was employed on NIH money as a “research subject advocate,” overseeing patient safety at Cornell’s Children’s Clinical Research Center. Only a few months into that job, Sarafoglou realized she was seeing all sorts of problems with the $23 million NIH grant for which New was the principal investigator, including
financial and ethical irregularities
. For example, Sarafoglou noted
concerning irregularities
on New’s IRB materials. Sarafoglou first tried raising the alarm within Cornell. This led to an internal investigation that found nothing especially concerning. The
internal Cornell report
, which I obtained via FOIA, praised Maria New for her storied career and suggested
Sarafoglou
needed replacing.

Unsatisfied with Cornell’s response, Sarafoglou contacted the OHRP with her concerns, documenting them with thousands of pages of internal paperwork. Although OHRP proceeded to investigate, the agency did so at the usual glacial pace, perhaps because Sarafoglou had sent huge quantities of evidence of systemic problems in Cornell’s pediatric research. With the investigation ultimately involving the Department of Justice, things got hot, and Sarafoglou was given notice that her position was being terminated. About a year after she had called on OHRP to investigate, Sarafoglou sent an
anguished message
to the agency: “It seems that my academic career is over. I just wish I had [had] the foresight to know the pain to me and damage to my career that filing with OHRP would cause.”

Based on what I found when I FOIA’ed the OHRP investigation Sarafoglou initiated in 2003, it appears a major point of concern was IRB records at Cornell that made no sense. External reviewers looking at Cornell’s pediatric research records found misleading consent forms as well as “at least one protocol in which a significant number of subjects were enrolled an [sic] on whom no documentation of
informed consent could be found
.” One reviewer concluded that, although the people at Cornell clearly cared about children, “The IRB members interviewed did not appear to have a thorough understanding of the additional protections for
children as subjects of research
.” In an
angry memo
that seems to have been written by Sarafoglou, someone complained that New was claiming “130 or 160 patients have been accrued each year [to New’s IRB-approved CAH studies] but [there is] not one single dropout or patient studied under another protocol,” a virtual impossibility. Yet the records from Cornell show
New reporting to her IRB
, in her annual applications for renewal, that not a single potential subject refused to be in, withdrew from, or had a complaint about her IRB-approved study protocol. Moreover,
in a letter to her IRB
, New claimed with regard to a study on prenatal dex for CAH that, “To our knowledge, there have been no adverse events in patients due to studies performed,” even while she cited in that letter
a publication she had co-authored
which had reported adverse events for exposed mothers and their offspring! Incidentally, all medical researchers know that IRB-reportable “adverse events” include
any
medical problems while in the study, not only those you can pin to the intervention. So what are the odds studies involving subjects who are pregnant women and developing fetuses would not involve
any
reportable adverse events? Again, this is virtually impossible.

From 2003 to 2005, in response to Sarafoglou’s whistleblowing, OHRP ultimately
undertook a massive review
of Cornell pediatric research. OHRP found so many problems, they took the
extraordinary step of requiring review
by Cornell’s IRB of all active pediatric research at Cornell. One of the projects about which OHRP had pointed questions at that time was New’s supposed research on prenatal dexamethasone for CAH. In a
letter dated May 24, 2004
, OHRP asked Cornell to “Please clarify whether the subjects described in the
Journal of Clinical Endocrinology and Metabolism
[1995 publication] entitled ‘Extensive Personal Experience: Prenatal Treatment and Diagnosis of Congenital Adrenal Hyperplasia[’]. . . were enrolled in a research study. If they were, please provide a copy of the complete IRB-approved protocol for these studies.” What OHRP was asking was not just whether Cornell’s IRB had given New
permission
to do a study, but whether she had actually had the hundreds of pregnant women research subjects
enrolled
in a formal study by signing the consent forms. After
a lot of back-and-forth
in which Cornell said they were having trouble finding the records, and in which Cornell reminded OHRP that New was now gone from Cornell, OHRP just decided to stop tracking what had happened to the pregnant women given dex. They just had too much else to sort out.