The following is an update of September 3, 2010. For an archive of the previous home page, go here.

In order to update this page promptly, we are attaching here a letter to those who signed the original Letter of Concern as well as our follow up inquiries to the OHRP and the FDA. You can see the letters from the OHRP and the FDA to which this refers by clicking here.

---------------------------

Dear signers to the prenatal dex Letters of Concern,

Ellen Feder and I received letters yesterday afternoon from the OHRP and the FDA. We attach them here. As you will see, their answers are incomplete and confusing. Ellen and I wrote back asking for clarification on a number of points this morning, and I also attach our messages from this morning so you can see some of what doesn't make sense to us.

We are greatly disappointed that the concerns we named in the Letter of Concern remain basically unaddressed. We still don't know why this use was believed to be acceptable by some, we still don't know how many women and children were explicitly or tacitly experimented upon, we still don't know what those women were told. And we don't understand why the FDA seems to have no problem with a clinician directly advertising an off-label use of a class C pregnancy drug as "safe for mother and child" when five major medical societies and two major support groups say it should not be used outside of a controlled, IRB-approved clinical trial.

We think what we're dealing with here is legal versus ethical, but even where the laws are concerned, the OHRP and the FDA have not given us enough explanation or documentation to show that no regulations were violated.

As we wait for clarifications, we just want you to be aware that we have FOIA'ed materials along with Anne Tamar-Mattis of Advocates of Informed Choice, and in doing so, we have found two things worth relating: 

(1) Dr. Frank Chervenak, Dr. McCullough's second author on the AJOB target article, was named "key personnel" as  a consultant on at least one of Dr. New's grant, a fact in direct contradiction to Dr. McCullough's claim to me on May 17, 2010, that "None of the authors of the paper: has any economic, professional, or any other kind of conflict of interest with regard to the content of our paper; has collaborated with Dr. New in her research, been funded on her grants, or served in any advisory capacity to her in her research".

(2) In keeping with the findings we presented in our last Bioethics Forum post on prenatal dex and the prevention of lebsianism and "masculine" behaviors in girls and women, Anne Tamar-Mattis, JD, of Advocates for Informed Choice has found numerous pieces of evidence that some of Dr. New's grant applications to the NIH for folllow-up studies on those treated specifically named as an interest seeing whether prenatal dex could reduce "behavioral masculinization" in girls with CAH, including in terms of making them more likely to turn out as wives and mothers. Here are just two of several relevant passages found by Anne in the grants:

(a) "The overall objective is to fill the gap of knowledge about the long-term consequences of early-prenatal DEX treatment on childhood development on the one hand, and the success of DEX in suppressing behavioral masculinization in the sub-sample of girls with definitive congenital adrenal hyperplasia on the other."

(b) "The spectrum of behavioral effectes ranges from mild or marked tomboyish behavior of childhood to increased adolescent/adult bisexuality and lesbianism; through full male identification with request for sex reassignment surgery and legal gender change in adolescence or adulthood...In addition, the genital abnormalities and often multiple corrective surgeries needed affect social interaction, self image, romantic and sexual life, and fertilitiy.  As a consequence, many of these patients, and the majority of wemen with the salt-losing variant, appear to remain childless and single. Preventive prenatal dexamethasone exposeure is expected to improve this situation." 

FYI, Heino Meyer-Bahlburg, who was mentored by John Money, is the main psychological collaborator in most of these studies. He's now part of the DSM committee shaping material on transgender individuals.

Ellen and I have long been talking about how the prenatal dex situation has seemed to mirror the Tuskegee Syphilis study: a population seen as "sexually abnormal" treated without normal ethics in lousy scientific studies in plain sight of colleagues, etc. This morning we talked about how it is worth remembering that ethics and history scholars found the government's investigation of Tuskegee woefully lacking, and just plain wrong in some factual respects. We had hoped, however, that the government response in this case would be more sensible. We will press for further clarification.

Ellen and I thank you again for your help, and we'll keep you posted.

Our best to you.

Alice

Alice Dreger, Ph.D.

Professor of Clinical Medical Humanities and Bioethics 

Feinberg School of Medicine

Northwestern University

-------------

From:      Alice Dreger

Subject:     follow-up questions

Date: September 3, 2010 9:43:55 AM GMT-04:00

To: Dr. Robert Nelson, FDA

Cc: Dr. Ellen Feder, American University; Anne Tamar-Mattis, JD, Advocates for Informed Choice; Dr. Diane Murphy, FDA

Dear Dr. Nelson,

Yesterday afternoon, the OHRP provided us your memo regarding prenatal dexamethasone (attached). We sincerely appreciate your work on this matter and have the following questions and requests for you, the responses to which will facilitate the understanding of your findings among professional ethicists and patient advocates.

1. You indicate that Dr. New "received an IND exemption from FDA in 1996 under 21 CFR 312.2(b) for the administration of dexamethasone during pregnancy for the purpose of preventing virilization in females with congenital adrenal hyperplasia." Please provide us a copy of the documentation of that exemption. (A PDF scan is fine.)

2. Please also explain whether this exemption had any specific beginning and ending date, if it is not clear from the copy.

3. Please provide us information (preferably original documentation) about why this exemption was given and what evidence and ethical considerations were taken into account when the exemption was given. We are interested, for example, in why the FDA considered first-trimester treatment with a Class C drug to be acceptable as an experimental treatment aimed at a non-lethal condition when at least 7 out of 8 of the fetuses exposed would not even have the targeted non-lethal condition. (We are trying to understand the limits of what the FDA will provide an exemption for, or at least the limits as they existed in 1996. Perhaps if those limits have changed, you can educate us about where to learn more about the historical shift.)

4. Dr. New directly advertises her clinical services regarding prenatal dx for CAH to prospective patients by saying that "the treatment has been found safe for mother and child." (Quote from http://www.newchf.org/testing.php) Is the reason the FDA allows her to declare this off-label use of a pregnancy class C drug "safe for mother and child" in advertisements for her own clinic that she does not work for the maker of the drug? 

5. Is the FDA presently concerned about doctors advertising off-label uses directly to prospective patients (including pregnant women) as safe and/or effective?

6. Could we (in general) reasonably expect the FDA to be disproportionately alert where DTC advertising of off-label first-trimester treatments specifically designed to change fetus's bodies for non-lethal conditions is concerned?

7. In producing your findings, were you privy to the most recent consensus regarding this off-label use from the American Academy of Pediatrics, the Lawson Wilson Pediatric Endocrine Society, the European Society for Paediatric Endocrinology, the European Society for Endocrinology, and the Society for Pediatric Urology? (If you were, it would seem you were aware of what their literature review showed, and what they concluded, somewhat differently from you. If you were not, we would be happy to share it with you.)

8. In producing your findings, did you ascertain what percentage of untreated affected females will have a urogenital sinus that results in problems requiring surgical correction? Relatedly, are you aware that the most recent consensus of the 5 medical societies mentioned in question 7 acknowledges that "The condition being treated, while fraught with emotional complexities, is directed toward a cosmetic outcome rather than aiming to preserve life or intellectual capacity"? (Emphasis added.)

9. In producing your findings, were you aware of any evidence that ambiguous genitalia represent a threat to the health (physical or mental) of those who have them? If so, what is that evidence?

My colleagues and I would appreciate a prompt written reply so that we can better understand your findings as we share them with others. Please feel free to answer in a series of responses if you have the answers to some of these items now, and will have the answers to the others later. Thank you.

Alice Dreger, Ph.D.

Professor of Clinical Medical Humanities and Bioethics 

Feinberg School of Medicine

Northwestern University

---------

From:     Alice Dreger

Subject: Re: OHRP's Determinations RE: Dexamethasone in Pregnant Women Allegations

Date: September 3, 2010 8:52:38 AM GMT-04:00

To: Kristina Borror, Ph.D., HHS; Lisa Buchanan, HHS

Cc: Ellen Feder, Ph.D., American University; Anne Tamar-Mattis, JD, Advocates for Informed Choice

Dear Dr. Borror:

Thank you for your message of yesterday. In order for members of the professional ethics and patient advocacy communities to understand your findings, we need more information from you.

1. You indicate "Dr. New conducted 3 studies while employed at WCMC involving provision of dexamethasone to pregnant women at risk of carrying a female fetus with CAH." Would you please clarify the precise nature of these studies, namely the specific methodology for each? Please also advise if you are aware of the actual study methodology varying from the methodology described in the application to the IRB.

2. What was the number of subjects enrolled for each of these three studies? (If any subjects dropped out of the study, we would like to know how many dropped out and for what reasons.)

3. We would also like to know the dates of each study, including the start and end dates of each study.

4. Would you please provide the informed consent form for each of these studies so that we can see why you have concluded that the women were adequately informed?

5. You indicate that Dr. New wrote one prescription for prenatal dexamethasone for CAH at MSSM. How many did she write for prenatal dexamethasone for CAH at WCMC?

My colleagues and I would appreciate a prompt written reply so that we can better understand your findings as we share them with others. Thank you.

Alice Dreger, Ph.D.

Professor of Clinical Medical Humanities and Bioethics

Feinberg School of Medicine

Northwestern University