fetaldex.org

letter to Columbia University

 

Monday, February 22, 2010


David Hirsch, Ph.D.

Executive Vice President for Research

Columbia University

535 W 116th St.

313 Low Library 

New York, NY  10027


Dear Dr. Hirsch:


I write today on behalf of myself and Alice Dreger, Ph.D., Professor of Clinical Medical Humanities and Bioethics at Northwestern University’s Feinberg School of Medicine.


We write with a concern regarding human subjects of one of your researchers, Heino Meyer-Bahlburg, Dr. rer. nat, in Columbia University Medical Center’s Department of Psychiatry. Dr. Meyer-Bahlburg has been the lead author on several publications following up on the administration of dexamethasone to pregnant women, an off-label use aimed at preventing fetal development of ambiguous genitalia.


We want to be clear we do not believe Dr. Meyer-Bahlburg himself has violated IRB regulations, but we have reason to suspect that the subject population he is working with for this research may have been developed through ethically, scientifically, and legally problematic methods.


By way of background, on February 3, we and 30 of our colleagues who are also professional researchers in Bioethics and allied fields formally raised an alarm about this use of prenatal dexamethasone. We communicated our concerns to: (1) the FDA Office of Pediatric Therapeutics; (2) the HSS Office for Human Research Protections; (3) Mount Sinai School of Medicine (the home institution of Dr. Maria New, who has been Dr. Meyer-Bahlburg’s chief collaborator in this work); (4) Florida International University (Dr. New’s secondary institution); and (5) Weill Medical School of Cornell University (where most of the work we are about to describe was based).


We expressed our alarm regarding multiple aspects of this treatment, including most especially that hundreds of women and their babies were administered this risky Class C steroid off-label in what appears to have been an experiment but without the benefit of IRB oversight.


At that time we did not write to you because it was clear that Dr. Meyer-Bahlburg had IRB approval for the follow-up studies. However, since that time, a closer examination of the situation leads us to believe that the Columbia University IRB perhaps should have been asking where the subjects of those follow-up studies were coming from, and whether they had been protected with IRB oversight specifically when the pregnant women were given the experimental drug.


It appears to us that the group working with Dr. Maria New did not have IRB approval to run a treatment trial of prenatal dexamethasone, at least not in the vast majority of the many hundreds of cases. 


There is enough ambiguity in the paper by Cerame et al.1 that we think that that study may have involved IRB approval for a treatment trial of prenatal dexamethasone for CAH. The rest of the papers do not seem to indicate any IRB approval for a treatment trial. It appears that this group of researchers may have had IRB approval at times to do CVS, DNA analysis, and follow-up studies, such that it appears they were working this up as an experiment on which they planned to publish results that were systematic and generalizable. Indeed, the researchers published many times on the results, drawing systematic and generalizable conclusions.2-9


This suggests they should have gotten IRB approval to do the intervention at the center of this research, namely the off-label administration of this Class C steroid to pregnant women.


By 1999, it appears there were at least 403 instances of diagnosis and treatment;7 by 2001, at least 532;8 by 2003, at least 600.10 There seems to have been a consistent pattern here of gathering data on the drug's effects and publishing on that data. All of this looks like a prospective treatment trial, which would of course require IRB approval and oversight. But we don't see evidence of IRB approval and oversight for treatment trials involving over 600 pregnant women and their fetuses.


We are also alarmed by what appears to be the active promotion by Dr. New of this off-label use as “safe for mother and child.”10, 11 We are concerned that the women and babies studied by Dr. Meyer-Bahlburg may have been recruited to treatment under claims that were inappropriate ethically, scientifically, and legally in terms of FDA regulations of claims. (As we understand it, in response to our concerns, the FDA is now looking into this promotion.)


We suppose one might argue that the drug use was not, in fact, experimental. That would seem to be belied by the substantial research and publication by researchers (including Dr. Meyer-Bahlburg) on the individuals treated via Dr. New2-9 which suggests the researchers understood this to be highly experimental, at least for purposes of grants and publications. We recommend you see also the claim made to the NIH by a grant on which Dr. Meyer-Bahlburg is a sub-investigator: “The long-term effects of this treatment, however, have not been evaluated.”12 This again suggests an understanding that the administration of the drug remains experimental.


Any argument that the administration of this drug was not experimental is also belied by the views of other prominent clinician-researchers as we summarize here chronologically:


1997, Secle and Miller: “we recommend that it be subject to prior approval and regulation by appropriate institutional review boards (IRBs).”13


1999, Miller: “the prenatal treatment of CAH remains an experimental therapy and, hence, must only be done with fully informed consent in controlled prospective trials approved by human experimentation committees.”14


2001 Ad Hoc Writing Committee, Section on Endocrinology and Committee on Genetics of the American Academy of Pediatrics: “the Academy Committee unanimously agrees that prenatal glucocorticoid therapy for CAH should be confined to centers doing controlled prospective, long-term studies. The memory of the tragedies associated with prenatal use of DES (diethylstilbestrol) and thalidomide demands no less.”15, 16


2002, Ritzen: “future treatments should be undertaken as part of prospective clinical trials, approved by ethics committees. This will ensure correct information to parents about pros and cons of this treatment. Also, such studies will shorten the time until conclusive evidence for its safety has been collected, be it short-term treatment [...] or long-term.”17


2002, Joint Statement of the European Society for Pediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society: “We believe that this specialized and demanding therapy should be undertaken by designated teams using nationally or multinationally approved protocols, subject to institutional review boards or ethics committees in recognized centers. Written informed consent must be obtained after the balanced review of the risks and benefits of treatment. Families and clinicians should be obliged to undertake prospective follow-up of prenatally treatment children whether they have CAH or not.”18


2003, Hughes: “it must be recognised that prenatal treatment of CAH by maternal administration of dexamethasone remains experimental, and long-term effects are unknown. Thus, it is mandatory that all treated pregnancies be conducted as part of nationally organized clinical trials that include standardised monitoring both throughout the pregnancy and postnatally.”19


2004, Forest: “the prenatal treatment of CAH remains an experimental therapy and, hence, must only be done with fully informed consent in controlled prospective trials approved by human experimentation committees at centres that see enough of these patients to collect meaningful data.”20


2004, Lajic et al.: “we strongly feel that the efforts must continue to collect as much data as possible, and despite the long-term commitment and lack of immediate feedback, we maintain our standpoint and do not offer treatment outside the frames of the follow-up study.”21


2008, Speiser: “The long-term safety of gestational dexamethasone should be monitored prospectively.”22


2008, Miller: “It is this author's opinion that this experimental treatment is not warranted and should not be pursued, even in prospective clinical trials.”23


The group working under the leadership of Dr. New seems to have been alone in considering this drug not experimental enough to run as a prospective treatment trial with IRB oversight, but experimental enough to follow quite extensively in studies, grants, and publications. What has happened here appears to be a de facto treatment trial on many hundreds of pregnant women, without IRB oversight, at least some of whom appear to have been recruited with claims of safety and efficacy.10, 11 This may be ongoing. This is very serious indeed.


If we are correct in our understanding of what has happened, there are important ethical questions raised by the use of this patient population for follow-up studies, particularly by researchers affiliated with Dr. New, including Dr. Meyer-Bahlburg. There are also important scientific questions raised by what appears to have been such a poorly controlled trial. We are also very concerned by the disjuncture between what Dr. New advertises on her Foundation's website (“Dr. New maintains contact with all children treated prenatally”11) and the substantial number of patients missing from the follow-up studies on which she is a coauthor with Dr. Meyer-Bahlburg. We wonder under what understanding these women are still being recruited to an experimental treatment for which they may later be studied by Columbia researchers.


Studies of prenatal dexamethasone give us substantial reason for concern for these mothers' and children's physical and mental well-being, particularly given that this usage is aimed at preventing a cosmetic issue (one not shown to increase psychosocial risk, a point Dr. Dreger has long made to Dr. Meyer-Bahlburg) and that 87.5% of the mothers started on prenatal dexamethasone will not even be carrying a fetus that is 46,XX 21-hydroxylase deficient. Studies have already shown some adverse effects on exposed children.5, 24, 25  In addition, some researchers have raised concerns about possible epigenetic effects that might even impact the well-being of these children’s children.25


We do not find evidence that animal studies have shown that prenatal dexamethasone is likely to be safe in humans; on the contrary, studies showing harm to animals exposed prenatally to dexamethasone have been used by Dr. Meyer-Bahlburg to try to figure out what defects he might find in the exposed children.9 This certainly looks to us like an improper move to human experimentation on pregnant women of a Class C steroid without satisfactory establishment of safety in animal studies. That this human experimentation may even be done without IRB oversight astonishes us.


We have provided a version of this letter to the other institutions to whom we have already asked to conduct investigations, as well as to The Endocrine Society and the Lawson Wilkins Pediatric Endocrine Society.


We call upon Columbia University to examine what has happened in this instance and what role Columbia may have knowingly or unknowingly played in the possible violation of the rights of these women and their babies. We also call on you to agree with us that this experimental treatment should cease immediately and that extensive follow-up studies on the mothers and children used in this major human experiment should be conducted by researchers independent of Drs. New and Meyer-Bahlburg.


We presume we do not need to remind you, as the AAP suggested in their communication, how long it took before the realities of DES and thalidomide became well-known enough to stop their usage.


Thank you for your consideration of this letter. Please feel free to share this research and communication as you deem necessary.  


Signed:


Ellen K. Feder, Ph.D. (corresponding author)

Associate Professor and Acting Chair

Department of Philosophy and Religion

American University


Alice Dreger, Ph.D.

Professor of Clinical Medical Humanities and Bioethics 

Feinberg School of Medicine

Northwestern University



Notes:


1.Cerame BI, Newfield RS, Pascoe L, et al. Prenatal diagnosis and treatment of 11beta-hydroxylase deficiency congenital adrenal hyperplasia resulting in normal female genitalia. J Clin Endocrinol Metab 1999;84:3129-34.

2.Speiser PW, Laforgia N, Kato K, et al. First trimester prenatal treatment and molecular genetic diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency). J Clin Endocrinol Metab 1990;70:838-48.

3.Karaviti LP, Mercado AB, Mercado MB, et al. Prenatal diagnosis/treatment in families at risk for infants with steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia). J Steroid Biochem Mol Biol 1992;41:445-51.

4.Mercado AB, Wilson RC, Cheng KC, Wei JQ, New MI. Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 1995;80:2014-20.

5.Trautman PD, Meyer-Bahlburg HF, Postelnek J, New MI. Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 1995;20:439-49.

6.Trautman PD, Meyer-Bahlburg HF, Postelnek J, New MI. Mothers' reactions to prenatal diagnostic procedures and dexamethasone treatment of congenital adrenal hyperplasia. J Psychosom Obstet Gynaecol 1996;17:175-81.

7.Carlson AD, Obeid JS, Kanellopoulou N, Wilson RC, New MI. Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment. J Steroid Biochem Mol Biol 1999;69:19-29.

8.New MI, Carlson A, Obeid J, et al. Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 2001;86:5651-7.

9.Meyer-Bahlburg HF, Dolezal C, Baker SW, Carlson AD, Obeid JS, New MI. Cognitive and motor development of children with and without congenital adrenal hyperplasia after early-prenatal dexamethasone. J Clin Endocrinol Metab 2004;89:610-4.

10.Kitzinger E. Prenatal diagnosis & treatment for classical CAH (at http://www.caresfoundation.org/productcart/pc/news_letter/winter02-03_page_9.htm). In: CARES Foundation Newsletter; 2003.

11.New M. Prenatal diagnosis and treatment of congenital adrenal hyperplasia (at http://www.newchf.org/testing.php). In: The Maria New Children's Hormone Foundation; 2010.

12.New M. Determining the long-term effects of prenatal dexamethasone treatment in children with 21-hydroxylase deficiency and their mothers (at http://clinicaltrials.gov/ct2/show/NCT00617292). In. Mount Sinai Medical Center: NIH Office of Rare Diseases; 2008.

13.Seckl JR, Miller WL. How safe is long-term prenatal glucocorticoid treatment? JAMA 1997;277:1077-9.

14.Miller WL. Dexamethasone treatment of congenital adrenal hyperplasia in utero: an experimental therapy of unproven safety. J Urol 1999;162:537-40.

15.Frias J LL, Oberfield SE, Pang S, and Silverstein J. For the AAP Ad Hoc Writing Commitee, in reply to Maria New. Pediatrics 2001;107:805.

16.Erratum. (at http://pediatrics.aappublications.org/cgi/content/full/107/6/1450). Pediatrics 2001;107:1450.

17.Ritzen EM. Prenatal dexamethasone treatment of fetuses at risk for congenital adrenal hyperplasia: benefits and concerns. Semin Neonatol 2001;6:357-62.

18.Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippell WG, Speiser PW. Consensus statement on 21-hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society. Horm Res 2002;58:188-95.

19.Hughes IA. Management of fetal endocrine disorders. Growth Horm IGF Res 2003;13 Suppl A:S55-61.

20.Forest MG. Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod Update 2004;10:469-85.

21.Lajic S, Nordenstrom A, Ritzen EM, Wedell A. Prenatal treatment of congenital adrenal hyperplasia. Eur J Endocrinol 2004;151 Suppl 3:U63-9.

22.Speiser PW. Prenatal treatment of classic CAH with dexamethasone (pro). Endocrine News (Tri-Point Series) 2008:15-6.

23.Miller WL. Prenatal treatment of classic CAH with dexamethasone (con). Endocrine News (Tri-Point Series) 2008:16-8.

24.Hirvikoski T, Nordenstrom A, Lindholm T, et al. Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. J Clin Endocrinol Metab 2007;92:542-8.

25.Lajic S NA, Hirvikoski T. Long-term outcome of prenatal treatment of Congenital Adrenal Hyperplasia. In: WL FCaM, ed. Disorders of the Human Adrenal Cortex. Endocrine Development ed. Basel: Karger; 2008:82-98.



[Columbia has not responded, not even to acknowledge receipt of our letter.]