Microsoft word - opt memo to ohrp 08-30-2010.doc
DEPARTMENT OF HEALTH & HUMAN SERVICES
Office of Pediatric TherapeuticsOffice of the Commissioner10903 New Hampshire Ave., WO32-5216Silver Spring, MD 20993-0002Tel (301) 796-8665; FAX (301) 847-8619
Robert M. Nelson, M.D., Ph.D.
Pediatric Ethicist and Lead Medical OfficerOffice of Pediatric Therapeutics, Office of the Commissioner, FDA
Dianne Murphy, M.D., DirectorOffice of Pediatric Therapeutics, Office of the Commissioner, FDA
Kristina C. Borror, Ph.D.
Director, Division of Compliance OversightOffice for Human Research Protections, DHHS
Allegations concerning research activities conducted by Dr. Maria New at WeillCornell Medical College (WCMC) and Mount Sinai School of Medicine (MSSM)
On February 3, 2010, a “Letter of Concern from Bioethicists” was sent to report suspectedregulatory and ethics violations by Dr. Maria New in the use of dexamethasone duringpregnancy for the purpose of preventing genital virilization associated with congenital adrenalhyperplasia in females. Copies of this letter were submitted to the FDA Office of PediatricTherapeutics, the Office for Human Research Protections, and universities where Dr. New hasheld or holds appointments.
Dexamethasone treatment must be initiated in the 6th to 7th week of gestation, before sexualdifferentiation of genitalia occurs. Treatment is discontinued once the fetus is identified as beingunaffected or male by chorionic villus sampling, usually performed at 10-12 weeks of gestation.
If the fetus is female and affected (i.e., “at risk”), dexamethasone is continued until birth. For thisindication, dexamethasone is administered at a very low dose of 20 micrograms/kg/day of pre-pregnancy weight in 3 divided doses.
The submitted letter contained the following allegations:
1. Research on the use of dexamethasone for the prevention of virilization in “at risk”
fetuses was conducted by Dr. New without appropriate IRB oversight.
2. Dr. New has publicly promoted dexamethasone as safe and effective for this use, when
dexamethasone has not been approved for this indication by the FDA.
In addition to the above allegations, the letter outlined three major concerns about therisk/benefit profile of administering dexamethasone:
3. Prenatal dexamethasone treatment results in detrimental changes to the brains of children
who are exposed, including problems with working memory, verbal processing, andanxiety;
MEMORANDUM (Page 2 of 4)
4. Animal studies have also indicated reason to be concerned about prenatal
5. Genital virilization is only a cosmetic issue for which alternative postnatal treatments
In response to the Letter of Concern, the Office of Pediatric Therapeutics (OPT) spoke withrepresentatives from a number of offices within the Center for Drug Evaluation and Research,including the Division of Scientific Investigation, the Pediatric and Maternal Health Staff and theDivision of Reproductive and Urologic Products in the Office of New Drugs, and the Division ofDrug Marketing, Advertising, and Communications. In addition, the HHS Office for HumanResearch Protections (OHRP) requested investigations by the universities identified by the Letterof Concern. The results of these investigations have been reviewed by OPT, and discussed withOHRP. The findings of this investigation are summarized below.
1. Dr. New’s research was (specifically, three studies at WCMC between 1985 and 2004)
and continues to be conducted (specifically, one study at MSSM) under appropriate IRBoversight, based on the available documentation.
2. Existing data are insufficient to draw conclusions regarding the risk/benefit claims made
in the Letter of Concern. Dexamethasone appears to reduce virilization of affectedfemales without causing fetal malformations. High-dose dexamethasone has knownadverse effects on growth and development in animals, but similar effects at low doseshave not been proven. Further prospective studies are required to determine whetherprenatal treatment with dexamethasone should be routinely recommended. We discussthis issue in more depth below.
3. 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 preventingvirilization in females with congenital adrenal hyperplasia.
4. The current administration of dexamethasone to pregnant women in order to prevent
genital virilization in “at risk” females does not constitute a “clinical investigation” as thedrug is being prescribed based on the clinical judgment of the women’s personalphysicians who are then referring the women for follow-up in Dr. New’s IRB-approvedresearch protocol.
5. The use of dexamethasone for the prevention of genital virilization in “at risk” females
has not been approved by the FDA. Dexamethasone is thus being used for this “offlabel” as part of the clinical practice of medicine. Dexamethasone has not been found tobe safe and effective for this indication by FDA.
6. FDA regulations that prohibit the promotion of “off label” use of medications apply to a
sponsor, and not to physicians using the medication as part of the practice of medicine.
MEMORANDUM (Page 3 of 4)
Discussion of the Safety of using Dexamethasone during Pregnancy:
We now summarize our assessment of the safety issues posed by this treatment in children.
One study assessed the frequency and etiology of white-matter changes and temporal lobeatrophy demonstrable on MRI in a group of children and young adults with congenital adrenalhyperplasia (Nass, 1997). The authors noted that exposure to excess glucocorticoids in theprocess of treatment for congenital adrenal hyperplasia was a theoretically appealing explanationfor these MRI findings. However, there is no clear dose-response relationship between theglucocorticoids and the MRI findings, and no correlation between MRI findings and neurologicalexaminations.
Data on memory and processing in children who were treated prenatally with dexamethasone forCAH are small, conflicting, and difficult to interpret. Different methods of assessment were usedwith children at different age groups, and some studies have focused on parental perceptionrather than student performance. In general, no differences were observed betweendexamethasone-treated children and controls in parental ratings of cognitive or motordevelopment or school performance (Meyer-Bahlburg, 2004). Although an increase in socialanxiety was observed in the CAH-unaffected dexamethasone-treated group when children ratedthemselves, parental ratings did not concur. Visuospacial working memory was mildly poorer inthe dexamethasone-treated group, but the difference was not statistically significant (Hirvikoski,2007). Dexamethasone-treated individuals also had poorer verbal working memory andperception of school performance than controls (Hirvikoski, 2007). However, the authors werelater unable to reproduce these findings, and on further analysis concluded that they were due toa small sample size (Hirvikioski, 2008).
A number of studies of dexamethasone administration have been conducted in animals, includingrats, rabbits, and primates. While adverse effects ranging from impaired memory to anexaggerated cortisol response to mild stress have been found, the animal models have beendesigned to imitate either the treatment of premature infants or have used very high doses ofdexamethasone (Lajic, 2008). The NOAEL has not been determined, and there are few animaldata using lower doses of dexamethasone that would be consistent with the prenatal indication inCAH. One study in fetal sheep suggested that early exogenous dexamethasone directly increasesfetal adrenal activation but not anterior pituitary function (Braun, 2009).
Girls with CAH in its more severe forms present with a persistent urogenital sinus, in which theurethra and vagina fail to separate into separate channels. Surgical reconstruction to separate theurinary and reproductive tracts in childhood is necessary to prevent urinary incontinence andinfections leading to renal damage as well as to allow normal urination and future sexualfunction (Diamond et al. 2010). Even uncomplicated clitoromegaly may require surgery tocorrect, which poses medical risks to the child.
The observational nature and small sample size of the whole body of literature pertaining todexamethasone in this setting significantly weaken inferences about the benefits and harms oftreatment. Dexamethasone seems to be associated with reduction in virilization of affectedfemales without significant maternal or fetal adverse effects (Fernández-Balsells, 2010). Thereare no data on long term follow-up of physical and metabolic outcomes in children exposed to
MEMORANDUM (Page 4 of 4)
dexamethasone. High-dose dexamethasone has known adverse effects on growth anddevelopment in animals, but similar effects at low doses have not been proven. Furtherprospective studies are required to determine whether prenatal treatment with dexamethasoneshould be routinely recommended.
1. Braun T, Li S, Sloboda DM, Li W, Audette MC, Moss TJ, Matthews SG, Polglase G,
Nitsos I, Newnham JP, Challis JR. Effects of maternal dexamethasone treatment in earlypregnancy on pituitary-adrenal axis in fetal sheep. Endocrinology. 2009Dec;150(12):5466-77.
2. Diamond, D, Ecker J, Holm I, Kornetsky S, Mitchell C, Spack N. 2010 Not fetal
cosmetology. The Hastings Center Bioethics Forum, March 8, 2010. Available athttp://www.thehastingscenter.org/Bioethicsforum/Post.aspx?id=4528&blogid=140,Accessed August 16, 2010.
3. Fernández-Balsells MM, Muthusamy K, Smushkin G, Lampropulos JF, Elamin MB, Abu
Elnour NO, Elamin KB, Agrwal N, Gallegos-Orozco JF, Lane MA, Erwin PJ, MontoriVM, Murad MH. Prenatal Dexamethasone Use For The Prevention Of Virilization InPregnancies At Risk For Classical Congenital Adrenal Hyperplasia due to 21 hydroxylase(CYP21A2) deficiency: A Systematic Review And Meta-Analyses. Clin Endocrinol(Oxf). 2010 Jun 9.
4. Hirvikoski T, Nordenström A, Lindholm T, Lindblad F, Ritzén EM, Wedell A, Lajic S.
Cognitive functions in children at risk for congenital adrenal hyperplasia treatedprenatally with dexamethasone. J Clin Endocrinol Metab. 2007 Feb;92(2):542-8.
5. Hirvikoski, T., A. Nordenström, T. Lindholm, F. Lindblad, E.M. Ritzén, and S. Lajic.
2008. Long-term follow-up of prenatally treated children at risk for congenital adrenalhyperplasia: does dexamethasone cause behavioural problems? European Journal ofEndocrinology 159 309–316.
6. Lajic S, Nordenström A, Hirvikoski T. Long-term outcome of prenatal treatment of
congenital adrenal hyperplasia. Endocr Dev. 2008;13:82-98.
7. 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 afterearly-prenatal dexamethasone. J Clin Endocrinol Metab. 2004 Feb;89(2):610-4.
8. Nass R, Heier L, Moshang T, Oberfield S, George A, New MI, Speiser PW.Magnetic
resonance imaging in the congenital adrenal hyperplasia population: increased frequencyof white-matter abnormalities and temporal lobe atrophy. J Child Neurol. 1997Apr;12(3):181-6.
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