1590 Calaveras Avenue
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Division of Dockets Management
Food and Drug Administration
Department of Health and Human Services
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Rockville, MD 20852
February 5, 2018
Re: Docket Number FDA-2015-P-0876—Re Citizen Petition to Withdraw Approval for 17α-Hydroxyprogesterone Caproate (“17-OHPC,” Including Brand “Makena”) as a Drug Used in Pregnancy, Pending Fetal Germline Impact Assessment
To the Commissioner of the Food and Drug Administration:
The FDA received the undersigned’s above-referenced petition on March 19, 2015. Having received no response after nearly three years, the petitioner again asks that the FDA act expeditiously to grant the petition. (The petition can be found online here.)
The petitioner’s February 2017 letter entreating to the FDA to take some action to consider the petition emphasized the unequivocal drug vulnerabilities of fetal germline to intentional, high-dose persistent EDC exposures such as 17-OHPC. However, other urgent and perhaps more obvious reasons to withdraw approval for 17-OHPC have also surfaced, including the following:
(1) 17-OHPC is ineffective at reducing preterm birth.
The evidence is now clear that administration of 17-OHPC is ineffective at reducing risk for recurrent preterm birth. In keeping with previous findings from other studies, a 2017 prospective cohort study demonstrated this synthetic hormone did not reduce the rate of recurrent preterm birth. (Nelson DB, McIntire DD, McDonald J, et al. 17-alpha Hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort study. American Journal of Obstetrics and Gynecology, 2017;216(6):600.e1–600.e9 [also discussing how earlier research failed to document a benefit of this drug]).
(2) 17-OHPC increases risk of maternal diabetes in the exposed mother.
The above-mentioned study also found the drug increased the risk for the mother developing gestational diabetes. Id. This represents a significant adverse outcome that is not included in warnings given the patient before administration of this hormone-disrupting chemical.
(3) 17-OHPC causes long-term adverse neurodevelopmental effects in offspring.
It is well documented that perturbations of sex steroids can adversely affect neurodevelopment in affected fetuses. (Gore AC, Martien KM, Gagnidze K, Pfaff, P. Implications of Prenatal Steroid Perturbations for Neurodevelopment, Behavior, and Autism. Endocr Rev. 2014;35(6):961–991.) Many regions of the developing brain are sensitive to progestins, including neural circuits important for complex cognitive behaviors later in life. (Willing J, Wagner CK. Exposure to the Synthetic Progestin, 17α-Hydroxyprogesterone Caproate During Development Impairs Cognitive Flexibility in Adulthood. Endocrinology 2016;157(1)1:77–82.)
A recent study (Id.) documented adverse long-term consequences of 17-OHPC exposure during development on cognitive behavior of offspring. Administration of the drug to gestating rats led to dopaminergic innervation of specific lamina of prelimbic mPFC in juveniles, consistent with the possibility of impaired synaptic pruning. Additionally, 17-OHPC exposure impaired cognitive flexibility in adulthood—neurocognitive effects reminiscent of those often associated with developmental disorders such as attention-deficit hyperactivity disorder and autism. (Id.) The-treated rats were slower to make a cognitive switch to a new rule and continued to perseverate on the old rule longer than controls. (Id.) Abnormal levels of progesterone receptor activity and/or progesterone receptor activity at improper times during this critical period of connectivity may significantly alter the development of important behavioral neural circuits. (Id.)
(4) A safer alternative to 17-OHPC is readily available.
Daily vaginal progesterone (either suppository or gel) started at about 16 weeks’ gestation has been found to be a preferable alternative to weekly 17-OHPC injection for prevention of spontaneous preterm birth in women with singleton gestations and prior spontaneous preterm birth. (Saccone G, Khalifeh A, Elimian A, Bahramis E, et al. Vaginal progesterone vs intramuscular 17α-hydroxy- progesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol, 2017;49: 315–321.) Compared with intramuscular 17-OHPC, vaginal progesterone was associated with at least seven benefits: (1) reduced risk of recurrent SPTB; (2) fewer adverse maternal side effects; (3) fewer NICU admissions; (4) lower cost; (5) better maternal compliance; (6) women’s preferred choice; and (7) greater satisfaction. (Id.)
In closing, the FDA was created by Congress to safeguard the public from pharmaceutical products that confer more risk than benefit, yet today, in spite of ever-mounting evidence that 17-OHPC is an ineffective and dangerous gestational toxicant, the agency does nothing but sit on its hands in a seemingly permanent state of paralysis. The diethylstilbestrol (DES) catastrophe has already alerted the FDA to the reality that minute perturbations inflicted by synthetic steroid hormones on developing fetuses can cause outsize, horrific long-term effects.
The time to withdraw the FDA’s misguided approval for 17-OHPC is now. The health and welfare of three generations is at stake: the exposed mother, the exposed offspring, and per my original petition, the exposed fetal germ cells.
Thank you again for your consideration of this petition. Though three years have passed I still eagerly await your response.
Very truly yours,
Jill Gilbert Escher
Robert Heflich, PhD, Director, Division of Genetic and Molecular ToxicologyUS FDA
Rosalie Elespuru, PhD, Research Biologist, CDRH/OSEL/DBCMSUS, US FDA
Manju G Manjanatha, PhD, Division of Genetic & Molecular Toxicology, US FDA
Thomas Gellhaus, MD, president, American College of Obstetricians and Gynecologists
Alfred Abuhamad, MD, president, Society for Maternal Fetal Medicine
UPDATE: Here is the FDA's February 2018 ruling on the March 2015 petition (pdf). Commentary on this is forthcoming.