Through 2012, our R&D resources were focused on developing progesterone vaginal gel 8% to reduce the risk of preterm birth in women with premature cervical shortening. Preterm birth is a serious public health problem, affecting 10 to 12% of all pregnancies in the United States. The economic impact of preterm birth is significant, costing more than $26 billion annually, with the average preterm infant costing approximately $52,000. A short cervical length at mid-pregnancy is the single most powerful predictor of preterm birth.
Courtesy of the National Institutes of Health In April 2007, we reported that data from a Phase III clinical trial that evaluated progesterone vaginal gel 8% (PROCHIEVE) for the prevention of preterm birth in women with a prior preterm birth earlier than 35 weeks show a delay in cervical shortening in patients treated with PROCHIEVE versus placebo. The data further suggest a correlation between cervical length, progesterone administration, and both a reduction in the likelihood of preterm birth and an improvement in infant outcomes. The data were published in the peer-reviewed journal Ultrasound in Obstetrics & Gynecology in October 20071. Access Publication . In 2008, we initiated the PREGNANT (PROCHIEVE Extending GestatioN A New Therapy) study, a randomized, double-blind, placebo-controlled Phase III clinical trial evaluating PROCHIEVE to reduce the risk of preterm birth in women with a short cervical length as measured by transvaginal ultrasound at mid-pregnancy. In October 2008, we announced a collaboration with the Perinatology Research Branch (PRB) of the Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH), under which we amended the study protocol to reflect the addition of nine NIH sponsored sites and an increase in the number of patients from 300 to 450. In December 2010, Columbia and Watson jointly reported positive top-line PREGNANT study results; the study was published in Ultrasound in Obstetrics & Gynecology in July 20112. The published results indicate that administration of PROCHIEVE from mid-pregnancy until term in women with a premature cervical shortening as confirmed by transvaginal ultrasound was associated with a statistically significant reduction in the rate of preterm birth at ≤32 6/7 weeks, the primary endpoint of the study, vs. placebo gel. Improvement in infant outcome was noted with PROCHIEVE. The incidence and profile of adverse events in patients receiving PROCHIEVE was comparable to placebo, which was as expected given the product's documented safety history. Access Publication. Based on these positive results, we submitted a new drug application (NDA 22-139) for progesterone vaginal gel 8% for the reduction of risk of preterm birth in women with short uterine cervical length regardless of other risk factors in the mid-trimester of pregnancy to the U.S. Food and Drug Administration (FDA); NDA 22-129 was accepted for filing.
Data submitted to the FDA in support of approval of NDA 22-139 included results from the PREGNANT study, which showed that women with a short uterine cervical length as measured by trans-vaginal ultrasound between 19 and <24 weeks of gestation who were treated with progesterone vaginal gel 8% had a significantly lower risk of preterm birth at ≤ 32 6/7 weeks gestation compared to those who were treated with placebo (p=0.022). This study included women with and without a prior history of preterm birth. Progesterone vaginal gel 8% was also associated with a significant reduction in the risk of preterm birth at ≤ 34 6/7 weeks gestation (p=0.012).
On December 14, 2011, Columbia Laboratories announced that a meta-analysis of data from five double-blind, placebo-controlled trials of vaginal progesterone, including the PREGNANT study, found that administering vaginal progesterone to asymptomatic women with a sonographic short cervix in the mid-trimester of pregnancy significantly reduces the risk of preterm birth and neonatal morbidity. The meta-analysis was published in the American Journal of Obstetrics and Gynecology (AJOG), the journal of the Society for Maternal-Fetal Medicine (SMFM)3. The February 2012 issue of AJOG also contained a related editorial4.
The Advisory Committee for Reproductive Health Drugs of the FDA reviewed NDA 22-139 on January 20, 2012. While panel members generally agreed that progesterone vaginal gel 8% is safe, the Committee stated that more information is needed to support approval. Read related press release.
On February 10, 2012 Columbia transferred NDA 22-139 to Watson Pharmaceuticals; Watson now has full rights and regulatory responsibility for all activities and sponsor obligations relating to this application.
On February 24, 2012, Watson received a complete response letter from the FDA. The complete response letter stated that the effect of treatment with progesterone vaginal gel 8% in reducing the risk of preterm birth in women with a short uterine cervical length at ≤ 32 6/7 weeks gestation (p=0.022) did not meet the level of statistical significance generally expected to support the approval of the product in the U.S. market from a single trial. Although not part of the requirements communicated to the sponsor during pre-Phase III meetings, the FDA also raised the issue of robustness in efficacy in the U.S. sub-cohort as compared to the overall efficacy of the trial. In the complete response letter, FDA stated that additional clinical work would be required to support the approval.
In October 2012, the American College of Obstetricians and Gynecologists issued Practice Bulletin 130, in which vaginal progesterone is recommended as a management option to reduce the risk of preterm birth in asymptomatic women with a singleton gestation without a prior preterm birth with an incidentally identified short cervical length ≤20mm before or at 24 weeks of gestation.
On October 25, 2012, the FDA denied a Formal Dispute Resolution Request (FDRR) related to NDA 22-139. Watson had filed the FDRR in August 2012.
1 De Franco, EA et al., Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial. Ultrasound in Obstetrics & Gynecology, 30: 697–705. 2 Hassan SS, Romero R et al., Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound in Obstetrics & Gynecology, 38: 18–31. 3 Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. American Journal of Obstetrics and Gynecology 2012; 206: 124.e1-19. 4 Combs CA, Vaginal progesterone for asymptomatic cervical shortening and the case for universal screening of cervical length. American Journal of Obstetrics and Gynecology 2012; 206: 101-103. PROCHIEVE® is a registered trademark of Actavis, Inc (formerly Watson Pharmaceuticals, Inc).