Public Citizen Urges FDA to Ban Medication Used to Prevent Preterm Birth

Health Letter, February 2020

By Meena Aladdin, M.S., Ph.D.

Hydroxyprogesterone caproate injection (MAKENA) is a synthetic hormone that was approved by the Food and Drug Administration (FDA) in 2011 for the prevention of preterm birth in women with a history of spontaneous preterm birth.[1] On Oct. 8, 2019, Public Citizen and an expert in maternal-fetal medicine petitioned the Food and Drug Administration to remove Makena from the market because evidence from a recently completed clinical trial demonstrates that it is not effective.

Preterm birth, which is defined as birth prior to 37 weeks of pregnancy,[2] is a significant public health problem that affects one out of every ten infants in the U.S.[3] It is a complex disorder that most often occurs spontaneously.[4] Black race, low or high maternal age, infections, carrying more than one fetus (twins, triplets or more), smoking, and late prenatal care are just some of the many risk factors associated with preterm birth.[5] Babies born too prematurely may experience lifetime disability, developmental delays and even death.[6]

Concerns about effectiveness prior to Makena’s approval

Hydroxyprogesterone was initially approved by the FDA in 1956 under the brand name DELALUTIN to treat several different gynecological and obstetrical conditions, including the treatment of habitual or threatened miscarriage.[7] However, by 1973, the FDA had concluded that this drug was not effective for this or any other pregnancy-related condition.[8]

In 2000 — at the request of the drug’s manufacturer, Bristol-Myers Squibb — the FDA withdrew approval of Delalutin because the drug had not been marketed for several years.[9] However, hydroxyprogesterone remained available exclusively through pharmacy compounding with limited FDA oversight.

The FDA approved hydroxyprogesterone again in 2011 as the brand-name product Makena solely to reduce the risk of preterm birth in certain high-risk women, under a process known as accelerated approval. This process allows the FDA to fast-track the approval of a new drug that has been studied for safety and effectiveness in treating a serious or life-threatening disease or condition and that is likely to provide meaningful therapeutic (clinical) benefits to patients over existing treatments.

The accelerated approval process allows the FDA to approve a drug based on its effect on a surrogate endpoint or outcome that is considered reasonably likely to predict meaningful clinical benefit. But for a drug approved under the accelerated approval pathway, the FDA can require that the manufacturer conduct another trial after approval (known as a postmarket trial) to verify that the drug does have meaningful clinical benefit. If the required postmarket trial fails to show such benefit, the FDA can withdraw approval of the drug.

The FDA’s 2011 accelerated approval of Makena was based largely on evidence from a single, randomized, placebo-controlled clinical trial that was rife with flaws. Results of the trial, which was funded by the National Institutes of Health (NIH), were published in 2003 in the New England Journal of Medicine.[10]

The trial enrolled 463 women with a history of spontaneous preterm birth who were at 15 weeks to 20 weeks and three days of pregnancy at 19 medical centers in the U.S. Two-thirds of the women were randomly assigned to weekly injections of hydroxyprogesterone and one-third to weekly injections of a placebo. These injections continued until the women either delivered their babies or reached 36 weeks of pregnancy. The primary outcome of the trial was preterm delivery before 37 weeks of pregnancy, which is a surrogate outcome.

The NIH-funded trial found a significant decrease in the rates of preterm births prior to 37 weeks of pregnancy in women who received hydroxyprogesterone compared with those who received placebo.

However, an FDA statistical expert raised serious concerns about the design and conduct of the NIH-funded trial.[11] For example, the statistical expert noted that the trial was not designed for drug approval and that preterm delivery before 37 weeks of pregnancy was not an appropriate surrogate endpoint to establish whether the drug is effective for reducing the rate of fetal and neonatal (newborn) health problems and death — the key meaningful clinical outcomes related to preterm birth. The statistical expert repeatedly opposed approval of Makena because data from that trial had failed to provide convincing evidence that the drug was effective.

Moreover, a large majority (16 of 21 members) of an FDA advisory committee that was convened in 2006 to consider whether the agency should approve Makena concluded that a reduction in preterm birth before 37 weeks of pregnancy was not an adequate surrogate endpoint for predicting a reduction in fetal and neonatal (newborn) health problems.[12]

Despite these concerns, the FDA eventually approved Makena but required that the drug’s manufacturer complete a larger postmarket clinical trial to confirm that the drug provides clinically meaningful benefit.

Postmarket trial fails to show any benefit

The required postmarket clinical trial, which was not completed until more than seven years after the drug was approved, failed to demonstrate that Makena provided clinically meaningful benefit. The trial enrolled about 1,700 pregnant women with a history of spontaneous preterm birth, 75% of whom were from outside the U.S.[13] The postmarket trial’s design was similar to, but significantly better than, that of the preapproval trial. Notably, the trial’s primary endpoints were preterm birth before 35 weeks of pregnancy and, most importantly, an overall measure of neonatal health problems and death.[14]

On March 8, 2019, AMAG Pharmaceuticals, the current manufacturer of Makena, announced the key results of the PROLONG trial: there were no statistically significant differences between the hydroxyprogesterone and placebo groups in the rate of preterm birth prior to 35 weeks of pregnancy or the rate of overall neonatal health problems and death.[15] The study also did not find any differences between the two study groups in the rates of other adverse pregnancy outcomes, such as miscarriage and stillbirth, or the rates of preterm birth before 32 or 27 weeks of pregnancy.[16]

Public Citizen’s petition and other actions

On Oct. 8, 2019, Public Citizen and an expert on maternal-fetal medicine petitioned the FDA to withdraw approval of Makena.[17] In our petition, we emphasized that the drug never should have been approved by the FDA in 2011 under the accelerated approval pathway given the serious flaws identified in the conduct and design of the NIH-funded trial. We also argued that the failure of the much larger and better designed postmarket PROLONG trial to show any meaningful clinical benefit of Makena necessitated removal of the drug from the market. We asserted that it was inconceivable that the FDA would have approved Makena if the results of the PROLONG trial had been available prior to approval.

On Oct. 29, Public Citizen testified at a meeting of an FDA advisory committee that was convened to consider whether Makena should remain on the market. We urged the committee to recommend that the FDA withdraw Makena from the market because there was a lack of substantial evidence demonstrating that the drug is effective for preventing preterm birth and complications of preterm birth.[18]

Most of the committee (nine of 16 members) voted in favor of removing Makena from the market. A larger majority of the committee (13 members) also voted that the postmarket trial failed to verify that Makena provides meaningful clinical benefits in terms of reducing neonatal health problems and death. Finally, the committee unanimously agreed that there was not substantial evidence showing that Makena reduces the risk of preterm birth. Although the recommendations of advisory committees are nonbinding, the FDA typically follows their recommendations. At press time, FDA action on our petition was pending.

What You Can Do

If you are pregnant and have had a history of spontaneous preterm birth, do not take Makena or any product that contains hydroxyprogesterone. Instead, talk to your doctor about ways to help mitigate the risk of preterm birth.

Maternal health is an important determinant of preterm birth, so if you are an expecting mother, do not drink alcohol, smoke cigarettes or use other tobacco products. Seeking proper prenatal care early on in pregnancy is critical to ensuring the health of the expecting mother and fetus. If you do have an underlying chronic condition that increases the risk of preterm birth, such as diabetes or high blood pressure, talk to your doctor about continually monitoring your blood sugar, heart rate and blood pressure.


References

[1] Food and Drug Administration. Letter to Hologic, Inc. February 3, 2011. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/021945s000ltr.pdf. Accessed January 9, 2020.

[2] World Health Organization. Preterm birth. https://www.who.int/news-room/fact-sheets/detail/preterm-birth. Accessed January 9, 2020.

[3] Centers for Disease Control and Prevention. Preterm birth. October 21, 2020. https://www.cdc.gov/reproductivehealth/maternalinfanthealth/pretermbirth.htm. Accessed January 9, 2019.

[4] World Health Organization. Preterm birth. https://www.who.int/news-room/fact-sheets/detail/preterm-birth. Accessed January 9, 2020.

[5] Centers for Disease Control and Prevention. Factors associated with preterm birth. https://www.cdc.gov/reproductivehealth/MaternalInfantHealth/PDF/PretermBirth-Infographic.pdf. Accessed January 9, 2020.

[6] Centers for Disease Control and Prevention. Preterm Birth. October 21, 2019. https://www.cdc.gov/reproductivehealth/maternalinfanthealth/pretermbirth.htm. Accessed January 9, 2020.

[7] Food and Drug Administration. Office director memo for NDA 021945. February 3, 2011. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/021945Orig1s000ODMemo.pdf. Accessed January 9, 2020.

[8] Food and Drug Administration. Medroxyprogesterone, acetate; norethindrone; norethindrone acetate; progesterone; and hydroxyprogesterone acetate: Follow-up. Federal Register. October 10, 1973. 38(195):27947-27949.

[9] Food and Drug Administration. Lilly Research Laboratories et al.; withdrawal of approval of 28 new drug applications. Federal Register. September 13, 2000. 65(178):55264-55265.

[10] Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caprote. N Eng J Med. 348(24):2379-2385

[11] Food and Administration. Statistical review(s) of NDA 21945. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/021945Orig1s000StatR.pdf. Accessed January 9, 2020.

[12] Food and Drug Administration. Summary minutes of the Advisory Committee for Reproductive Health Drugs. August 29, 2006. https://wayback.archiveit.org/7993/20170404053134/https://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4227M1.pdf. Accessed January 9, 2020.

[13] ClinicalTrials.gov. Confirmatory study of 17P versus vehicle for the prevention of preterm birth in women with a previous singleton spontaneous preterm delivery (PROLONG). URL. Accessed January 9, 2020.

[14] AMAG Pharmaceuticals Inc. AMAG Pharmaceuticals announces topline results from the PROLONG trial evaluating MAKENA (hydroxyprogesterone. March 8, 2019. https://www.amagpharma.com/news/amag-pharmaceuticals-announces-topline-results-from-the-prolong-trial-evaluating-makena-hydroxyprogesterone-caproate-injection/. Accessed December 12, 2019.

[15] AMAG Pharmaceuticals. AMAG Pharmaceuticals announces topline results from the PROLONG trial evaluating Makena (hydroxyprogesterone caproate injection). AMAG Pharma. March 8, 2019. https://www.amagpharma.com/news/amag-pharmaceuticals-announces-topline-results-from-the-prolong-trialevaluating-makena-hydroxyprogesterone-caproate-injection/. Accessed January 9, 2020.

[16] Food and Drug Administration. FDA briefing document for the October 29, 2019, meeting of the Bone, Reproductive, and Urologic Drugs Advisory Committee. https://www.fda.gov/media/132003/download. Accessed January 9, 2020.

[17] Public Citizen. Petition to the FDA to withdraw approval of Makena from the market. October 8, 2019. https://www.citizen.org/wp-content/uploads/2493.pdf. Accessed January 9, 2020.

[18] Public Citizen. Testimony before the FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee regarding hydroxyprogesterone caproate (Makena). October 29, 2019. https://www.citizen.org/article/testimony-before-the-fdas-bone-reproductive-and-urologic-drugs-advisory-committee-regarding-hydroxyprogesterone-caproate-makena/. Accessed January 9, 2020.