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Two-and-a-half years after it first proposed doing so, the US Food and Drug Administration (FDA) has made a final decision to immediately withdraw Makena from the market, a hydroxyprogesterone caproate injection approved by the agency in 2011 to reduce the risk of pre-term birth.
“It is tragic that the scientific research and medical communities have not yet found a treatment shown to be effective in preventing preterm birth and improving neonatal outcomes—particularly in light of the fact that this serious condition has a disparate impact on communities of color, especially Black women,” said FDA Commissioner Robert Califf. “Fundamentally, however, the touchstone of FDA drug approval is a favorable benefit-risk assessment; without that favorable assessment, the drug should not have the status of being FDA-approved.”
FDA’s decision comes after Makena’s manufacturer, Covis Pharma, agreed to voluntarily withdraw the drug from the market. In a press release announcing the withdrawal on 7 March 2023, the company said they continue to support Makena in a narrower indication of women at the highest risk of pre-term birth, but would “voluntarily withdraw the product and work with the FDA to effectuate an orderly wind-down.”
“We recognize the attention the agency has directed to this issue, particularly given the complexity around withdrawing a drug with mixed efficacy data and a positive safety profile, and welcome the opportunity to discuss an appropriate wind-down plan for patients,” Raghav Chari, PhD, Covis’s chief executive officer, said in the release.
FDA rebuffed Covis’s request to delay the effective date of the withdrawal to allow current patients to complete their courses of the drug and to exhaust its remaining inventory. “We decline to do so,” Califf and FDA’s Chief Scientist Namandjé Bumpus wrote in their final decision to withdraw the drug. “Given our conclusions regarding the unfavorable benefit-risk assessment for Makena as discussed above, FDA’s continued approval of Makena and its generic versions is unwarranted and inappropriate.”
However, the two left the door open to FDA exercising enforcement discretion with regard to the wind down and the possibility of compounding the drug after it is withdrawn, deferring to the Center for Drug Evaluation and Research (CDER) on both matters.
The multi-year withdrawal process spotlights the challenges FDA faces in withdrawing drugs with accelerated approval from the market. Despite the requirement for postmarket confirmatory evidence for drugs approved via the pathway, confirmatory trials are often late and FDA has largely relied on drugmakers to voluntarily withdraw their products or indications when confirmatory trials fail to demonstrate effectiveness. (RELATED: Study: Half of confirmatory studies for accelerated approvals are late, Regulatory Focus 4 April 2023; OIG raises concerns about accelerated approval pathway, Regulatory Focus 30 September 2022)
Timeline of Makena’s approval
Makena was originally approved by the FDA in 2011 under the accelerated approval pathway based on the results of Trial 002, a randomized, placebo-controlled trial of 463 women with a history of pre-term birth who received either hydroxyprogesterone caproate or placebo. Trial 002 showed the drug reduced the risk of birth before 37 weeks but was not designed to assess whether hydroxyprogesterone caproate had a neonatal benefit. FDA approved Makena under the accelerated approval but required Covis Pharma to conduct a postmarket study to confirm whether the drug provided a clinical benefit to newborns.
The results of that study, Trial 003, were released in 2019, 3 years after the trial was expected to be completed. In Trial 003, researchers evaluated 1,708 women in nine countries who received Makena or placebo. The results failed to show that Makena reduced the risk of pre-term birth before 35 weeks compared to placebo (11.0% vs. 11.5%), and at 37 weeks (23.1% vs. 21.9%). There was also no significant difference in clinical benefit for neonates between Makena and placebo as measured by a composite neonatal outcome (5.4% vs. 5.2%).
When FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee met to review Trial 003, they voted 9-7 to recommend the agency withdraw Makena’s approval from the market (RELATED: Makena Withdrawal? A Look at the Timeline and Other Accelerated Approvals, Regulatory Focus 01 November 2019). FDA’s Center for Drug Evaluation and Research (CDER) made their case for withdrawal in a presentation in October 2020, and Makena’s then-manufacturer, AMAG Pharmaceuticals, requested a public hearing on the matter (RELATED: FDA seeks withdrawal of Makena, generics from market, Regulatory Focus 05 October 2020; RELATED: Makena indication may fall based on post-approval data, Regulatory Focus 06 November 2020).
A resulting meta-analysis published by the Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) research team in The Lancet found that intramuscular 17-hydroxyprogesterone caproate (17-OHPC) reduced the risk of birth at 34 weeks among women with high-risk singleton pregnancies. FDA’s CDER stood by their decision to recommend Makena’s withdrawal from the market based on results of the EPPPIC meta-analysis, while AMAG, which had since been acquired by Covis Pharma, claimed in a press release that the “EPPPIC study reaffirms 17-OHPC for reducing early preterm birth in high-risk, singleton pregnancies.” (RELATED: FDA, unmoved by new meta-analysis, still recommends Makena withdrawal, Regulatory Focus 29 March 2021)
FDA’s Obstetrics, Reproductive, and Urologic Drugs Advisory Committee voted 14-1 to recommend the agency remove Makena from the market in an October 2022 meeting, voting 15-0 that Trial 003 did not show a neonatal benefit, and 13-1 that Makena did not reduce the risk of pre-term birth in women with a history of pre-term birth. A post-hearing submission from CDER, published in March 2023, reaffirmed CDER’s support for withdrawing Makena from the market.
Accelerated approval’s downsides
Commenting on the news, Joseph Ross, MD, professor of medicine and public health at Yale School of Medicine, said Makena’s approval and the struggle to withdraw it from the market serves as an example of the accelerated approval pathway’s downsides.
“To me, this situation illustrates the number of ways that the FDA’s accelerated approval program can go wrong,” Ross said. “When a company receives marketing authorization on the basis of very uncertain evidence because of the serious unmet clinical need for patients, but then delays conducting the confirmatory trials to verify benefit, and then refuses to withdraw the product despite clear evidence that the benefit cannot be verified, the system is not working in the best interests of patients.”
Daniel G. Aaron, MD, JD, Heyman Fellow at Harvard Law School in Cambridge, Mass., and incoming associate professor of law at the SJ Quinney College of Law at the University of Utah, said Covis Pharma’s refusal to withdraw the drug “highlights how difficult it is for FDA to withdraw a drug against a company’s wishes.”
“During its decade on the market, Makena offered little benefit to patients, yet caused them adverse effects and wasted precious health care dollars. It also may have disrupted the development of drugs with greater therapeutic promise,” Aaron said.
Disagreement on withdrawal timeframe
Ross said he was “not impressed” in the delay between FDA proposing to withdraw Makena following the drug’s negative confirmatory trial, the “clear advisory panel vote recommending withdrawal,” and the manufacturer’s response.
“All evidence suggests that the product does not reduce the risk of preterm birth nor improve the health of babies born to women with a history of unexplained preterm birth. Once the lack of benefit was established, a company should immediately move to withdraw the product so as not to expose patients to unnecessary treatments that may pose harm,” he said.
Aaron said that Covis’s preemptive announcement that it will voluntarily withdraw the drug shows the company realized “it is on the backfoot.”
“It has little momentum,” he said. “As in chess, where you don’t need to take the opponent’s king, Covis is in ‘checkmate.’”
Aaron noted that the move may have been designed to buy time by insisting the drug “remains approved” but continuing to sell it until in the interim. “Agreeing to withdraw the drug in the future may paint Covis in a better light even, as it likely knows what FDA’s final decision will be. Therefore, the announcement does not change much,” he said.
Covis Pharma delaying a decision “has bought it more time to sell its drug and potentially to deplete its inventory” and “is likely just an extension of sales,” Aaron explained.
“The disagreement about the timeline for withdrawal highlights the financial interest of Covis vis-à-vis the public-health interest of FDA,” he said.
Could FDORA have helped?
When asked if amendments passed in the Food and Drug Omnibus Reform Act (FDORA) would have an impact for drugs on a similar trajectory in the future, Ross explained that the new authorities in FDORA “give the FDA the power to request that confirmatory trials are initiated before a company receives accelerated approval, streamlines the process for withdrawing drugs when postmarketing studies are negative or delayed, and requires companies to provide confirmatory trial status reports to the FDA every 6 months.”
“All of these legislative changes decrease the likelihood of a company like Covis delaying their postmarketing requirement studies and delaying the withdrawal of an ineffective product in the future,” he said.
Aaron said he isn’t so sure the recent amendments to accelerated approval would create a significant change in how Makena would have been handled by FDA. “Makena was approved largely because FDA accepted inferior evidence to address the serious public health impact of preterm birth. In a future similar situation, the reforms do not change this basic calculus or meaningfully constrain FDA from approving products with inferior evidence based on the well-meaning desire to help patients,” he said.
“On the flip side, when FDA realizes it has erred, the reforms do provide expedited procedures to withdraw a drug,” Aaron explained. “Still, these procedures are still quite lengthy. And FDA must continue to be careful about avoiding lawsuits from manufacturers.”
The agency’s actions surrounding withdrawing Makena, however, are “encouraging” because a future company in a similar situation “may know FDA means business and withdraw its drug, thus obviating some of the lengthy procedures,” he noted.
“More broadly, FDA faces significant challenges to its authority and to its funding,” Aaron said. “Reforms and tweaks are not enough to strengthen the agency.”
FDA Statement, Withdrawal Decision
“It is tragic that the scientific research and medical communities have not yet found a treatment shown to be effective in preventing preterm birth and improving neonatal outcomes—particularly in light of the fact that this serious condition has a disparate impact on communities of color, especially Black women,” said FDA Commissioner Robert Califf. “Fundamentally, however, the touchstone of FDA drug approval is a favorable benefit-risk assessment; without that favorable assessment, the drug should not have the status of being FDA-approved.”
FDA’s decision comes after Makena’s manufacturer, Covis Pharma, agreed to voluntarily withdraw the drug from the market. In a press release announcing the withdrawal on 7 March 2023, the company said they continue to support Makena in a narrower indication of women at the highest risk of pre-term birth, but would “voluntarily withdraw the product and work with the FDA to effectuate an orderly wind-down.”
“We recognize the attention the agency has directed to this issue, particularly given the complexity around withdrawing a drug with mixed efficacy data and a positive safety profile, and welcome the opportunity to discuss an appropriate wind-down plan for patients,” Raghav Chari, PhD, Covis’s chief executive officer, said in the release.
FDA rebuffed Covis’s request to delay the effective date of the withdrawal to allow current patients to complete their courses of the drug and to exhaust its remaining inventory. “We decline to do so,” Califf and FDA’s Chief Scientist Namandjé Bumpus wrote in their final decision to withdraw the drug. “Given our conclusions regarding the unfavorable benefit-risk assessment for Makena as discussed above, FDA’s continued approval of Makena and its generic versions is unwarranted and inappropriate.”
However, the two left the door open to FDA exercising enforcement discretion with regard to the wind down and the possibility of compounding the drug after it is withdrawn, deferring to the Center for Drug Evaluation and Research (CDER) on both matters.
The multi-year withdrawal process spotlights the challenges FDA faces in withdrawing drugs with accelerated approval from the market. Despite the requirement for postmarket confirmatory evidence for drugs approved via the pathway, confirmatory trials are often late and FDA has largely relied on drugmakers to voluntarily withdraw their products or indications when confirmatory trials fail to demonstrate effectiveness. (RELATED: Study: Half of confirmatory studies for accelerated approvals are late, Regulatory Focus 4 April 2023; OIG raises concerns about accelerated approval pathway, Regulatory Focus 30 September 2022)
Timeline of Makena’s approval
Makena was originally approved by the FDA in 2011 under the accelerated approval pathway based on the results of Trial 002, a randomized, placebo-controlled trial of 463 women with a history of pre-term birth who received either hydroxyprogesterone caproate or placebo. Trial 002 showed the drug reduced the risk of birth before 37 weeks but was not designed to assess whether hydroxyprogesterone caproate had a neonatal benefit. FDA approved Makena under the accelerated approval but required Covis Pharma to conduct a postmarket study to confirm whether the drug provided a clinical benefit to newborns.
The results of that study, Trial 003, were released in 2019, 3 years after the trial was expected to be completed. In Trial 003, researchers evaluated 1,708 women in nine countries who received Makena or placebo. The results failed to show that Makena reduced the risk of pre-term birth before 35 weeks compared to placebo (11.0% vs. 11.5%), and at 37 weeks (23.1% vs. 21.9%). There was also no significant difference in clinical benefit for neonates between Makena and placebo as measured by a composite neonatal outcome (5.4% vs. 5.2%).
When FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee met to review Trial 003, they voted 9-7 to recommend the agency withdraw Makena’s approval from the market (RELATED: Makena Withdrawal? A Look at the Timeline and Other Accelerated Approvals, Regulatory Focus 01 November 2019). FDA’s Center for Drug Evaluation and Research (CDER) made their case for withdrawal in a presentation in October 2020, and Makena’s then-manufacturer, AMAG Pharmaceuticals, requested a public hearing on the matter (RELATED: FDA seeks withdrawal of Makena, generics from market, Regulatory Focus 05 October 2020; RELATED: Makena indication may fall based on post-approval data, Regulatory Focus 06 November 2020).
A resulting meta-analysis published by the Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) research team in The Lancet found that intramuscular 17-hydroxyprogesterone caproate (17-OHPC) reduced the risk of birth at 34 weeks among women with high-risk singleton pregnancies. FDA’s CDER stood by their decision to recommend Makena’s withdrawal from the market based on results of the EPPPIC meta-analysis, while AMAG, which had since been acquired by Covis Pharma, claimed in a press release that the “EPPPIC study reaffirms 17-OHPC for reducing early preterm birth in high-risk, singleton pregnancies.” (RELATED: FDA, unmoved by new meta-analysis, still recommends Makena withdrawal, Regulatory Focus 29 March 2021)
FDA’s Obstetrics, Reproductive, and Urologic Drugs Advisory Committee voted 14-1 to recommend the agency remove Makena from the market in an October 2022 meeting, voting 15-0 that Trial 003 did not show a neonatal benefit, and 13-1 that Makena did not reduce the risk of pre-term birth in women with a history of pre-term birth. A post-hearing submission from CDER, published in March 2023, reaffirmed CDER’s support for withdrawing Makena from the market.
Accelerated approval’s downsides
Commenting on the news, Joseph Ross, MD, professor of medicine and public health at Yale School of Medicine, said Makena’s approval and the struggle to withdraw it from the market serves as an example of the accelerated approval pathway’s downsides.
“To me, this situation illustrates the number of ways that the FDA’s accelerated approval program can go wrong,” Ross said. “When a company receives marketing authorization on the basis of very uncertain evidence because of the serious unmet clinical need for patients, but then delays conducting the confirmatory trials to verify benefit, and then refuses to withdraw the product despite clear evidence that the benefit cannot be verified, the system is not working in the best interests of patients.”
Daniel G. Aaron, MD, JD, Heyman Fellow at Harvard Law School in Cambridge, Mass., and incoming associate professor of law at the SJ Quinney College of Law at the University of Utah, said Covis Pharma’s refusal to withdraw the drug “highlights how difficult it is for FDA to withdraw a drug against a company’s wishes.”
“During its decade on the market, Makena offered little benefit to patients, yet caused them adverse effects and wasted precious health care dollars. It also may have disrupted the development of drugs with greater therapeutic promise,” Aaron said.
Disagreement on withdrawal timeframe
Ross said he was “not impressed” in the delay between FDA proposing to withdraw Makena following the drug’s negative confirmatory trial, the “clear advisory panel vote recommending withdrawal,” and the manufacturer’s response.
“All evidence suggests that the product does not reduce the risk of preterm birth nor improve the health of babies born to women with a history of unexplained preterm birth. Once the lack of benefit was established, a company should immediately move to withdraw the product so as not to expose patients to unnecessary treatments that may pose harm,” he said.
Aaron said that Covis’s preemptive announcement that it will voluntarily withdraw the drug shows the company realized “it is on the backfoot.”
“It has little momentum,” he said. “As in chess, where you don’t need to take the opponent’s king, Covis is in ‘checkmate.’”
Aaron noted that the move may have been designed to buy time by insisting the drug “remains approved” but continuing to sell it until in the interim. “Agreeing to withdraw the drug in the future may paint Covis in a better light even, as it likely knows what FDA’s final decision will be. Therefore, the announcement does not change much,” he said.
Covis Pharma delaying a decision “has bought it more time to sell its drug and potentially to deplete its inventory” and “is likely just an extension of sales,” Aaron explained.
“The disagreement about the timeline for withdrawal highlights the financial interest of Covis vis-à-vis the public-health interest of FDA,” he said.
Could FDORA have helped?
When asked if amendments passed in the Food and Drug Omnibus Reform Act (FDORA) would have an impact for drugs on a similar trajectory in the future, Ross explained that the new authorities in FDORA “give the FDA the power to request that confirmatory trials are initiated before a company receives accelerated approval, streamlines the process for withdrawing drugs when postmarketing studies are negative or delayed, and requires companies to provide confirmatory trial status reports to the FDA every 6 months.”
“All of these legislative changes decrease the likelihood of a company like Covis delaying their postmarketing requirement studies and delaying the withdrawal of an ineffective product in the future,” he said.
Aaron said he isn’t so sure the recent amendments to accelerated approval would create a significant change in how Makena would have been handled by FDA. “Makena was approved largely because FDA accepted inferior evidence to address the serious public health impact of preterm birth. In a future similar situation, the reforms do not change this basic calculus or meaningfully constrain FDA from approving products with inferior evidence based on the well-meaning desire to help patients,” he said.
“On the flip side, when FDA realizes it has erred, the reforms do provide expedited procedures to withdraw a drug,” Aaron explained. “Still, these procedures are still quite lengthy. And FDA must continue to be careful about avoiding lawsuits from manufacturers.”
The agency’s actions surrounding withdrawing Makena, however, are “encouraging” because a future company in a similar situation “may know FDA means business and withdraw its drug, thus obviating some of the lengthy procedures,” he noted.
“More broadly, FDA faces significant challenges to its authority and to its funding,” Aaron said. “Reforms and tweaks are not enough to strengthen the agency.”
FDA Statement, Withdrawal Decision
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