Dilemma in Withdrawing a Drug Approved Through Accelerated Approval Pathway

Last week, NPR reported that premature birth medication Makena did not work and debate was on whether the Makena should be pulled from the market.

• Premature Birth Medication Makena Doesn't Work, Research Shows
• Will Preterm Delivery Drug Makena Be Pulled From the Market?

Makena was approved through the FDA's accelerated approval pathway. To encourage the industry to develop the medications for serious diseases, FDA has four different programs to speed up the drug development process.

• Priority Review
• Breakthrough Therapy
• Accelerated Approval
• Fast Track

One of these four programs is 'accelerated approval' - allowing the drug approval based on a surrogate endpoint, but the sponsor is required to conduct a confirmatory trial. According to FDA's website:

The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.
Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug. If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.

If the confirmatory trial is positive, the accelerated approval program works great. However, if the confirmatory trial is negative, the situation becomes ugly. Once a drug is approved and marketed, it is difficult to pull the drug off the market (even though the confirmatory study did not show the clinical benefit). FDA will face pressures from patients' advocate group, the medical experts, and the sponsors.

It is not uncommon to pull off the approved drug from the market due to the safety concern. We have seen many examples of this. Here are some high profile examples:

• GSK ordered to withdraw diabetes drug – Avandia
• US restricts, Europe withdraws, Avandia
• FDA withdraws restrictions on GSK's Avandia
• Merck Announces Voluntary Worldwide Withdrawal of VIOXX
• Heart Risk Prompts FDA to Pull IBS Agent Tegaserod (Zelnorm)

However, it is very rare to pull off the approved drug from the market due to the efficacy reason even if the drug is approved through the accelerated approval pathway that entitles FDA to withdraw the drug if the confirmatory study shows no clinical benefit. 

Makena was approved by the FDA to reduce the risk of preterm delivery. The approval was through the accelerated approval pathway and based on a 463-patient, randomized, double-blind clinical trial of women 16 to 43 years old, pregnant with a single fetus, and with a history of spontaneous preterm birth. The surrogate endpoint is "the frequency of delivery before 37 weeks of gestation".

See FDA label for Makena

as a requirement for the accelerated approval pathway, the sponsor conducted a confirmatory trial (PROLONG study) using more clinically meaningful endpoints - co-primary efficacy endpoints: 

• the rate of preterm birth < 35 weeks, 0 days of gestation in women with a previous singleton spontaneous preterm delivery
• the rate of neonatal mortality or morbidity

Unfortunately, the confirmatory trial failed. There was no significant difference in preterm birth at less than 35 weeks gestation between the intervention and control groups (11.0% vs 11.5%, respectively, RR 0.95, 95% CI 0.71-1.26), nor was there a difference in neonatal morbidity index (5.6% vs 5.0%, RR 1.12, 95% CI 0.68-1.61),

The debate is on. Should Makena be pulled from the market? We will see. 

Several years ago, the same situation happened for Genentech's Avastin for breast cancer indication. With a lot of controversies, the FDA finally decided to withdraw Avastin for breast cancer indication. 

On November 18, 2011, the US Food and Drug Administration (US FDA) announced that breast cancer indication for Avastin (bevacizumab) had been withdrawn after concluding that the drug has not been shown to be safe and effective for the treatment of breast cancer. The specific indication that was withdrawn was for the use of bevacizumab in metastatic breast cancer, with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.

The US FDAs decision has been met with emotion and confusion among the public and health professionals.