Continuation of marketing approval of a product differs between the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Marketing applications approved by the EMA are valid for 5 years and must be renewed to continue marketing of the product. If conditional approval was granted by EMA, a yearly reassessment is required. In the US, the situation is quite different. Once an application is approved by FDA, this approval continues unless the company requests that FDA withdraw the application or the FDA initiates a withdrawal process.
Regulations governing the withdrawal process in the US
In the US, drugs are approved under the Food, Drug and Cosmetic Act and biologics are licensed under the Public Health Services Act. For products which have received full approval, i.e. safety and efficacy have been demonstrated, the process for withdrawal of an application or indication for a drug or revocation of a license for a biologic follows the procedures in 21 CFR 314.5 and 21 CFR 601.92, respectively. The specific criteria are listed in these regulations. As part of this process, FDA must allow for a hearing on the withdrawal proposal unless the company waives the right to the hearing. When a “finding that there is an imminent hazard to the public health” for a drug or “danger to health” for a biologic is determined by FDA, the process for withdrawal remains the same; however, the hearing should be expedited. One difference between the process for drugs and biologics is stated in 21 CFR 601.6, where there is a provision for biologic license suspension.
When a product was granted marketing approval under the accelerated approval process, FDA may request that an application be withdrawn if confirmatory studies have failed to demonstrate the clinical benefit of the product. When this has been the case, many times after the failure of more than one confirmatory study, the company generally voluntarily withdraws the product or the indication in question upon urging from FDA. An example of this was action on certain oncology indications of checkpoint inhibitors through the advisory committee process (See Thought Leadership Blog: Revolutionizing the approach to treating cancer: Then and Today – Part 3 for more details). However, if there is no agreement between the two parties, withdrawal actions can be a lengthy process, as described in the examples below.
I am reminded of the blog that was posted on PROMETRIKA’s Regulatory Corner entitled, The Pathway to Approval for Two Gene Therapy Products. In this blog, one of the products discussed was ELEVIDYS (delandistrogene moxeparvovec-rokl) for treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene, for which FDA had granted accelerated approval on June 22, 2023. This accelerated approval was converted to full approval on June 20, 2024 for individuals at least 4 years of age who are ambulatory and have a confirmed mutation in the DMD gene. In addition, at the same time, the DMD indication in non-ambulatory patients was given accelerated approval. The package insert for this product included a warning for acute serious liver injury.
You may ask why have I described the story of ELEVIDYS in this discussion of FDA’s process for withdrawal of a marketing application. In July 2025, this product was in the news again. Unfortunately, there had arisen a safety issue related to the potential of the product to induce liver injury, which resulted in the deaths of two patients. As both patients were non-ambulatory, shipments to non-ambulatory patients were paused and the FDA and the company agreed to place a black box warning, the highest level of warning that FDA can place on an approved product, for acute liver injury (ALI) and acute liver failure (ALF). On July 25, 2025 FDA requested and received voluntary suspension of product distribution as it investigated the safety concerns. This suspension was lifted by FDA on July 28, 2025.
Note that, during this same time period, on July 24, 2025, the EMA issued a negative opinion, refusing to approve the product.
FDA authority and the withdrawal process
The FDA request that shipments of ELEVIDYS be temporarily paused raised concerns as to what authority the FDA has to withdraw a product from the market, as well as the steps and timeline.
For many of the products that have been withdrawn from the market due to safety, it has been the company that has requested the withdrawal rather than the FDA. Prominent examples include Vioxx (rofecoxib), a nonsteroidal anti-inflammatory drug (NSAID) that was withdrawn from the market due to increased cardiovascular risks by Merck & Co. in 2004 and Baycol (cerivastatin), a statin drug for the treatment of high cholesterol and triglycerides, that was withdrawn from the market due to its association with a serious and potentially fatal muscle condition called rhabdomyolysis by Bayer Corporation in 2001. In April 2020, FDA requested manufacturers to withdraw all prescription and over-the-counter (OTC) ranitidine drugs from the market immediately due to the presence of a carcinogenic impurity that increases in the product over time.
Case histories of 2 withdrawals initiated by FDA
Without the voluntary action of the company, the withdrawal process as currently outlined can be a long one, as evidenced by the following two examples.
The first is the market withdrawal of phenformin, begun in 1977. The FDA Endocrinology and Metabolism Advisory Committee suggested that phenformin be taken off the market by October 1976. This was due to a significant risk of potentially fatal lactic acidosis. The FDA started official actions in May 1977 that eventually led to phenformin’s withdrawal from the US market on November 15, 1978 (More et al).
Another interesting example is the metastatic breast cancer indication for Avastin (bevacizumab), which received accelerated approval on February 22, 2008. When the confirmatory studies did not demonstrate clinical benefit, FDA proposed withdrawing this indication on December 16, 2010. The company requested a hearing on January 18, 2011, and on November 18, 2011, the FDA commissioner announced that breast cancer indication for Avastin had been withdrawn. The supplement to remove the indication from the label was received by FDA on December 15, 2011 and approved December 20, 2011.
As is evident from the examples presented, when the company is in agreement that there is a significant safety concern that impacts continued marketing of a product, the path for voluntary withdrawal can be swift. When the two parties are not in agreement, withdrawal can be a lengthy process, potentially taking years rather than days or months.
More S, Sawarkar K, Dhait G, Shobhane A. Regulatory Profile of Phenformin with its Adverse Event in USA and Rest of the World. International Journal of Development Research 2023;13(04): 62455-62460. Available at https://doi.org/10.37118/ijdr.26577.04.2023
