A new study by the research group Datamonitor has found that complete response letters are sent by the US Food and Drug Administration (FDA) in response to nearly half of all new drug and biologic applications (NDAs, BLAs), resulting in lengthy delays while sponsors work to correct deficiencies or conduct new studies.
Complete response letters (CRLs), as established in 21 CFR 314.110, are sent to sponsors if FDA determines that an application is not approvable in its current form. The letters then describe the deficiency, provide a complete review of the data submitted in support of the application, and recommend the actions necessary to support future approval. These can include stronger data (if the current batch was insufficient in statistical strength), new study designs, or additional studies to look at a particular safety signal.
The length of time it takes for a product to go through the entire review process, from the start of an investigative clinical trials phase to the submission of an application, opens companies to a considerable amount of uncertainty. Because the rules, guidance documents and even risk paradigms can change in the time it takes for a product to come to market, the environment a product is conceived in can be very different than the one in which it is reviewed.
The Difficulties of a CRL
The Datamonitor study casts new light on many of those difficulties. The study looked at 346 NDAs and BLAs submitted after 1 October 2008, when FDA moved away from its "approvable" and "unapprovable" letters to the more descriptive CRLs.
Of those NDAs and BLAs, 281 (81%) received approval from the agency, of which 200 (71%) received approval during the first round of review. The remaining 81 submissions (29%) were approved during subsequent second, third (and beyond) submissions. Earlier studies, such as a 2012 analysis by the industry trade organization BIO, found that subsequent submissions have a far lower rate of approval. Only 1.4% of submissions made after the third round of submissions obtained approval , BIO found.
Complete response letters featured prominently in these reviews, Datamonitor found. One hundred and forty-six (42%) of all submissions received a CRL, of which 55% later obtained approval. Approximately a third of the submissions were withdrawn, while another 16% were still undergoing review by regulators.
The delays caused by these CRLs could in some cases be substantial. The median delay was 13 months for Class 2 (generally major) resubmissions, though those delays could be as short as 3.5 months and as long as 26 months. Class 1 (generally less serious) resubmissions had a median time of 4.4 months (range = 1.5 to 9.1 months).
Reading the Tea Leaves of a Press Release
Also of interest was Datamonitor's analysis of how companies announced the CRLs.
"By analyzing the eventual outcomes of CRLs mentioned in press releases, Datamonitor has concluded that, when a company responds to a CRL by emphasizing that no additional clinical trials are required (a typical response), the approval delay is likely to be 7-14 months," it wrote. "If a company notes that the FDA is seeking 'long-term' data, it can be assumed that the approval delay will be in the upper range, at 13-14 months."
"Ambiguity in a press release about whether additional clinical trials are required can be taken to mean that further trials will be required," it added.
The entire synopsis of the study can be found online here.