FDA Cracks Down on Incomplete Applications

Under pressure to meet tight deadlines for reviewing and approving a growing volume of applications for new drugs, generics, and medical products, FDA is rejecting submissions that are incomplete or unsatisfactory right from the start. Review staffers are refusing to file (or receive or accept) applications until the sponsor provides all data and information needed to conduct more one-cycle reviews. With the rise in breakthrough drugs and treatments for rare conditions that qualify for accelerated or priority reviews, the agency has become more rigorous in scrutinizing applications for completeness before starting a formal assessment.

This means more refusal-to-file (RTF) letters to sponsors. That can be devastating for companies like Celgene Corp., which recently disclosed that FDA rejected an application for its promising new multiple sclerosis therapy ozanimod. Celgene explained in a press release that FDA found its nonclinical and clinical pharmacology data in the application “insufficient to permit a complete review.” The firm hoped to meet with review staff as soon as possible to learn what additional information was needed to resubmit the NDA.

Many sponsors don’t publicly announce receipt of an RTF letter, preferring to keep the rejection private unless it has a “material” impact on the firm’s finances, which often is the case for smaller biopharma companies. FDA reports that it issued more than 70 RTF letters for drugs between 2010 and 2017, but less than half were publicly acknowledged by firms. Some RTFs may apply to supplemental applications, where rejection may have less impact on the firm.

While cracking down on submissions that fail to meet standards, FDA also is offering more advice and assistance to help sponsors get applications right the first time. The Center for Drug Evaluation and Research (CDER) issued draft guidance in December 2017 explaining the purpose of its RTF policy and clarifying what qualifies as “incomplete” in an application  [see https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM588242.pdf ]. FDA notes that RTF letters reflect not just inadequate data, but “omissions of clearly necessary information” that prevent further review action. CDER and industry agreed to tighten up requirements for “complete” applications as part of a program to improve its first-cycle review process under the Prescription Drug User Fee Act (PDUFA) program of 2012. That policy gives CDER 60 days to file a submission or inform the applicant of an RTF decision; sponsors have 30 days during this period to submit missing information to avoid such action. One rationale for rejecting applications upfront is to inform the sponsor more quickly of deficiencies that will prevent approval, rather than waiting to issue a complete response letter at the end of the review process.

Medical device makers also gained updated guidances in January 2018 on refuse-to-accept policies of the Center for Devices and Radiological Health (CDRH). These feature checklists to identify key elements for complete applications and provide specifics for submitting necessary information on device-drug combination products [see https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM315014.pdf . and https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM313368.pdf ].

Incomplete applications are particularly prevalent with abbreviated new drug applications (ANDAs) for generic drugs. FDA refused to receive nearly 150 ANDAs in 2017 and more than 240 the year before. Inadequate stability and dissolution data are the main deficiencies, plus incomplete English translations. The high ANDA rejection rate seems to be going down, as the Office of Generic Drugs works to boost its first-cycle approval rate as part of FDA’s initiative to inject more competition in prescription drug markets. CDER issued draft guidance in October 2017 to clarify its RTR policy for generics and reduce the volume of deficient applications coming in [see https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM578368.pdf ].