Drugs

Multiple Problems in 505(b)(2) Approvals: Tufts Study

An analysis by the Tufts Center for the Study of Drug Development and Sakai Regulatory Consulting found multiple issues with the 505(b)(2) drug regulatory pathway, including longer approval times than for new molecular entities (NMEs) and fewer expedited review designations than NMEs. As reported in the center’s latest Impact Report, the 505(b)(2) pathway allows for a more streamlined development and approval process by allowing drug sponsors to use data, such as FDA findings of safety and effectiveness, previously generated for a reference drug.

The Tufts analysis covers 2009 through 2015 and shows that while 505(b)(2) applications accounted for 63% of 451 original NDAs approved by FDA, the approvals had an average approval time nearly five months longer than for NMEs. “This suggests,” the report says, “that despite these applications being based on previously approved products, drug developers should not anticipate that a 505(b)(2) application will necessarily result in a shorter approval time or limited FDA requirements. As with any drug development program, it is important to engage proactively with FDA to better understand the data needed to bridge a 505(b)(2) program with the approved reference product.”

The data show that the proportion of total applications approved as 505(b)(2) NDAs on an annual basis remained fairly consistent over the seven-year period, ranging from 59% to 69%. The most common changes from the reference drug, as defined in the 505(b)(2) guidance, were for new formulations or manufacturers (38%), new dosage forms (37%), and new combinations (17%).

The report says that the longer approval times for 505(b)(2) applications — nearly five months longer than for NMEs — is noteworthy, given that review time goals mandated by PDUFA 5 for 505(b)(2) applications are two months shorter than for NMEs.

Some 43% of NMEs were granted priority review, Tufts says, compared to 14% of 505(b)(2)s. Most 505(b)(2) applications granted an expedited review designation had a priority review designation (32 out of 41 products). Ten of the priority review 505(b)(2) applications were granted fast-track designation. Most of the nine 505(b)(2) applications that received orphan drug designation were for products being used in some form to treat rate indications without an approved NDA.

Only 49% of 505(b)(2) applications were approved on the first cycle between 2009 and 2015, compared to 78% of all NME applications for 2014 and 85% for 2015. The report shows that average approval time of 10.9 months for 505b)(2)s approved on the first cycle was, on average, close to the PDUFA mandated goal of 12 months for NMEs with a standard review designation. If more than one review cycle was required, the average approval time for 505(b)(2) applications was more than 25 months.

Mean approval time for 505(b)(2)s varied by chemical type and average approval time was not affected by priority review designation.

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