The Public Health Service Act (PHSA) now requires that submission of certain applications pursuant to the drug, device or biologics provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA) or the PHSA be accompanied by a certification attesting that all applicable clinical trial registration and posting requirements have been met. See Section 402(j)(5)(B) of the PHSA; 42 U.S.C. §282(j)(5)(B). This certification requirement became law as part of the new clinical trial transparency regime enacted by §801 of the Food and Drug Administration Act Amendments of 2007 (FDAAA), Pub. L. 110-85, 121 STAT. 823, 904. The underlying provisions in the PHSA require that “applicable clinical trials” be registered and that certain information about them be publicly disclosed. (See 42 U.S.C. §282(j)(1)).
Although the U.S. Food and Drug Administration (FDA) has developed a new Form 3674 for use in meeting the statutory certification requirement, there remains a substantial degree of uncertainty about the universe of submissions that require an accompanying Form 3674 certification. This uncertainty arises from both the generality of the statutory certification language itself and the fact that it is intended to certify compliance with registration and posting requirements, that only apply to “applicable clinical trials” and hence do not necessarily apply to each and every clinical trial conducted by anyone at any time for any reason. To be sure, original new drug applications, premarket approval applications for medical devices and biologics license applications that contain information from clinical trials require an accompanying Form 3674 at the time of initial submission. But there are myriad other submissions that the regulated community makes to FDA under the drug, device and biologics provisions of the FFDCA, and there are many open questions about whether and when an accompanying Form 3674 must be filed with them.
In an effort to provide at least some clarification on the point, FDA last week announced the availability of a Draft Guidance that identifies a number of categories for which an accompanying Form 3674 certification is not required at the time of submission.
These categories are the following:
- Chemistry and manufacturing amendments to Investigational New Drug Applications (INDs)
- Non-clinical pharmacology/toxicology amendments to INDs
- IND Safety Reports
- Single Patient INDs
- Meeting requests
- Investigational Device Exemption Applications (IDEs)
Marketing and Post-Marketing Applications/Submissions
- Chemistry and manufacturing amendments and supplements to Biologics License Applications (BLAs) and New Drug Applications (NDAs) Non-clinical pharmacology/toxicology amendments and supplements to BLAs and NDAs
- Humanitarian Device Exemptions (HDEs) and Premarket Approval Application (PMA) 30 Day Notices
- ANDA amendments and supplements that contain no in-vivo bioequivalence information
- ANDA, BLA and NDA promotional materials
- BLA and NDA Safety Reports
- ANDA, BLA, NDA, HDE and PMA mandatory and voluntary adverse event or medical device reports
- Meeting requests
- 510(k)s that contain no clinical data
Nonetheless many unanswered questions remain. In fact, the Draft Guidance explicitly states that inclusion on the list does not necessarily represent a categorical exclusion from the certification requirement: “We recognize that there may be times that the types of submissions discussed above do, in fact, contain information that refers to, relates to, or includes information on an applicable clinical trial that the registry and results databases are intended to capture. In those cases, you should consider whether a certification is appropriate and contact us if you need additional guidance.” Examples of submissions for which applicability of the certification requirements remains unclear include compassionate use INDs that involve several subjects (single patient INDs appear to be excluded) and ANDA submissions that “do contain” in vivo bioequivalence information. The implications for the generic drug approval process of the certifications and related registration and posting is an important consequence of that question, but is not addressed in the Draft Guidance.
FDA has acknowledged that the Draft Guidance as it now stands is not the last word on the subject and that it will be updated in the future to address other submissions that typically do not need to be accompanied by a certification. In the meantime, however, the existing Draft Guidance itself creates a good deal of ambiguity in areas that it does address, and still leaves open many questions in areas that it does not address.