FDA Clarifies that FDAAA Clinical Trial Certification Requirement Applies to IND Submissions; Questions Remain About ANDA Bioequivalence Study Registration

September 8, 2008

On March 5, 2008, FDA published a notice in the Federal Register announcing an opportunity for public comment on a proposed collection of information concerning the new clinical trial certification requirement created by Title VIII of the FDA Amendments Act (“FDAAA”).  We previously reported on this new requirement here and here. 

Pursuant to PHS Act § 402(j)(5)(B), as amended by FDAAA § 801(a)(2), drug and device sponsors must include a certification (Form FDA 3674) with their regulatory submissions that they have complied with new PHS Act § 402(j), under which the responsible party of an “applicable clinical trial” must submit to the National Institutes of Health certain required information for inclusion in the clinical trial data bank at ClinicalTrials.gov.  Specifically, PHS Act § 402(j)(5)(B) states:

At the time of submission of an application under [FDC Act §§ 505, 515, 520(m), or PHS Act § 351], or submission of a report under [FDC Act § 510(k)], such application or submission shall be accompanied by a certification that all applicable requirements of [PHS Act § 402(j)] have been met.  Where available, such certification shall include the appropriate National Clinical Trial control numbers.

Since FDA published its March 2008 notice, several issues have been raised about the applicability of the new certification requirement.  Chief among these concerns is whether INDs are subject to the new requirement.  Indeed, several comments were submitted to FDA questioning whether IND submissions are “applications” in the terminology of the FDC Act.  For example, the Biotechnology Industry Organization (“BIO”) contends in a docket submission that “an IND submission is not an ‘application’ within the meaning of the FD&C Act” because FDC Act § 505(i) (concerning INDs) “does not refer to INDs as ‘applications’ but as ‘submissions’ for purposes of obtaining an ‘exemption,’” and that “the legislative history of Title VIII of FDAAA makes clear that Congress considered – and expressly rejected – the application of the certification requirement to INDs.”  The Pharmaceutical Research and Manufacturers of America (“PhRMA”) makes similar arguments in its docket submission.

On August 25, 2008, FDA published a second Federal Register notice announcing that a proposed collection of information concerning the FDAAA clinical trial certification requirement was submitted to the Office of Management and Budget for review and clearance.  In that notice, FDA addresses several issues, including those issues raised by BIO and PhRMA about IND submissions, and states:

FDA does not agree with these conclusions.  FDA agrees that the word “application” is not used in section 505(i) of the FD&C Act in reference to an IND.  However, section 505(i)(1) directed the Secretary of Health and Human Services to issue regulations exempting from the requirements of section 505 of the FD&C Act drugs intended solely for investigational use.  The regulations issued by FDA under this authority define an IND as “an investigational new drug application.”  21 CFR 312.3 (emphasis added).  Furthermore, these regulations repeatedly use the term “application” in reference to an IND.  Therefore, FDA considers an IND to be an application under section 505 of the FD&C Act .  Congress is familiar with FDA regulations and could have specifically exempted INDs from the certification process by directly excluding 505(i) from the scope of section 402(j)(5)(B) of the PHS Act. . . .  Congress understood the difference between marketing applications and IND submissions and exemptions.  FDA has concluded that the reference to section 505 of the FD&C Act was simply a streamlined reference to all applications and submissions possible under section 505 of the FD&C Act.

Several comments also questioned whether or not the clinical trial certification requirement should apply to trials over which the manufacturer/sponsor had no control – e.g., published reports of clinical studies included in a 505(b)(2) application.  FDA responded –

The certification provision, section 402(j)(5)(B) of the PHS Act, does not make a distinction between trials conducted by the sponsor and trials relied upon in the application but conducted by entities other than the sponsor.  FDA is aware that sponsors or applicants will be required to certify as to trials they did not conduct or register in the clinical trials data bank.  FDA has addressed this concern by requiring the submitter to declare that the information submitted is accurate, true, and complete “to the best of her/his knowledge.”

FDA also adds to the August 2008 notice an estimated annual reporting burden for ANDAs.  The March 2008 notice did not include ANDAs in the burden calculation, “but have since been determined to require a certification form . . . .”  We previously reported that it has been unclear whether a company submitting an ANDA containing the results of an in vivo bioequivalence study must certify on Form FDA 3674 that new PHS Act § 402(j) applies and that the studies have been registered at ClinicalTrials.gov.  That is, it has been unclear whether an in vivo bioequivalence study is an “applicable clinical trial” subject to the PHS Act § 402(j) databank registration requirements.  Although FDA’s August 2008 notice does not address specifically whether an in vivo bioequivalence study is an “applicable clinical trial,” its “determination” that the clinical trial certification must accompany ANDA submissions announced in that notice may be a signal that FDA is headed in the direction of concluding that in vivo bioequivalence studies are, in fact, “applicable clinical trials” that must be registered.  FDA is reportedly in the process of drafting a guidance document that will provide the Agency’s interpretation of the scope of the term “applicable clinical trial” and that should provide greater clarity to industry on the types of studies to which FDA believes PHS Act § 402(j) applies.   

By Kurt R. Karst    

Categories: Drug Development