FDA Issues Final Guidance on Submitting Certifications of Compliance with Clinical Trial Registration Requirements Under FDAAA Title VIII – Open Questions Remain

January 21, 2009

By Anne Marie Murphy

As we have reported previously, Title VIII of the Food and Drug Administration Amendments Act of 2007 (“FDAAA”) amended the Public Health Service Act (“PHS Act”) by adding new section 402(j), 42 U.S.C. § 282(j), which greatly expands the types of clinical trials that must be registered as well as the information on such trials that must be submitted to the clinical trials data bank, www.ClinicalTrials.gov.  One of the provisions requires that a certification of compliance accompany certain human drug, biological, and device applications and submissions to FDA:

(B) CERTIFICATION TO ACCOMPANY DRUG, BIOLOGICAL PRODUCT, AND DEVICE SUBMISSIONS. –  At the time of submission of an application under section 505 of the Federal Food, Drug, and Cosmetic Act, section 515 of such Act, section 520(m) of such Act, or section 351 of this Act, or submission of a report under section 510(k) of such Act, such application or submission shall be accompanied by a certification that all applicable requirements of this subsection have been met.

PHS Act § 402(j)(5)(B), 42 U.S.C. § 282(j)(5)(B).

The certification requirement went into effect on December 26, 2007.  Failure to submit a required certification or knowingly submitting a false certification are now prohibited acts under section 301(jj) of the Federal Food, Drug, and Cosmetic Act (“FDC Act”). 

Instead of identifying submissions that do not need a certification (as was done in the earlier draft guidance), in the final guidance FDA has identified those submissions that do require a certification.  FDA expects that the following application/submissions (including resubmissions) will be accompanied by a certification:

• Initial investigational new drug applications (“INDs”) and new protocol submissions to existing INDs;
• New drug applications (“NDAs”) and efficacy supplements to approved NDAs;
• Biologics license applications (“BLAs”) and efficacy supplements to approved BLAs;
• Abbreviated new drug applications (“ANDAs”);
• Premarket approval applications (“PMAs”);
• PMA panel track supplements;
• Humanitarian device exemptions (“HDEs”); and
• 510(k)s that refer to or include information on a clinical trial.

FDA takes the position in the final guidance that the plain language of the statutory requirement to submit a certification applies to all NDAs, BLAs, ANDAs, PMAs, PMA panel track supplements, HDEs, 510(k)s, and supplements or resubmissions of any such applications or reports.  FDA explains, however, that amendments to such pending applications are not “independently ‘applications’” and therefore need not be accompanied by a certification.  In addition, FDA indicates that it intends to exercise its enforcement discretion and not require that supplements to approved applications, other than efficacy supplements, be accompanied by a certification.

FDA’s explanation for its position that INDs and new protocol submissions to existing INDs must be accompanied by a certification is less cogent.  FDA’s reasoning is that an IND is authorized under section 505(i) of the FDC Act and defined by regulation as “an investigational new drug application.” 21 C.F.R. § 312.23(a) (emphasis added).  With regard to new protocol submissions to existing INDs, the guidance indicates that such a submission is “the investigational stage analog to an efficacy supplement to an NDA or BLA.” 

The final guidance leaves open the following question:  What is the meaning of a certification that accompanies a new IND or a new protocol submission to an existing IND?  The statutory requirement to register a clinical study does not take effect until 21 days after the first study subject has been enrolled, PHS Act § 402(j)(2)(C)(ii), 42 U.S.C. § 282(j)(2)(C)(ii), but a clinical study protocol must be submitted to an IND before the study begins.  Indeed, a new IND must be submitted to FDA at least 30 days before any clinical study is initiated.  Thus, the IND sponsor has to certify compliance with a requirement that has not yet taken effect.  PhRMA’s comments on the earlier draft guidance make this point, but it is not addressed in the final guidance.