FDA Issues Draft Guidance on FDAAA Clinical Trial Certification Requirement; Additional Guidance is Necessary to Add Clarity

April 24, 2008

Earlier this year, we reported on a provision in Title VIII of the FDA Amendments Act (“FDAAA”) requiring the responsible party of an “applicable clinical trial” (for both drugs and devices) to certify that the new requirements of Public Health Service Act (“PHS Act”) § 402(j) have been met.  Under PHS Act § 402(j), 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.  Currently, only descriptive information about the trial design and enrollment is required to be registered at ClinicalTrials.gov, however certain results of those studies will also be required to be posted within the next few years.

New PHS Act § 402(j)(1)(A) defines an “applicable drug clinical trial” to mean “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .”  An “applicable device clinical trial” is defined to mean “a prospective clinical study of health outcomes comparing an intervention with a device subject to section 510(k), 515, or 520(m) of the [FDC Act] against a control in human subjects (other than a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes); and a pediatric postmarket surveillance as required under [FDC Act § 522].”  Pursuant to new PHS Act § 402(j)(5)(B), drug and device sponsors must include a certification with their regulatory submissions that they have complied with new PHS Act § 402(j).  In December 2007, FDA announced the availability of a new form (Form FDA 3674) to accompany certain applications to meet the certification requirement.

Since the new certification requirement went into effect in December 2007, there has been significant debate within the drug and device industries as to the applicability of PHS Act § 402(j) to certain submissions.  For example, with respect to drugs, it has been unclear whether a company submitting an Abbreviated New Drug Application (“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 to some companies whether an in vivo bioequivalence study is an “applicable drug clinical trial” subject to the PHS Act § 402(j) databank registration requirements and whether a generic applicant must certify on Form FDA 3674 that the PHS Act § 402(j) requirements have been met.  Under FDC Act § 301(jj), as amended by FDAAA, the failure to submit a certification, knowingly submitting a false certification, failing to submit required clinical trial information to ClinicalTrials.gov, and submitting false or misleading information to ClinicalTrials.gov is a prohibited act subject to a new civil monetary penalties provision, as well as to other enforcement sanctions under the FDC Act.   

On April 18, 2008, FDA announced the availability of a draft guidance document providing the Agency’s current thinking regarding whether some types of information and documents submitted to FDA must be accompanied by Form FDA 3674.  The draft guidance document lists several submissions to FDA that typically do not require a Form FDA 3674, including CMC amendments and supplements, meeting requests, safety reports, promotional materials for review, and “ANDA amendments and supplements that contain no in vivo bioequivalence information,” leaving open the possibility that ANDA submissions that do contain in vivo bioequivalence determinations also need to have a Form FDA 3674.  FDA notes in the Federal Register notice accompanying the draft guidance document that “[w]hile we intend the draft guidance to assist submitters in determining whether to submit a certification based on the type of document being submitted to FDA, this guidance does not address, nor does it make a recommendation on, all possible information and documents that may be submitted to FDA. . . . We will continue to review the types of information and documents that a certification typically does not need to accompany.” 

Because of the limited nature of FDA’s draft guidance document, it is still unclear to many in the drug and device industries whether new PHS Act § 402(j) applies to certain submissions – such as an initial IND submission containing a clinical trial protocol.  By regulation (21 C.F.R. § 312.40), the sponsor must wait 30 days before beginning such trials, but the study does not need to be registered under the law until 21 days after the first patient is enrolled.  FDA frequently requires modifications to protocols, or even places them on clinical hold.  If protocols were required to be registered upon initial submission to FDA, it would force the sponsor and NIH to edit the information in ClinicalTrials.gov whenever FDA made such modifications.  Would the sponsor then need to re-certify to FDA?  It would seem that all of the statutory objectives would be met if the Form FDA 3674 certification was required when the results of a study were submitted to the IND. In addition, it is unclear whether new PHS Act § 402(j) applies to ANDAs containing the results of in vivo bioequivalence studies.  This is a critical issue because many ANDA companies deem the existence of bioequivalence studies (which ordinarily do not require an IND) as trade secret or confidential commercial information, particularly from the NDA holder.  Moreover, bioequivalence studies are simply not large enough to discover previously unknown safety information and few companies or medical journals, for that matter, are interested in publishing the results of such studies.  Finally, if ANDAs applicants are also forced (ultimately) to post their bioequivalence results so that they can submit Form FDA 3674, will that open FDA to second-guessing by the NDA holder? 

Help might be on the way, however.  We have learned that FDA is in the process of drafting another draft guidance document that will provide the Agency’s interpretation of the scope of the terms “applicable drug clinical trial” and “applicable device clinical trial.”  That draft guidance, once issued, should provide greater clarity to industry on the types of studies to which PHS Act § 402(j) applies.   

By Kurt R. Karst & David B. Clissold