GPhA Presses NIH on Clinical Study Registration Issues; Requests Clarification of “Elaborations” Document

By Kurt R. Karst –      

We previously reported (here and here) on concerns as to whether a company submitting an ANDA (or a 505(b)(2) application) containing the results of an in vivo bioequivalence study must certify on Form FDA 3674 that new Public Health Service Act (“PHS Act”) § 402(j), as added by Title VIII of the FDA Amendments Act (“FDAAA”), applies and that in vivo bioequivalence studies  have to been registered at ClinicalTrials.gov.  PHS Act § 402(j)(1)(A) defines an “applicable drug clinical trial,” which is subject to the databank registration requirements,  to mean, in relevant part, “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .” (emphasis added).  In a recent comment submitted to the National Institutes of Health (“NIH”), the Generic Pharmaceutical Association (“GPhA”) requests that NIH clarify that a clinical endpoint bioequivalence study should not be considered an “applicable drug clinical trial.”

In December 2008, NIH issued a draft document, titled “Elaboration of Definitions of Responsible Party and Applicable Clinical Trial” discussing, among other things, the applicability of the FDAAA Title VIII requirements to bioequivalence studies.  The draft “elaborations” document was updated in March 2009 to clarify that it “represent[s] the [NIH’s] current thinking on this topic.” According to the draft document:

In the agency’s view, a clinical investigation designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product, or to demonstrate comparative bioavailability of two products (such as for purposes of submitting an abbreviated new drug application under 21 USC § 355(j) or a new drug application as described in 21 USC § 355(b)(2)) is considered to be a controlled clinical investigation. In this case, the control generally would be the previously approved drug product.

Although a bioequivalence study is a controlled clinical investigation, the draft guidance goes on to note that:

Under certain circumstances, a clinical investigation designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product, or to demonstrate comparative bioavailability of two products (such as for purposes of submitting an abbreviated new drug application under 21 USC § 355(j) or a new drug application as described in 21 USC § 355(b)(2)) will be considered to be a Phase 1 clinical investigation under 21 CFR § 312.21 for purposes of determining whether a particular clinical trial is an “applicable drug clinical trial” under Title VIII of PL 110‐85 (section 402(j)(1)(A)(iii) of the PHS Act).  Although Phase 1 clinical investigations are generally designed to fit sequentially within the development plan for a particular drug, and to develop the data that will support beginning Phase 2 studies, 21 CFR § 312.21(a) does not limit Phase 1 trials to that situation.  Bioequivalence or comparative bioavailability studies that fall within the scope of the studies described in 21 CFR § 320.24(b)(1), (2), and (3) share many of the characteristics of Phase 1 clinical investigations as described in 21 CFR § 312.21(a), and therefore will be considered to be Phase 1 trials for purposes of Title VIII of PL 110-85. However, bioequivalence or comparative bioavailability trials that fall within the scope of 21 CFR § 320.24(b)(4) do not share the characteristics of Phase 1 trials as described in 21 CFR § 312.21(a), and thus would not be considered to be Phase 1 trials for purposes of Title VIII of PL 110-85.

Elaborations Document at 10 (emphasis added).

Bioequivalence studies that fall within the scope of 21 CFR § 320.24(b)(4) and that are not exempt from reporting on ClinicalTrials.gov are generally clinical endpoint studies.  According to an FDA Manual of Policies and Procedures, such studies are typically “applied to dosage forms intended to deliver the active moiety locally, forms that are not intended to be absorbed, or drug products for which traditional pharmacokinetic studies are not feasible,” such as drug products in topical dosage forms. 

In advance of an April 20, 2009 public meeting to solicit input on issues that NIH will consider as it develops regulations to expand the clinical trial registry and results data bank in accordance with FDAAA Title VIII, GPhA submitted a letter to NIH requesting that the agency reconsider its position that a clinical endpoint bioequivalence study is an  “applicable drug clinical trial” that must be registered on ClinicalTrials.gov.  According to GPhA:

We agree with NIH’s determination that most bioequivalence studies are “Phase I” studies and therefore excluded from the “applicable drug clinical trial” definition.  However, we disagree with NIH’s decision to include bioequivalence studies that use clinical endpoints to establish bioequivalence within such definition.  NIH’s position is inconsistent and without scientific merit.  There is no basis to distinguish between bioequivalence studies based solely on the endpoints used to establish bioequivalence.  These studies are not intended to prove the safety or efficacy of a drug product.  In contrast, Section 505(j) states that these studies are only permitted to include information and data sufficient to compare the bioavailability of the reference (i.e., innovator) and test (i.e., generic drug).  ANDA applicants are permitted to establish bioequivalence in a variety of ways, but the end result is always the same—a comparison of the rate and extent to which the active ingredient becomes available at the site of action.  All bioequivalence studies are performed for the same underlying reason and therefore should receive similar treatment under the ClinicalTrials.gov database.  Specifically, they are all “Phase I” studies that are excluded from the definition of “applicable drug clinical trial.”

The GPhA letter also takes issue with a statement in the draft “elaborations” document, which states: 

When a clinical investigation includes sites both within the U.S. (including any territory of the U.S.) and outside of the U.S., if any of those sites is using (for purposes of the clinical investigation) a drug that is subject to section 505 of the FDC Act, then the agency will consider the entire clinical investigation to be an “applicable drug clinical trial,” assuming that it meets the rest of the statutory definition.  A clinical investigation that is being conducted entirely outside of the U.S. (i.e., does not have any sites in the U.S. or in any territory of the U.S.) may be an “applicable drug clinical trial,” depending on where the drug being used in the clinical investigation is manufactured. If the drug is manufactured in the U.S. or any territory of the U.S., and is exported for study in another country under an IND, pursuant to 21 CFR § 312.110, or pursuant to section 802 of the FDC Act, then the drug is considered to be subject to section 505 of the FDC Act or section 351 of the PHS Act (as applicable), and the clinical investigation may be an “applicable drug clinical trial,” if it meets the other statutory criteria.  If the drug is manufactured outside of the U.S. or its territories, the trial sites are all outside of the U.S., and the trial is not being conducted under an IND, then it would not be considered to be subject to section 505 of the FDC Act or section 351 of the PHS Act, and the clinical investigation would not be an “applicable drug clinical trial.”

Elaborations Document at 8 (emphasis added).

According to GPhA, the exemption highlighted above “will disadvantage U.S. companies and provide an incentive to move operations outside of the U.S.”

A videocast of the April 20, 2009 public meeting at which GPhA and several other organizations and firms that have submitted public comment to NIH will present, including PhRMA and BIO, can be viewed here.