FDA Grants Osmotica Citizen Petition; Decision Affirms RLD Change and Choice Policies and Implements MMA RLD Change Prohibition Provisions

By Kurt R. Karst -     

On November 25, 2008, FDA granted in full a citizen petition (petition supplements are available here and here) submitted by Osmotica Pharmaceutical Corp. earlier this year requesting that FDA determine that any company with a pending Abbreviated New Drug Application ("ANDA") for a proposed Venlafaxine HCl Extended-Release Tablets drug product, and in particular Sun Pharmaceutical Industries Ltd. ("Sun"), be required to submit to FDA a new ANDA citing Osmotica's approved Venlafaxine HCl Extended-Release Tablets drug product as the Reference Listed Drug ("RLD"), and that FDA require any such ANDA applicant to conduct new bioequivalence studies comparing its proposed drug product to Osmotica's approved drug product.  FDA's 26-page decision: (1) affirms FDA's longstanding "RLD Change Policy," which requires a generic applicant with a pending ANDA subject to an approved suitability petition to change RLD and provide appropriate bioequivalence information once the Agency approves an application for the drug product covered by the suitability petition; (2) affirms FDA's "RLD Choice Policy," under which a generic applicant must choose the most pharmaceutically equivalent listed drug as the RLD; and (3) and implements FDC Act § 505(j)(2)(D)(i), which was added to the statute in 2003 by the Medicare Prescription Drug, Improvement, and Modernization Act ("MMA") and precludes an applicant with a pending ANDA from amending that application to change RLD.  It is the first citizen petition covered under FDC Act § 505(q) that FDA has granted in full - see the FDA Law Blog FDC Act § 505(q) Citizen Petition Tracker.

Osmotica's May 30, 2008 citizen petition concerns FDA's May 20, 2008 approval of Osmotica's 505(b)(2) application (NDA #22-104) for Venlafaxine HCl Extended-Release Tablets, and FDA's March 30, 2005 decision approving a suitability petition submitted pursuant to FDC Act § 505(j)(2)(C) for a dosage form change from Venlafaxine HCl Extended-Release Capsules (i.e., Wyeth's EFFEXOR XR) to Venlafaxine HCl Extended-Release Tablets.  Sun had submitted an ANDA to FDA pursuant to FDA's suitability petition decision seeking approval of Venlafaxine HCl Extended-Release Tablets – pharmaceutically the same drug product FDA approved under Osmotica's NDA.

Under FDA's RLD Choice Policy, a generic applicant should refer to the approved pharmaceutical equivalent designated by FDA as the RLD as it basis for ANDA submission.  As FDA explained in a 2004 citizen petition response (page 9, note 13):

if a tablet and a capsule are approved for the same moiety with patents listed for the tablet and none listed for the capsule, an ANDA applicant seeking approval for a tablet should cite the approved tablet as the [RLD].  It should not circumvent the patents on the tablet by citing the capsule as the [RLD] and filing a suitability petition under [FDC Act § 505(j)(2)(C)] and 21 CFR 314.93 seeking to change to a tablet dosage form.

Under FDA's longstanding RLD Change Policy, the Agency has required a generic applicant with a pending ANDA subject to an approved suitability petition to change RLD and provide appropriate bioequivalence information once the Agency approved an application for the drug product covered by the suitability petition.  For example, after FDA approved NDAs for Carboplatin Injection drug products that were also the subject of pending ANDAs submitted pursuant to an approved suitability petition, the Agency required generic applicants to change RLD.  FDA has also required generic applicants to take the same action in an Rx-to-OTC switch scenario, where the Agency approved a new NDA for an OTC drug product – thus creating a new RLD listed in the Orange Book to which generic applicant must cite.

FDA's RLD Change Policy became particularly important with the enactment of the MMA in 2003.  The MMA amended the FDC Act to add § 505(j)(2)(D)(i), which states: "[a]n applicant may not amend or supplement an [ANDA] to seek approval of a drug referring to a different listed drug from the listed drug identified in the application as submitted to [FDA]."  A similar provision was added to FDC Act § 505(b)(4)(A) with respect to 505(b)(2) applications.  That provision states: "[a]n applicant may not amend or supplement [a 505(b)(2) application] to seek approval of a drug that is a different drug than the drug identified in the application as submitted to [FDA]."  Thus, given FDA's RLD Change and Choice Policies, a generic applicant must cite the most appropriate RLD, and must change RLD (for a pending application) when a pharmaceutically equivalent listed drug is approved.  However, the MMA precludes an ANDA applicant with a pending application from changing RLD.  Instead, Osmotica argued in its citizen petition that a new application must be submitted citing the appropriate RLD, and such application must contain the required bioequivalence data comparing the proposed generic drug to the new RLD (in this case, Osmotica's approved Venlafaxine HCl Extended-Release Tablets drug product).

In October 2004, FDA issued a draft guidance document discussing, among other things, FDC Act § 505(j)(2)(D)(i).  FDA's draft guidance document states, in relevant part:

All changes that would have the effect of seeking approval for a drug product different from the listed drug cited in the initial submission (e.g., different active ingredient, dosage form, route of administration) should be made in a new application.  When the Orange Book identifies as a separate listed drug a product with the characteristics (e.g., active ingredient, dosage form, route of administration) for which the applicant is seeking approval, the applicant should submit a separate ANDA referencing the corresponding listed drug.  The applicant should not submit a supplement or amendment to its pending or approved application to seek approval for such a change.
     
In the Federal Register notice announcing the availability of the draft guidance, FDA stated:

A situation that is not considered in this guidance is that where a pending ANDA was submitted referencing a [suitability] petition approved under [FDC Act § 505(j)(2)(C)], and another application is approved for the product described in the petition before the pending ANDA is approved.  FDA has not completed its analysis of this situation, and therefore the draft guidance does not cover it.

Despite the apparent uncertainty in 2004, however, FDA has completed its analysis and has determined that a generic applicant with a pending ANDA subject to an approved suitability petition must submit a new ANDA citing the appropriate RLD when the drug product described in the approved suitability petition is approved under an NDA.  FDA's petition response states:     

our requirement that an applicant with a pending ANDA subject to an approved suitability petition change the RLD upon FDA approval of an NDA for the same drug product described in the approved suitability petition reflects the Agency's judgment that considerations regarding an ANDA's limited reliance on an approved suitability petition are outweighed by the need for a clear determination of therapeutic equivalence for a generic drug product and protection of intellectual property rights accorded an NDA holder. . . .

[T]his approach reduces the potentially confusing proliferation of pharmaceutically equivalent drug products that have not demonstrated therapeutic equivalence, and ensures that ANDAs for venlafaxine HCl extended-release tablets will be therapeutically equivalent and thus substitutable for the RLD, Osmotica's venlafaxine HCl extended-release tablets. . . .

FDA's policy of requiring all pending ANDA applicants to change their basis for ANDA submission upon approval of an NDA for the same drug product described in the suitability petition is intended to ensure that ANDA applicants do not circumvent the patent certification requirements of section 505(j)(2)(A)(vii)-(viii) of the Act through the suitability petition process.  In addition, our policy would appropriately protect any marketing exclusivity that has been granted to the newly-approved RLD.

In the case of Sun's pending ANDA for Venlafaxine HCl Extended-Release Tablets, FDA determined that:

an ANDA for venlafaxine HCl extended-release tablets submitted based upon an approved suitability petition that was pending at the time of approval of Osmotica's NDA 22-104 and that seeks approval for a pharmaceutically equivalent drug product must be withdrawn, as the ANA is required to reference the corresponding approved strengths of Osmotica's venlafaxine HCl extended-release tablets as its RLD, and section 505(j)(2)(D)(i) of the Act precludes such a change from being submitted as an amendment to an ANDA.  If Sun or any other applicant wishes to pursue approval of an ANDA for venlafaxine HCl extended-release tablets, it must submit a new ANDA containing data and information required by section 505(j) of the Act for approval (including, but not limited to, a demonstration of bioequivalence to the RLD, Osmotica's venlafaxine HCl extended-release tablets).

FDA's citizen petition response also applies to 505(b)(2) applications pursuant to FDC Act § 505(b)(4)(A).  FDA states in the context that "[o]ur interpretation of the MMA provisions related to the Hatch-Waxman Amendments upholds the legislative balance of facilitating the availability of generic drug products that meet the statutory requirements for approval while protecting innovator intellectual property rights (and allowing for an early resolution of any patent infringement litigation)" that:

We note that our interpretation of § 505(b)(4)(A) of the Act, also added by the MMA, for 505(b)(2) applications is influenced by and intended to be consistent with section 505(j)(2)(D)(i) regarding ANDAs.  Accordingly, a 505(b)(2) applicant may not amend or supplement a 505(b)(2) application to seek approval of a drug that relies on the Agency's finding of safety and/or effectiveness for a drug that is different from the drug identified in a previous submission of the application.

The importance of FDA's citizen petition response cannot be overstated.  It has significant implications – and creates significant risk – for generic companies that rely on the suitability petition process.  And for 505(b)(2) applicants, it also creates a risk of application resubmission and underscores the importance of carefully choosing the appropriate listed drug(s).