FDA Clarifies that 3-Year Exclusivity can be Granted for the Removal of Labeling Information

August 24, 2008

Under the FDC Act and FDA’s implementing regulations, a sponsor may qualify for a 3-year period of market exclusivity for a “change” to an approved drug product if the application contains: (1) “reports of new clinical investigations (other than bioavailability studies);” (2) that were “essential to approval” of the application; and (3) that were “conducted or sponsored by” the applicant.  All three of these criteria must be satisfied in order to qualify for 3-year exclusivity.  Each criterion is defined in FDA’s implementing regulations at 21 C.F.R. § 314.108. 

The question of whether a drug product change eligible for 3-year exclusivity is limited to labeling additions, or whether labeling deletions can also qualify for exclusivity, has not been clearly stated by FDA.  For example, in an October 1996 citizen petition response (FDA Docket No. #1995P-0366/PDN1), FDA commented (in the context of an Rx-to-OTC switch) that an argument that:

a “significant innovation” or a “new condition of use” is required to receive marketing exclusivity for a change under [FDC Act §§ 505(c)(3)(E)(iv) and 505(j)(5)(F)(iv)] is incorrect.  Under these paragraphs of [FDC Act § 505], a “change” approved in a supplement to a 505(b) application is awarded marketing exclusivity for three years if the supplement is approved after September 24, 1984; the supplement contains “reports of new clinical investigations (other than bioavailability studies);” the investigations are “essential to the approval of the supplement;” and the investigations are “conducted or sponsored by the person submitting the supplement.”  Thus, the standard under the [FDC Act] for determining whether a change in a supplement is granted marketing exclusivity is whether the change is supported by new clinical investigations that are essential to the approval of the supplement.   

Thus, according to FDA, all that is required to qualify an applicant for 3-year exclusivity is that a “change” meet the three statutory criteria.  If it does, then it is the type of “change” intended by Congress to qualify for 3-year exclusivity.  Accordingly, a “change” that is a deletion of labeling information could qualify for 3-year exclusivity.  And in fact that is exactly what FDA determined in a recent case.

On July 7, 2005, FDA approved NDA # 21-794 for ACZONE (dapsone) Gel, 5%, for the treatment of acne vulgaris.  At the time of initial NDA approval, the “Indications and Usage” labeling section included the following information:

Glucose 6-phosphate dehydrogenase (G6PD) levels should be obtained prior to initiating therapy with ACZONEÔ Gel, 5%. In patients with a history of anemia and predisposition to increased hemolytic effect with dapsone (e.g., glucose-6-phosphate dehydrogenase deficiency), closer follow-up for blood hemoglobin levels and reticulocyte counts should be implemented (see PRECAUTIONS). Alternatively, other therapies for acne than ACZONEÔ Gel, 5%, may be considered.  

Similar information was included in the “Precautions” and “Adverse Events” labeling sections, along with information based on the G6PD-deficient subjects enrolled in the applicant’s clinical studies. 

According to FDA’s summary basis of approval for NDA # 21-794, the Agency required this labeling information due to concerns, based on FDA’s experience with oral dapsone, that hemolysis could be exaggerated in individuals with low plasma G6PD, and because the applicant’s clinical studies “did not enroll adequate numbers of subjects with [G6PD] deficiency . . . to be able to make reasonable conclusions about the safety of ACZONE in this population.”  The applicant agreed to conduct a postmarketing study in G6PD-deficient patients with acne vulgaris to further evaluate the risk of hematological adverse events with the use of ACZONE Gel in this population.  The results of that study were submitted to FDA in an NDA supplement (NDA #21-794/S-005) in May 2007, which FDA approved in March 2008.

The March 2008 approval significantly revised the ACZONE Gel labeling to show that the drug product is safer than originally thought with respect to G6PD-deficient patients, thereby permitting broader use of the drug.  Specifically, the statement quoted above from the “Indications and Usage” labeling section (as well as related statements in the “Precautions” and “Adverse Events” labeling sections) requiring an invasive medical test was removed (because it is now unnecessary), and new information was added to the “Warnings and Precautions” labeling section on hematological effects in G6PD-deficient patients and to the “Use in Specific Populations” labeling section discussing in detail the results of the applicant’s clinical study in G6PD-deficient patients. 

Although FDA approved NDA #21-794/S-005 in March 2008, it was not until the issuance of the most recent Orange Book Cumulative Supplement in mid-August 2008 that FDA officially granted exclusivity for the ACZONE Gel supplement.  The decision to grant exclusivity resulted in the creation of a new exclusivity code: M-76 – REMOVAL OF SCREEN REQUIREMENT IN PTS WITH G6PD DEFICIENCY PRIOR TO INITIATING ACZONE TREATMENT; REMOVAL OF BLOOD COUNT & RETICULOCYTE MONITORING DURING TREATMENT IN G6PD DEFICIENT PTS AND IN PATIENTS WITH HISTORY OF ANEMIA.  Given the unusual delay in granting exclusivity, it would appear that FDA wrestled with the issue, but ultimately concluded that any “change” meeting the statutory requirements is eligible for 3-year exclusivity.

By Kurt R. Karst

Categories: Hatch-Waxman