A Flurry of Generic Drug Labeling Carve-Out Citizen Petitions; Scorecard Updated

By Kurt R. Karst –      

Since we last updated our popular Generic Drug Labeling Carve-Out Citizen Petition Scorecard in February 2011, there have been several new citizen petitions submitted to FDA raising questions about FDA approval of ANDAs with labeling that omits information protected by periods of patent or non-patent market exclusivity, or with labeling that is otherwise not the “same as” that of the Reference Listed Drug (e.g., tablet scoring).  Two recent citizen petitions of interest (here and here) concern AstraZeneca’s (“AZ’s”) quetiapine fumarate, approved as SEROQUEL (quetiapine fumarate) Tablets (NDA No. 020639) and SEROQUEL XR (quetiapine fumarate) Extended-Release Tablets (NDA No. 022047). 

SEROQUEL is listed in the Orange Book with a single patent – U.S. Patent No. 4,879,288 (“the ‘288 patent”) – the pediatric exclusivity for which expires on March 26, 2012.  The Orange Book also lists three periods of 3-year new clinical investigation exclusivity: “I-560” exclusivity (“MAINTENANCE TREATMENT FOR BIPOLAR I DISORDER, AS ADJUNCTIVE THERAPY TO LITHIUM OR DIVALPROEX”) the pediatric exclusivity for which expires on November 13, 2011, and two periods of “NPP” (New Patient Population) exclusivity from NDA supplement approvals for the treatment of schizophrenia in adolescents 13 to 17 years of age and the treatment of bipolar mania in children and adolescents 10 to 17 years of age.  The pediatric exclusivity applicable to the two periods of exclusivity coded as NPP expire on June 2, 2013. 

SEROQUEL XR is listed in the Orange Book with two patents – the ‘288 patent and U.S. Patent No. 5,948,437 (“the ‘437 patent”).  The ‘437 patent expires on May 28, 2017, but is subject to a period of pediatric exclusivity that expires on November 28, 2017.  The Orange Book also lists several periods of 3-year new clinical investigation exclusivity, four of which have expired but are subject to unexpired periods of pediatric exclusivity: (1) “I-618” (“ADJUNCTIVE THERAPY IN THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD)”) which expires on December 2, 2012; (2) “I-576” (“ADJUNCTIVE THERAPY IN THE TREATMENT OF BIPOLAR MANIA”) the pediatric exclusivity for which expires on April 8, 2012; (3) “I-574” (“MONOTHERAPY IN THE TREATMENT OF BIPOLAR DEPRESSION”) the pediatric exclusivity for which expires on April 8, 2012; (4) “D-117” (“50 MG TABLET FOR INITIATION OF DOSE TITRATION FOR BIPOLAR DISORDER”) the pediatric exclusivity for which expires on April 8, 2012; and (5) “I-575” (“MONOTHERAPY IN THE TREATMENT OF BIPOLAR MANIA”) the pediatric exclusivity for which expires on April 8, 2012.   

AZ’s two quetiapine fumarate petitions, which cite FDA’s February 2011 petition response concerning labeling carve-outs for generic versions of XYZAL (levocetirizine dihydrochloride) to support their position, are presumably intended to fit hand-in-glove with one another.  Both petitions raise issues with the omission of information in Table 2 of the products’ labeling concerning glucose-related data and information, and with the omission of information on suicide (contained in both the black box warnings and the “Warnings and Precautions” labeling sections for each product).  In each case, AZ argues that the omission of specific, protected information in generic drug labeling would make the generic product less safe or effective for the remaining non-protected conditions of use of SEROQUEL or SEROQUEL XR.

Of particular interest is the SEROQUEL petition, in which AZ argues against the omission of certain information protected by exclusivity FDA granted with respect to SEROQUEL XR approvals – specifically, by the periods of 3-year exclusivity concerning the treatment of bipolar disorder and MDD.  According to AZ:

FDA has periodically required AstraZeneca to revise its label to include new information concerning the use of Seroquel.  Some of this new information in the Seroquel label is based on Seroquel XR protected data that cannot be included in a generic drug’s labeling until the associated data exclusivity periods have expired.  If FDA were to permit a generic to omit such information from its labeling – after requiring its inclusion in the labeling for Seroquel – the agency would run afoul of the Administrative Procedure Act's prohibition on arbitrary and capricious agency action.

We also note a second addition under the subheading “FDA Citizen Petition Responses Not Permitting a Labeling Carve-Out.”  In May, FDA granted in part and denied in part a Citizen Petition concerning generic COLCRYS (colchicine) Tablets, which is approved under three NDAs (the parent application of which is NDA No. 022352) for the prophylaxis and treatment of gout flares in adults, and for the treatment of familial mediterranean fever in adults and children 4 years or older.  The 27-page petition response is interesting for a variety of reasons (and is a must-read for FDA’s interpretation of FDC Act § 505(b)(2) and policies concerning the granting of exclusivity), but for our purposes here, FDA appears to have determined (page 24) that certain labeling information concerning acute gout flares protected by a period of 3-year new clinical investigation exclusivity cannot be omitted from generic drug labeling.  According to FDA:

It is well-recognized that recent colchicine use (i.e., for prophylaxis of gout flares) increases the susceptibility to toxicity related to additional doses of colchicine.  To the extent that a healthcare provider determines it is necessary to use colchicine for treatment of an acute gout flare in a patient receiving colchicine for prophylaxis, adequate information about potential toxicity of colchicine dosing would be important to minimize the risk of cumulative toxicity.  Accordingly, the labeling for a single-ingredient colchicine product seeking approval for prophylaxis of gout flares should inform healthcare providers that the lower dose colchicine regimen evaluated in the AGREE trial is adequate to treat an acute gout flare that may occur during chronic colchicine use.  In addition, a Medication Guide for any subsequent colchicine product would be expected to contain information similar to the Medication Guide for Colcrys.

Below is our updated scorecard.

Generic Drug Labeling Carve-Out Citizen Petition Scorecard

FDA Citizen Petition Responses Permitting a Labeling Carve-Out

• FDA Response, Docket Nos. 2001P-0495, 2002P-0191, FDA-2002-P-0003 (June 11, 2002) – ULTRAM (tramadol HCl)
• FDA Response, Docket Nos. 2001P-0495/PRC, 2002P-0191/PRC, FDA-2002-P-0003/PRC (Mar. 31, 2003) – ULTRAM (tramadol HCl)
• FDA Response, Docket No. FDA-2003-P-0074 (Apr. 6, 2004) – REBETOL (ribavirin)
• FDA Response, Docket No. FDA-2005-P-0368 (Dec. 1, 2006) – OXANDRIN (oxandrolone)
• FDA Response, Docket No. FDA-2006-P-0274 (Mar. 13, 2008) – ETHYOL (amifostine)
• FDA Response, Docket No. FDA-2007-P-0169 (Apr. 25, 2008) – MARINOL (dronabinol)
• FDA Response, Docket No. FDA-2008-P-0304 (June 18, 2008) – ALTACE (ramipril)
• FDA Response, Docket No. FDA-2008-P-0069 (July 28, 2008) – CAMPTOSAR (irinotecan HCl)
• FDA Response, Docket No. FDA-2006-P-0073 (Nov. 18, 2008) – PULMICORT Respules (budesonide inhalation suspension)
• FDA Response, Docket Nos. FDA-2008-P-0343 & FDA-2008-P-0411 (Dec. 4, 2008) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2008-P-0343/PRC and PSA & FDA-2008-P-0411 (June 16, 2009) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2009-P-0411 – ACTOS (pioglitazone HCl) & ACTOPLUS MET (March 15, 2010) (pioglitazone HCl; metformin HCl)
• FDA Response, Docket No. FDA-2009-P-0601 (June 17, 2010) – NAROPIN (ropivacaine HCl monohydrate)
• FDA Response, Docket No. FDA-2010-P-0087 (July 30, 2010) – LYRICA (pregabalin) 
• FDA Response, Docket No. FDA-2010-P-0545 (February 24, 2011) – XYZAL (levocetirizine dihydrochloride)
• FDA Response, Docket No. FDA-2011-P-0128 (May 11, 2011) – XIBROM/BROMDAY (bromfenac)

FDA Citizen Petition Responses Not Permitting a Labeling Carve-Out

• FDA Response, Docket No. FDA-2003-P-0002 (Sept. 20, 2004) – RAPAMUNE (sirolimus)
• FDA Response, Docket No. FDA-2010-P-0614 (May 25, 2011) – COLCRYS (colchicine)

Pending Labeling Carve-Out Citizen Petitions

• Docket No. FDA-2007-P-0294 – ACTOS (pioglitazone)
• Docket No. FDA-2007-P-0113 – THALOMID (thalidomide)
• Docket No. FDA-2009-P-0581 – BAYTRIL (enrofloxacin) (Animal Drug)
• Docket No. FDA-2009-P-0597 – Fluticasone Propionate and/or Salmeterol Xinafoate Products
• Docket No. FDA-2010-P-0403 – VAGIFEM (estradiol)
• Docket No. FDA-2011-P-0482 – VAGIFEM (estradiol)
• Docket No. FDA-2011-P-0662 – SEROQUEL (quetiapine fumarate)
• Docket No. FDA-2011-P-0663 – SEROQUEL XR (quetiapine fumarate)
• Docket No. FDA-2011-P-0702 – DORYX (doxycycline hyclate)

BPCA Section 11 Pediatric Labeling Citizen Petitions

• FDA Response, Docket No. FDA-2001-P-0053 (January 24, 2002) – BPCA Implementation
• FDA Response, Docket No. FDA-2002-P-0289 (May 21, 2003) – ALPHAGAN (brimonidine)
• FDA Response, Docket No. FDA-2010-P-0545 (February 24, 2011) – XYZAL (levocetirizine dihydrochloride) 

Withdrawn or “Dead” Labeling Carve-Out Citizen Petitions

• Docket Nos. FDA-2004-P-0426 & FDA-2003-P-0081; FDA Letter – SKELAXIN (metaxalone) (see our previous post here)
• Docket No. FDA-2001-P-0445 – NEURONTIN (gabapentin) Capsules