A 505(b)(2) NDA in Search of a Basis for Submission and Approval; the Curious Case of Morphine Sulfate Oral Solution

By Kurt R. Karst –      

We’re always interested in cases where things, at first glance, just don’t seem to add up.  If we cannot find an explanation, we may put the case to the side for a while, and wait until an explanation becomes available.  That’s what happened when we saw the June 23, 2011 approval letter for Lannett Holdings, Inc.’s (“Lannett’s”) NDA No. 201517 for Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL), which was submitted pursuant to FDC Act § 505(b)(2).  The approval letter states that the NDA, dated February 26, 2010, was  received by (i.e., submitted to) FDA on March 1, 2010.  Shortly before FDA received Lannett’s NDA submission, the Agency, on January 25, 2010, approved a supplement to Roxane Laboratories, Inc.’s (“Roxane’s”) NDA No. 022195 (also submitted as a 505(b)(2) application) for Morphine Sulfate Oral Solution.  With that supplement, FDA approved a new strength: 100 mg per 5 mL (20 mg per mL).  What perplexed us is how FDA was able to accept Lannett’s application as a 505(b)(2) NDA in light of the Agency’s prior approval of the same drug product.  (Both drug products are approved for the same use: for the management of moderate to severe acute and chronic pain in opioid-tolerant patients.)  In other words, why didn’t FDA refuse to accept Lannett’s 505(b)(2) application and instead require that the application be submitted as an ANDA?

The premise of FDC Act § 505(j) is that an ANDA drug is a duplicate of the brand name drug (i.e., the Reference Listed Drug (“RLD”)).  Draft FDA guidance generally defines the term “duplicate” to mean:

drug products that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients, and that meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity disintegration times and/or dissolution rates. 

Elsewhere, FDA has stated that the word “duplicate” means “a product that is the same as the listed drug with respect to active ingredient, dosage form, route of administration, strength, and conditions of use, among other characteristics.”

FDA’s regulation at 21 C.F.R. § 314.101(d)(9) states that “FDA may refuse to file an application if . . . . [t]he application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the act.”  21 C.F.R. § 314.101(d)(9).  FDA explained how the Agency interprets this regulation in a June 2004 response to a citizen petition (Docket No. FDA-2003-P-0338).  In that case, which concerned a then-pending 505(b)(2) application for Loratadine Tablets, 10 mg, FDA determined that an intervening NDA approval for the same drug product does not bar the Agency from approving a pending 505(b)(2) application.  Specifically, FDA ruled that 21 C.F.R. § 314.101(d)(9) “bars 505(b)(2) applications for products eligible for approval under section 505(j) of the Act only if the product described in a 505(b)(2) application may be approved via section 505(j) at the time of the application’s submission” (emphasis added).  A 505(b)(2) application submitted to FDA before the approval of another NDA – an intervening NDA – that would otherwise render the 505(b)(2) application drug product a duplicate of an approved drug is, according to FDA, unaffected by the intervening NDA approval. 

More recently, FDA discussed the Agency’s intervening NDA approval policy as part of a May 17, 2012 decision granting a citizen petition to designate VELTIN (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025% (NDA No. 050803) as a second RLD in the Orange Book.  A comment submitted to FDA contended, among other things, that VELTIN could have been submitted via an ANDA given the intervening approval of NDA No. 050802 for ZIANA (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025%.  According to FDA, however:

Because there were no pharmaceutically equivalent products approved at the time that Veltin was submitted, it would not have been appropriate for the Veltin application to be submitted as a 505(j) application.  Although we approved the Ziana NDA while the Veltin application was under review, our policy is that we do not require applicants to withdraw and resubmit applications if another pharmaceutically equivalent drug product is subsequently approved.  Therefore, the 505(b)(2) NDA was an appropriate pathway for Veltin’s application.

(It should be noted that under somewhat analogous circumstances, FDA has decided – Docket No. FDA-2008-P-0329 – that the intervening approval of an NDA after the submission of an ANDA made pursuant to an approved suitability petition, and where the NDA approval renders the pending ANDA a duplicate of an approved drug, requires the generic applicant to submit a new ANDA citing the newly approved NDA drug product as the RLD.)

Given FDA’s regulation at 21 C.F.R. § 314.101(d)(9), we were hard pressed to come up with a simple explanation as to how FDA could have accepted Lannett’s application for Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL), as a 505(b)(2) NDA given the previous approval of the same drug product under NDA No. 022195.  After all, FDA’s intervening NDA approval policy interpreting 21 C.F.R. § 314.101(d)(9) did not seem to fit the facts here.  Then, when FDA recently made available the Summary Basis of Approval for NDA No. 201517, an explanation was provided.  According to FDA’s Summary Review: 

The question of evaluating this application as a 505(b)(2) as opposed to an ANDA has been discussed.  The concentration of sorbitol contained in Lannett’s morphine sulfate 100 mg per 5 mL (20 mg per mL) product is high enough that there is a theoretical possibility that doses of morphine sulfate oral solution at or in excess of 300 mg total dose may result in a different relative morphine exposure than doses below 300 mg.  The potential effect of sorbitol on morphine sulfate absorption is based on the effects of sorbitol concentration on ranitidine, a [Biopharmaceutics Classification System (“BCS”)[ class 3 drug.  However, the BCS classification of morphine sulfate oral solution is not clear, and therefore, it is not clear if this concern is relevant for morphine sulfate.

One approach to determining whether there is an effect of the sorbitol concentration on the absorption of morphine would be to perform a pharmacokinetic [sic]. Performing such a study with a dose of 300 mg of immediate-release morphine, even with naltrexone blockade, poses an unacceptable level of risk for opioid toxicity.  Therefore, given that such a study is impracticable, at this time we do not believe that bioequivalence can be effectively investigated, nor can Lannett’s product be AB rated to Roxane’s morphine sulfate oral solution 100 mg per 5 mL (20 mg per mL).  Additionally, because such a bioequivalence study cannot be performed, this product is not appropriate as an ANDA; approval requires a clinical judgment on whether this drug is safe and effective for use.

Quite an interesting theory.  And FDA’s Summary Review for NDA No. 201517 appears to be the only documentation of this theory. 

Just as interesting is the history of Lannett’s efforts to market its Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL), drug product without NDA approval.  As we previously reported, Lannett (along with Cody Laboratories, Inc.) sued FDA in July 2010 concerning the alleged grandfather status of Cody/Lannett’s marketed unapproved Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL).  The lawsuit stems from FDA’s March 2009 Warning Letters to Cody and Lannett (among other companies) to stop manufacturing certain unapproved narcotic drugs, including morphine sulfate oral solutions. 

Cody/Lannett raised three issues in the litigation: (1) FDA’s alleged determination that Cody/Lannett’s product is a “new drug;” (2) FDA’s alleged failure to develop an administrative record for its determination that Cody/Lannett’s Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL), product is a “new drug;” and (3) FDA’s alleged disparate treatment of Cody/Lannett’s standard review NDA compared to Roxane’s priority review NDA.  Ultimately, the U.S. Court of Appeals for the Tenth Circuit affirmed a November 2010 decision from the U.S. District Court for the District of Wyoming granting FDA’s Motion to Dismiss the case.  The Tenth Circuit also dismissed as moot Cody/Lannett’s claim of disparate treatment at FDA concerning the same drug submitted under an NDA.  One has to wonder whether or not there is any relationship between FDA’s decision discussed above concerning the basis for submission and approval of NDA No. 201517 and the litigation. 

Following that court battle, and perhaps in an effort to obtain final agency action to file a new lawsuit, Lannett petitioned FDA (Docket No. FDA-2012-P-0053), requesting that the Agency affirm, pursuant to the 1938 “grandfather clause” of the FDC Act, the grandfather status of morphine sulfate (see our previous post here).  Another Lannett petition (Docket No. FDA-2012-P-0189), seeks a similar determination with respect to certain Oxycodone HCl and Cocaine HCl drug products.  Both petitions are pending at FDA.