Stereoisomer Orphan Drug “Sameness” – Another Interesting Counterpoint to FDA’s First Permitted Commercial Marketing or Use PTE Determinations

By Kurt R. Karst & Frank J. Sasinowski –      

Earlier this week, we posted on a recent district court decision affirming the validity of a Patent Term Extension (“PTE”) for a patent covering an enantiomer of a previously approved racemate.  The court’s decision relied heavily on previous FDA and U.S. Patent and Trademark Office (“PTO”) PTE decisions concerning patents covering an enantiomer of a previously approved racemate.  In each case, FDA determined that the approval of the enantiomer NDA represented the first permitted commercial marketing or use of the product.  That is, FDA determined for PTE qualification purposes that a particular enantiomer drug product approval represented the first approval of that active ingredient.  We noted in the post, however, that:

Notwithstanding previous enantiomer patent PTE decisions, . . . FDA has for decades treated single enantiomers of approved racemates as previously approved drugs not eligible for five-year new chemical entity exclusivity (but eligible for three-year new clinical investigation exclusivity).  For example, FDA stated in the preamble to its 1989 proposed regulations implementing the Hatch-Waxman Amendments that “FDA will consider whether a drug contains a previously approved active moiety on a case-by-case basis.  FDA notes that a single enantiomer of a previously approved racemate contains a previously approved active moiety and is therefore not considered a new chemical entity.” 

Another part of FDA – the Office of Orphan Products Development (“OOPD”) – has weighed in (albeit informally) on the issue of the “newness” of an enantiomer in a previously approved racemate.  And that Office’s policy appears to be consistent with FDA’s enantiomer non-patent market exclusivity policy. 

FDA’s March 2008 approval of Spectrum Pharmaceuticals, Inc.’s (“Spectrum’s”) FUSILEV (levoleucovorin) and decision to grant a period of seven-year orphan drug exclusivity appears to offer some indication of a counterpoint to the Agency’s first permitted commercial marketing or use determinations for PTE purposes.  FUSILEV is comprised of the pharmacologically active enantiomer of leucovorin, which FDA initially approved as a new molecular entity in June 1952 under NDA No. 8-107. 

According to FDA’s Orphan Drug Designation and Approval List, the Agency designated and approved Spectrum’s levoleucovorin as an orphan drug on August 1, 1991 and March 7, 2008, respectively, for “use in conjunction with high-dose methotrexate in the treatment of osteosarcoma.”  (The actual approval was for “rescue after high-dose methotrexate therapy in osteosarcoma and to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.”)  These decisions were made notwithstanding FDA’s earlier designation and approval of leucovorin as an orphan drug for “rescue use after high dose methotrexate therapy in the treatment of osteosarcoma.”

Under the Orphan Drug Act (“ODA”) and FDA’s implementing regulations at 21 C.F.R. Part 316, marketing an orphan drug in the United States is a two-step process.  First, a company must obtain orphan drug designation from FDA.  In the case where a drug sponsor requests orphan drug designation for a drug that is otherwise the same drug as an approved orphan drug, and is intended for the same orphan indication as the approved orphan drug, FDA’s regulations state that the drug sponsor must include in its request for orphan drug designation “a plausible hypothesis that its drug may be clinically superior to the first drug.”  Second, a company must obtain FDA’s approval of a marketing application to market the product for the orphan condition.
  
Once FDA approves a marketing application for a designated drug, the Agency may not approve another company’s version of the “same drug” for the same disease or condition for seven years, unless the subsequent drug is different from the approved orphan drug,  or because the sponsor of the first approved product either cannot assure the availability of sufficient quantities of the drug or consents to the approval of other applications.  A drug is different from an approved orphan drug if it is either demonstrated to be chemically or structurally distinct from an approved orphan drug, or “clinically superior” to the approved orphan drug. 

The degree of chemical or structural similarity that allows FDA to determine whether two drugs are “the same” depends on whether the drugs are small molecules or macromolecules.  In the case of small molecules, “the same” means the identical chemical structure.  FDA’s orphan drug regulations define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways:
 
(1) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;
(2) greater safety in a substantial portion of the target populations; or
(3) demonstration that the drug makes a major contribution to patient care.

FDA’s decision to designate Spectrum’s levoleucovorin as an orphan drug occurred prior to the promulgation of FDA’s orphan drug regulations in December 1992, and therefore, does not provide any insight into enantiomer/racemate “sameness” orphan drug issues.  (We understand that FDA is in the process of drafting revised orphan drug regulations.)  FDA’s 2008 approval decision and grant of orphan drug exclusivity, however, could have, under certain circumstances, involved an FDA “sameness” analysis if FDA considered an enantiomer in a previously approved racemate to be the “same drug” for orphan drug purposes.  And, indeed, it is our understanding, based on informal interactions with FDA, that the Agency’s current interpretation of the ODA and its implementing regulations is that an enantiomer in a previously approved racemate that is intended for the same orphan disease or condition as the previously approved racemate is the “same drug” and that clinical superiority must be shown to obtain orphan drug exclusivity (and a plausible hypothesis of clinical superiority provided to obtain orphan drug designation).  In other words, FDA (or at least OOPD), for orphan drug purposes, apparently considers a particular enantiomer contained in a previously approved racemate the “same drug” as a previously approved drug, which triggers the need for a clinical superiority showing. 

If FDA does, in fact, consider an enantiomer contained in a previously approved racemate as the “same drug” as a previously approved drug for orphan drug purposes, then such treatment is consistent with the Agency’s treatment of an enantiomer in a previously approved racemate as a “previously approved active moiety [that is] not considered a new chemical entity” eligible for five-year exclusivity under the Hatch-Waxman Amendments.  This policy is, in turn, consistent with FDA’s Policy Statement for the Development of New Stereoisomeric Drugs, which states that most stereoisomers should “be treated as separate drugs and developed accordingly,” and that “[w]here both enantiomers are fortuitously found to carry desirable but different properties, development of a mixture of the two, not necessarily the racemate, as a fixed combination might be reasonable.”  That makes FDA’s first permitted commercial marketing or use determinations for PTE purposes an outlier.  FDA has never, to our knowledge, explained the apparent discrepancy.