The Unusual Case of the “MC-to-PC” Orphan Drug Designation/Approval

By Kurt R. Karst –      

FDA’s recent approval of Antisoma Research Limited’s orphan drug, oral fludarabine phosphate, with 7 years of orphan drug exclusivity for the treatment of certain adult patients with B-cell chronic lymphocytic leukemia got us thinking about the unusual case of the major contribution to patient care – the so-called “MC-to-PC” – orphan drug designation and approval. 

The FDC Act (§ 527) provides a 7-year period of exclusive marketing to the first sponsor who obtains marketing approval for a designated orphan drug.  The scope of orphan drug exclusivity is broad; it prevents FDA approval of ANDAs, “full” 505(b)(1) NDAs, and 505(b)(2) applications.  Orphan drug exclusivity begins on the date that a marketing application is first approved for the designated orphan drug. 

Once FDA approves a marketing application for a designated drug, the Agency may not approve another firm’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.  (FDA may, however, approve a second application for the same drug for a different use.)  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. 

FDA’s orphan drug regulations (21 C.F.R. Part 316) 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:

(a) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;
(b) greater safety in a substantial portion of the target population; or
(c) demonstration that the drug makes a major contribution to patient care.

To support a claim of “clinical superiority” based on a demonstration of a major contribution to patient care, FDA has acknowledged that it will do so only in “unusual circumstances.”  In the preamble to FDA’s final orphan drug regulations, the Agency commented that:

convenient treatment location; duration of treatment; patient comfort; improvements in drug efficiency; advances in the ease and comfort of drug administration; longer periods between doses; and potential for self administration . . . when applicable to severe or life threatening diseases, might sometimes be legitimately considered to bear on whether a drug makes a major contribution to patient care.  However, this determination will have to be made on a case-by-case basis. 

As to how much superiority could constitute a “major contribution to patient care,” FDA also remarked that:

There is no way to quantify such superiority in a general way.  The amount and kind of superiority needed would vary depending on many factors, including the nature and severity of the disease or condition, the quality of the evidence presented, and diverse other factors. . .  While comparative trials are, of course, preferred and will usually be required, it is possible that, in some circumstances, a demonstration of a major contribution to patient care can be made without such trials. 

Other than the recent oral fludarabine phosphate designation and approval (see FDA’s orphan drug designation list here, which identifies the oral fludarabine phosphate designation as a MC-to-PC precedent based on a change from an intravenous to oral dosage form), we are aware of only two instances in which FDA has designated and approved an orphan drug based on a MC-to-PC demonstration: 

• In 1998, FDA determined that Novartis’ reformulated SANDOSTATIN LAR (octreotide) was “clinically superior” to a previously approved subcuteaneous dosage form of SANDOSTATIN, because “patients can be managed with one injection per month instead of sixty to ninety injections.”  
• In 2007, FDA determined that Indevus’ histrelin acetate implant drug product, SUPPRELIN LA, was “clinically superior” to SUPPRELIN on the basis that “a single histrelin subcutaneous implant could provide therapeutic blood levels for a period of 1 year versus 365 daily injections of Supprelin.” 

A MC-to-PC counter-precedent is found in Fisons’ attempt to obtain FDA approval for PNEUMOPENT (pentamidine isethionate).  On June 15, 1989 (before FDA’s orphan drug regulations were proposed), FDA approved American Pharmaceutical Partners’ aerosolized NEBUPENT (pentamidine isethionate) for primary and secondary prophylaxis of Pneumocystis Carnii Pneumonia (“PCP”).  NEBUPENT was approved for administration (300mg once every four weeks) through a nebulizer using compressed air by trained medical personnel.  Fisons subsequently sought FDA approval for PNEUMOPENT, also an aerosolized pentamidine product for the prevention of PCP.  However, PNEUMOPENT could be self-administered through a small ultrasonic nebulizer.  Fisons (and several AIDS groups) urged FDA to approve PNEUMOPENT despite NEBUPENT’s orphan drug exclusivity, arguing that PNEUMOPENT made a “major contribution to patient care” because: (1) PNEUMOPENT could be self administered at home whereas NEBUPENT required administration in an institutional setting; (2) PNEUMOPENT required about half the time per treatment as NEBUPENT; and (3) Fisons developed a unit-dose ampule for PNEUMOPENT that avoided the use of a syringe and sterile water to reconstitute NEBUPENT.  FDA reportedly did not accept that these differences established a sufficient MC-to-PC rationale.