By Kurt R. Karst –
The Major Contribution to Patient Care (“MC-to-PC”) basis for demonstrating that an orphan drug is clinical superiority, and is therefore not the “same drug” as a previously approved orphan drug containing the same active moiety, is supposed to be a pretty rare event. Though still rare, we’ve been seeing greater use of the clinical superiority argument and greater acceptance of MC-to-PC theories by FDA’s Office of Orphan Products Development. Indeed, it was just last week that we posted on one such case concerning cysteamine bitartrate (PROCYSBI) (see our previous post here). That precedent added to the three other instances of which we were aware that MC-to-PC theories were accepted by FDA (see our previous post here). Now another case has come to light.
MC-to-PC clinical superiority is one of the three bases the sponsor of an orphan drug can use to argue that the company’s drug is different from a previously approved orphan drug, thus making the company’s product eligible for orphan drug designation and orphan drug exclusivity (and, where applicable, the ability to “break” another sponsor’s unexpired orphan drug exclusivity). Specifically, FDA’s orphan drug regulations provide that a drug is “different” from an approved orphan drug if it is “clinically superior” to the approved orphan drug. A clinically superior drug is “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 population; or (3) demonstration that the drug makes a MC-to-PC.
There is only one instance where FDA found a drug to be clinically superiority based on greater effectiveness. In 2002, FDA determined that Serono’s REBIF (interferon beta-1a) (BLA No. 103780) was clinically superior to Biogen’s AVONEX (interferon beta-1a) (BLA No. 103628) for the treatment of relapsing-remitting multiple sclerosis based on data from a head-to-head clinical trial demonstrating improved efficacy of REBIF over AVONEX in the frequency of multiple sclerosis exacerbations. To support a claim of clinical superiority based on superior safety, the second product must, as discussed in the preamble to FDA’s 1992 final orphan drug regulations and in FDA’s orphan drug regulations, provide “[g]reater safety in a substantial portion of the target populations.” Even “a small demonstrated improvement in efficacy or diminution in adverse reactions may be sufficient to allow a finding of clinical superiority.” There are several (less than 10 that we know of) instances in which greater safety has been OOPD’s basis for designating and orphan drug and granting orphan drug exclusivity.
To support a MC-to-PC claim of clinical superiority, FDA has acknowledged in the Agency’s regulations that it will do so only in “unusual circumstances.” In the preamble to FDA’s final 1992 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 might constitute a “major contribution to patient care,” FDA also remarked:
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.
The latest MC-to-PC precedent concerns NYMALIZE (nimodipine) Oral Solution, 60 mg/20 mL, which FDA approved pursuant to the FDC Act’s 505(b)(2) NDA procedures on May 10, 2013 under NDA No. 203340 for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in adult patients with Subarachnoid Hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V). Previously, FDA had approved – thougth not under the FDC Act’s orphan drug provisions – another nimodipine drug product for the same use as NYMALIZE: Bayer’s NIMOTOP (nimodipine) Capsules (NDA No. 018869; approved on December 28, 1988).
The original sponsor of NYMALIZE had requested orphan drug designation, but did not provide an adequate explanation for clincal superiority, according to OOPD’s review of the orphan drug designation request. The sponsor implied that there were two advantages to an oral solution dosage form of nimodipine: an oral solution dosage form eliminates the need to extract the capsule contents with a syringe, which could reduce the incidence of accidental intravenous administration, and an oral solution would allow for more precise dosing and would provide another option for patients who may not require nasogastric administration but who have difficulty swallowing oral capsules. OOPD treated these two arguments as greater safety and MC-to-PC clinical superiority arguments, respectively.
Ultimately, OOPD consulted the FDA Review Division responsible for review of the NYMALIZE IND and NDA, and asked whether the oral solution dosage form was important, and whether it could be considered clinically superior based on safety or MC-to-PC grounds. The FDA Review Division’s response paved the way for OOPD’s designation and orphan-exclusive approval. According to the FDA Review Division:
The oral solution is a very big deal to us in the Neurology Division. It represents a major safety initiative that we have undertaken to eliminate a rare, but persistent error that may be, and has been, fatal. We feel it will provide greater safety in a substantial portion of the target population and will provide a major contribution to patient care over the currently available product. We feel the proposed oral solution represents a major advantage over the current product and anticipate withdrawing the current product from the market following approval of an oral solution.
Despite the FDA Review Division’s statement on greater safety, OOPD determined that MC-to-PC would be the basis for designation and for granting exclusivity:
In this application, while the sponsor has not provided evidence of greater effectiveness, nor has shown that the product will provide safety in a substantial portion of the target population, rationale has been provided that the oral solution formulation of nimodipine constituters a major contributiojn to patient care given the major safety initiative undertaken by FDA to eliminate this rare but persistent medication error that had resulted in patient death.
The orphan-exclusive approval of NYMALIZE is a prime example of how a sponsor can make relatively small changes to a previously approved drug, and without much investment from a non-clinical and clinical perspective, to reap significant benefits. Indeed, the NYMALIZE NDA largely relied on FDA’s previous approval of NIMOTOP for approval. According to FDA’s review documents, the NYMALIZE 505(b)(2) NDA included no clinical data and was the sponsor was granted a biowaiver. The application contained only chemistry and manufacturing controls data, as well data from short-term animal toxicity studies.