Orphan Drug Clinical Superiority: An Overview of Precedents Shows that MC-to-PC Clinical Superiority is Not so Unusual

By Kurt R. Karst –

For several years now we have been following instances in which FDA designated, and later approved, a drug (including a biological product) as an “orphan drug” on the basis that it is not the “same drug” as a previously approved product containing the same active moiety (or, in the case of macromolecules, containing the same principal molecular structural features) for the same orphan condition because the subsequent product is “clinically superior” to the prior product.  In those instances, the subsequent product can be approved notwithstanding an unexpired period of 7-year orphan drug exclusivity for another product that is otherwise the same orphan drug, and/or the subsequent product can earn a period of orphan drug exclusivity. 

Unfortunately, there is no FDA database that compiles the various drug products approved on the basis of a clinical superiority determination. FDA’s Orphan Drug Designations and Approvals Database, although it sometimes provides a hint as to whether or not a product was designated or approved on some clinical superiority basis, is generally opaque on the issue.  That means to find precedents folks generally have to sift through approval documents, submit FOIA requests to FDA, or otherwise look for “magic language” in company press releases announcing FDA’s grant of an orphan drug designation (or orphan drug approval).

We’ve tried to lift the veil of darkness by posting on clinical superiority precedents as we come across them, for example, here, here, here, and here.  With our recent discovery of yet another clinical superiority precedent – yet again involving the so-called Major Contribution to Patient Care (“MC-to-PC”) basis for demonstrating that an orphan drug is clinical superiority to another drug that is otherwise the same drug – we thought it was high time to put together a list of precedents.  But before we get to that list and the precedent we recently found, some background is in order, particularly for those folks new to the orphan drug space. . . .

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:

(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 major contribution to patient care.

To support a claim of “clinical superiority” based on greater effectiveness, generally the same kind of evidence is needed as that required to support a comparative effectiveness claim for two different drugs. That is, the second drug must demonstrate an improvement as assessed by “effect on a clinically meaningful endpoint in adequate and well-controlled clinical trials.”  FDA’s regulations also provide that, “in most cases, direct comparative clinical trials would be necessary” to demonstrate greater effectiveness. 

To support a claim of “clinical superiority” based on superior safety, the second product must provide “[g]reater safety in a substantial portion of the target populations, for example, by the elimination of an ingredient or contaminant that is associated with relatively frequent adverse effects.” FDA’s regulations also state that “[i]n some cases, direct comparative clinical trials will be necessary.”

With respect to a MC-to-PC “clinical superiority” claim, FDA states in the Agency’s regulations that it make such determinations only in “unusual circumstances.” While MC-to-PC determinations are made on a case-by-case basis, 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.”

Although MC-to-PC clinical superiority decisions are supposed to be unusual, of the three clinical superiority bases FDA lays out in the Agency’s orphan drug regulations, it appears that it is the most common basis accepted by FDA’s Office of Orphan Products Development (“OOPD”) (at least in recent years). A precedent that recently came to our attention involves Sotalol Hydrochloride Injection, which FDA approved on July 2, 2009 under NDA 022306 for use as a substitute for oral sotalol in patients who are unable to take sotalol orally.  (Oral sotalol is indicated for maintenance of normal sinus rhythm in patients with history of highly symptomatic atrial fibrillation/flutter, and for treatment of documented life-threatening ventricular arrhythmias.)  The approved indication really says it all insofar as FDA’s clinical superiority basis is concerned; however, additional detail on the determination is provided in OOPD’s Orphan Drug Designation Review Memorandum.

Precedents for each of the three clinical superiority bases are grouped below. Each precedent concerns an approved product for which clinical superiority was determined by FDA to be necessary to break another sponsor’s orphan drug exclusivity, and/or for a sponsor to qualify for orphan drug exclusivity.  Other clinical superiority precedents exist, but they have either not yet come to fruition (e.g., because a product was merely designated based on a plausible hypothesis of clinical superiority and the product has not progressed to the FDA approval stage where FDA has to more closely examine the issue of clinical superiority), or a company’s bid for orphan drug exclusivity was unsuccessful (e.g., because the product for which designation was granted based on a plausible hypothesis of clinical superiority was approved for a use broader than the designated use, or because the sponsor failed to demonstrate clinical superiority . . . an issue that has been litigated in recent years – see here).  For example, we understand that EPANED (enalapril) for Oral Solution (NDA 204308), although designated for the treatment of hypertension in pediatric patients, failed to demonstrate clinical superiority; and SOTOLYZE (sotalol hydrochloride) Oral Solution (NDA 205108) was approved for a use broader than the orphan drug-designated use: for the treatment of documented life-threatening ventricular arrhythmias and the maintenance of normal sinus rhythm in pediatric and adults patients with history of highly symptomatic atrial fibrillation/flutter.  To the extent FDA Law Blog readers are aware of additional clinical superiority approval precedents, we’re all ears.

Greater Effectiveness Clinical Superiority Determinations

• In 2002, FDA determined (here and here) that Serono’s REBIF (interferon beta-1a) (BLA 103780) was “clinically superior” to Biogen’s AVONEX (interferon beta-1a) (BLA 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.  The effect of FDA’s approval of REBIF is that it broke AVONEX’s orphan drug exclusivity with respect to the marketing of REBIF only. 

Greater Safety Clinical Superiority Determinations

• In 1992, FDA determined that Armour’s MONONINE (coagulation factor IX) (BLA 103597) was clinically superior to Alpha Therapeutic’s ALPHANINE (coagulation factor IX) (BLA 103249).  This determination was based on manufacturing data in the MONONINE BLA that allowed FDA to conclude that the viral inactivation process used in manufacturing MONONINE “may result in a product less likely to transmit hepatitis C infection than . . . AlphaNine,” and further, that the prospect of improved viral safety allowed FDA to conclude that MONONINE was “probably a safer drug,” and thus approval of MONONINE was not blocked by ALPHANINE’s orphan drug exclusivity. 
• In 1996, FDA determined that Biogen’s AVONEX (interferon beta-1a) (BLA 103628) was clinically superior to Berlex’s BETASERON (interferon beta-1b) (BLA 103471) based on a reduced risk in AVONEX of one adverse event (injection site necrosis) associated with BETASERON.  FDA made its clinical superiority determination by comparing the labeled reports for BETASERON versus the injection site reaction attack rate and severity in the AVONEX pivotal study. 
• In 1997, FDA determined that Genetics Institute’s BENEFIX (coagulation factor IX) (BLA 103677) was clinically superior to MONONINE and ALPHANINE based on the fact that “BeneFix™ is inherently less likely to transmit human blood-born viruses and other infectious agents, and is also less likely to transmit animal-derived zoonotic agents.” 
• In 1997, FDA determined that Fujisawa’s AMBISOME (amphotericin B) (NDA 050740) was clinically superior to Enzon’s ABELCET (amphotericin B) (NDA 050724) based on the fact that “AmBisome appears to have a reduced frequency of the typical amphotericin B infusion reactions as compared to Abelcet, particularly with respect to hypotension and tachycardia, dyspnea, hypoxia or ‘severe asthma.’” 
• In 2010, FDA determined that United Therapeutics Corp.’s TYVASO (treprostinil) Solution for Inhalation (NDA 022387) was clinically superior to the company’s REMODULIN (treprostinil) Injection (NDA 021272), thus granting the company a second period of ODE for a second generation drug product.  Specifically, FDA determined that TYVASO, as an inhaled prostacyclin analogue, represents an important safety gain compared to prostacyclin analogues that had to be given subcutaneously or via a central venous line.  The widespread and severe nature of the pain associated with subcutaneous treprostinil and the risks of sepsis and death from the intravenous administration of treprostinil via indwelling venous catheter made the inhaled product clinically superior. 

MC-to-PC Clinical Superiority Determinations

• In 1998, FDA determined that Novartis’ reformulated SANDOSTATIN LAR (octreotide) (NDA 021008) was clinically superior to a previously approved subcutaneous dosage form of SANDOSTATIN (NDA 019667), because “patients can be managed with one injection per month instead of sixty to ninety injections.” 
• In 2007, FDA determined that Indevus’s histrelin acetate implant drug product, SUPPRELIN LA (NDA 022058), was clinically superior to SUPPRELIN (NDA 019836) 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.” 
• In 2008, FDA determined that Antisoma’s Fludarabine Phosphate 10 mg Tablets for Oral Use (NDA 022273) was clinically superior to FLUDARA (fludarabine phosphate) for Injection (NDA 020038) because of a change in dosage form from injection to oral (a change identified by FDA as constituting a major contribution in the preamble to the Agency’s orphan drug regulations).
• In 2009, FDA determined that Academic Pharmaceuticals’s Sotalol Hydrochloride Injection (NDA 022306) was clinically superior to BETAPACE (sotalol HCl) Tablets (NDA 021151 and NDA 019865) because of a change in dosage form from oral to injectable and for patients unable to use the oral dosage form of the drug (e.g., because of surgery, intubation, acute illness, etc.).
• In 2011, FDA determined that Arbor's NYMALIZE (nimodipine) Oral Solution, 60 mg/20 mL (NDA 203340), was clinically superior to Bayer’s NIMOTOP (nimodipine) Capsules (NDA 018869) on the basis that the oral formulation “represents a major safety initiative that [FDA has] undertaken to eliminate a rare, but persistent error that may be, and has been, fatal.”  Specifically, it addressed the concern arising from health care providers extracting the capsule contents with a syringe and administering it intravenously. 
• In 2013, FDA determined that Raptor’s PROCYSBI (cysteamine bitartrate) Delayed-release Capsules (NDA 203389) was clinically superior to Mylan’s CYSTAGON (cysteamine bitartrate) Capsules (NDA 020392) based on a new dosing regimen.  According to FDA, “[s]ince it is recognized that cysteamine must be dosed at a strict q6h regimen to achieve its maximum benefit in cystinosis patients and that it is documented that many patients with cystinosis are unable to follow a strict q6h regimen throughout their lifetime, a q12h cysteamine product that can maintain cystine at the [white blood cell] levels to achieve maximum benefit can provide a MC to PC over a q6h cysteamine product.” 
• In 2015, FDA determined that Eagle’s RYANODEX (dantrolene sodium) for Injectable Suspension (NDA 205579) was clinically superior to DANTRIUM IV (dantrolene sodium for injection) (NDA 018264) on the basis that “the ability of the anesthesiologist to reconstitute and administer Ryanodex within one minute allowed the anesthesiologist to concentrate on continued supportive care and treatment of the patient with malignant hyperthermia compared to treatment with the previously approved dantrolene product that required up to one hour to reconstitute and administer, which would not allow the anesthesiologist to fully concentrate on the other aspects of treatment and support of the patient.” 

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