‘Clin­i­cal su­pe­ri­or­i­ty’: di­azepam nasal spray il­lus­trates FDA pa­ra­me­ters for or­phan drug ex­clu­siv­i­ty

Thanks to the last user fee agree­ment, known as the FDA Reau­tho­riza­tion Act of 2017, the agency can now ex­plain why a new­ly ap­proved or­phan drug is clin­i­cal­ly su­pe­ri­or to pre­vi­ous­ly ap­proved or­phan drugs and there­fore should be award­ed sev­en years of or­phan drug ex­clu­siv­i­ty.

Since 2017, the FDA has on­ly ex­plained how five treat­ments can be con­sid­ered clin­i­cal­ly su­pe­ri­or, with the lat­est com­ing last Fri­day for Neurelis Phar­ma­ceu­ti­cals’ Val­to­co (di­azepam nasal spray). The FDA ex­plains how di­azepam was pre­vi­ous­ly ap­proved as a gel ad­min­is­tered rec­tal­ly where­as Val­to­co’s in­tranasal route of ad­min­is­tra­tion is eas­i­er to use.

“In the con­text of when this drug is to be giv­en, typ­i­cal­ly in the mid­dle of a seizure event, it is in­her­ent­ly eas­i­er to ad­min­is­ter the drug to a pa­tient in­tranasal­ly than rec­tal­ly,” the FDA said.

The four oth­er drugs to ob­tain such clin­i­cal su­pe­ri­or­i­ty find­ings and win the or­phan ex­clu­siv­i­ty from the FDA since 2017 in­clude:

  • Pfiz­er’s My­lotarg (gem­tuzum­ab ozogam­icin) in Sep­tem­ber 2017, af­ter it was ini­tial­ly with­drawn from the mar­ket fol­low­ing an ac­cel­er­at­ed ap­proval in 2000, but was ap­proved lat­er for a low­er dose and dif­fer­ent sched­ule that was found to have less ear­ly mor­tal­i­ty, less he­pa­to­tox­i­c­i­ty, less veno-oc­clu­sive dis­ease, more rapid platelet re­cov­ery and less he­m­or­rhage, the FDA said.
  • CSL Behring’s Hizen­tra (Im­mune Glob­u­lin Sub­cu­ta­neous (Hu­man), 20% Liq­uid) in March 2018 be­cause the pre­vi­ous­ly ap­proved in­tra­venous for­mu­la­tion re­quires a cen­tral ve­nous ac­cess de­vice, which is as­so­ci­at­ed with an in­creased risk of throm­boem­bol­ic events and ac­cess-as­so­ci­at­ed in­fec­tions.
  • Astel­las Phar­ma’s Pro­graf (tacrolimus gran­ules for oral sus­pen­sion) in May 2018 be­cause “tacrolimus gran­ules for oral sus­pen­sion pro­vides an age ap­pro­pri­ate for­mu­la­tion for pe­di­atric pa­tients that avoids the se­vere risks as­so­ci­at­ed with er­ro­neous­ly com­pound­ed tacrolimus,” the FDA said.
  • No­var­tis’ Sig­ni­for LAR (pasireotide) in June 2018 for the treat­ment of Cush­ing’s dis­ease be­cause FDA said the dos­ing reg­i­men of the long-act­ing re­lease (once month­ly) pro­vides a ma­jor con­tri­bu­tion to pa­tient care over the dos­ing reg­i­men of the pre­vi­ous, im­me­di­ate re­lease (twice-dai­ly) ver­sion.

Mov­ing for­ward, drug de­vel­op­ers look­ing to ob­tain this “clin­i­cal­ly su­pe­ri­or” tag for their or­phan prod­ucts should look to 21 CFR 316.3(b)(3), which de­fines how a drug can pro­vide a sig­nif­i­cant ther­a­peu­tic ad­van­tage over an al­ready ap­proved drug (that is oth­er­wise the same drug) in one or more of the fol­low­ing three ways:

“(i) Greater ef­fec­tive­ness than an ap­proved drug (as as­sessed by ef­fect on a clin­i­cal­ly mean­ing­ful end­point in ad­e­quate and well con­trolled clin­i­cal tri­als). Gen­er­al­ly, this would rep­re­sent the same kind of ev­i­dence need­ed to sup­port a com­par­a­tive ef­fec­tive­ness claim for two dif­fer­ent drugs; in most cas­es, di­rect com­par­a­tive clin­i­cal tri­als would be nec­es­sary; or

(ii) Greater 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. In some cas­es, di­rect com­par­a­tive clin­i­cal tri­als will be nec­es­sary; or

(iii) In un­usu­al cas­es, where nei­ther greater safe­ty nor greater ef­fec­tive­ness has been shown, a demon­stra­tion that the drug oth­er­wise makes a ma­jor con­tri­bu­tion to pa­tient care.”

For more on the de­ter­mi­na­tions, the FDA pub­lish­es sum­maries of the clin­i­cal su­pe­ri­or­i­ty find­ings when a drug is el­i­gi­ble for or­phan drug ex­clu­siv­i­ty. The FDA Law Blog al­so of­fers more in­for­ma­tion on some of the su­pe­ri­or­i­ty de­ter­mi­na­tions be­fore 2017.

RAPS: First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.


Zachary Brennan

managing editor, RAPS

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