Reg­u­la­to­ry in­tel­li­gence: Up­date on re­gen­er­a­tive med­i­cine ad­vanced ther­a­pies des­ig­na­tions

This ar­ti­cle dis­cuss­es the scope and pur­pose of the spe­cial des­ig­na­tion for Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­pies (RMAT) cre­at­ed by the pas­sage of the 21st Cen­tu­ry Cures Act. The au­thors ex­plain the ben­e­fits ex­pect­ed to be re­al­ized with RMAT, such as keep­ing the US glob­al­ly com­pet­i­tive in the field. They pro­vide a tal­ly of prod­ucts re­ceiv­ing the spe­cial des­ig­na­tion to date and a cur­rent count, by year, of prod­ucts for which RMAT des­ig­na­tion has been re­quest­ed.

In­tro­duc­tion

Sec­tion 3033 of the 21st Cen­tu­ry Cures Act, ti­tled “Ac­cel­er­at­ed Ap­proval for Re­gen­er­a­tive Ad­vanced Ther­a­pies,” cre­at­ed a spe­cial des­ig­na­tion for Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­pies (RMAT). A prod­uct is el­i­gi­ble for RMAT des­ig­na­tion if it is a re­gen­er­a­tive med­i­cine ther­a­py, such as cell ther­a­py, ther­a­peu­tic tis­sue en­gi­neer­ing prod­uct, hu­man cell and tis­sue prod­uct, gene ther­a­py or any com­bi­na­tion prod­uct us­ing such ther­a­pies or prod­ucts, and is in­tend­ed to treat, mod­i­fy, re­verse or cure a se­ri­ous or life-threat­en­ing dis­ease or con­di­tion and pre­lim­i­nary clin­i­cal ev­i­dence in­di­cates that the drug has the po­ten­tial to ad­dress un­met med­ical needs for such dis­ease or con­di­tion.

Oth­er na­tion­al bod­ies have in re­cent years made spe­cial reg­u­la­to­ry pro­vi­sions to rec­og­nize the val­ue of re­gen­er­a­tive med­i­cine prod­ucts. For ex­am­ple, Japan’s SAKI­GAKE des­ig­na­tion,  was in­tro­duced in 2015 to pro­mote R&D of re­gen­er­a­tive med­i­cines and oth­er in­no­vate phar­ma­ceu­ti­cals and med­ical de­vices.

RMAT des­ig­na­tion has helped keep the US com­pet­i­tive in the glob­al field, while ad­dress­ing spe­cif­ic needs and re­quire­ments of re­gen­er­a­tive med­i­cine ad­vanced ther­a­py prod­ucts. The ben­e­fits of an RMAT des­ig­na­tion are the same as the ben­e­fits for break­through ther­a­pies and in­clude in­ter­ac­tions with FDA to ex­pe­dite de­vel­op­ment and re­view of the prod­uct and con­sid­er­a­tion of the prod­uct for pri­or­i­ty re­view or ac­cel­er­at­ed ap­proval. Re­ceiv­ing RMAT des­ig­na­tion al­so al­lows for in­creased flex­i­bil­i­ty in clin­i­cal tri­al de­sign, for in­stance, in the num­ber of clin­i­cal tri­al sites. De­vel­op­ers al­so have the po­ten­tial to use pa­tient reg­istry da­ta and oth­er re­al-world sources in post-ap­proval path­ways.

While de­vel­op­ers seek­ing break­through des­ig­na­tion are re­quired to show that their ther­a­peu­tic can­di­date would pro­vide a sub­stan­tial im­prove­ment over ex­ist­ing ther­a­pies, RMAT des­ig­na­tion on­ly re­quires that the ther­a­py have the po­ten­tial to ad­dress un­met med­ical need.

With RMAT des­ig­na­tions avail­able for more than two years, what have we seen so far?

Table 1 pro­vides FDA’s lat­est tal­ly of RMAT des­ig­na­tions by year. On­ly 2018 rep­re­sents a full year. For 2019, the num­ber of re­quests is at a high­er rate (19 re­quests through 10 April 2019) but the num­ber grant­ed is about the same rate as for 2018 (about 1.5 re­quests grant­ed per month).

Table 1. Met­rics on RMAT Re­quests by Year1
Fis­cal Year To­tal Re­quests
Re­ceived
Grant­ed De­nied With­drawn
2017 31 11 18 2
2018 47 18 27 2
2019 19 4 8 1

So far, no RMAT-des­ig­nat­ed prod­ucts have re­ceived mar­ket­ing ap­proval and no RMAT des­ig­na­tions have been re­port­ed with­drawn or re­scind­ed.

Fig­ure 1 pro­vides met­rics on des­ig­na­tion re­quests by ther­a­peu­tic area as of Sep­tem­ber 2018. The largest cat­e­go­ry is neu­rol­o­gy, fol­lowed by on­col­o­gy. This is sur­pris­ing be­cause sci­en­tif­ic pub­li­ca­tions of re­gen­er­a­tive med­i­cines for on­col­o­gy far out­pace those for neu­rol­o­gy.2

Fig­ure 2 pro­vides met­rics on des­ig­na­tion re­quests by prod­uct type as of March 2019. The great­est num­ber of des­ig­na­tion re­quests have been for cell ther­a­py prod­ucts with al­lo­gene­ic prod­ucts out­pac­ing au­tol­o­gous prod­ucts.

Fig­ure 1. RMAT Des­ig­na­tion Re­quests by Ther­a­peu­tic Area3

Fig­ure 2. RMAT des­ig­na­tion re­quests by prod­uct type4


Table 2 pro­vides a list­ing of the pub­licly an­nounced RMAT des­ig­na­tions. Twen­ty-eight have been an­nounced so far. There have been 33 RMAT des­ig­na­tions grant­ed as of 1 April 2019,3 thus five are cur­rent­ly unan­nounced.

Table 2. List­ing of Pub­licly An­nounced RMAT Des­ig­na­tions
Prod­uct Name Spon­sor Date Award­ed De­scrip­tion
HU­MA­CYL  Hu­ma­cyte 20 March 2017 acel­lu­lar ves­sel for vas­cu­lar ac­cess in he­modial­y­sis pa­tients
RVT-802  En­zy­vant 17 April 2017 al­lo­gene­ic thymic tis­sue for Di­ge­orge Syn­drome
jCell  jCyte 2 May 2017 hu­man reti­nal prog­en­i­tor cells for re­tini­tis pig­men­tosa
Ixmy­lo­cel-T  Veri­cel 10 May 2017 au­tol­o­gous ex­pand­ed mul­ti­cel­lu­lar ther­a­py for heart fail­ure due to is­chemic di­lat­ed car­diomy­opa­thy
Strat­a­Graft Mallinck­rodt 18 Ju­ly 2017 tis­sue en­gi­neered full thick­ness re­gen­er­a­tive skin tis­sue for deep par­tial thick­ness burns
ATIR101  Kiadis 20 Sep­tem­ber 2017 cell ther­a­py for leukemia
Lenti­Glo­bin  Blue­bird 1 Oc­to­ber 2017 gene ther­a­py for sick­le cell dis­ease
AST-OP­CI  As­te­r­ias 2 Oc­to­ber 2017 cell ther­a­py for spinal cord in­jury
Mul­ti­Stem  Ather­sys 5 Oc­to­ber 2017 cell ther­a­py is­chemic stroke
JCAR017  Juno (Cel­gene) 1 No­vem­ber 2017 car-t ther­a­py for re­lapsed or re­frac­to­ry dif­fuse large b-cell lym­phoma
CE­VA101  Cel­l­va­tion (Fortress Biotech) 8 No­vem­ber 2017 cell ther­a­py for trau­mat­ic brain in­jury
MPC-150-IM 
Revas­cor
Mesoblast 21 De­cem­ber 2017 mes­enchy­mal pre­cur­sor cell ther­a­py for heart fail­ure
EB-101  Abeona 29 Jan­u­ary 2018 gene ther­a­py for re­ces­sive dy­s­troph­ic epi­der­mol­y­sis bul­losa
CAP-1002  Capri­cor 5 Feb­ru­ary 2018 cell ther­a­py for duchenne mus­cu­lar dy­s­tro­phy
Am­nioFix  MiMedx 9 March 2018 tis­sue en­gi­neered al­lo­gene­ic mi­cronized de­hy­drat­ed hu­man am­nion/chori­on mem­brane for os­teoarthri­tis of the knee
ABO-102  Abeona 23 April 2018 gene ther­a­py for San­fil­ip­po Syn­drome type a
VM202 Vi­roMed May 2018 gene ther­a­py for painful di­a­bet­ic pe­riph­er­al neu­ropa­thy
NSR-REP1  Night­star Ther­a­peu­tics 14 June 2018 gene ther­a­py for choroi­dere­ma
CLBS14-NOR­DA  Cal­adrius Bio­sciences 19 June 2018 No-Op­tion Re­frac­to­ry Dis­abling Angi­na (NOR­DA)
VY-AADC  Voy­ager 21 June 2018 gene ther­a­py for Parkin­son’s dis­ease
Romye­lo­cel-L  Celler­ant 2 Ju­ly 2018 cell ther­a­py for pre­ven­tion of in­fec­tions dur­ing neu­trope­nia
AT132 Au­dentes Ther­a­peu­tics 21 Au­gust 2018 gene ther­a­py for X-linked my­otubu­lar my­opa­thy
Avance Ax­o­Gen 29 Oc­to­ber 2018 tis­sue en­gi­neered nerve graft for pe­riph­er­al nerve re­pair
P-BC­MA-101 Po­sei­da Ther­a­peu­tics No­vem­ber 5, 2018 gene mod­i­fied CAR-T cell ther­a­py for re­lapsed/re­frac­to­ry mul­ti­ple myelo­ma
Li­fileu­cel Io­vance Bio­ther­a­peu­tics 6 No­vem­ber 2018 adop­tive gene-mod­i­fied cell ther­a­py for metasta­t­ic melanoma
RP-L102 Rock­et Phar­ma­ceu­ti­cals 27 No­vem­ber 2018 lentivi­ral vec­tor-based gene ther­a­py for Fan­coni ane­mia
FCR001 Ta­laris Ther­a­peu­tics (Re­generex) 18 April 2019 al­lo­gene­ic cell ther­a­py for im­mune tol­er­ance in kid­ney trans­plant
ECT-001 Ex­CellThera 23 April 2019 mul­ti­ple myelo­ma, high-risk leukemia, and oth­er hema­to­log­ic ma­lig­nan­cies

In the fol­low­ing month, the Al­liance for Re­gen­er­a­tive Med­i­cine plans to launch a data­base uti­liz­ing pub­licly avail­able and com­pa­ny-pro­vid­ed in­for­ma­tion to cre­ate a pub­lic list of RMAT re­cip­i­ents, as well as oth­er ex­pe­dit­ed ap­proval des­ig­na­tions award­ed in the Unit­ed States, Eu­rope, and Japan.

Clear­ly, the RMAT des­ig­na­tion pro­gram has been very ac­tive for FDA and pop­u­lar for spon­sors. We look for­ward to see­ing the first prod­ucts ap­proved un­der this pro­gram.

Ref­er­ences

  1. Cu­mu­la­tive CBER Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­py (RMAT) Des­ig­na­tion Re­quests Re­ceived by Fis­cal Year. FDA web­site. https://www.fda.gov/vac­cines-blood-bi­o­log­ics/cel­lu­lar-gene-ther­a­py-prod­ucts/cu­mu­la­tive-cber-re­gen­er­a­tive-med­i­cine-ad­vanced-ther­a­py-rmat-des­ig­na­tion-re­quests-re­ceived-fis­cal. Ac­cessed 6 May 2019.
  2. Based on PubMed search com­par­ing “re­gen­er­a­tive med­i­cine on­col­o­gy” to “re­gen­er­a­tive med­i­cine neu­rol­o­gy” or “cell gene ther­a­py neu­rol­o­gy” to “cell gene ther­a­py on­col­o­gy,” 3 May 2019.
  3. Bryan WW. “Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­py (RMAT) Des­ig­na­tion.” Amer­i­can So­ci­ety of Gene and Cell Ther­a­py. Li­ai­son Meet­ing. 13 Sep­tem­ber 2018.
  4. From Wil­son Bryan pre­sen­ta­tion to the Al­liance for Re­gen­er­a­tive Med­i­cine Li­ai­son Meet­ing on 28 March 2019.

Janet Lynch Lam­bert joined the Al­liance for Re­gen­er­a­tive Med­i­cine (ARM) in 2017 as the or­ga­ni­za­tion’s first CEO. She most re­cent­ly served as the act­ing head of en­gage­ment for the All of Us Re­search Pro­gram at the Na­tion­al In­sti­tutes of Health and as head of the Out­reach Of­fice in the Of­fice of the NIH Di­rec­tor. Pri­or to join­ing NIH, she was vice pres­i­dent of gov­ern­ment re­la­tions and head of the Wash­ing­ton of­fice of Life Tech­nolo­gies.

William Si­et­se­ma is vice pres­i­dent, glob­al reg­u­la­to­ry af­fairs at Cal­adrius Bio­sciences, a com­pa­ny that fo­cus­es on in­no­v­a­tive cell ther­a­pies for dif­fi­cult-to-treat dis­eases. Pri­or to Cal­adrius, he was glob­al reg­u­la­to­ry lead at Am­gen and vice pres­i­dent, glob­al reg­u­la­to­ry con­sult­ing and sub­mis­sions at Kendle In­ter­na­tion­al/INC Re­search and ad­junct pro­fes­sor of phar­ma­ceu­ti­cal sci­ences at the Uni­ver­si­ty of Cincin­nati, Col­lege of Phar­ma­cy. He may be con­tact­ed at william@si­et­se­ma.com.


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.

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