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.

A New Fron­tier: The In­ner Ear

What happens when a successful biotech venture capitalist is unexpectedly diagnosed with a chronic, life-disrupting vertigo disorder? Innovation in neurotology.

That venture capitalist was Jay Lichter, Ph.D., and after learning there was no FDA-approved drug treatment for his condition, Ménière’s disease, he decided to create a company to bring drug development to neurotology. Otonomy was founded in 2008 and is dedicated to finding new drug treatments for the hugely underserved community living with balance and hearing disorders. Helping patients like Jay has been the driving force behind Otonomy, a company heading into a transformative 2020 with three clinical trial readouts: Phase 3 in Ménière’s disease, Phase 2 in tinnitus, and Phase 1/2 in hearing loss. These catalysts, together with others in the field, highlight the emerging opportunity in neurotology.
Otonomy is leading the way in neurotology
Neurotology, or the treatment of inner ear neurological disorders, is a large and untapped market for drug developers: one in eight individuals in the U.S. have moderate-to-severe hearing loss, tinnitus or vertigo disorders such as Ménière’s disease.1 With no FDA-approved drug treatments available for these conditions, the burden on patients—including social anxiety, lower quality of life, reduced work productivity, and higher rates of depression—can be significant.2, 3, 4

Joe Jimenez, Getty

Ex-No­var­tis CEO Joe Jimenez is tak­ing an­oth­er crack at open­ing a new chap­ter in his ca­reer — and that in­cludes a new board seat and a $250M start­up

Joe Jimenez is back.

The ex-CEO of Novartis has taken a board seat on Century Therapeutics, the Versant and Bayer-backed startup focused on coming up with a brand new twist on cell therapies for cancer — a field where Jimenez made his mark backing the first personalized CAR-T approved for use.

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Can we make the an­tibi­ot­ic mar­ket great again?

The standard for-profit model in drug development is straightforward. Spend millions, even billions, to develop a medicine from scratch. The return on investment (and ideally a tidy profit) comes via volume and/or price, depending on the disease. But the string of big pharma exits and slew of biotech bankruptcies indicate that the model is sorely flawed when it comes to antibiotics.

The industry players contributing to the arsenal of antimicrobials are fast dwindling, and the pipeline for new antibiotics is embarrassingly sparse, the WHO has warned. Drugmakers are enticed by greener pastures, compared to the long, arduous and expensive path to antibiotic approval that offers little financial gain as treatments are typically priced cheaply, and often lose potency over time as microbes grow resistant to them.

Stephen Hahn, AP

The FDA un­veils a new reg­u­la­to­ry frame­work to speed along gene ther­a­pies, re­ward­ing the lead­ing play­ers

Bioregnum Opinion Column by John Carroll

The emphasis at the FDA over the past 5 years or so has been on assisting drug developers as much as they can to speed up regulatory reviews and push more drugs into the market. And they are now crafting a final set of regulations aimed at flagging through a whole new generation of gene therapies in clinical testing at a rapid clip.

In a set of 6 prospective guidances posted on the FDA web site Tuesday morning, FDA commissioner Stephen Hahn committed the agency to staying flexible in handing out designations that are critical to gaining early approvals for drugs that claim to be once-and-done but don’t have anything close to the data needed to prove it.

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Patrik Jonsson, the president of Lilly Bio-Medicines

Who knew? Der­mi­ra’s board kept watch as its stock price tracked Eli Lil­ly’s se­cret bid­ding on a $1.1B buy­out

In just 8 days, from December 6 to December 14, the stock jumped from $7.88 to $12.70 — just under the initial $13 bid. There was no hard news about the company that would explain a rise like that tracking closely to the bid offer, raising the obvious question of whether insider info has leaked out to traders.

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Mike Bloomberg (AP IMAGES)

Mike Bloomberg joins a grow­ing cho­rus of De­mo­c­ra­t­ic pres­i­den­tial can­di­dates threat­en­ing to go af­ter drug patents

As the mayor of New York City, Mike Bloomberg had a few modest ideas about lowering prescription drug prices in the Big Apple that gained little traction. Now on the campaign trail on a faint hope of clinching the Democratic presidential nomination, the billionaire has some bigger plans — including one that would alter the patent system central to the biopharma business.

In a barebones drug pricing plan posted on Monday, Bloomberg came out blasting President Donald Trump for failing to deliver his promise to lower drug prices, and then making misleading claims about them. The price of over 3,000 drugs still increased at a rate five times higher than inflation in the first six months of 2019, he wrote.

The FTC and New York state ac­cuse Mar­tin Shkre­li of run­ning a drug mo­nop­oly. They plan to squash it -- and per­ma­nent­ly ex­ile him

Pharma bro Martin Shkreli was jailed, publicly pilloried and forced to confront some lawmakers in Washington riled by his move to take an old generic and move the price from $17.50 per pill to $750. But through 4 years of controversy and public revulsion, his company never backed away from the price — left uncontrolled by a laissez faire federal policy on a drug’s cost.

Now the FTC and the state of New York plan to pry his fingers off the drug once and for all and open it up to some cheap competition. And their lawsuit is asking that Shkreli — with several years left on his prison sentence — be banned permanently from the pharma industry.

UP­DAT­ED: Ac­celeron res­ur­rects block­buster hopes for so­tater­cept with pos­i­tive PhII — and shares rock­et up

Acceleron $XLRN says that its first major trial readout of 2020 is a success.

In a Phase II study of 106 patients with pulmonary arterial hypertension (PAH), Acceleron’s experimental drug sotatercept hit its primary endpoint: a significant reduction in pulmonary vascular resistance. The drug also met three different secondary endpoints, including the 6-minute walking test.

“We’re thrilled to report such positive topline results from the PULSAR trial,” Acceleron CEO Habib Dable said in a statement. The company said in a conference call they plan on discussing a Phase III trial design with regulators.

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J&J's Spra­va­to gets no love from NICE, jeop­ar­diz­ing its prospects in the UK

UK’s cost-effectiveness watchdog NICE is taking the same track laid out by ICER — J&J’s pharmaceutical version of the hallucinogenic anesthetic ketamine, Spravato, is low value for money. On Tuesday, the agency refused to endorse the therapy for inclusion as a reimbursable drug on the UK’s National Health System.

Cognizant of the myriad of approved antidepressants that often don’t work, EU regulators endorsed J&J’s low-dose, nasal-spray formulation of ketamine last month for treatment-resistant depression.