A go-go FDA is open­ing up the fast lane to re­gen­er­a­tive med ap­provals

The FDA on Thurs­day launched a new pol­i­cy frame­work for re­gen­er­a­tive med­i­cine, build­ing off a pre­vi­ous frame­work from 2005, as part of ef­forts to bring new cell, stem cell and tis­sue prod­ucts to pa­tients as ef­fi­cient­ly as pos­si­ble while man­ag­ing the pro­lif­er­a­tion of un­scrupu­lous ac­tors hawk­ing un­proven ther­a­pies.

FDA’s an­nounce­ment in­clud­ed the re­lease of two new draft guid­ance doc­u­ments – one on ways to ex­pe­dite ap­provals for re­gen­er­a­tive med­i­cines for se­ri­ous con­di­tions and one on med­ical de­vices used with re­gen­er­a­tive ther­a­pies – and two fi­nal guid­ance doc­u­ments of­fer­ing clar­i­ty on when cell and tis­sue-based prod­ucts would be ex­cept­ed from the reg­u­la­tions and clar­i­fy­ing how the agency in­ter­prets the reg­u­la­to­ry de­f­i­n­i­tions of “min­i­mal ma­nip­u­la­tion” and “ho­mol­o­gous use.”

“We’re adopt­ing a risk-based and sci­ence-based ap­proach that builds up­on ex­ist­ing reg­u­la­tions to sup­port in­no­v­a­tive prod­uct de­vel­op­ment while clar­i­fy­ing the FDA’s au­thor­i­ties and en­force­ment pri­or­i­ties,” FDA Com­mis­sion­er Scott Got­tlieb said in a state­ment. “This will pro­tect pa­tients from prod­ucts that pose po­ten­tial sig­nif­i­cant risks, while ac­cel­er­at­ing ac­cess to safe and ef­fec­tive new ther­a­pies.”

But the new guid­ance doc­u­ments were not re­leased along­side any new warn­ing let­ters or en­force­ment ac­tions against a grow­ing mar­ket of un­ap­proved di­rect-to-con­sumer (DTC) stem cell prod­ucts.

Leigh Turn­er, as­so­ciate pro­fes­sor at the Uni­ver­si­ty of Min­neso­ta Cen­ter for Bioethics and co-au­thor of an ar­ti­cle in Cell about DTC stem cell clin­ics, told Fo­cus that FDA still has yet to crack down on these un­scrupu­lous com­pa­nies prof­it­ing off un­proven treat­ments, not­ing the mar­ket is “quite large, quite ac­tive and there’s been a long time with­out mean­ing­ful over­sight.”

Turn­er took is­sue with a pro­vi­sion in the “min­i­mal ma­nip­u­la­tion” and “ho­mol­o­gous use” fi­nal guid­ance that says FDA will use dis­cre­tion in en­force­ment over the next 36 months. “To me, it’s a mat­ter of what is the en­force­ment ac­tiv­i­ty go­ing to be over that time frame. If it’s a 3-year pe­ri­od where FDA won’t do much, that strikes me as a green light for the in­dus­try” sell­ing un­ap­proved prod­ucts.

“If I ran one of these [DTC stem cell] clin­ics in Flori­da or Cal­i­for­nia, I would see to­day’s ac­tion by FDA to mean busi­ness as usu­al,” he added.

An FDA spokesper­son clar­i­fied to Fo­cus via email, “The FDA does not in­tend to ex­er­cise such en­force­ment dis­cre­tion for those HCT/Ps [hu­man cells, tis­sues, and cel­lu­lar and tis­sue-based prod­ucts] that pose a po­ten­tial sig­nif­i­cant safe­ty con­cern. Go­ing for­ward, the FDA will ap­ply a risk-based ap­proach to en­force­ment tak­ing in­to ac­count how prod­ucts are be­ing ad­min­is­tered as well as the dis­eases and con­di­tions for which they are be­ing used.

“Specif­i­cal­ly, un­der lim­it­ed con­di­tions, when a prod­uct re­quires an in­ves­ti­ga­tion­al new drug ap­pli­ca­tion (IND) or pre­mar­ket ap­proval (bi­o­log­ics li­cense ap­pli­ca­tions or BLAs), the agency in­tends to fo­cus its en­force­ment ac­tions on prod­ucts that pose high­er risks.  For ex­am­ple, ac­tions re­lat­ed to prod­ucts ad­min­is­tered by high­er-risk routes of ad­min­is­tra­tion (e.g., those ad­min­is­tered by in­tra­venous in­jec­tion or in­fu­sion, aerosol in­hala­tion, in­traoc­u­lar in­jec­tion, or in­jec­tion or in­fu­sion in­to the cen­tral ner­vous sys­tem) will be pri­or­i­tized over those as­so­ci­at­ed with a low­er risk (e.g., those ad­min­is­tered by in­tra­der­mal, sub­cu­ta­neous, or in­tra-ar­tic­u­lar in­jec­tion).”

Back­ground

The 21st Cen­tu­ry Cures Act (Cures Act) cre­at­ed what’s known as the Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­py (RMAT) des­ig­na­tion (pre­vi­ous­ly known as the RAT des­ig­na­tion), which can be used to speed the re­view of cell ther­a­pies, ther­a­peu­tic tis­sue en­gi­neer­ing prod­ucts, hu­man cell and tis­sue prod­ucts or any com­bi­na­tion prod­uct us­ing such ther­a­pies or prod­ucts.

Pe­ter Marks, di­rec­tor of FDA’s Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search (CBER), said on Tues­day that as of last Fri­day, the agency has re­ceived 34 RMAT des­ig­na­tion re­quests, act­ed on 31 re­quests and grant­ed 11 RMAT des­ig­na­tions. Hu­ma­cyte and Veri­cel are two ex­am­ples of com­pa­nies that have al­ready re­ceived the RMAT des­ig­na­tion.

Ad­van­tages of the RMAT des­ig­na­tion in­clude all the ben­e­fits of the fast track and break­through des­ig­na­tions, in­clud­ing ear­ly in­ter­ac­tions be­tween the agency and spon­sors.

But as op­posed to the break­through des­ig­na­tion, the RMAT des­ig­na­tion does not re­quire ev­i­dence to in­di­cate that the drug may of­fer a sub­stan­tial im­prove­ment over avail­able ther­a­pies, ac­cord­ing to one of the draft guid­ances re­leased Thurs­day.

And like break­through des­ig­na­tions, RMAT des­ig­na­tions do not mean the prod­uct will be ap­proved and do not change the statu­to­ry stan­dards for demon­stra­tion of safe­ty and ef­fec­tive­ness need­ed for ap­proval.

In ad­di­tion to cre­at­ing the RMAT, Sec­tion 3034 of the Cures Act al­so man­dates that FDA is­sue guid­ance clar­i­fy­ing how FDA will eval­u­ate de­vices used in the re­cov­ery, iso­la­tion or de­liv­ery of RMATs, which al­so was re­leased on Thurs­day.

Guid­ance and Ex­am­ples

In spelling out how FDA de­ter­mines what should be con­sid­ered for an RMAT des­ig­na­tion, one of the draft guid­ances notes that CBER in­tends to con­sid­er “the rig­or of da­ta col­lec­tion; the na­ture and mean­ing­ful­ness of the out­comes; the num­ber of pa­tients or sub­jects, and the num­ber of sites, con­tribut­ing to the da­ta; and the sever­i­ty, rar­i­ty, or preva­lence of the con­di­tion.”

The draft of­fers two hy­po­thet­i­cal ex­am­ples of pre­lim­i­nary clin­i­cal ev­i­dence that CBER would con­sid­er suf­fi­cient, what an RMAT re­quest should con­tain and con­sid­er­a­tions in clin­i­cal tri­al de­sign.

The oth­er draft guid­ance spec­i­fies that de­vices in­tend­ed for use with a spe­cif­ic RMAT may be con­sid­ered a com­bi­na­tion prod­uct. It al­so ad­dress­es how FDA in­tends to sim­pli­fy and stream­line its ap­pli­ca­tion of reg­u­la­to­ry re­quire­ments for com­bo de­vices and cell or tis­sue prod­ucts; what, if any, in­tend­ed us­es or spe­cif­ic at­trib­ut­es would re­sult in a de­vice used with a re­gen­er­a­tive ther­a­py that would make it a Class III de­vice; fac­tors to con­sid­er in de­ter­min­ing whether a de­vice may be la­beled for use with a spe­cif­ic RMAT or class of RMATs; when a de­vice may be lim­it­ed to a spe­cif­ic in­tend­ed use; and ap­pli­ca­tion of the least bur­den­some ap­proach to demon­strate how a de­vice may be used with more than one cell type.

Both draft guid­ance doc­u­ments will have 90-day com­ment pe­ri­ods.

The two fi­nal guid­ance doc­u­ments to­geth­er su­per­sede a 2014 draft guid­ance re­lat­ed to adi­pose tis­sue and the one on defin­ing ho­mol­o­gous use and min­i­mal ma­nip­u­la­tion fi­nal­izes a draft from De­cem­ber 2014 on min­i­mal ma­nip­u­la­tion of hu­man cells, tis­sues, and cel­lu­lar and tis­sue-based prod­ucts (HCT/Ps) and an­oth­er draft from Oc­to­ber 2015 on the ho­mol­o­gous use of HCT/Ps.

In one fi­nal­ized guid­ance, FDA says, “Ho­mol­o­gous use means the re­pair, re­con­struc­tion, re­place­ment, or sup­ple­men­ta­tion of a re­cip­i­ent’s cells or tis­sues with an HCT/P that per­forms the same ba­sic func­tion or func­tions in the re­cip­i­ent as in the donor. This cri­te­ri­on re­flects the Agency’s con­clu­sion that there would be in­creased safe­ty and ef­fec­tive­ness con­cerns for HCT/Ps that are in­tend­ed for a non-ho­mol­o­gous use, be­cause there is less ba­sis on which to pre­dict the prod­uct’s be­hav­ior, where­as HCT/Ps for ho­mol­o­gous use can rea­son­ably be ex­pect­ed to func­tion ap­pro­pri­ate­ly.”

FDA al­so de­fines “min­i­mal ma­nip­u­la­tion” as: “1) For struc­tur­al tis­sue, pro­cess­ing that does not al­ter the orig­i­nal rel­e­vant char­ac­ter­is­tics of the tis­sue re­lat­ing to the tis­sue’s util­i­ty for re­con­struc­tion, re­pair, or re­place­ment; 2) For cells or non­struc­tur­al tis­sues, pro­cess­ing that does not al­ter the rel­e­vant bi­o­log­i­cal char­ac­ter­is­tics of cells or tis­sues.”

The oth­er guid­ance fi­nal­izes a draft from 2014 and of­fers sev­en ques­tions and an­swers de­scrib­ing which es­tab­lish­ments are not re­quired to com­ply with cer­tain re­quire­ments if they re­move HCT/Ps from an in­di­vid­ual and im­plant them in­to the same in­di­vid­ual dur­ing the same sur­gi­cal pro­ce­dure.

In terms of the ways FDA has adapt­ed its reg­u­la­to­ry mod­el to meet the “rev­o­lu­tion­ary na­ture of the prod­ucts,” Got­tlieb point­ed to the ex­am­ple of “how we’re con­sid­er­ing in­no­v­a­tive tri­al de­signs where­by in­di­vid­ual aca­d­e­m­ic in­ves­ti­ga­tors would fol­low the same man­u­fac­tur­ing pro­to­cols and share com­bined clin­i­cal tri­al da­ta in sup­port of ap­proval from the FDA. This is an in­no­v­a­tive way of mak­ing sure that small in­ves­ti­ga­tors who are work­ing with cells that are be­ing man­u­fac­tured in ways that ren­der them sub­ject to our cur­rent laws and reg­u­la­tions — be­cause the cells are, for ex­am­ple, more than ‘min­i­mal­ly ma­nip­u­lat­ed.’”


First pub­lished here. Reg­u­la­to­ry Fo­cus is the flag­ship on­line pub­li­ca­tion of the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety (RAPS), the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care and re­lat­ed prod­ucts, in­clud­ing med­ical de­vices, phar­ma­ceu­ti­cals, bi­o­log­ics and nu­tri­tion­al prod­ucts. Email news@raps.org for more in­for­ma­tion.

Author

Zachary Brennan

managing editor, RAPS

Nick Leschly via Getty

UP­DAT­ED: Blue­bird shares sink as an­a­lysts puz­zle out $1.8M stick­er shock and an un­ex­pect­ed de­lay

Blue­bird bio $BLUE has un­veiled its price for the new­ly ap­proved gene ther­a­py Zyn­te­glo (Lenti­Glo­bin), which came as a big sur­prise. And it wasn’t the on­ly un­ex­pect­ed twist in to­day’s sto­ry.

With some an­a­lysts bet­ting on a $900,000 price for the β-tha­lassemia treat­ment in Eu­rope, where reg­u­la­tors pro­vid­ed a con­di­tion­al ear­ly OK, blue­bird CEO Nick Leschly said Fri­day morn­ing that the pa­tients who are suc­cess­ful­ly treat­ed with their drug over 5 years will be charged twice that — $1.8 mil­lion — on the con­ti­nent. That makes this drug the sec­ond most ex­pen­sive ther­a­py on the plan­et, just be­hind No­var­tis’ new­ly ap­proved Zol­gens­ma at $2.1 mil­lion, with an­a­lysts still wait­ing to see what kind of pre­mi­um can be had in the US.

Gene ther­a­pies seize the top of the list of the most ex­pen­sive drugs on the plan­et — and that trend has just be­gun

Anyone looking for a few simple reasons why the gene therapy field has caught fire with the pharma giants need only look at the new list of the 10 most expensive therapies from GoodRx.

Two recently approved gene therapies sit atop this list, with Novartis’ Zolgensma crowned the king of the priciest drugs at $2.1 million. Right below is Luxturna, the $850,000 pioneer from Spark, which Roche is pushing hard to acquire as it adds a gene therapy group to the global mix.

Endpoints News

Basic subscription required

Unlock this story instantly and join 53,000+ biopharma pros reading Endpoints daily — and it's free.

Ted Love. HAVERFORD COLLEGE

Glob­al Blood Ther­a­peu­tics poised to sub­mit ap­pli­ca­tion for ac­cel­er­at­ed ap­proval, with new piv­otal da­ta on its sick­le cell dis­ease drug

Global Blood Therapeutics is set to submit an application for accelerated approval in the second-half of this year, after unveiling fresh data from a late-stage trial that showed just over half the patients given the highest dose of its experimental sickle cell disease drug experienced a statistically significant improvement in oxygen-wielding hemoglobin, meeting the study's main goal.

Endpoints News

Basic subscription required

Unlock this story instantly and join 53,000+ biopharma pros reading Endpoints daily — and it's free.

In a boost to Rit­ux­an fran­chise, Roche nabs quick ap­proval for po­latuzum­ab ve­dotin

Roche’s lat­est an­ti­body-drug con­ju­gate has crossed the FDA fin­ish line, gain­ing an ac­cel­er­at­ed ap­proval a full two months ahead of sched­ule.

Po­livy, or po­latuzum­ab ve­dotin, is a first-in-class drug tar­get­ing CD79b — a pro­tein promi­nent in B-cell non-Hodgkin lym­phoma. It will now be mar­ket­ed for dif­fuse large B-cell lym­phoma as part of a reg­i­men that al­so in­cludes the chemother­a­py ben­damus­tine and a ver­sion of rit­ux­imab (Rit­ux­an).

J&J gains an en­thu­si­as­tic en­dorse­ment from Pres­i­dent Don­ald Trump for their big new drug Spra­va­to

Pres­i­dent Don­ald Trump has lit­tle love for Big Phar­ma, but there’s at least one new drug that just hit the mar­ket which he is en­am­ored with.

Trump, ev­i­dent­ly, has been read­ing up on J&J’s new an­ti-de­pres­sion drug, Spra­va­to. And the pres­i­dent — who of­ten likes to break out in­to a full-throat­ed at­tack on greedy drug­mak­ers — ap­par­ent­ly en­thused about the ther­a­py in a meet­ing with of­fi­cials of Vet­er­ans Af­fairs, which has long grap­pled with de­pres­sion among vet­er­ans.

An in­censed Cat­a­lyst Phar­ma sues the FDA, ac­cus­ing agency of bow­ing to po­lit­i­cal pres­sure and break­ing fed­er­al law

Af­ter hint­ing it was ex­plor­ing the le­gal­i­ty of the FDA’s ap­proval of a ri­val drug from fam­i­ly-run com­pa­ny Ja­cobus Phar­ma­ceu­ti­cals, Cat­a­lyst Phar­ma­ceu­ti­cals on Wednes­day filed a law­suit against the health reg­u­la­tor — ef­fec­tive­ly ac­cus­ing the agency of bow­ing to po­lit­i­cal pres­sure sur­round­ing sky­rock­et­ing drug prices.

Be­fore Cat­a­lyst’s Fir­dapse (which car­ries an av­er­age an­nu­al list price of $375,000) was sanc­tioned for use in Lam­bert-Eaton myas­thenic syn­drome (LEMS) by the FDA, hun­dreds of pa­tients had been able to ac­cess a sim­i­lar drug from com­pound­ing phar­ma­cies for a frac­tion of the cost, or Ja­cobus’ for free, as part of an FDA-rat­i­fied com­pas­sion­ate use pro­gram. But the ap­proval of the Cat­a­lyst drug — ac­com­pa­nied by mar­ket ex­clu­siv­i­ty span­ning sev­en years — ef­fec­tive­ly pre­clud­ed Ja­cobus and com­pound­ing phar­ma­cies from sell­ing their ver­sions.

Plagued by de­lays, As­traZeneca HQ costs soar to £750M as it edges to­ward 2020 com­ple­tion

In the lat­est up­date on As­traZeneca’s de­lay-prone HQ project, the phar­ma gi­ant re­vealed that the cost of con­struc­tion has swelled to £750 mil­lion ($956 mil­lion) — more than dou­ble the orig­i­nal es­ti­mate in 2013.

The move-in date is still in 2020, a spokesper­son con­firmed, af­ter As­traZeneca pushed pro­ject­ed com­ple­tion from 2016 to 2017, and then to the spring of 2019. While the ini­tial plan called for a £330 mil­lion (then $500 mil­lion) in­vest­ment, the cost bal­looned to £500 mil­lion ($650 mil­lion), and more in the most re­cent up­date.

Fresh analy­sis spot­lights car­dio ben­e­fit of J&J's In­vokana in di­a­betes pa­tients with­out his­to­ry of CV dis­ease

In­vokana sales may be mut­ed, but the di­a­betes drug is set to get some love af­ter its mak­er J&J un­veiled da­ta at the Amer­i­can Di­a­betes As­so­ci­a­tion meet­ing on Tues­day sug­gest­ing the med­i­cine can con­fer a car­dio­vas­cu­lar ben­e­fit in pa­tients who do not have pre­ex­ist­ing CV dis­ease.

Back in April, J&J had re­port­ed that in the late-stage CRE­DENCE study, the SGLT2 drug scored a 30% re­duc­tion in the risk of a com­pos­ite of ail­ments: a pro­gres­sion to the dou­bling of serum cre­a­ti­nine, end-stage kid­ney dis­ease and re­nal or car­dio­vas­cu­lar death. In terms of sec­ondary end­points, the drug was al­so found be heart-pro­tec­tive: low­er­ing the risk of CV death and hos­pi­tal­iza­tion for heart fail­ure by 31%, as well as ma­jor ad­verse CV events by 20%. In March, the com­pa­ny sub­mit­ted an ap­pli­ca­tion to ex­pand In­vokana’s la­bel to re­flect its im­pact on chron­ic kid­ney dis­ease.

Sil­i­con Val­ley's most an­tic­i­pat­ed slide deck just dropped. What does it mean for bio­phar­ma's dig­i­tal teams?

These aren’t the typ­i­cal slides you’d see at End­points — no mol­e­cules, clin­i­cal pro­grams, or p-val­ues. In­stead, we’ll talk dig­i­tal and in­ter­net trends, fac­tors that elite glob­al brands — re­gard­less of in­dus­try — must first mea­sure and un­der­stand be­fore de­ploy­ing prod­ucts in­to the world. That’s a con­cept that most of our Big Phar­ma au­di­ence is in tune with. Dig­i­tal aware­ness is key to suc­cess in the dis­cov­ery, de­vel­op­ment, and mar­ket­ing of new bio­phar­ma­ceu­ti­cals, and most of the ma­jors now have a chief dig­i­tal of­fi­cer: No­var­tis, Sanofi, and Pfiz­er, just to name a few.