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.

Australia’s Avance Clinical: no IND required and a 43.5% rebate on clinical spend for CGT biotechs

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The cell and gene therapies (CGT) sector offers unprecedented opportunities for patient disease management across virtually all therapeutic areas. However, finding the right accredited clinical teams to take a therapy through to the clinic and manage the regulatory process can be a major challenge for biotechs with a CGT product.

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Thanks­giv­ing edi­tion: Top 15 End­points sto­ries of 2021; Can you name that vac­cine?; Mer­ck­'s Covid an­tivi­ral dis­ap­points; FDA nom­i­nee's in­dus­try ties; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Happy Thanksgiving to all those who are celebrating it — although, if we are being honest, this week’s abbreviated edition is really for those who are not. Wherever you’re tuning in from, we appreciate your support, hope you find this recap helpful and we wish you a wonderful weekend.

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Mar­ket­ingRx roundup: Am­gen, Lil­ly, Bio­haven mi­graine brand re­call low, study says; No­var­tis looks to re­make drug launch mod­el

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UP­DAT­ED: FDA hits the red light on an ear­ly-stage AML study af­ter a pa­tient dies

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Joan Perel­ló set out 17 years ago to de­vel­op a drug. And to­day he's be­ing re­ward­ed with a $424M biotech buy­out

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