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.

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