FDA lays down the law on gene ther­a­py, of­fer­ing guid­ances on both dis­eases and pro­ce­dures

As first an­nounced in Jan­u­ary, the FDA’s Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search (CBER) on Wednes­day of­fered a swath of new draft guid­ance doc­u­ments on hu­man gene ther­a­pies — of­fer­ing a look at what it ex­pects from an in­dus­try that’s be­gin­ning to take off.

The six guid­ance doc­u­ments fo­cus on de­vel­op­ing he­mo­phil­ia, rare dis­ease and reti­nal dis­or­der gene ther­a­pies, and in­clude one on chem­istry, man­u­fac­tur­ing and con­trol (CMC) in­for­ma­tion, one on long term fol­low-up ob­ser­va­tion­al stud­ies col­lect­ing da­ta on ad­verse events and one on the test­ing of retro­vi­ral vec­tor-based ther­a­pies.

Last De­cem­ber, the FDA ap­proved a new gene ther­a­py, priced at $850,000, from Spark Ther­a­peu­tics for the treat­ment of chil­dren and adult pa­tients with an in­her­it­ed form of vi­sion loss that may re­sult in blind­ness. And back in 2016, FDA be­gan to see the num­ber of gene and cell ther­a­py ap­pli­ca­tions spike.

Last No­vem­ber, the FDA al­so an­nounced its pol­i­cy frame­work for re­gen­er­a­tive med­i­cine, in­clud­ing a draft guid­ance that de­scribes the ex­pe­dit­ed pro­grams, such as the break­through ther­a­py des­ig­na­tion, and the re­gen­er­a­tive med­i­cine ad­vanced ther­a­py (RMAT)  des­ig­na­tion, that may be avail­able to spon­sors of these ther­a­pies. Com­pa­nies have al­ready weighed in on such guid­ance.

(Links to guid­ance doc­u­ments are in head­ers be­low).


The 15-page draft guid­ance pro­vides rec­om­men­da­tions on the clin­i­cal tri­al de­sign and re­lat­ed de­vel­op­ment of co­ag­u­la­tion fac­tor VI­II (he­mo­phil­ia A) and IX (he­mo­phil­ia B) ac­tiv­i­ty as­says, in­clud­ing how to ad­dress dis­crep­an­cies in fac­tor VI­II and fac­tor IX ac­tiv­i­ty as­says.

The draft guid­ance al­so in­cludes rec­om­men­da­tions re­gard­ing pre­clin­i­cal and clin­i­cal con­sid­er­a­tions to sup­port de­vel­op­ment of he­mo­phil­ia gene ther­a­pies (GTs), as well as in­for­ma­tion on ex­pe­dit­ed pro­grams and com­mu­ni­ca­tion with the FDA.

Rare Dis­ease

This 14-page draft guid­ance pro­vides rec­om­men­da­tions on de­vel­op­ing a GT prod­uct in­tend­ed to treat a rare dis­ease in adult and/or pe­di­atric pa­tients. The guid­ance re­lates to the man­u­fac­tur­ing, pre­clin­i­cal, and clin­i­cal tri­al de­sign is­sues for all phas­es of the clin­i­cal de­vel­op­ment pro­gram.

“Such in­for­ma­tion is in­tend­ed to as­sist spon­sors in de­sign­ing clin­i­cal de­vel­op­ment pro­grams for such prod­ucts, where there may be lim­it­ed study pop­u­la­tion size and po­ten­tial fea­si­bil­i­ty and safe­ty is­sues as well as is­sues re­lat­ing to the in­ter­pretabil­i­ty of bioac­tiv­i­ty/ef­fi­ca­cy out­comes that may be unique to rare dis­eases or to the na­ture of the GT prod­uct it­self,” the FDA said.

Reti­nal Dis­or­ders

This 13-page draft guid­ance pro­vides rec­om­men­da­tions to stake­hold­ers de­vel­op­ing GTs for reti­nal dis­or­ders af­fect­ing adult and pe­di­atric pa­tients. The fo­cus per­tains to is­sues spe­cif­ic to GT prod­ucts for reti­nal dis­or­ders and pro­vides rec­om­men­da­tions re­lat­ed to prod­uct de­vel­op­ment, pre­clin­i­cal test­ing and clin­i­cal tri­al de­sign.


This 54-page draft guid­ance pro­vides spon­sors of a GT in­ves­ti­ga­tion­al new drug ap­pli­ca­tion (IND) with rec­om­men­da­tions re­gard­ing CMC in­for­ma­tion re­quired to as­sure prod­uct safe­ty, iden­ti­ty, qual­i­ty, pu­ri­ty and strength (in­clud­ing po­ten­cy) of the in­ves­ti­ga­tion­al prod­uct.

The draft ap­plies to GTs and to com­bi­na­tion prod­ucts that con­tain a hu­man gene ther­a­py in com­bi­na­tion with a drug or de­vice.

“The field of gene ther­a­py has pro­gressed rapid­ly since FDA is­sued the April 2008 guid­ance. There­fore, FDA is up­dat­ing the guid­ance to pro­vide cur­rent FDA rec­om­men­da­tions re­gard­ing the CMC con­tent of a gene ther­a­py IND,” the FDA said.

When fi­nal­ized, the draft is in­tend­ed to su­per­sede the doc­u­ment en­ti­tled “Guid­ance for FDA Re­view­ers and Spon­sors: Con­tent and Re­view of Chem­istry, Man­u­fac­tur­ing, and Con­trol (CMC) In­for­ma­tion for Hu­man Gene Ther­a­py In­ves­ti­ga­tion­al New Drug Ap­pli­ca­tions (INDs),” from April 2008.

Long Term Fol­low-Up

This 36-page draft guid­ance pro­vides spon­sors with rec­om­men­da­tions re­gard­ing the de­sign of pro­to­cols for long term fol­low-up ob­ser­va­tion­al stud­ies for the col­lec­tion of da­ta on de­layed ad­verse events fol­low­ing the ad­min­is­tra­tion of a GT.

When fi­nal­ized, the draft is in­tend­ed to su­per­sede the doc­u­ment en­ti­tled “Guid­ance for In­dus­try: Gene Ther­a­py Clin­i­cal Tri­als–Ob­serv­ing Par­tic­i­pants for De­layed Ad­verse Events” from No­vem­ber 2006. This draft, when fi­nal­ized, is al­so in­tend­ed to sup­ple­ment the guid­ance dis­cussed be­low.

Test­ing of Retro­vi­ral Vec­tor-Based Hu­man Gene Ther­a­pies

This 16-page draft pro­vides spon­sors of retro­vi­ral vec­tor-based hu­man GTs with rec­om­men­da­tions re­gard­ing the test­ing for repli­ca­tion com­pe­tent retro­virus (RCR) dur­ing the man­u­fac­ture of retro­vi­ral vec­tor-based prod­ucts, and dur­ing fol­low-up mon­i­tor­ing of pa­tients who have re­ceived retro­vi­ral vec­tor-based prod­ucts.

“Rec­om­men­da­tions in­clude the iden­ti­fi­ca­tion and amount of ma­te­r­i­al to be test­ed, and gen­er­al test­ing meth­ods,” the FDA said. “In ad­di­tion, rec­om­men­da­tions are pro­vid­ed on mon­i­tor­ing pa­tients for ev­i­dence of retro­vi­ral in­fec­tion af­ter ad­min­is­tra­tion of retro­vi­ral vec­tor-based gene ther­a­py prod­ucts.”

When fi­nal­ized, the draft is in­tend­ed to su­per­sede the doc­u­ment en­ti­tled “Guid­ance for In­dus­try: Sup­ple­men­tal Guid­ance on Test­ing for Repli­ca­tion Com­pe­tent Retro­virus in Retro­vi­ral Vec­tor Based Gene Ther­a­py Prod­ucts and Dur­ing Fol­low-up of Pa­tients in Clin­i­cal Tri­als Us­ing Retro­vi­ral Vec­tors,” from No­vem­ber 2006.

The draft guid­ance, when fi­nal­ized, is al­so in­tend­ed to sup­ple­ment the long term fol­low-up and CMC guid­ance doc­u­ments dis­cussed above.

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. 


Zachary Brennan

managing editor, RAPS

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