'N of 1' ther­a­pies ad­dressed in draft FDA guid­ance

Rec­og­niz­ing the pace at which drug de­vel­op­ers are mov­ing ever fur­ther in­to in­di­vid­u­al­ized med­i­cine, the FDA has is­sued a draft guid­ance ad­dress­ing sub­mis­sion process­es for some hy­per-spe­cial­ized treat­ments.

The new doc­u­ment, which gives high-lev­el guid­ance for in­ves­ti­ga­tion­al new drug (IND) sub­mis­sions of in­di­vid­u­al­ized an­ti-sense oligonu­cleotides (ASOs), takes in­to con­sid­er­a­tion that these “N of 1” ther­a­pies come with “a set of chal­lenges and con­sid­er­a­tions not seen with the typ­i­cal drug in­ter­ven­tion,” ac­cord­ing to a state­ment from Pa­trizia Cavaz­zoni, MD, the act­ing di­rec­tor of FDA’s Cen­ter for Drug Eval­u­a­tion and Re­search (CDER).

Cavaz­zoni not­ed that many of the rare dis­eases treat­ed by tai­lored ASOs are rapid­ly pro­gres­sive, so time is of the essence if the af­fect­ed in­di­vid­ual is to be helped by the treat­ment. Al­so, much ASO re­search and treat­ment is car­ried out in aca­d­e­m­ic set­tings by in­ves­ti­ga­tors who may have less FDA ex­pe­ri­ence than tra­di­tion­al drug de­vel­op­ers.

The draft guid­ance em­pha­sizes the im­por­tance of ini­ti­at­ing in­ter­ac­tion with FDA as soon as pos­si­ble, to in­clude es­tab­lish­ing a com­mu­ni­ca­tion plan.

Be­cause of the in­di­vid­u­al­ized na­ture of these ther­a­pies, pa­tients and fam­i­ly mem­bers may func­tion more as col­lab­o­ra­tors than re­search sub­jects and may in some cas­es at­tend spon­sor-FDA meet­ings. FDA clar­i­fies in the guid­ance that “what­ev­er the spon­sor or FDA shares at a meet­ing about the ap­pli­ca­tion may be con­sid­ered a pub­lic dis­clo­sure of the spon­sor’s con­fi­den­tial in­for­ma­tion.” Ac­cord­ing­ly, FDA will ask for writ­ten clar­i­fi­ca­tion of whether hav­ing that at­tendee present will con­sti­tute pub­lic dis­clo­sure and rec­om­mends that the spon­sor con­sid­er con­fi­den­tial­i­ty agree­ments with an at­ten­dees.

If a con­fi­den­tial­i­ty agree­ment is in place, “FDA gen­er­al­ly would not con­sid­er the pres­ence of that out­side par­tic­i­pant at a sched­uled meet­ing be­tween the spon­sor and FDA to trig­ger uni­form ac­cess with re­spect to in­for­ma­tion dis­cussed at that meet­ing,” ac­cord­ing to the guid­ance.

The draft guid­ance al­so lays out gen­er­al ex­pec­ta­tion for IND sub­mis­sions and the con­tent and for­mat for the pre-IND meet­ing pack­age for ASO prod­ucts.

FDA pro­vides di­rec­tion for spon­sors on the con­tent of re­search IND ap­pli­ca­tions as well. These ap­pli­ca­tions should in­clude a jus­ti­fi­ca­tion for the in­di­vid­u­al­ized ASO drug prod­uct. FDA ac­knowl­edges that “it is un­like­ly that hu­man da­ta will be avail­able at the time of the ini­tial IND sub­mis­sion.” Ac­cord­ing­ly, the pri­mar­i­ly non­clin­i­cal da­ta and chem­istry, man­u­fac­tur­ing and con­trols da­ta will sup­port the IND.

The guid­ance al­so ad­dress­es eth­i­cal and hu­man sub­ject pro­tec­tion con­sid­er­a­tions, safe­ty re­port­ing, and an­nu­al re­port­ing re­quire­ments.

FDA notes in the in­tro­duc­tion to the draft guid­ance that on­ly the IND sub­mis­sion process is ad­dressed, and that lat­er con­sid­er­a­tions in­clud­ing mar­ket­ing and long-term treat­ment are ex­clud­ed from the scope of the guid­ance. Al­so, nei­ther non­clin­i­cal and clin­i­cal da­ta guide­lines, nor prod­uct qual­i­ty re­quire­ments are with­in the scope of the guid­ance.

In an Oc­to­ber 2019 New Eng­land Jour­nal of Med­i­cine ed­i­to­r­i­al, CDER head Janet Wood­cock, MD and Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search (CBER) head Pe­ter Marks, MD, PhD laid out some of the so­ci­etal and eth­i­cal chal­lenges in­volved in de­vel­op­ing a reg­u­la­to­ry frame­work for in­di­vid­u­al­ized ther­a­pies. In ad­di­tion to con­sid­er­a­tions for in­di­vid­ual pa­tients and their fam­i­lies, the reg­u­la­tors asked, “On a larg­er scale, we need to con­sid­er how such trun­cat­ed pro­grams fit in­to the spec­trum of drug de­vel­op­ment in gen­er­al: what are the dif­fer­ences be­tween treat­ing one, ten, or thou­sands of pa­tients?”

The agency must al­so grap­ple with scal­ing is­sues for these ther­a­pies, not­ed Wood­cock and Marks: “Al­though the FDA and oth­er reg­u­la­tors typ­i­cal­ly al­low stream­lined pre­clin­i­cal da­ta gen­er­a­tion for rare, se­ri­ous dis­eases, pro­grams for a sin­gle pa­tient are like­ly to set the floor for the min­i­mum pre­clin­i­cal eval­u­a­tion. How should this be es­ca­lat­ed for slight­ly more preva­lent dis­eases of equal se­ri­ous­ness?”

Though these treat­ments may be tai­lored to an in­di­vid­ual’s ge­net­ics, the broad­er ap­proach may even­tu­al­ly stand to ben­e­fit many, said Cavaz­zoni, who called the draft guid­ance a “first step” along the way to bring­ing ef­fec­tive in­di­vid­u­al­ized treat­ments to pa­tients safe­ly. “We al­so are op­ti­mistic that de­vel­op­ment of these in­di­vid­u­al­ized drug prod­ucts may spur gene se­quenc­ing that leads to the de­vel­op­ment of ad­di­tion­al in­di­vid­u­al­ized drug prod­ucts for the same dis­ease (though per­haps caused by a dif­fer­ent mu­ta­tion),” she said.

RAPS: 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.

Janet Woodcock (AP Images)

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5AM Ven­tures: Fu­el­ing the Next Gen­er­a­tion of In­no­va­tors

By RBC Capital Markets
With Andy Schwab, Co-Founder and Managing Partner at 5AM Ventures

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