FDA of­fers first thoughts on neu­rode­gen­er­a­tive dis­ease gene ther­a­pies

The FDA has is­sued draft guid­ance on the de­vel­op­ment, test­ing, and tri­al de­sign for hu­man gene ther­a­pies for neu­rode­gen­er­a­tive dis­eases. The doc­u­ment, re­leased on Tues­day, al­so high­lights ap­proval path­ways for these nov­el prod­ucts.

The draft guid­ance, which ap­plies to prod­ucts for both adult and pe­di­atric pop­u­la­tions, em­pha­sizes the im­por­tance of ear­ly com­mu­ni­ca­tion with FDA be­fore the sub­mis­sion of an in­ves­ti­ga­tion­al new drug (IND) ap­pli­ca­tion. The agency point­ed to IN­TER­ACT meet­ings, which can be used to dis­cuss is­sues in a prod­uct’s ear­ly pre­clin­i­cal pro­gram, and pre-IND meet­ings, which oc­cur lat­er in de­vel­op­ment but pri­or to the sub­mis­sion of an ap­pli­ca­tion.

Ear­ly in­ter­ac­tion with FDA’s Of­fice of Tis­sues and Ad­vanced Ther­a­pies (OTAT), part of the Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search, may in­clude prod­uct-spe­cif­ic con­sid­er­a­tions re­lat­ed to the eval­u­a­tion of drug prod­uct pu­ri­ty, iden­ti­fy, po­ten­cy, and strength.

FDA al­so rec­om­mends that spon­sors eval­u­ate the ef­fect of man­u­fac­tur­ing process changes on the prod­uct’s crit­i­cal qual­i­ty at­trib­ut­es (CQAs). In cas­es where the ef­fect is not im­me­di­ate­ly iden­ti­fi­able, spon­sors should con­sid­er con­duct­ing a two-part risk analy­sis prospec­tive­ly look­ing at pre- and post-change prod­uct, as well as ret­ro­spec­tive­ly an­a­lyz­ing post-change prod­uct sam­ples that have been pre­served.

When de­vel­op­ing pre­clin­i­cal stud­ies for gene ther­a­py prod­ucts, the agency rec­om­mends fo­cus­ing on five over­all ob­jec­tives:

  • Iden­ti­fi­ca­tion of a bi­o­log­i­cal­ly ac­tive dose range
  • Rec­om­men­da­tions for an ini­tial clin­i­cal dose lev­el, dose-es­ca­la­tion sched­ule, and dos­ing reg­i­men
  • Es­tab­lish­ment of fea­si­bil­i­ty and rea­son­able safe­ty of the pro­posed clin­i­cal route of ad­min­is­tra­tion
  • Sup­port of pa­tient el­i­gi­bil­i­ty cri­te­ria
  • Iden­ti­fi­ca­tion of po­ten­tial tox­i­c­i­ties and phys­i­o­log­ic pa­ra­me­ters to guide clin­i­cal mon­i­tor­ing

When con­sid­er­ing pe­di­atric, first-in-hu­man clin­i­cal tri­als where there is “more than a mi­nor in­crease over min­i­mal risk,” the agency is call­ing on spon­sors to de­sign a pre­clin­i­cal pro­gram that in­cludes stud­ies show­ing the po­ten­tial for di­rect ben­e­fit of the gene ther­a­py. “Pre­clin­i­cal ev­i­dence to sup­port a prospect of di­rect ben­e­fit is most im­por­tant when clin­i­cal ev­i­dence of ef­fec­tive­ness is not avail­able from adult sub­jects with the same dis­ease,” FDA wrote.

FDA sug­gest­ed that in­no­v­a­tive clin­i­cal de­signs — not on­ly ran­dom­ized, place­bo-con­trolled tri­als (RCTs) — could be used for clin­i­cal de­vel­op­ment for mono­genic dis­or­ders with a well-char­ac­ter­ized patho­gen­e­sis and patho­phys­i­ol­o­gy, such as in­fan­tile spinal mus­cu­lar at­ro­phy due to mu­ta­tions in the sur­vival mo­tor neu­ron 1 gene. How­ev­er, tra­di­tion­al RCTs are like­ly more ap­pro­pri­ate for neu­rode­gen­er­a­tive dis­eases with a poor­ly un­der­stood eti­ol­o­gy and a vari­able nat­ur­al his­to­ry, such as spo­radic amy­otroph­ic lat­er­al scle­ro­sis or spo­radic Alzheimer’s dis­ease.

But spon­sors are ad­vised to at least con­sid­er in­no­v­a­tive tri­al de­signs — adap­tive de­signs, en­rich­ment de­signs, dose-con­trolled stud­ies, or his­tor­i­cal con­trols — for any neu­rode­gen­er­a­tive dis­or­der.

When plan­ning pe­di­atric tri­als, FDA rec­om­mends that spon­sors first ob­tain pre­lim­i­nary safe­ty and ef­fec­tive­ness da­ta in adults. If no pri­or adult da­ta is avail­able, spon­sors should pro­vide a ra­tio­nale as to why adults stud­ies are not eth­i­cal or fea­si­ble.

In any clin­i­cal tri­als that are in­tend­ed to sup­port a mar­ket­ing ap­pli­ca­tion, FDA ad­vis­es that the pri­ma­ry ef­fi­ca­cy end­points should be ei­ther clin­i­cal­ly mean­ing­ful end­points or sur­ro­gate end­points that are “rea­son­ably like­ly” to pre­dict a clin­i­cal ben­e­fit.

An ef­fect on a clin­i­cal­ly mean­ing­ful end­point would gen­er­al­ly be used to sup­port a mar­ket­ing ap­pli­ca­tion un­der the tra­di­tion­al ap­proval path­way, while sur­ro­gate end­points could be used to sup­port ac­cel­er­at­ed ap­proval. “Use of a sur­ro­gate end­point may be ap­pro­pri­ate when a [gene ther­a­py] prod­uct di­rect­ly tar­gets an un­der­ly­ing, well-un­der­stood and well-doc­u­ment­ed mono­genic change that caus­es a se­ri­ous neu­rode­gen­er­a­tive dis­or­der,” the agency wrote. “In these cas­es, the [gene ther­a­py] prod­uct could al­ter the un­der­ly­ing ge­net­ic de­fect and there­by treat or cure the dis­ease.”

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)

End­points poll: Janet Wood­cock takes the (in­ter­im) helm at the FDA. And a large ma­jor­i­ty of our read­ers want her to stay there

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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

Key Points

Prescription Digital Therapeutics, cell therapy technologies, and in silico medicines will be a vital part of future treatment modalities.
Unlocking the potential of the microbiome could be the missing link to better disease diagnosis.
Growing links between academia, industry, and venture capital are spinning out more innovative biotech companies.
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The firehose of biopharma news is gushing these days.

That’s why broader and deeper is the theme for 2021 at Endpoints. You can expect new coverage outside our core R&D focus, with deeper reporting in some key areas. When John Carroll and I launched Endpoints nearly five years ago, we were wading in waist-high waters. Now we’re a team of 25 full-time staffers (and growing) with plans to cover the flood of biopharma news, Endpoints-style.

Janet Woodcock and Joshua Sharfstein (AP, Images)

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Mike Grey, Plexium chairman (Horizon Therapeutics)

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