Next-gen­er­a­tion se­quenc­ing: FDA of­fers guid­ance to stream­line path to mar­ket

The FDA on Thurs­day fi­nal­ized two guid­ance doc­u­ments re­lat­ed to next-gen­er­a­tion se­quenc­ing (NGS) and draft­ed new guid­ance on in­ves­ti­ga­tion­al in vit­ro di­ag­nos­tics (IVDs) in on­col­o­gy tri­als – all of which of­fer rec­om­men­da­tions to pro­vide test de­vel­op­ers with a more ef­fi­cient path to mar­ket.

The fi­nal­ized guid­ance doc­u­ments pro­vide NGS test de­vel­op­ers with rec­om­men­da­tions for de­sign­ing, de­vel­op­ing and val­i­dat­ing tests, as well as us­ing ge­net­ic vari­ant data­bas­es to sup­port clin­i­cal va­lid­i­ty.

Jef­frey Shuren

“The rapid adop­tion of NGS tech­nolo­gies in re­search and clin­i­cal set­tings is help­ing to iden­ti­fy count­less new ge­net­ic vari­ants. How­ev­er, in­for­ma­tion about ge­net­ic vari­ants is gen­er­al­ly stored in a man­ner that is not pub­licly ac­ces­si­ble,” ex­plained Jef­frey Shuren, di­rec­tor of FDA’s Cen­ter for De­vices and Ra­di­o­log­i­cal Health. “To­day’s re­lease of the FDA’s fi­nal guid­ance on ge­net­ic vari­ant data­bas­es will help change this par­a­digm by en­cour­ag­ing da­ta shar­ing and the ac­cu­mu­la­tion in pub­lic data­bas­es of ev­i­dence sup­port­ing the clin­i­cal va­lid­i­ty of ge­nom­ic tests to help pro­vide an even more ef­fi­cient path to mar­ket.”

The 7-page draft guid­ance, mean­while, de­scribes how spon­sors of cer­tain on­col­o­gy tri­als can use an op­tion­al stream­lined sub­mis­sion process to de­ter­mine whether use of an in­ves­ti­ga­tion­al IVD — in­clud­ing those that in­cor­po­rate NGS tech­nol­o­gy — in a tri­al of in­ves­ti­ga­tion­al can­cer drug or bi­o­log­i­cal prod­ucts is con­sid­ered sig­nif­i­cant risk, non­signif­i­cant risk or ex­empt from re­view.

Scott Got­tlieb

“This is a step to­ward our goal of hav­ing a com­mon fil­ing for a drug and di­ag­nos­tic sys­tem where the drug is co-de­vel­oped with a di­ag­nos­tic test,” FDA Com­mis­sion­er Scott Got­tlieb said in re­marks on Thurs­day.

Back­ground

NGS can en­able doc­tors to look across mil­lions of DNA changes that may de­ter­mine whether a per­son has or is at risk of de­vel­op­ing a ge­net­ic dis­ease, or to in­form treat­ment de­ci­sions, FDA ex­plained.

“The rapid adop­tion of NGS-based tests in both re­search and clin­i­cal prac­tice is lead­ing to iden­ti­fi­ca­tion of an in­creas­ing num­ber of ge­net­ic vari­ants (e.g., path­o­gen­ic, be­nign, and of un­known sig­nif­i­cance), in­clud­ing rare vari­ants that may be unique to a sin­gle in­di­vid­ual or fam­i­ly,” FDA said.

To date, FDA has au­tho­rized three NGS on­co-pan­els:

  • Foun­da­tionOne CDx, which was ap­proved in No­vem­ber 2017, and can de­tect ge­net­ic mu­ta­tions in 324 genes;
  • MSK-IM­PACT, al­so ap­proved in No­vem­ber 2017, which can de­tect ge­net­ic mu­ta­tions in 468 genes; and
  • On­comine Dx Tar­get Test, ap­proved in June 2017, which can de­tect ge­net­ic mu­ta­tions in 23 genes.

“Oth­er tests us­ing NGS tech­nol­o­gy au­tho­rized by FDA to date in­clude: Prax­is Ex­tend­ed RAS Pan­el (de­tects two genes) and Foun­da­tion­Fo­cus BR­CA (al­so de­tects two genes),” an FDA spokesper­son told Fo­cus.

“These pan­els can ac­cel­er­ate can­cer drug de­vel­op­ment and im­prove clin­i­cal out­comes by re­duc­ing pa­tient screen­ing time and costs. These tech­nolo­gies can help re­duce the risks as­so­ci­at­ed with the need for mul­ti­ple tis­sue biop­sies. And these plat­forms can be rapid­ly up­dat­ed to de­tect new onco­genes or gene vari­ants as these mark­ers are iden­ti­fied by re­searchers,” Got­tlieb ex­plained.

In 2017, FDA al­so took sev­er­al ac­tions to stream­line the de­vel­op­ment and re­view of a va­ri­ety of ge­net­ic-based tests – au­tho­riz­ing a third-par­ty op­tion for au­tho­riz­ing tu­mor pro­fil­ing tests, and out­lin­ing stan­dard­ized de­vel­op­ment cri­te­ria for con­sumer car­ri­er screen­ing tests to al­low for their mar­ket­ing with­out pri­or agency re­view. FDA al­so es­tab­lished such cri­te­ria for ge­net­ic health risk tests and pro­posed to al­low their mar­ket­ing af­ter a one-time agency re­view.

Fi­nal Guid­ance

One 41-page guid­ance fi­nal­ized Thurs­day, known as “Con­sid­er­a­tions for De­sign, De­vel­op­ment, and An­a­lyt­i­cal Val­i­da­tion of Next Gen­er­a­tion Se­quenc­ing (NGS)–Based In Vit­ro Di­ag­nos­tics (IVDs) In­tend­ed to Aid in the Di­ag­no­sis of Sus­pect­ed Germline Dis­eases,” pro­vides rec­om­men­da­tions for de­sign­ing, de­vel­op­ing and val­i­dat­ing NGS-based tests.

The guid­ance of­fers per­spec­tive on what the agency looks for in pre­mar­ket sub­mis­sions to de­ter­mine a test’s an­a­lyt­i­cal va­lid­i­ty, in­clud­ing how well the test de­tects the pres­ence or ab­sence of a ge­nom­ic change.

The oth­er 16-page guid­ance is­sued Thurs­day, ti­tled “Use of Pub­lic Hu­man Ge­net­ic Vari­ant Data­bas­es to Sup­port Clin­i­cal Va­lid­i­ty for Ge­net­ic and Ge­nom­ic-Based In Vit­ro Di­ag­nos­tics,” de­scribes how test de­vel­op­ers may re­ly on clin­i­cal ev­i­dence from FDA-rec­og­nized pub­lic data­bas­es to sup­port clin­i­cal claims.

The guid­ance de­scribes how prod­uct de­vel­op­ers can use these data­bas­es to sup­port the clin­i­cal val­i­da­tion of NGS tests that they are de­vel­op­ing. These pub­lic data­bas­es may in­clude re­sources like Clin­Gen, which is main­tained by the Na­tion­al In­sti­tutes of Health (NIH). Us­ing FDA-rec­og­nized data­bas­es will pro­vide test de­vel­op­ers with an ef­fi­cient path for mar­ket­ing clear­ance or ap­proval of a new test.

On 26 April, FDA will hold a we­bi­nar on the two fi­nal guid­ance doc­u­ments.


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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