Amalia M. Issa|Adrian Thorogood|Yann Joly|Bartha Maria Knoppers
Accelerating evidence gathering and approval of precision medicine therapies: the FDA takes aim at rare mutations
McGill University and Génome Québec Innovation Centre|Target (United States)|University of the Sciences|McGill University and Génome Québec Innovation Centre|McGill University and Génome Québec Innovation Centre|McGill University and Génome Québec Innovation Centre
patient heterogeneity drug response led alternative models randomized clinical trial rct drug development enabled evolution newer regulatory frameworks recent years 2012 us food drug administration fda published popularly used guidance industry enrichment strategies clinical trials support approval human drugs biological products1us food drug administration guidance industry enrichment strategies clinical trials support approval human drugs biological products 2012 httpwwwfdagovdownloadsdrugsguidancecomplianceregulatoryinformationguidancesucm332181pdf accessed january 8 2018google scholar enrichment strategies refer priori identification selection subpopulations patients often basis molecular profiling increase likelihood efficacy particular treatment intervention1us food drug administration guidance industry enrichment strategies clinical trials support approval human drugs biological products 2012 httpwwwfdagovdownloadsdrugsguidancecomplianceregulatoryinformationguidancesucm332181pdf accessed january 8 2018google scholar recently fda released draft guidance industry developing targeted therapies lowfrequency molecular subsets disease2us food drug administration guidance industry developing targeted therapies lowfrequency molecular subsets disease guidance industry december 2017 httpswwwfdagovdownloadsdrugsguidancecomplianceregulatoryinformationguidancesucm588884pdf accessed december 20 2017google scholar provides flexibility evidence standards show drug works lowfrequency mutations ie molecular alterations strictly simplicity use shorthand mutations paper although guidance applies broad set molecular alterations new guidance fda proposes provide sponsors strategy identifying determining clinical trial eligibility different patients variable molecular modifications notably new guidance provides broad recommendations going beyond traditional enrichment strategies allow grouping patients different molecular subtypes low frequency guidance forms part fdas efforts advance development availability safe effective targeted treatments rare diseases well common diseases due rare mutations3us food drug administration statement fda commissioner scott gottlieb md new fda efforts support efficient development targeted therapies december 15 2017 httpswwwfdagovnewseventsnewsroompressannouncementsucm589248htm accessed december 20 2017google scholar focusing molecular subtypes low frequency allowing grouping trial eligibility fda signaling change evidentiary standards change implications pharmaceutical industry sponsors also multiple actors drug development process paper examine impact changing evidentiary standards conduct clinical trials drug approvals prescriber duties patients well need data sharing fda guidance states clinical trial assays designed detect possible molecular alterations comprise group expected respond3us food drug administration statement fda commissioner scott gottlieb md new fda efforts support efficient development targeted therapies december 15 2017 httpswwwfdagovnewseventsnewsroompressannouncementsucm589248htm accessed december 20 2017google scholar typically enrichment design strong biomarker identify subgroup patients treatment expected particularly effective allows enrollment small sample size adequately powered detect appropriate treatment effect eg phase iii studies 0025 onesided statistical significance accepted concept precision medicine including fda authors agreement within clinical study predictive biomarker able distinguish subgroup patients benefit biomarker positive benefit biomarker negative treatment4amur lavange l zineh buckmangarner woodcock j biomarker qualification toward multiple stakeholder framework biomarker development regulatory acceptance utilization1stn280dc2bc2mjjs1shsq3d3d101002cpt136clin pharmacol ther 2015 98 3446google scholar5saad ed paoletti x burzykowski buyse precision medicine needs randomized clinical trials101038nrclinonc20178nat rev clin oncol 2017 14 317323google scholar new fda draft guidance explicitly cautions sponsors use analytically valid assays however discussion provided clinical validity concerns might arise course using biomarkers identify molecular alterations low frequency fda acknowledges low numberswould settings preclude meaningful empirical inferences treatment benefits risks3us food drug administration statement fda commissioner scott gottlieb md new fda efforts support efficient development targeted therapies december 15 2017 httpswwwfdagovnewseventsnewsroompressannouncementsucm589248htm accessed december 20 2017google scholar nevertheless new guidance presumes extrapolation across multiple subsets may possible despite low frequency absence patients subsets3us food drug administration statement fda commissioner scott gottlieb md new fda efforts support efficient development targeted therapies december 15 2017 httpswwwfdagovnewseventsnewsroompressannouncementsucm589248htm accessed december 20 2017google scholar new evidence standards thus appear favor internal validity external validity address explicitly sponsors interpret departure accepted standards evidence rigorous rct design conduct presents challenges given many stakeholders rely rcts evidence clinical validity utility creation integration data support lowfrequency molecular drug indications require new collaborative approaches data generation researchers clinical laboratories genetic databases need data sharing evident upstream support clinical trial inclusion criteria downstream enhanced pharmacosurveilllance approval upstream unlikely sponsors able generate data rare mutations example approach pioneered cystic fibrosis transmembrane conductance regulator cftr gene depended part evidence genetic database progressively populated researchers clinical laboratories6tsui lc dorfman r cystic fibrosis gene molecular genetic perspective101101cshperspecta009472cold spring harb perspect med 2013 3 a009472google scholar higher standards genetic databases need developed perhaps even regulated ensure quality data reliance external databases sponsors raise concerns database transparent aggregation curation interpretation variants data quality possible conflicts interest indeed previous fda draft guidance initiated discussions establishing standards even certification variant databases drugs approved lower evidentiary standards fda guidance also calls enhanced postapproval patient surveillance clinical data sharing emerging norm clinicians laboratories7acmg board directors laboratory clinical genomic data sharing crucial improving genetic health care position statement american college medical genetics genomics1cas528dc2bc2sxhtfygslfl101038gim2016196genet med 2017 19 721722google scholar fda sponsors need take greater leadership role promoting funding data sharing including rare mutations drug labels support rigorous patient monitoring data sharing current use offlabel prescribing offset lower evidentiary standard fda draft guidance calls detailed labeling information accompany drugs including information level evidence supporting rare molecular indications stakeholders prescribers payers traditionally work assumption indications including molecular indications based clinical trial data fda guidance calls labels include transparent description limited evidentiary basis rare molecular indications commendable shift demand greater scientific literacy accountability part health professionals prescribing drug medicines approved specifically treat rare diseases8austin cp et alfuture rare diseases research 20172027 irdirc perspective101111cts12500clin transl sci 2017 11 2127google scholar significant amount offlabel use rare diseases status quo puts significant responsibility clinicians offlabel use might standard care many patients dire need new drugs manage rare condition however offlabel prescribing may expose physicians legal claims medical malpractice informed consent insufficient sound medical judgment based available evidence9eguale b et alassociation offlabel drug use adverse drug events adult population101001jamainternmed20156058jama intern med 2016 176 5563google scholar properly exercised furthermore possible new guidance would require patients tested relevant biomarkers practice routinely carried offlabel prescribing guidance could help ensure opposed evidence generated clinical trials rare mutations addition approach could help inform prescriber patient shared decisionmaking selecting therapy one caveat however prescribers need explain complex labels drugs indicated indication supported limited evidence new guidance may change clinical practice impact patient care addition effects changing drug labels prescriber duties particularly salient question likely new treatment approved new evidentiary standards would used clinical practice given clinicians typically use rcts evidence clinical validity utility accepting groupings patients particular molecular variations given clinical study may windfall industry sponsors looking identify right patient drug however within real world context clinical practice may less useful identifying right drug patient ultimately desired health outcome nevertheless new guidance provides opportunities clinical research lowfrequency mutations rare common diseases may ultimately beneficial patients hitherto underserved respect targeted treatments fda leading international efforts encourage adoption precision medicine improve accessibility drugs individuals rare disease change ultimately mean patients rare diseases draft guidance may improve incentives sponsors run small trials ultimately improving evidence base therapeutic options patients might encourage sponsors regulators determine molecular indications according standard albeit lowered evidentiary standards rather putting onus clinicians rely offlabel use indeed offlabel use might new guidance become onlabel use adverse outcomes reported postmarket surveillance mechanisms success depend innovation collaboration multiple stakeholders including prescribers regulators payers patients