Feature
SPOTLIGHT
Post-market confirmatory trials are planned for eteplirsen but have been delayed , and results are not expected until 2024 .
In the hematology arena , the accelerated approval of the drug selinexor incited a similar debate over limited data in 2019 when it was approved for myeloma , and then in 2020 when it received an additional indication for diffuse large B-cell lymphoma ( DLBCL ). Regarding the DLBCL approval , critics contested that the treatment is associated with only modest activity and high adverse event burden , with an unknown effect on survival or quality of life .
“ There are no direct comparisons of the toxicity profiles of selinexor versus other conventional therapies , but based on the toxicities described with selinexor in the STORM trial for relapsed / refractory myeloma and the SADAL trial in DLBCL , it is likely that gastrointestinal toxicities are more frequent with selinexor than with other commonly used regimens ,” said David Iberri , MD , of Stanford Medicine in California , when asked to comment on the findings of the SADAL trial . 16 The pivotal SADAL trial also had a primary endpoint of overall response rate , meaning that , until longer-term and comparative data are available , “ clinicians lack the data necessary to have an informed discussion with patients regarding potential benefits and risks of selinexor versus other regimens ,” he added . “ In my opinion , FDA approval should have been deferred until efficacy could be confirmed in a randomized phase III study with the primary endpoint of overall survival .”
What Does the Future Hold ?
Not all experts agreed on where the FDA is headed or if the recent controversies signal a permanent loosening of restrictions . Some researchers who spoke with ASH Clinical News predicted that the agency is unlikely to make major adjustments to the approval process anytime soon , while others think that the group may add restrictions that lengthen the time it takes for drugs to make it to market .
“ Commenters have noted FDA ’ s increasing use of accelerated programs over the past decade , often with a view that the increase is driven by a loosening of our approval standards ,” said Mr . Kohler . “ In reality , the FDA ’ s standards have not changed . Instead , the increased use of expedited approval pathways is directly related to the increasing numbers and scope of these programs provided by Congress , as well as the kinds of medicines that are being developed and the types of diseases that are being studied .”
Dr . Rajkumar echoed that statement , pointing out that , with the exception of the breakthrough therapy designation , the approval pathways and designations haven ’ t changed in more than a decade . “ We now have more drugs going through the pathway , but the processes are the same as they have always been ,” he said .
As it has done for every other aspect of life , however , the COVID-19 pandemic has led to a reappraisal of priorities in the drug approval arena : In June , three Republican senators introduced the Promising Pathways Act , which “ requires the FDA to establish a rolling , real-time , priority review pathway to evaluate provisional approval applications for drugs intended to treat , prevent , or diagnose serious or life-threatening diseases or conditions – including those that pose a threat of epidemic or pandemic ( e . g ., COVID-19 ).” 17
“ The FDA ’ s standards have not changed . ... The increased use of expedited approval pathways is directly related to the increasing numbers and scope of these programs provided by Congress .”
— Charles Kohler , FDA spokesperson
Others have advocated for reform at the FDA . In a commentary accompanying Dr . Darrow ’ s 2020 analysis , Joshua Sharfstein , MD , Vice Dean for Public Health Practice and Community Engagement at Johns Hopkins Bloomberg School of Public Health in Baltimore , Maryland , laid out four steps to improve the U . S . drug approval system . 18 First , he argues , the FDA and Congress need to revise the existing pathways to promote more meaningful competition for orphan drugs being used for non-orphan diseases and to ensure that drugs that receive fast track and breakthrough therapy designations are highly likely to produce major clinical advances for patients .
Next , the FDA should strengthen its oversight of post-market studies . Third and fourth , he wrote , the FDA should reconsider its special marketing exclusivity incentives , some of which end up being extremely expensive . The incentives could be made conditional on the completion of post-market trials to incentivize pharmaceutical companies to complete them in a timely manner .
Dr . Darrow said that Congress tends to tighten requirements on medicines as a response to tragedy and loosen them between tragedies . “ There ’ s a long history of the FDA of responding to tragedy : The 1902 Biologics Control Act was passed after people died based on tainted antiserum . The 1937 act was passed after people died from a poisonous antibiotic . More recently , we ’ ve seen tightened regulation following compounding errors [ in pharmacies ] that led to contamination and a number of deaths ,” he said . “ But , between all of those tragedies , there has been pressure to relax the requirements .”
In the near future , he said , “ I would expect that there will be a continued trend to relax requirements until the next tragedy occurs . It ’ s unfortunate , but that ’ s what history has shown us .” — By Emma Yasinski
References 1 . Mullard A . 2019 FDA drug approvals . Nat Rev Drug Discov . 2020 ; 19:79-84 . 2 . FDA . The Road to the Biotech Revolution - Highlights of 100 Years of Biologics Regulation . Accessed October 8 , 2020 , from https :// www . fda . gov / about-fda / histories-product-regulation / road-biotech-revolution-highlights-100-yearsbiologics-regulation .
3 . FDA . Sulfanilamide Disaster . Accessed October 8 , 2020 , from https :// www . fda . gov / files / about % 20fda / published / The-Sulfanilamide-Disaster . pdf .
4 . FDA . Orphan Drug Act - Relevant Excerpts . Accessed October 8 , 2020 , from https :// www . fda . gov / industry / designating-orphan-product-drugs-andbiological-products / orphan-drug-act-relevant-excerpts .
5 . FDA . Fast Track . Accessed October 8 , 2020 , from https :// www . fda . gov / patients / fast-track-breakthrough-therapy-accelerated-approval-priorityreview / fast-track .
6 . FDA . Accelerated Approval . Accessed October 8 , 2020 , from https :// www . fda . gov / patients / fast-track-breakthrough-therapy-accelerated-approvalpriority-review / accelerated-approval .
7 . FDA . Priority Review . Accessed October 8 , 2020 , from https :// www . fda . gov / patients / fast-track-breakthrough-therapy-accelerated-approval-priorityreview / priority-review .
8 . FDA . Breakthrough Therapy . Accessed October 8 , 2020 , from https :// www . fda . gov / patients / fast-track-breakthrough-therapy-accelerated-approvalpriority-review / breakthrough-therapy .
9 . Darrow JJ , Avorn J , Kesselheim AS . FDA approval and regulation of pharmaceuticals , 1983-2018 . JAMA . 2020 ; 323:164-176 .
10 . Hwang TJ , Franklin JM , Chen CT , et al . Efficacy , safety , and regulatory approval of Food and Drug Administration – designated breakthrough and nonbreakthrough cancer medicines . J Clin Oncol . 2018 ; 36:1805-1812 .
11 . Zhang AD , Puthumana J , Downing NS , et al . Assessment of clinical trials supporting US Food and Drug Administration approval of novel therapeutic agents , 1995-2017 . JAMA Netw Open . 2020 ; 3 : e203284 .
12 . Shepshelovich D , Tibau A , Goldvaser H , et al . postmarketing modifications of drug labels for cancer drugs approved by the US Food and Drug Administration between 2006 and 2016 with and without supporting randomized controlled trials . J Clin Oncol . 2018 ; 36:1798-1804 .
13 . Undark . FDA documents reveal depths of internal rancor over drug ’ s approval process . August 2 , 2017 . Accessed October 8 , 2020 , from https :// undark . org / 2017 / 08 / 02 / fda-eteplirsen-janet-woodcock /.
14 . Parent Project Muscular Dystrophy ( PPMD ). PPMD applauds FDA for landmark approval of first-ever disease-modifying drug to treat Duchenne muscular dystrophy . Accessed October 8 , 2020 , from https :// www . prnewswire . com / newsreleases / ppmd-applauds-fda-for-landmark-approval-of-first-ever-diseasemodifying-drug-to-treat-duchenne-muscular-dystrophy-300330263 . html .
15 . Thomas K . Insurers battle families over costly drug for fatal disease . The New York Times , June 22 , 2017 . Accessed October 8 , 2020 , from https :// www . nytimes . com / 2017 / 06 / 22 / health / duchenne-muscular-dystrophy-drugexondys-51 . html .
16 . ASH Clinical News . Evaluating selinexor in patients with relapsed / Refractory DLBCL . September 1 , 2020 . Accessed October 8 , 2020 , from https :// www . ashclinicalnews . org / news / literature-scan / evaluating-selinexor-patientsrelapsed-refractory-dlbcl / 4 /.
17 . Mike Braun Senate website . Senator Braun & colleagues introduce Promising Pathway Act for patients with serious and life-threatening illnesses . June 4 , 2020 . Accessed October 8 , 2020 , from https :// www . braun . senate . gov / senator-braun-colleagues-introduce-promising-pathway-act-patientsserious-and-life-threatening .
18 . Sharfstein JM . Reform at the FDA — in need of reform . JAMA . 2020 ; 323:123-124 .
30 ASH Clinical News November 2020