FDA will al­low ob­ser­va­tion­al stud­ies as part of a push for re­al world ev­i­dence, new frame­work says

The FDA on Thurs­day un­veiled a new frame­work dis­cussing how the agency will use re­al-world ev­i­dence (RWE) and re­al-world da­ta (RWD) to help com­pa­nies win new in­di­ca­tions for ap­proved drugs and bi­o­log­ics, ex­pand la­bels or sat­is­fy post-ap­proval study re­quire­ments.

Specif­i­cal­ly, the agency says its pro­gram will eval­u­ate the use of RWE to sup­port changes to la­bel­ing about drug prod­uct ef­fec­tive­ness, in­clud­ing adding or mod­i­fy­ing an in­di­ca­tion, such as a change in dose, dose reg­i­men or route of ad­min­is­tra­tion; new pop­u­la­tions; or the ad­di­tion of com­par­a­tive ef­fec­tive­ness or safe­ty in­for­ma­tion.

“The RWE frame­work will al­so con­sid­er the eval­u­a­tion of ob­ser­va­tion­al clin­i­cal stud­ies us­ing RWD to sup­port prod­uct ef­fec­tive­ness de­ter­mi­na­tions,” the FDA said.

For de­ter­mi­na­tions on how to use RWE, the agency said it will con­sid­er the fol­low­ing on a case-by-case ba­sis:

  • Whether the RWD are fit for use
  • Whether the tri­al or study de­sign used to gen­er­ate RWE can pro­vide ad­e­quate sci­en­tif­ic ev­i­dence to an­swer or help an­swer the reg­u­la­to­ry ques­tion
  • Whether the study con­duct meets FDA reg­u­la­to­ry re­quire­ments (e.g., for study mon­i­tor­ing and da­ta col­lec­tion)

“FDA in­tends to use this three-part ap­proach to eval­u­ate in­di­vid­ual sup­ple­men­tal ap­pli­ca­tions, as ap­pro­pri­ate, and more gen­er­al­ly to guide FDA’s RWE Pro­gram,” the frame­work says.

In ad­di­tion to of­fer­ing ex­am­ples of cur­rent us­es of RWD for ev­i­dence gen­er­a­tion (more be­low), sec­tions of the frame­work deal with as­sess­ing da­ta re­li­a­bil­i­ty and rel­e­vance and ad­dress­ing gaps in RWD sources.

Un­der the sec­tion on the po­ten­tial for study de­signs us­ing RWD to sup­port ef­fec­tive­ness, the frame­work fo­cus­es on ran­dom­ized de­signs us­ing RWD, non-ran­dom­ized tri­als, sin­gle-arm tri­als with RWD con­trol and ob­ser­va­tion­al stud­ies.

“In con­sid­er­ing whether da­ta gath­ered through ob­ser­va­tion­al study de­signs are ap­pro­pri­ate to gen­er­ate RWE for the pur­pose of sup­port­ing ef­fec­tive­ness de­ter­mi­na­tions, FDA in­tends to eval­u­ate mul­ti­ple ques­tions of in­ter­est that could af­fect the abil­i­ty to draw a re­li­able causal in­fer­ence, in­clud­ing, for ex­am­ple, the role of ex­ist­ing ev­i­dence (e.g., the nat­ur­al his­to­ry of the dis­ease) and how the in­clu­sion of a more di­verse pop­u­la­tion can re­sult in a het­ero­gene­ity of treat­ment ef­fects mak­ing it dif­fi­cult to de­tect small­er ef­fect sizes,” the agency says.

But the agency al­so cau­tions that the po­ten­tial lack of trans­paren­cy, es­pe­cial­ly in ret­ro­spec­tive ob­ser­va­tion­al stud­ies, which do not have to be reg­is­tered on clin­i­cal­tri­als.gov, cou­pled with the fact that ret­ro­spec­tive analy­ses can be con­duct­ed mul­ti­ple times and rel­a­tive­ly in­ex­pen­sive­ly with vary­ing study de­sign el­e­ments, “makes it pos­si­ble to con­duct nu­mer­ous ret­ro­spec­tive stud­ies un­til the de­sired re­sult is ob­tained and then sub­mit on­ly fa­vor­able re­sults as if they were the re­sult of a sin­gle study with a pre­spec­i­fied pro­to­col.”

The FDA said it will con­sid­er poli­cies to pre­vent such prac­tices, in­clud­ing rec­om­men­da­tions from ex­perts and oth­er stake­hold­ers. The agency al­so said it will is­sue guid­ance about ob­ser­va­tion­al study de­signs us­ing RWD, in­clud­ing whether and how these stud­ies might pro­vide RWE to sup­port prod­uct ef­fec­tive­ness in reg­u­la­to­ry de­ci­sion­mak­ing.

Back­ground and Ex­am­ples

The cre­ation of this frame­work was built in­to the 21st Cen­tu­ry Cures Act, which di­rect­ed FDA to build an RWE pro­gram to in­clude in­for­ma­tion de­scrib­ing sources of RWE, gaps in da­ta col­lec­tion, stan­dards and method­olo­gies for col­lect­ing and an­a­lyz­ing RWE, and pri­or­i­ty ar­eas, chal­lenges and po­ten­tial pi­lot op­por­tu­ni­ties to ad­dress the over­ar­ch­ing Cures re­quire­ments.

For the pur­pos­es of this frame­work, the FDA said it de­fines RWD and RWE as fol­lows:

  • RWD are da­ta “re­lat­ing to pa­tient health sta­tus and/or the de­liv­ery of health care rou­tine­ly col­lect­ed from a va­ri­ety of sources.”
  • RWE is the “clin­i­cal ev­i­dence about the us­age and po­ten­tial ben­e­fits or risks of a med­ical prod­uct de­rived from analy­sis of RWD.”

And the agency has al­ready be­gun us­ing RWD and RWE in some post-mar­ket in­stances.

Scott Got­tlieb

“To give some ex­am­ples, our use of RWD and RWE, de­rived from our Sen­tinel sys­tem, elim­i­nat­ed the need for post­mar­ket­ing stud­ies on nine po­ten­tial safe­ty is­sues in­volv­ing five prod­ucts; mak­ing our post­mar­ket eval­u­a­tion of safe­ty time­li­er and more ef­fec­tive,” FDA com­mis­sion­er Scott Got­tlieb said in a state­ment.

In more cas­es, ac­tive post-mar­ket risk iden­ti­fi­ca­tion and analy­sis is re­plac­ing the need for ran­dom­ized con­trolled post-mar­ket­ing stud­ies as a more ef­fec­tive, com­pre­hen­sive, and achiev­able tool for post-mar­ket eval­u­a­tion. And as a re­sult, these tools are be­com­ing an in­creas­ing­ly im­por­tant part of pre-mar­ket re­views, Got­tlieb not­ed.

In the pre-mar­ket space in on­col­o­gy, for ex­am­ple, Got­tlieb said that the FDA cur­rent­ly has new drug ap­pli­ca­tions un­der re­view where RWD and RWE are “help­ing to in­form our on­go­ing eval­u­a­tion as one com­po­nent of the to­tal com­ple­ment of in­for­ma­tion that we’re eval­u­at­ing.”

RWD and RWE can be par­tic­u­lar­ly help­ful when eval­u­at­ing treat­ments for un­com­mon con­di­tions or rare tu­mor types. Across the pond, the EMA said late last month that com­pa­nies de­vel­op­ing cer­tain he­mo­phil­ia treat­ments should col­lect da­ta from pa­tient reg­istries rather than small clin­i­cal tri­als.

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.

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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Lat­est news: It’s a no on uni­ver­sal boost­ers; Pa­tient death stuns gene ther­a­py field; In­side Tril­li­um’s $2.3B turn­around; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Next week is shaping up to be a busy one, as our editor-in-chief John Carroll and managing editor Kyle Blankenship lead back-to-back discussions with a great group of experts to discuss the weekend news and trends. John will be spending 30 minutes with Jake Van Naarden, the CEO of Lilly Oncology, and Kyle has a brilliant panel lined up: Harvard’s Cigall Kadoch, Susan Galbraith, the new head of cancer R&D at AstraZeneca, Roy Baynes at Merck, and James Christensen at Mirati. Don’t miss out on the action — sign up here.

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Mi­rati's KRAS drug looks like the fa­vorite in colon can­cer with new da­ta, putting the pres­sure square on Am­gen

With Amgen already providing proof-of-concept for KRAS inhibitors with its sotorasib, Mirati Therapeutics is piecing together a follow-up effort in lung cancer with data it thinks are superior. But in colon cancer, where solo sotorasib has turned in a dud, Mirati may now have a strong case for superiority.

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President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

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The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.

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Today, we’re highlighting some of the data releases that flew under the radar at #ESMO21 — whether from early-stage drugs looking to make a mark or older stalwarts with interesting follow-up data.

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AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

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Merck Research Laboratories CMO Roy Baynes

Mer­ck­'s Keytru­da un­corks full da­ta on lat­est ad­ju­vant win — this time in melanoma — adding bricks to ear­ly can­cer wall

In recent months, the battle for PD-(L)1 dominance has spilled over into early cancer with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo all alone on the front lines. Keytruda now has another shell in its bandolier, and it could spell a quick approval.

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Mer­ck flesh­es out Keytru­da win in first-line cer­vi­cal can­cer, adding more fire­pow­er to its ear­ly can­cer push

Merck has worked hard to bring its I/O blockbuster Keytruda into earlier and earlier lines of therapy, and now the wonder drug appears poised to make a quick entry into early advanced cervical cancer.

A combination of Keytruda and chemotherapy with or without Roche’s Avastin cut the risk of death by 33% over chemo with or without Avastin (p=<0.001) in first-line patients with persistent, recurrent or metastatic cervical cancer, according to full data from the Phase III KEYNOTE-826 study presented Saturday at #ESMO21.