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.


Zachary Brennan

managing editor, RAPS

John Chiminski, Catalent CEO - File Photo

'It's a growth play': Catal­ent ac­quires Bris­tol-My­er­s' Eu­ro­pean launch pad, ex­pand­ing glob­al CD­MO ops

Catalent is staying on the growth track.

Just two months after committing $1.2 billion to pick up Paragon and take a deep dive into the sizzling hot gene therapy manufacturing sector, the CDMO is bouncing right back with a deal to buy out Bristol-Myers’ central launchpad for new therapies in Europe, acquiring a complex in Anagni, Italy, southwest of Rome, that will significantly expand its capacity on the continent.

There are no terms being offered, but this is no small deal. The Anagni campus employs some 700 staffers, and Catalent is planning to go right in — once the deal closes late this year — with a blueprint to build up the operations further as they expand on oral solid, biologics, and sterile product manufacturing and packaging.

This is an uncommon deal, Catalent CEO John Chiminski tells me. But it offers a shortcut for rapid growth that cuts years out of developing a green fields project. That’s time Catalent doesn’t have as the industry undergoes unprecedented expansion around the world.

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In­vestor day prep at Mer­ck in­cludes a new strat­e­gy to pick up the pace on M&A — re­port

Mer­ck’s re­cent deals to buy up two bolt-on biotechs — Ti­los and Pelo­ton — weren’t an aber­ra­tion. In­stead, both ac­qui­si­tions mark a new strat­e­gy to beef up its dom­i­nant can­cer drug op­er­a­tions cen­tered on Keytru­da while look­ing to ad­dress grow­ing con­cerns that too many of its eggs are in the one I/O bas­ket for their PD-1 pro­gram. And Mer­ck is go­ing af­ter more small- and mid-sized buy­outs to calm those fears.

The top 10 block­buster drugs in the late-stage pipeline — Eval­u­ate adds 6 new ther­a­pies to heavy-hit­ter list

Vertex comes in for a substantial amount of criticism for its no-holds-barred tactical approach toward wresting the price it wants for its commercial drugs in Europe. But the flip side of that coin is a highly admired R&D and commercial operation that regularly wins kudos from analysts for their ability to engineer greater cash flow from the breakthrough drugs they create.

Both aspects needed for success in this business are on display in the program backing Vertex’s triple for cystic fibrosis. VX-659/VX-445 + Tezacaftor + Ivacaftor — it’s been whittled down to 445 now — was singled out by Evaluate Pharma as the late-stage therapy most likely to win the crown for drug sales in 5 years, with a projected peak revenue forecast of $4.3 billion.

The latest annual list, which you can see here in their latest world preview, includes a roster of some of the most closely watched development programs in biopharma. And Evaluate has added 6 must-watch experimental drugs to the top 10 as drugs fail or go on to a first approval. With apologies to the list maker, I revamped this to rank the top 10 by projected 2024 sales, instead of Evaluate's net present value rankings.

It's how we roll at Endpoints News.

Here is a quick summary of the rest of the top 10:

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Dave Barrett, Brian Chee, Amir Nashat, Amy Schulman. Polaris

Bob Langer's first port of call — Po­laris Part­ners — maps $400M for ninth fund

Health and tech ven­ture group Po­laris Part­ners, which counts Alec­tor, Al­ny­lam and Ed­i­tas Med­i­cine as part of its port­fo­lio, is set­ting up its ninth fund, rough­ly two years af­ter it closed Po­laris VI­II with $435 mil­lion in the bank, sur­pass­ing its tar­get by $35 mil­lion.

The Boston-based firm, in an SEC fil­ing, said it in­tends to raise $400 mil­lion for the fund. Po­laris — which rou­tine­ly backs com­pa­nies mold­ed out of the work done in the lab of pro­lif­ic sci­en­tist Bob Langer of MIT  — typ­i­cal­ly in­vests ear­ly, and sticks around till com­pa­nies are in the green. Like its peers at Flag­ship and Third Rock, Po­laris is all about cham­pi­oning the lo­cal biotech scene with a steady flow of start­up cash.

Partners Innovation Fund

David de Graaf now has his $28.5M launch round in place, build­ing a coen­zyme A plat­form in his lat­est start­up

Long­time biotech ex­ec David de Graaf has the cash he needs to set up the pre­clin­i­cal foun­da­tion for his coen­zyme A me­tab­o­lism com­pa­ny Comet. A few high-pro­file in­vestors joined the ven­ture syn­di­cate to sup­ply Comet with $28.5 mil­lion in launch mon­ey — enough to get it two years in­to the plat­form-build­ing game, with­in knock­ing dis­tance of the clin­ic.

Canaan jumped in along­side ex­ist­ing in­vestor Sofinno­va Part­ners to co-lead the round, with par­tic­i­pa­tion by ex­ist­ing in­vestor INKEF Cap­i­tal and new in­vestor BioIn­no­va­tion Cap­i­tal.

Step­ping on Roche's toes, Mer­ck cuts in­to SCLC niche with third-line Keytru­da OK

In the in­creas­ing­ly crowd­ed check­point race, small cell lung can­cer has been a rare area where Roche, a sec­ond run­ner-up, has a lead over the en­trenched lead­ers Mer­ck and Bris­tol-My­ers Squibb. But Mer­ck is fi­nal­ly mak­ing some head­way in that di­rec­tion with the lat­est ap­proval for its PD-1 star.

The lat­est green light en­dors­es Keytru­da in the third-line treat­ment of metasta­t­ic SCLC, where it would be giv­en to pa­tients whose dis­ease ei­ther don’t re­spond to or re­lapse af­ter chemother­a­py, which would have fol­lowed at least one pri­or line of ther­a­py.

Right back at you, Pfiz­er: BeiGene and a Pfiz­er spin­out launch a new­co to de­vel­op a MEK/BRAF in­hibitor that could ri­val $11.4B com­bo

A day af­ter Pfiz­er bought Ar­ray and its ap­proved can­cer com­bo, BeiGene and Pfiz­er spin­out Spring­Works have part­nered in launch­ing a new biotech that has an eye on the very same mar­ket the phar­ma gi­ant just paid bil­lions for. And they’re plan­ning on us­ing an ex-Pfiz­er drug to do it.

In a nut­shell, Chi­na’s BeiGene is toss­ing in a pre­clin­i­cal BRAF in­hibitor — BGB-3245, which cov­ers both V600 and non-V600 BRAF mu­ta­tions — for a big stake in a new, joint­ly con­trolled biotech called Map­Kure with Bain-backed Spring­Works.

Sanofi aligns it­self with Google to stream­line drug de­vel­op­ment

Tech­nol­o­gy is bleed­ing in­to health­care, and big phar­ma is rid­ing the wave. Sanofi $SNY ap­point­ed its first chief dig­i­tal of­fi­cer this Feb­ru­ary, fol­low­ing the foot­steps of its peers. By May, the French drug­mak­er and some of its big phar­ma com­pa­tri­ots joined forces with Google par­ent Al­pha­bet’s Ver­i­ly unit to aug­ment clin­i­cal tri­al re­search. On Tues­day, the Parisian com­pa­ny tied up with Google to ac­cess its cloud com­put­ing and ar­ti­fi­cial in­tel­li­gence tech to spur the de­vel­op­ment of new ther­a­pies.

Af­ter watch­ing its share price soar on a Bloomberg re­port and heat­ed ru­mors, Bio­haven stock takes a bil­lion-dol­lar bath

Back in April, Biohaven Pharmaceutical became one hot biotech stock $BHVN based on a report in Bloomberg that some “potential bidders” had been kicking the tires at the biotech, which has a lead drug for migraines. Then the rumor mill really started to smoke when execs canceled a presentation at an investor conference a little more than a week ago.

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