New­ly pro­posed, must-pass bi­par­ti­san leg­is­la­tion that pays the FDA over the next five years for its re­views of new med­ical prod­ucts may al­so in­clude new pro­vi­sions al­low­ing the FDA to re­quire con­fir­ma­to­ry tri­als to be un­der­way pri­or to grant­i­ng ac­cel­er­at­ed ap­provals.

The shift would spell bad news for com­pa­nies that win ac­cel­er­at­ed ap­provals but drag their feet in con­duct­ing the re­quired con­fir­ma­to­ry tri­als.

The House En­er­gy & Com­merce com­mit­tee's bill, nec­es­sary for the user fee reau­tho­riza­tions to be com­plet­ed by the end of Sep­tem­ber, would al­so stream­line the FDA's abil­i­ty to with­draw ac­cel­er­at­ed ap­provals when con­fir­ma­to­ry tri­als fail.

Leav­ing any hint of par­ti­san­ship to the dust, the sub­com­mit­tee on health of the House­'s en­er­gy and com­merce com­mit­tee came to­geth­er across both sides of the aisle to sup­port not on­ly the user fee reau­tho­riza­tions that pro­vide for the ma­jor­i­ty of FDA's bud­get, but al­so the add-on bills that would re­form the agen­cy's ac­cel­er­at­ed ap­proval path­way among oth­er mea­sures.

On the ac­cel­er­at­ed ap­proval front, the bill, which ad­vanced to the full com­mit­tee next week by a unan­i­mous vote of 30-0, would al­low the FDA to re­quire con­fir­ma­to­ry tri­als to be un­der­way pri­or to grant­i­ng these ap­provals as part of re­forms to shore up com­pa­nies that drag their feet on such tri­als. It would al­so stream­line the FDA’s abil­i­ty to with­draw ac­cel­er­at­ed ap­provals when con­fir­ma­to­ry tri­als fail, and it re­quires the agency to ex­plain it­self when not re­quir­ing a con­fir­ma­to­ry tri­al.

Kick­ing off with an up­beat tone at Wednes­day's markup, sub­com­mit­tee chair An­na Es­hoo (D-CA) said that the House can pass these user fee reau­tho­riza­tions and the ad­di­tion­al bills "with plen­ty time" be­fore the fi­nal Sep­tem­ber dead­line.

Like col­leagues on both side of the aisle, Es­hoo praised the clin­i­cal tri­al di­ver­si­ty rid­er pro­vi­sions in the bill, as well as oth­ers that the FDA needs to catch up with its 2-year in­spec­tion back­log, and on lev­el­ing the play­ing field for US and for­eign in­spec­tions.

How­ev­er, one of the few groups tak­ing is­sue with the cur­rent rid­ers in the House is the in­dus­try lob­by­ing group PhRMA.

Phar­ma­cy ben­e­fit man­agers ⁠— the much-ma­ligned mid­dle­men of the phar­ma­ceu­ti­cal sup­ply chain ⁠— took the brunt of ques­tion­ing from sen­a­tors on both sides of the aisle on Thurs­day at a com­merce com­mit­tee hear­ing.

Echo­ing re­cent and sim­i­lar ques­tions from the FTC, front and cen­ter at the Sen­ate hear­ing were the an­ti-com­pet­i­tive prac­tices of PBMs, like ar­ti­fi­cial­ly in­flat­ing the list prices of cer­tain drugs while col­lect­ing a grow­ing por­tion of re­bates, and in­creas­ing out-of-pock­et costs for con­sumers along the way.

Sen. Richard Blu­men­thal (D-CT) of­fered sev­er­al re­al life ex­pe­ri­ences show­ing how PBMs have had a detri­men­tal im­pact on peo­ple's lives. He of­fered the ex­am­ple of a woman in Con­necti­cut who told his of­fice that PBMs got in the way of her tak­ing her nec­es­sary can­cer drugs pri­or to the ap­proval of a gener­ic ver­sion, which had high­er out-of-pock­et costs.

"What we see in the re­al world is that pa­tients don't have ac­cess to drugs at af­ford­able prices and the kinds of leg­is­la­tion we've in­tro­duced are re­spond­ing to a felt need in the re­al world. I've heard mul­ti­ple sto­ries of can­cer pa­tients be­ing de­nied cov­er­age," Blu­men­thal said.

Robin Feld­man, a wit­ness at the hear­ing and pro­fes­sor at the UC Hast­ings Col­lege of Law, ex­plained how PBM­s' in­ter­ests are best served when list prices are high.

"Every­one is ben­e­fit­ing oth­er than the con­sumer," Feld­man said in ex­plain­ing the var­i­ous stake­hold­ers.

So what to do? Right now, both Con­gress and the FTC seem keen to just shine a brighter light on the in­dus­try as a whole.

The FDA's top vac­cine leader told a con­gres­sion­al com­mit­tee on Fri­day af­ter­noon that al­though the adult vac­cines had to meet a 50% thresh­old for ef­fi­ca­cy against Covid-19 in­fec­tions, that same stan­dard will not need to be met for the vac­cines for the youngest group of chil­dren, for which a vac­cine is not yet avail­able.

The agency is cur­rent­ly re­view­ing da­ta from Mod­er­na's two-shot vac­cine for this youngest group as it awaits fur­ther da­ta from Pfiz­er on its po­ten­tial three-dose shot. Mod­er­na has said its vac­cine is 51% ef­fec­tive in chil­dren 6 months to 2 years of age and 37% ef­fec­tive in 2- to 5-year-olds. The agency al­so pre­vi­ous­ly sched­uled and then can­celed an ad­comm to re­view da­ta on two dos­es of Pfiz­er's vac­cine for chil­dren un­der the age of 5.

Ac­cord­ing to a read­out of the meet­ing from the House se­lect sub­com­mit­tee on the coro­n­avirus cri­sis, Marks ex­plained that the FDA would not with­hold au­tho­riza­tion — de­spite pre­vi­ous guid­ance — for a pe­di­atric vac­cine sole­ly be­cause it did not reach a 50% ef­fi­ca­cy thresh­old at block­ing symp­to­matic in­fec­tions. All of the oth­er adult and chil­dren's vac­cines cur­rent­ly au­tho­rized in the US have lost sig­nif­i­cant amounts of ef­fi­ca­cy due to the Omi­cron vari­ant, but they still re­main ef­fec­tive at re­duc­ing the risk of se­vere dis­ease, hos­pi­tal­iza­tion and death.

"If these vac­cines seem to be mir­ror­ing ef­fi­ca­cy in adults and just seem to be less ef­fec­tive against Omi­cron like they are for adults, we will prob­a­bly still au­tho­rize," Marks said.

As man­u­fac­tur­ing-re­lat­ed is­sues con­tin­ue to plague the bio­phar­ma in­dus­try and lead to dozens or more FDA re­jec­tions, or CRLs, each year, the agency on Mon­day re­leased new draft guid­ance spelling out how it as­sess­es qual­i­ty risks, sources of un­cer­tain­ty, and pos­si­ble mit­i­ga­tion strate­gies.

The FDA's prod­uct qual­i­ty as­sess­ment, ac­cord­ing to the 12-page draft, de­ter­mines whether an ap­pli­cant’s prod­uct de­vel­op­ment stud­ies, man­u­fac­tur­ing process, and con­trol strat­e­gy will con­sis­tent­ly re­sult in a fin­ished drug or bi­o­log­ic of ac­cept­able qual­i­ty when man­u­fac­tured at the fa­cil­i­ties named in the ap­pli­ca­tion.

"Typ­i­cal sources of prod­uct qual­i­ty-re­lat­ed un­cer­tain­ty may in­clude, but are not lim­it­ed to, gaps in cur­rent knowl­edge, such as pro­ject­ing per­for­mance at the end of shelf life based on ex­trap­o­la­tion giv­en the lim­it­ed sta­bil­i­ty da­ta pro­vid­ed for small mol­e­cule drug prod­ucts," the agency ex­plains, adding:

While point­ing to ICH's Q9 guide­line, the agency says that it con­ducts an in­ter­dis­ci­pli­nary as­sess­ment in which mem­bers of FDA's clin­i­cal, prod­uct qual­i­ty, non­clin­i­cal, phar­ma­col­o­gy, and bio­sta­tis­tics teams as­sess the rel­e­vant parts of an ap­pli­ca­tion and pro­vide key in­puts in­to the over­all ben­e­fits and risks.

The agency al­so of­fers sev­er­al ex­am­ples while ex­plain­ing that there's a cer­tain lev­el of flex­i­bil­i­ty as the agen­cy's un­der­stand­ing of the ther­a­peu­tic con­text and the clin­i­cal ben­e­fit may in­form the prod­uct qual­i­ty as­sess­ment and its con­clu­sions.

Gener­ic drugs rep­re­sent the vast ma­jor­i­ty of all drugs pre­scribed in the US.

But in some unique cas­es, the FDA ac­knowl­edges that there are doc­tors who are con­cerned about drugs with a nar­row ther­a­peu­tic win­dow (i.e., as the FDA says, "drugs where small dif­fer­ences in dose or blood con­cen­tra­tion may lead to se­ri­ous ther­a­peu­tic fail­ures or ad­verse drug re­ac­tions"), and there­fore may be more like­ly to pre­scribe brand-name prod­ucts over gener­ics in some cas­es.

But in one in­stance, where the Amer­i­can Thy­roid As­so­ci­a­tion (ATA) rec­om­mends that gener­ics not be used in some in­stances when the thy­roid hor­mone levothy­rox­ine is used, the FDA is now point­ing to new FDA-fund­ed re­al-world re­search that shows how switch­ing be­tween gener­ics proved to be sim­i­lar to stick­ing with the brand-name coun­ter­part.

For the study, the re­searchers dove in­to an ad­min­is­tra­tive claims data­base that linked lab test mea­sures of thy­roid func­tion of pa­tients un­der­go­ing treat­ment for hy­pothy­roidism with levothy­rox­ine, iden­ti­fy­ing and match­ing two dif­fer­ent pop­u­la­tions to com­pare the ef­fects of gener­ic switch­ing to sin­gle-prod­uct use.

"Their con­clu­sion is that switch­ing among dif­fer­ent gener­ic levothy­rox­ine prod­ucts was not as­so­ci­at­ed with clin­i­cal­ly sig­nif­i­cant changes in thy­roid func­tion (as in­di­cat­ed by sub­group av­er­age serum thy­rotropin lev­el). The re­searchers’ con­clu­sion — al­though ful­ly con­sis­tent with FDA pre­cepts of bioe­quiv­a­lence and, at the phar­ma­cy lev­el, prod­uct in­ter­change­abil­i­ty it­self — con­flicts with cur­rent ATA guide­line rec­om­men­da­tions that warn clin­i­cians about po­ten­tial changes in thy­roid func­tion as­so­ci­at­ed with levothy­rox­ine prod­uct switch­ing," the agency ex­plained yes­ter­day.

While for­mal­ly an­nounc­ing the with­draw­al of the pe­riph­er­al T-cell lym­phoma (PT­CL) in­di­ca­tion for Bris­tol My­ers Squib­b's Is­to­dax (ro­midepsin) for in­jec­tion (the com­pa­ny made a sim­i­lar an­nounce­ment last sum­mer) on Fri­day, the agency al­so said it's pulling Teva's 505(b)(2) ap­pli­ca­tion, af­ter the can­cer drug failed its con­fir­ma­to­ry tri­al.

The fi­nal an­nounce­ment on the with­draw­al comes more than ten years af­ter the FDA ini­tial­ly grant­ed an ac­cel­er­at­ed ap­proval for Is­to­dax in PT­CL in 2011, re­veal­ing again just how long it can take the agency to fi­nal­ize such a with­draw­al, even when con­fir­ma­to­ry re­sults show fail­ure. The House En­er­gy & Com­merce com­mit­tee re­cent­ly in­tro­duced a mea­sure that would shore up that ac­cel­er­at­ed ap­proval with­draw­al process, but com­pa­nies will still be able to take re­quests for with­drawals be­fore ad­comms.

While nei­ther Te­va nor BMS re­quest­ed a hear­ing to dis­cuss these with­drawals with FDA, the agency is still grap­pling with a hear­ing for an­oth­er ac­cel­er­at­ed ap­proval for the con­tro­ver­sial preterm birth drug Mak­e­na that failed its con­fir­ma­to­ry tri­al. It's been al­most 18 months since the FDA rec­om­mend­ed the with­draw­al of Mak­e­na.

In the case of Is­to­dax, how­ev­er, the mi­cro-earn­er for Bris­tol My­ers still will be ap­proved for its oth­er in­di­ca­tion of cu­ta­neous T-cell lym­phoma in pa­tients who have re­ceived at least one pri­or sys­temic ther­a­py. The pull won’t make much of a dif­fer­ence in terms of the drug­mak­er’s top line, but the re­sults are no­table as part of an in­dus­try-wide reck­on­ing for can­cer drugs that earn the FDA’s ac­cel­er­at­ed nod and even­tu­al­ly flop con­fir­ma­to­ry stud­ies.

More Chi­nese biotech com­pa­nies are be­ing called out as the SEC re­leas­es a fresh batch of US-list­ed com­pa­nies that may, in a few years, be in breach of a new law and face the threat of delist­ing.

Ab­b­Vie-part­nered I-Mab, Covid-19 vac­cine mak­er Sino­vac, CAR-T de­vel­op­er Gra­cell Biotech­nolo­gies, Sanofi al­ly Ada­gene and lit­tle-known Burn­ing Rock Biotech have joined BeiGene, Hutchmed and Zai Lab in a group iden­ti­fied un­der the Hold­ing For­eign Com­pa­nies Ac­count­able Act.

The move was not un­ex­pect­ed. The HF­CAA stip­u­lates that any for­eign com­pa­ny au­dit­ed by a firm that a US non­prof­it called Pub­lic Com­pa­ny Ac­count­ing Over­sight Board is un­able to re­view for three con­sec­u­tive years needs to be delist­ed. And be­cause Chi­nese laws cur­rent­ly bar au­di­tors from pro­vid­ing re­views to US au­thor­i­ties, biotech com­pa­nies that strad­dle coun­try lines are stuck be­tween a rock and a hard place.

As Sino­vac ex­plained in a state­ment, its iden­ti­fi­ca­tion re­sult­ed from the fil­ing of its an­nu­al re­port, which pro­vid­ed in­for­ma­tion about its au­di­tor, “sim­i­lar to oth­er com­pa­nies that have al­so been iden­ti­fied.”

“SINO­VAC has pre­vi­ous­ly dis­closed that its au­di­tor, the in­de­pen­dent reg­is­tered pub­lic ac­count­ing firm that is­sued the au­dit re­port in­clud­ed in its an­nu­al re­port filed with the SEC, is in a ju­ris­dic­tion cur­rent­ly list­ed as not be­ing able to be ful­ly in­spect­ed by the PCAOB, and thus the iden­ti­fi­ca­tion was ex­pect­ed,” the com­pa­ny wrote. “SINO­VAC will con­tin­ue to close­ly mon­i­tor de­vel­op­ments and ex­plore op­tions in re­la­tion to the HF­CAA.”

It stopped short of sug­gest­ing that it will con­sid­er chang­ing au­di­tors to skirt the prob­lem, some­thing Zai Lab, BeiGene and I-Mab al­ready did.

Cas­es of a syn­drome with rare and life-threat­en­ing blood clots in com­bi­na­tion with low lev­els of blood platelets war­rant lim­it­ing the au­tho­rized use of J&J's Covid-19 vac­cine, the FDA said Thurs­day.

The agency said it con­firmed a to­tal of 60 cas­es of what's known as throm­bo­sis with throm­bo­cy­tope­nia syn­drome, or TTS, in­clud­ing 9 deaths re­port­ed to the agen­cy's Vac­cine Ad­verse Event Re­port­ing Sys­tem, out of about 8 mil­lion dos­es of the one-dose shot ad­min­is­tered.

"Cas­es of TTS fol­low­ing ad­min­is­tra­tion of the Janssen COVID-19 Vac­cine have been re­port­ed in males and fe­males, in a wide age range of in­di­vid­u­als 18 years and old­er, with the high­est re­port­ing rate (ap­prox­i­mate­ly 8 cas­es per 1,000,000 dos­es ad­min­is­tered) in fe­males ages 30-49 years; over­all, ap­prox­i­mate­ly 15% of TTS cas­es have been fa­tal," the agency said in an up­dat­ed fact sheet for health care providers. "Cur­rent­ly avail­able ev­i­dence sup­ports a causal re­la­tion­ship be­tween TTS and the Janssen COVID-19 Vac­cine."

But the FDA al­so said, fol­low­ing sim­i­lar com­ments from CD­C's ad­vi­so­ry com­mit­tee in De­cem­ber, the vac­cine can still be avail­able for those whom oth­er au­tho­rized or ap­proved Covid-19 vac­cines (i.e. Pfiz­er/BioN­Tech's and Mod­er­na's mR­NA vac­cines) are not ac­ces­si­ble or clin­i­cal­ly ap­pro­pri­ate, and to adults who elect to re­ceive the Janssen vac­cine be­cause they would oth­er­wise not re­ceive a Covid vac­cine at all.

“We rec­og­nize that the Janssen COVID-19 Vac­cine still has a role in the cur­rent pan­dem­ic re­sponse in the Unit­ed States and across the glob­al com­mu­ni­ty. Our ac­tion re­flects our up­dat­ed analy­sis of the risk of TTS fol­low­ing ad­min­is­tra­tion of this vac­cine and lim­its the use of the vac­cine to cer­tain in­di­vid­u­als,” Pe­ter Marks, di­rec­tor of the FDA’s Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search, said in a state­ment.

Don't be alarmed: The FDA said Wednes­day that it's aware some Covid-19 pa­tients may see a reemer­gence of symp­toms af­ter com­plet­ing a treat­ment course of Pfiz­er's pill Paxlovid.

In some of these cas­es, Covid pa­tients even test­ed neg­a­tive and then pos­i­tive again.

But the agency is stop­ping short of mak­ing any new rec­om­men­da­tions re­gard­ing Paxlovid, and in­stead in­di­rect­ly re­fut­ed what Pfiz­er CEO Al­bert Bourla said on yes­ter­day's quar­ter­ly earn­ings call, and what an­oth­er ex­pert wrote in one of the New Eng­land Jour­nal of Med­i­cine's blogs.

While men­tion­ing this "re­bound" of symp­toms, Bourla told in­vestors "that was why the la­bel speaks about the sec­ond treat­ment that can be giv­en." A spokesper­son lat­er clar­i­fied to End­points News that Paxlovid's la­bel "does not pre­clude sub­se­quent pre­scrip­tions." Sim­i­lar­ly, Paul Sax, pro­fes­sor of med­i­cine at Har­vard, wrote to­day in an NE­JM blog that "the FDA and Pfiz­er have made it clear that the peo­ple who re­lapse are in fact el­i­gi­ble for re-treat­ment."

But the FDA is now say­ing that's not the case, in­stead telling health care providers on Wednes­day:

Af­ter re­ceiv­ing com­plaints from the SEC last spring, Bio­gen changed the way it re­ports up­front pay­ments to col­lab­o­ra­tors in its quar­ter­ly up­dates. But it ap­pears Bio­gen wasn’t the on­ly one who got the mes­sage.

Sev­er­al phar­ma gi­ants — in­clud­ing Eli Lil­ly, Mer­ck, Bris­tol My­ers Squibb, Ab­b­Vie and Pfiz­er — are mak­ing sim­i­lar changes in this year’s Q1 re­sults, ac­cord­ing to Mar­ket Watch, which first re­port­ed the news. The changes re­volve around cer­tain fig­ures that don’t com­ply with Gen­er­al­ly Ac­cept­ed Ac­count­ing Prin­ci­ples, al­so known as non-GAAP mea­sures.

Last March, the SEC ex­pressed con­cern over Bio­gen's ex­clu­sion of up­front pay­ments and pre­mi­ums paid for eq­ui­ty stakes from its non-GAAP R&D ex­pense and net in­come re­ports. In its re­sponse, Bio­gen said it ex­clud­ed those fig­ures to “bet­ter re­flect our core op­er­at­ing per­for­mance.”

“We be­lieve that ma­te­r­i­al up­front pay­ments and pre­mi­ums paid for the ac­qui­si­tion of re­lat­ed com­mon stock as­so­ci­at­ed with sig­nif­i­cant col­lab­o­ra­tive and li­cens­ing arrange­ments dif­fer from the nor­mal, re­cur­ring, cash ex­pens­es nec­es­sary to op­er­ate our busi­ness,” Bio­gen wrote in a let­ter back to the SEC.

The com­pa­ny added that non-GAAP met­rics are mere­ly sup­ple­ments to GAAP state­ments, and that it does not be­lieve its pre­sen­ta­tion of non-GAAP in­for­ma­tion was mis­lead­ing.

A month lat­er, the SEC re­spond­ed that Bio­gen’s ex­clu­sion of cer­tain pay­ments was “in­con­sis­tent” with SEC guid­ance, and be­gin­ning in the sec­ond quar­ter of 2021, the com­pa­ny be­gan in­clud­ing those fig­ures. Just this past quar­ter, Bio­gen al­so be­gan in­clud­ing ma­te­r­i­al pay­ments made on the ac­qui­si­tion of in-process R&D as­sets in its de­ter­mi­na­tion of non-GAAP net in­come.

AT-GAA, Am­i­cus Ther­a­peu­tics’ lead Phase III drug for Pompe dis­ease, was at the cen­ter of at­ten­tion dur­ing the Q1 call with in­vestors Mon­day. Ex­ecs talked about their high hopes for an ap­proval by the Ju­ly 29 PDU­FA date, and an­a­lysts were ask­ing ques­tions about launch prepa­ra­tion.

The FDA, though, needs more time to make a de­ci­sion.

Just af­ter the mar­ket closed on Tues­day, Am­i­cus put out word that the FDA has pushed back its re­view pe­ri­od by 90 days. The agency was deal­ing with two sep­a­rate ap­pli­ca­tions — a BLA for cipaglu­cosi­dase al­fa and an NDA for miglu­s­tat — for the two com­po­nents of AT-GAA, with PDU­FA dates sched­uled two months apart.

The de­lay marks an­oth­er speed bump for Am­i­cus, which was forced to call off a spin­out of its gene ther­a­py unit via a SPAC merg­er in the wake of a set­back.

By com­bin­ing a re­com­bi­nant hu­man acid α-glu­cosi­dase with an en­zyme sta­bi­liz­er, Am­i­cus had hoped it could bring a next-gen ap­proach to pa­tients with Pompe dis­ease. Al­though the drug, which was be­stowed break­through ther­a­py des­ig­na­tion, failed to beat Lu­mizyme, Sanofi’s en­zyme re­place­ment ther­a­py, in a Phase III tri­al, the biotech pushed ahead cit­ing (sta­tis­ti­cal­ly in­signif­i­cant) im­prove­ments in fa­vor of AT-GAA.

Am­i­cus said the FDA is still re­view­ing new­ly sub­mit­ted in­for­ma­tion as part of on­go­ing re­views, but that it is not re­lat­ed to re­quests for ad­di­tion­al clin­i­cal da­ta.

Be­sides, they not­ed, the ad­di­tion­al time should al­low for the agency to in­spect the man­u­fac­tur­ing sites of WuXi Bi­o­log­ics, its con­tract man­u­fac­tur­er, in Chi­na. Un­cer­tain­ty around that in­spec­tion had been a key caveat for ex­ecs who were oth­er­wise up­beat about an OK.