An FDA re­form agen­da: What would Com­mis­sion­er Scott Got­tlieb do in his first six months?

An ac­cel­er­at­ed ap­proval path­way for com­plex gener­ics, em­brac­ing killer apps, pub­lish­ing CRLs and a swift kick in the lead­er­ship at the FDA all fig­ure promi­nent­ly.

Pres­i­dent Trump has made it clear that he’s look­ing for a rev­o­lu­tion at the FDA, which in turn has raised fears that he’ll ap­point a rev­o­lu­tion­ary dereg­u­la­tor as com­mis­sion­er who will blow up a well es­tab­lished gold stan­dard on drug ap­provals.

Scott Got­tlieb

The on­ly name which has sur­faced as a se­ri­ous con­tender for the top job at the FDA who would al­so be wel­comed by most peo­ple in the bio­phar­ma in­dus­try is Scott Got­tlieb, a for­mer deputy com­mis­sion­er for pol­i­cy un­der George W. Bush, con­ser­v­a­tive com­men­ta­tor and lon­grun­ning crit­ic of the agency as it was han­dled un­der the Oba­ma ad­min­is­tra­tion.

As a lead­ing con­tender for this job, Got­tlieb’s nom­i­na­tion would con­form to the tra­di­tion of hav­ing a trained physi­cian in the com­mis­sion­er’s of­fice. And he would al­so be com­ing in as a re­former with an un­der­stand­ing of the in­ner work­ings at the FDA, able to swift­ly ex­e­cute a se­ries of changes that would meet Trump’s stat­ed goal of ac­cel­er­at­ing ap­provals and dra­mat­i­cal­ly low­er­ing some drug prices.

Like the rest of the se­ri­ous prospec­tive can­di­dates for this job, Got­tlieb has been keep­ing a low pub­lic pro­file, de­clin­ing re­quests for in­ter­views. Try­ing to ar­gue over a spe­cif­ic agen­da in news­pa­pers or on TV would on­ly threat­en his chances for the nom­i­na­tion, which in­sid­ers say is still like­ly weeks away.

But in a re­view of his pub­lic re­marks and back­ground dis­cus­sions with peo­ple fa­mil­iar with Got­tlieb’s think­ing, I’ve as­sem­bled a to-do list that would like­ly fig­ure promi­nent­ly in Got­tlieb’s first six months at the FDA.

Even if he doesn’t get the tap, Got­tlieb has laid out agency re­forms that would like­ly fig­ure promi­nent­ly at the FDA over the next four years; a mid­dle way be­tween an­ar­chy and a brit­tle, bu­reau­crat­ic sta­tus quo, re­vis­ing but not dis­man­tling the agency’s in­sis­tence that any new drug that hits the mar­kets has a clear risk/ben­e­fit pro­file for physi­cians and pa­tients to con­sid­er.

Easy pick­ings?

Got­tlieb does have some low hang­ing fruit to go af­ter, with a Re­pub­li­can con­trolled House and Sen­ate that are like­ly will­ing to go along.

First task: Re­form FDA rules for ap­prov­ing com­plex gener­ics. While most of the re­form­ers have con­cen­trat­ed on a back­log of thou­sands of ap­pli­ca­tions for gener­ic drugs, Got­tlieb has been say­ing for a few years now that the agency needs to have more flex­i­bil­i­ty in ap­prov­ing gener­ic ver­sions of com­plex ther­a­peu­tics, a mid­dle ground be­tween the sim­ple small mol­e­cule knock­offs that are rel­a­tive­ly easy to get through the FDA and biosim­i­lars, which have a spe­cif­ic ap­proval path­way.

These drugs in­clude some of the world’s biggest block­busters, in­clud­ing Co­pax­one and Ad­vair, which are on­ly now on the verge of see­ing re­al gener­ic com­pe­ti­tion long af­ter los­ing patent pro­tec­tion. But there’s a long list of these com­plex gener­ics that can be sped along — pro­vid­ed the Com­mis­sion­er can get the leg­is­la­tion need­ed to do that.

“Con­gress should con­sid­er leg­is­la­tion to mod­ern­ize the gener­ic drug frame­work to al­low FDA greater dis­cre­tion in the kinds of da­ta it re­lies on for its gener­ic ap­provals in this nar­row cat­e­go­ry of com­plex drugs,” Got­tlieb told a Sen­ate com­mit­tee in Oc­to­ber 2016, tes­ti­mo­ny that was high­light­ed in a note by Ja­mi Ru­bin at Gold­man Sachs a few days ago. “This would re­quire, for ex­am­ple, grant­i­ng FDA the abil­i­ty to ask for more than just bioe­quiv­a­lence and bioavail­abil­i­ty da­ta in mak­ing judg­ments around same­ness.”

“Con­gress should be tapped to give FDA the lat­i­tude to look at the sci­ence nec­es­sary to make com­fort­able and re­li­able de­ter­mi­na­tions,” he wrote in a col­umn for Forbes back in 2015. Com­mis­sion­er Got­tlieb work­ing with the Trump ad­min­is­tra­tion and bi­par­ti­san sup­port­ers in Con­gress could make short work of this.

Got­tlieb has said in the past that leg­is­la­tion is need­ed, but an ag­gres­sive com­mis­sion­er could go a long way to clear­ing the path for com­plex gener­ics. So look for some quick, broad guid­ance that would give de­vel­op­ers a clear reg­u­la­to­ry path for the class, toss­ing aside the more cum­ber­some case-by-case method that has been in use — of­ten long af­ter these ri­vals could have made it to the mar­ket.

The ad­van­tage here is that Got­tlieb could have a dra­mat­ic im­pact in a short pe­ri­od, point­ing to an ac­com­plish­ment that would earn a lot of sup­port from the pub­lic as well as law­mak­ers — even as in­di­vid­ual drug­mak­ers try to qui­et­ly spear any such threat to their own block­busters. Just pick­ing off the top 10 com­plex gener­ics would re­duce costs by bil­lions, ush­er­ing in new com­pe­ti­tion.

Chang­ing the rules on com­plex gener­ics to fa­cil­i­tate ap­provals while go­ing af­ter the back­log in gener­ics in gen­er­al will re­quire the agency to at least fill its emp­ty po­si­tions. That will re­quire an ear­ly ex­cep­tion to the pres­i­dent’s hir­ing freeze.

Get with the BTD pro­gram

Got­tlieb has been an un­abashed ad­mir­er of what FDA can­cer czar Rick Paz­dur has ac­com­plished with the break­through ther­a­py des­ig­na­tion when it comes to new can­cer drug ap­provals. On­col­o­gy R&D has been trans­formed over the past three years. De­vel­op­ment time­lines have been stream­lined and cut, in some cas­es by years, as reg­u­la­tors took a more flex­i­ble ap­proach to as­sess­ing da­ta and med­ical needs for dy­ing pa­tients.

But he isn’t at all sat­is­fied that the en­tire agency has got­ten with the BTD pro­gram. And he’s like­ly to ad­dress that quick­ly, putting in a team of reg­u­la­tors tasked with ramp­ing up the re­view process in spe­cif­ic di­vi­sions that have lagged be­hind.

This is not a top­ic that Got­tlieb has ad­dressed ex­ten­sive­ly in pub­lic over the past sev­en years, since a col­umn of his in the Wall Street Jour­nal cas­ti­gat­ed the FDA for stick­ing with bur­den­some tri­al re­quire­ments to land an ap­proval. Much has changed since then, which he has ac­knowl­edged. But much is still left to be done, a sub­ject he brought up last May in a speech he gave at IS­POR ti­tled “Ac­cel­er­at­ing Cures: Ad­dress­ing Un­met Pa­tient Need or Putting Pa­tients at Risk.”

In that speech, Got­tlieb fo­cused care­ful­ly on how the FDA han­dles new drugs for rare dis­eases. As re­searchers un­der­stand­ing of rare dis­eases has grown, he writes, it stands to rea­son that the FDA’s process for re­view­ing new drugs should speed up. But the re­verse hap­pened, as he il­lus­trat­ed with the reg­u­la­to­ry his­to­ry of Al­du­razyme, Hurler Syn­drome, or MPS 1. There are on­ly about 500 such pa­tients in the US.

Got­tlieb said:

As each of the sub­se­quent and dif­fer­ent en­zyme re­place­ment ther­a­pies tar­get­ing dis­tinct MPS dis­eases sought FDA ap­proval, the clin­i­cal tri­al re­quire­ments in­creased sub­stan­tial­ly. In oth­er words, as FDA got smarter about the mech­a­nism of these treat­ments, in­stead of us­ing that knowl­edge to stream­line de­vel­op­ment, the hur­dles grew sub­stan­tial­ly.

The use of bio­mark­ers as a sur­ro­gate end­point need­ed for a quick ap­proval is one way that the FDA can ad­vance.

The ex­per­tise at the FDA needs to be re­or­ga­nized, with a new ap­proach to eval­u­at­ing “tri­al de­sign, sta­tis­ti­cal analy­sis, and the prod­uct is­sues re­lat­ed to new plat­forms for pur­su­ing bi­o­log­i­cal tar­gets.”

(P)er­haps all drugs for ul­tra or­phan dis­eases should be re­viewed by a sep­a­rate di­vi­sion just fo­cused on these prod­ucts – a sort of skunk works for ul­tra or­phan prod­ucts — where there is more ex­per­tise in sta­tis­ti­cal ap­proach­es to clin­i­cal tri­al de­sign that in­volve open la­bel or sin­gle arm stud­ies that are some­times the on­ly fea­si­ble ap­proach in these dis­ease set­tings. Con­sul­tants from the rel­e­vant clin­i­cal re­view di­vi­sion could in­form the clin­i­cal as­pects of the re­view. Right now, it’s the clin­i­cal re­view di­vi­sion that dri­ves the process, with the ex­perts in the prod­uct and tri­al de­sign is­sues who serve as con­sul­tants to the process. This can en­able these oth­er con­sid­er­a­tions to be­come mar­gin­al­ized, even in cas­es where they are the more crit­i­cal and chal­leng­ing fea­tures.

New Bayesian ap­proach­es to sta­tis­ti­cal de­sign may help in cer­tain cas­es, he said. And Con­gress could spec­i­fy where FDA stan­dards could be ap­plied more flex­i­bly, help­ing reg­u­la­tors aban­don a rigid con­cep­tion that there’s one pre­em­i­nent stan­dard that has to be ap­plied in all cas­es.

The FDA al­so hasn’t just fa­cil­i­tat­ed new drug de­vel­op­ment over the last few years. It’s al­so added on new rules re­lat­ed to pre-mar­ket de­vel­op­ment, most no­tice­ably the car­dio­vas­cu­lar out­comes stud­ies for some new meds.

Those kinds of add-ons will be rolled back, mak­ing it less ex­pen­sive to get new di­a­betes drugs to the mar­ket — a big is­sue in that field — with a shift to post-mar­ket­ing stud­ies.

There’s a va­ri­ety of ways a new FDA un­der Got­tlieb could adopt new tech­nolo­gies and de­vel­op­ment de­signs that would both speed R&D ef­forts as well as low­er the front-end costs biotechs face to get through ear­ly-stage re­search. Mod­el­ing and sim­u­la­tion, not a new con­cept at the FDA, has al­ready been used to scale down the once epic scope of a de­vel­op­ment pro­gram. It’s helped in ear­ly dose se­lec­tion and iden­ti­fy­ing pa­tient sub­pop­u­la­tions most like­ly to ben­e­fit, in­clud­ing of­ten ne­glect­ed pe­di­atric pop­u­la­tions, that can be helped.

PDU­FA VI in­cludes a range of fea­tures aimed at speed­ing de­vel­op­ment, in­clud­ing the bet­ter use of bio­mark­ers, adap­tive tri­al de­signs and bet­ter use of all the var­i­ous FDA pro­grams for ac­cel­er­at­ing ap­provals, from BTD to or­phan drug des­ig­na­tions, which can al­so be more de­fined to avoid re­peats of de­flaza­cort, the Marathon steroid ap­proved for Duchenne MD and prices any­where from 50 to 70 times what it’s been sold for out­side the US.

Got­tlieb’s “killer apps”: get new de­vices on the mar­ket, mak­ing the FDA a fa­cil­i­ta­tor rather than an ob­sta­cle

Ap­ple’s Tim Cook has been gin­ger­ly walk­ing around the FDA when it comes to the new Ap­ple Watch and some of the health ap­pli­ca­tions he’s had in mind.

“We don’t want to put the watch through the Food and Drug Ad­min­is­tra­tion process,” Cook told The Tele­graph last fall. “I wouldn’t mind putting some­thing ad­ja­cent to the watch through it, but not the watch, be­cause it would hold us back from in­no­vat­ing too much, the cy­cles are too long. But you can be­gin to en­vi­sion oth­er things that might be ad­ja­cent to it — maybe an app, maybe some­thing else.”

You’ll find Google’s Ver­i­ly work­ing in the same space, for the same rea­sons, and with the same reg­u­la­to­ry con­cerns. Drug de­vel­op­ers have been in­creas­ing­ly whipped up about the op­por­tu­ni­ties here. Imag­ine a de­vice that could alert a pa­tient and physi­cian of heart risks, or a pend­ing episode of ma­jor de­pres­sion or schiz­o­phre­nia. How well are Parkin­son’s symp­toms be­ing con­trolled by a drug?

Ap­ples been play­ing a slow de­vel­op­ment game here, know­ing that they’re not go­ing to get any help from the FDA. That will have to change. The new FDA will make a point of open­ing up the reg­u­la­to­ry road­way on new med tech, en­cour­ag­ing play­ers like Ap­ple to dive deep­er.

And a per­son­al fa­vorite: Pub­lish­ing CRLs

Got­tlieb: “(T)he FDA should be re­quired to dis­close its rea­sons for re­ject­ing a drug.”

It’s a well known fact that de­vel­op­ers rou­tine­ly mis­rep­re­sent the con­tents of these re­jec­tion no­tices. Some big de­vel­op­ers, like Am­gen and No­var­tis, oc­ca­sion­al­ly don’t even both­er try­ing.

In his 2010 col­umn for the Wall Street Jour­nal, Got­tlieb signed off on his sup­port for that long-await­ed piece of re­form. Know­ing that the FDA will pub­lish these let­ters — or pro­vide the con­tents some oth­er way — would save a lot of time and grief spec­u­lat­ing about what’s hap­pen­ing. And it will keep de­vel­op­ers on the straight and nar­row path as they de­sign tri­als and map a reg­u­la­to­ry path­way most like­ly to suc­ceed.

The prospect of a pub­lic hang­ing at the FDA would fo­cus de­vel­op­ers’ minds won­der­ful­ly.

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

Fresh off Fer­Gene's melt­down, David Meek takes over at Mi­rati with lead KRAS drug rac­ing to an ap­proval

In the insular world of biotech, a spectacular failure can sometimes stay on any executive’s record for a long time. But for David Meek, the man at the helm of FerGene’s recent implosion, two questionable exits made way for what could be an excellent rebound.

Meek, most recently FerGene’s CEO and a past head at Ipsen, has become CEO at Mirati Therapeutics, taking the reins from founding CEO Charles Baum, who will step over into the role of president and head of R&D, according to a release.

Who are the women su­per­charg­ing bio­phar­ma R&D? Nom­i­nate them for this year's spe­cial re­port

The biotech industry has faced repeated calls to diversify its workforce — and in the last year, those calls got a lot louder. Though women account for just under half of all biotech employees around the world, they occupy very few places in C-suites, and even fewer make it to the helm.

Some companies are listening, according to a recent BIO survey which showed that this year’s companies were 2.5 times more likely to have a diversity and inclusion program compared to last year’s sample. But we still have a long way to go. Women represent just 31% of biotech executives, BIO reported. And those numbers are even more stark for women of color.

Jacob Van Naarden (Eli Lilly)

Ex­clu­sives: Eli Lil­ly out to crash the megablock­buster PD-(L)1 par­ty with 'dis­rup­tive' pric­ing; re­veals can­cer biotech buy­out

It’s taken 7 years, but Eli Lilly is promising to finally start hammering the small and affluent PD-(L)1 club with a “disruptive” pricing strategy for their checkpoint therapy allied with China’s Innovent.

Lilly in-licensed global rights to sintilimab a year ago, building on the China alliance they have with Innovent. That cost the pharma giant $200 million in cash upfront, which they plan to capitalize on now with a long-awaited plan to bust up the high-price market in lung cancer and other cancers that have created a market worth tens of billions of dollars.

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Vicente Anido (University of West Virginia via YouTube)

Aerie fires CEO af­ter lead pro­gram flop, com­ments about pri­ma­ry end­points be­ing 'not re­quired'

Aerie Pharmaceuticals CEO Vicente Anido has left the company less than a week after trying to chart a Phase III study in the wake of a serious Phase IIb flop.

Anido’s last day at Aerie was Friday, the biotech announced in a news release Tuesday morning, and Benjamin McGraw is taking his place in an interim role. The now former CEO was terminated without cause, according to an SEC filing.

The board has started looking for a full-time chief to take his place.

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When ef­fi­ca­cy is bor­der­line: FDA needs to get more con­sis­tent on close-call drug ap­provals, agency-fund­ed re­search finds

In the exceedingly rare instances in which clinical efficacy is the only barrier to a new drug’s approval, new FDA-funded research from FDA and Stanford found that the agency does not have a consistent standard for defining “substantial evidence” when flexible criteria are used for an approval.

The research comes as the FDA is at a crossroads with its expedited-review pathways. The accelerated approval pathway is under fire as the agency recently signed off on a controversial new Alzheimer’s drug, with little precedent to explain its decision. Meanwhile, top officials like Rick Pazdur have called for a major push to simplify and clarify all of the various expedited pathways, which have grown to be must-haves for sponsors of nearly every newly approved drug.

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Jay Bradner (Jeff Rumans for Endpoints News)

Div­ing deep­er in­to in­her­it­ed reti­nal dis­or­ders, No­var­tis gob­bles up an­oth­er bite-sized op­to­ge­net­ics biotech

Right about a year ago, a Novartis team led by Jay Bradner and Cynthia Grosskreutz at NIBR swooped in to scoop up a Cambridge, MA-based opthalmology gene therapy company called Vedere. Their focus was on a specific market niche: inherited retinal dystrophies that include a wide range of genetic retinal disorders marked by the loss of photoreceptor cells and progressive vision loss.

But that was just the first deal that whet their appetite.

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FDA hands ac­cel­er­at­ed nod to Seagen, Gen­mab's so­lo ADC in cer­vi­cal can­cer, but com­bo stud­ies look even more promis­ing

Biopharma’s resident antibody-drug conjugate expert Seagen has scored a clutch of oncology approvals in recent years, finding gold in what are known as “third-gen” ADCs. Now, another of their partnered conjugates is ready for prime time.

The FDA on Monday handed an accelerated approval to Seagen and Genmab’s Tivdak (tisotumab vedotin-tftv, or “TV”) in second-line patients with recurrent or metastatic cervical cancer who previously progressed after chemotherapy rather than PD-(L)1 systemic therapy, the companies said in a release.

Take­da snaps up the Japan­ese rights to an old Shire cast-off; Boehringer In­gel­heim ac­quires Abexxa Bi­o­log­ics

A week before the FDA is set to decide on Mirum Pharmaceuticals’ lead liver disease drug — an old Shire cast-off called maralixibat — Takeda is swooping in to secure the rights in Japan.

Maralixibat’s roots trace back to Lumena, which was snapped up by Shire for $260 million-plus back in 2014. While the candidate had failed mid-stage studies at Shire, Mirum believes better trial design and patient selection will deliver the wins it needs. The drug is currently in development for Alagille syndrome (a condition called ALGS in which bile builds up in the liver), progressive familial intrahepatic cholestasis (PFIC, which causes progressive liver disease) and biliary atresia (a blockage in the ducts that carry bile from the liver to the gallbladder).