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.

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

Jim Scholefield via PR Newswire

Mer­ck los­es its chief dig­i­tal of­fi­cer, spot­light­ing tal­ent hunt for the hottest ti­tle in Big Phar­ma

Over the last few years we’ve seen the chief digital officer title become one of the hottest commodities in Big Pharma as global organizations hunt the best talent to sharpen the cutting edge of their tech platforms.

But Merck just discovered how hard it may be to keep them focused on pharma.

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Tim Mayleben (file photo)

Es­pe­ri­on's goldilocks cho­les­terol fight­er wins FDA ap­proval — will its 'tra­di­tion­al' pric­ing ap­proach spur adop­tion?

It’s more effective than decades-old statins but not as good as the injectable PCSK9 — the goldilocks treatment for cholesterol-lowering, bempedoic acid, has secured FDA approval.

Its maker, Esperion Therapeutics, is betting that their pricing strategy — a planned list price of between $10 to $11 a day — will help it skirt the pushback the PCSK9 cholesterol fighters, Repatha and Praluent, got from payers for their high sticker prices.

The sky-high expectations for the pair of PCSK9 drugs that were first approved in 2015 quickly simmered — and despite a 60% price cut, coupled with data showing the therapies also significantly cut cardiovascular risk, sales have not really perked up.

Esperion is convinced that by virtue of being a cheaper oral therapy, bempedoic acid will hit that sweet spot in terms of adoption.

“We’re kind of like the old comfortable shoe,” Esperion’s chief commercial officer Mark Glickman remarked in an interview with Endpoints News ahead of the decision date. “It’s an oral product, once-daily and nontitratable — these are things that just resonate so true with patients and physicians and I think we’ve kind of forgotten about that.”

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James Collins, Broad Institute via Youtube

UP­DAT­ED: A space odyssey for new an­tibi­otics: MIT's ma­chine learn­ing ap­proach

Drug development is complex, expensive and comes with lousy odds of success — but in most cases, if you make it across the finish line brandishing a product with an edge (and play your cards right) it can be a lucrative endeavor.

As it stands, the antibiotic market is cursed — it harbors the stink of multiple bankruptcies, a dearth of innovation, and is consequently barely whetting the voracious appetites of big pharma or venture capitalists. Enter artificial intelligence — the biopharma industry’s cure-all for the pesky process of making a therapeutic, including data mining, drug discovery, optimal drug delivery, and addressable patient population.

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Gilead los­es two more patent chal­lenges on HIV pill, set­ting up court­room fight in Delaware

Gilead sustained two more losses in their efforts to rid themselves of an activist-backed patent lawsuit from the US government over a best-selling HIV pill.

Urged on by activists seeking to divert a portion of Gilead’s revenue to clinics and prevention programs, the Department of Health and Human Services made a claim to some of the patents for the best-selling HIV prevention drug, Truvada, also known as PrEP. Gilead responded by arguing in court that HHS’s patents were invalid.

Today, the US Patent and Trademark Office ruled that Gilead was likely to lose the last two of those challenges as well. The USPTO ruled against Gilead on the first two patents earlier this month.

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Kathy High (file photo)

Gene ther­a­py pi­o­neer Kathy High has left Spark af­ter com­plet­ing $4.3B union with Roche

Kathy High dedicated the past seven years of her life shepherding experimental gene therapies she’s developed at Children’s Hospital of Philadelphia toward the market as president and head of R&D at Spark Therapeutics. Now that the biotech startup is fully absorbed into Roche — with an FDA approval, a $4.3 billion buyout and a promising hemophilia program to boast — she’s ready to move on.

Roche confirmed her departure with Endpoints News and noted “she will take some well-deserved time off and then will begin a new chapter in a sabbatical at a university.”

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Tal Zaks (Moderna via YouTube)

For two decades, a new vac­cine tech­nol­o­gy has been slow­ly ap­proach­ing prime time. Now, can it stop a pan­dem­ic?

Two months before the outbreak, Moderna CMO Tal Zaks traveled from Cambridge, MA to Washington DC to meet with Anthony Fauci and the leaders of the National Institutes of Health.

For two years, Moderna had worked closely with NIH researchers to build a new kind of vaccine for MERS, one of the deadliest new viruses to emerge in the 21st century. The program was one test for a new technology designed to be faster, cheaper and more precise than the ways vaccines had been made for over a century. They had gathered evidence the technology could work in principle, and Fauci, the longtime head of the National Institute of Allergy and Infectious Diseases and a longtime advocate for better epidemic preparedness, wanted to see if it, along with a couple of other approaches, could work in a worst-case scenario: A pandemic.

“[We were] trying to find a test case for how to demonstrate if our technology could rapidly prepare,” Zaks told Endpoints News.

Zaks and Fauci, of course, wouldn’t have to wait to develop a new test. By year’s end, an outbreak in China would short circuit the need for one and throw them into 24/7 work on a real-world emergency. They also weren’t the only ones with new technology who saw a chance to help in a crisis.

An ocean away, Lidia Oostvogels was still on vacation and relaxing at her mother’s house in Belgium when her Facebook started changing. It was days after Christmas and on most people’s feeds, the news that China had reported a novel virus to the World Health Organization blurred into the stream of holiday sweaters and fir trees. But on Oostvogels’s feed, full of vaccine researchers and virus experts, speculation boiled: There was a virus in China, something contained to the country, but “exotic,” “weird,” and maybe having to do with animals. Maybe a coronavirus.

Lidia Oostvogels

“I was immediately thinking like, ‘Hey, this is something that if needed, we can play a role,'” Oostvogels told Endpoints.

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Christos Kyratsous (via LinkedIn)

He built a MERS treat­ment in 6 months and then the best Ebo­la drug. Now Chris­tos Kyrat­sous turns his sights on Covid-19

TARRYTOWN, NY — In 2015, as the Ebola epidemic raged through swaths of West Africa, Kristen Pascal’s roommates sat her down on their couch and staged an intervention.

“Are you sure this is what you want to be doing with your life?” she recalls them asking her.

Special report

Pascal, a research associate for Regeneron, had been coming home at 2 am and leaving at 6 am. At one point, she didn’t see her roommate for a week. For months, that was life in Christos Kyratsous’ lab as the pair led a company-wide race to develop the first drug that could effectively treat Ebola before the outbreak ended. For Pascal, that was worth it.

“I’m ok, I don’t have Ebola,” Pascal told them. “I see that death toll rising and I can’t not do something about it.”

Last August, Regeneron learned they had succeeded: In a large trial across West Africa, their drug, REGN-EB3, was vastly more effective than the standard treatments. It was surprise news for the company, coming just 10 months into a trial they thought would take several years and a major victory in the global fight against a deadly virus that killed over 2,000 in 2019 and can carry a mortality rate of up to 90%.

For Kyratsous and Pascal, though, it brought only fleeting reprieve. Just four months after the NIH informed them REGN-EB3 worked, Kyratsous was back in his office reading the New York Times for updates on a new outbreak on another continent, and wondering alongside Pascal and senior management whether it was time to pull the trigger again.

In late January, as the death toll swelled and the first confirmed cases outside China broke double digits, they made a decision. Soon they were back on the phone with the multiple government agencies and their coronavirus partners at the University of Maryland’s Level 3 bio lab. The question was simple: Can Kyratsous and his team use a process honed over two previous outbreaks, and create a treatment before the newest epidemic ends? Or worse, if, as world health experts fear, it doesn’t vanish but becomes a recurrent virus like the flu?

“Christos likes things immediately,” Matt Frieman, Regeneron’s coronavirus collaborator at the University of Maryland, told Endpoints. “That’s what makes us good collaborators: We push each other to develop things faster and faster.”

Kristen Pascal (Regeneron)

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The first time Regeneron tried to respond to a global outbreak, it was something of a systems test, Kyratsous explains from his office at Regeneron’s Tarrytown headquarters. Kyratsous, newly promoted, has crammed it with photos of his family, sketches of viral vectors and a shark he drew for his 3-year-old son. He speaks rapidly – an idiosyncrasy his press person says has only been aggravated this afternoon by the contents of his “Regeneron Infectious Diseases”-minted espresso glass – and he gesticulates with similar fluidity, tumbling through antibodies, MERS, the novel coronavirus, Ebola-infected monkeys.

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Bank­rupt an­tibi­otics mak­er Ar­a­digm turns to old part­ner/in­vestor for fi­nal $3M fire sale

Grifols once paid Aradigm $26 million for a stake in its inhaled antibiotics. But with Aradigm now in bankruptcy, the Spanish drugmaker is dishing out a final $3.2 million to buy it all.

The fire sale — which comes one year after Aradigm filed for Chapter 11 following a regulatory trifecta for disaster — will see Grifols obtain assets and IP to Apulmiq (formerly Pulmaquin and Linhaliq in Europe), Lipoquin and free ciprofloxacin. In addition to waiving its claims in the bankruptcy case, Grifols also agreed to milestone payments up to $3 million more upon any regulatory approvals.