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.

Con­quer­ing a silent killer: HDV and Eiger Bio­Phar­ma­ceu­ti­cals

Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV) that results in the most severe form of human viral hepatitis for which there is no approved therapy.

HDV is a single-stranded, circular RNA virus that requires the envelope protein (HBsAg) of the hepatitis B virus (HBV) for its own assembly. As a result, hepatitis delta virus (HDV) infection occurs only as a co-infection in individuals infected with HBV. However, HDV/HBV co-infections lead to more serious liver disease than HBV infection alone. HDV is associated with faster progression to liver fibrosis (progressing to cirrhosis in about 80% of individuals in 5-10 years), increased risk of liver cancer, and early decompensated cirrhosis and liver failure.
HDV is the most severe form of viral hepatitis with no approved treatment.
Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not appreciably impact HBsAg and have no impact on HDV. Investigational agents in development for HBV target multiple new mechanisms. Aspirations are high, but a functional cure for HBV has not been achieved nor is one anticipated in the forseeable future. Without clearance of HBsAg, anti-HBV investigational treatments are not expected to impact the deadly course of HDV infection anytime soon.

No­var­tis is ax­ing 150 ear­ly dis­cov­ery jobs as CNI­BR shifts fo­cus to the de­vel­op­ment side of R&D

Novartis is axing some 150 early discover jobs in Shanghai as it swells its staff on the drug development side of the equation in China. And the company is concurrently beefing up its investment in China’s fast-growing biotech sector with a plan to add to its investments in local VCs.

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Democratic presidential candidate, U.S. Sen. Elizabeth Warren (D-MA) speaks during the Nevada Democrats' "First in the West" event at Bellagio Resort & Casino on November 17, 2019 in Las Vegas, Nevada (Getty Images)

Eliz­a­beth War­ren pro­pos­es us­ing com­pul­so­ry li­cens­ing, an­titrust ac­tions to break bio­phar­ma’s con­trol of drug pric­ing — and here are the block­busters she’s tar­get­ing first

Nancy Pelosi’s drug pricing bill may have sparked some industrial strength headaches on the money side of biopharma, but Elizabeth Warren seems determined to become biopharma’s Nightmare on Pennsylvania Avenue.
Warren, one of the top-ranked candidates for the Democratic presidential nomination backing Medicare for all, is circulating a new plan that promises to break the industry’s grip on drug prices — and she has some very specific examples of how she would do it.
The Warren plan would rely on the federal government’s compulsory licensing powers to seize the IP of blockbuster drugs like Truvada and Harvoni to provide them at a fraction of what Gilead sells them for in the US. And she would throw some antitrust actions in as needed to rein in the price of Humira, AbbVie’s cash cow that continues to dominate the list of the most profitable therapeutics on the market.
Notably, she plans to rely on the powers already vested in the federal government, rather than suggest remedies that would require the assent of a deeply divided Congress.
In addition to the blockbusters on the list, Warren sends a clear signal that the same tactics would be used to beef up the supply of cheap antibiotics, as needed. And the same action could befall any other therapy patients can’t afford.

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Mer­ck’s $1B cash gam­ble pays off with a sur­pris­ing PhI­II car­dio suc­cess for Bay­er’s heart drug veri­ciguat

More than 3 years after Merck stepped up and paid $1 billion in cold, hard cash to gain the US commercial rights to Bayer’s high-risk heart drug vericiguat in a broad-ranging cardio alliance, the partners say their Phase III study has come through with promising data and a date with regulators.
We don’t have the data, and won’t until they put it out at an upcoming scientific session, but Merck touted the results, saying that their big Phase III VICTORIA study hit the primary endpoint  — with vericiguat combined with available therapies reducing “the risk of the composite endpoint of heart failure hospitalization or cardiovascular death in patients with worsening chronic heart failure with reduced ejection fraction (HFrEF) compared to placebo when given in combination with available heart failure therapies.”
Depending on the hard data, and how it breaks out with the combinations used, this drug could pose a threat to Novartis’ blockbuster drug Entresto, currently at $1.6 billion while analysts expect peak sales to hit $4 billion.
The drug is a soluble guanylate cyclase (sGC) stimulator, which Bayer and Merck have had high hopes for. Evidently, so did cardiologists. Cowen’s last analysis set potential sales at $400 million in 2024, but that number could go up significantly now.
Cowen’s Steve Scala noted this morning:
Vericiguat could be a lucrative product for Merck, and one with potentially under-appreciated value. At Cowen’s Therapeutics Conference in September 2019, 80% of specialists anticipated a positive result from VICTORIA whereas only 51% of investors shared this optimism.
Investigators recruited more than 5,000 patients at more than 600 centers in 42 countries for this study — one of the most expensive propositions in R&D. Millions of people in the US suffer from heart failure with reduced ejection fraction when the failing heart fails to contract properly to eject blood into the system. Bayer holds ex-US rights to the drug and also stands to earn cash from the $1.1 billion in milestones Merck agreed on for their collaboration.
Remarkably, the drug was pushed into Phase III despite failing the mid-stage trial — though investigators flagged a success at the high dose of 10 mg. In VICTORIA, researchers started patients at 2.5 mg and then titrated up to 5 and then 10 mg.

Alk­er­mes forges $950M biotech buy­out deal in a bold bet on an ear­ly-stage CNS drug plat­form

Alkermes $ALKS is investing $100 million cash and committing up to $850 million more in milestones in a big wager on a very early-stage CNS discovery platform. And the biotech is adding $20 million more to fund next year’s new research work on the platform it’s acquiring in today’s buyout with an eye to expanding the research work in oncology.

The biotech, helmed by Richard Pops, is buying Rodin Therapeutics, which had focused early on Alzheimer’s disease. Pops’ buyout, though, isn’t focused solely on the most troublesome sector in pharma R&D.

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(Image: Associated Press)

Amarin emerges from an ex­pert pan­el re­view with a clear en­dorse­ment for Vas­cepa and high odds of suc­cess when the FDA weighs in for­mal­ly

Several FDA experts who gathered Thursday to consider the landmark approval of Vascepa to reduce cardio events in an at-risk population voiced their unease about various aspects of the efficacy and safety data, or ultimately the population it should be used to treat. But the overwhelming belief that the data pointed to the drug’s benefit and clearly outweighed risks carried the day for Amarin.

The panel voted unanimously (16 to 0) to support the company’s positive data presentation — backing an OK for expanding the label to include reducing cardio risk. The vote points Amarin $AMRN down a short path to a formal decision by the FDA, with the odds heavily in its favor. Chances are the rest of the questions about the future of this drug will be hashed out in the label’s small print.

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Left to right: Arthur Pappas, Robert Nelsen, Peter Kolchinsky Doug Cole and David Beier

In rare po­lit­i­cal for­ay, top biotech in­vestors urge Con­gress to re­ject drug pric­ing bill

Thirteen of the top biotech venture capitalists in the country wrote a letter last week warning lawmakers that if Congress passes a drug pricing bill House Speaker Nancy Pelosi has put before lawmakers, they won’t be able to invest in biomedical research at their current rate, and patients will suffer.

“If policies such as those included within H.R. 3, the Lower Drug Costs Now Act, are passed, our ability to continue to invest in future biomedical innovation will be severely constrained, thus crushing the hopes of millions of patient waiting for the next breakthroughs to treat or cure their cancers, rare genetic diseases, Alzheimer’s, or other serious and life-threatening conditions,” they wrote in a letter addressed to the highest-ranking Democrats and Republicans in the House and Senate and acquired by Endpoints News. 

Dicer­na scores broad, 'rest of liv­er' deal with No­vo Nordisk, bag­ging $225M in cash to hit some 30 tar­gets with RNAi plat­form

Turns out Dicerna wasn’t done with deals yet after locking in $200 million upfront from Roche for a hepatitis B cocktail two weeks ago.

Novo Nordisk has signed on as the latest partner to its GalXC RNAi platform, handing over $175 million in cash to claim any and all targets of interest in liver-related cardio-metabolic diseases that are not already reserved in previous pacts. The Danish drugmaker — which has signaled its interest to expand considerably beyond its core diabetes franchise into areas like NASH — is also purchasing $50 million worth of Dicerna’s equity at a 25% premium of $21.93 per share. More research payments and milestones extending to the billions are on the line.

Gene ther­a­py wins the in­side track at EMA; PPD files for IPO

→ Gene therapy maker Orchard Therapeutics has been granted an accelerated assessment for OTL-200 by the EMA’s Committee for Medicinal Products for Human Use (CHMP). The gene therapy — in development in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy — being used towards the treatment of metachromatic leukodystrophy.

→ Pharmaceutical Product Development has announced that its parent company, PPD, Inc has submitted a draft to the SEC relating to the proposal of an IPO of the parent company’s common stock. Number of shares and price range have not yet been determined.