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.

Oxitec biologist releases genetically modified mosquitoes in Piracicaba, Brazil in 2016 [credit: Getty Images]

In­trex­on unit push­es back against claims its GM mos­qui­toes are mak­ing dis­ease-friend­ly mu­tants

When the hysteria of Zika transmission sprang into the American zeitgeist a few years ago, UK-based Oxitec was already field-testing its male Aedes aegypti mosquito, crafted to possess a gene engineered to obliterate its progeny long before maturation.

But when a group of independent scientists evaluated the impact of the release of these genetically-modified mosquitoes in a trial conducted by Oxitec in Brazil between 2013 and 2015, they found that some of the offspring had managed to survive — prompting them to speculate what impact the survivors could have on disease transmission and/or insecticide resistance.

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Pur­due threat­ens to walk away from set­tle­ment, asks to pay em­ploy­ees mil­lions in bonus­es

There are two updates on the lawsuit against Purdue Pharma over its role in fueling the opioid epidemic, as the Sackler family threatens to walk away from their pledge to pay out $3 billion if a bankruptcy judge does not stop outstanding state lawsuits against them. At the same time, the company has asked permission to pay millions in bonuses to select employees.

Purdue filed for chapter 11 bankruptcy this week as part of its signed resolution to over 2,000 lawsuits. The deal would see the Sackler family that owns Purdue give $3 billion from their personal wealth and the company turned into a trust committed to curbing and reversing overdoses.

As Nas­daq en­rolls the fi­nal batch of 2019 IPOs, how have the num­bers com­pared to past years?

IGM Biosciences’ upsized IPO haul, coming after SpringWorks’ sizable public debut, has revved up some momentum for the last rush of biotech IPOs in 2019.

With 39 new listings on the books and roughly two more months to go before winding down, Nasdaq’s head of healthcare listings Jordan Saxe sees the exchange marking 50 to 60 biopharma IPOs for the year.

“December 15 is usually the last possible day that companies will price,” he said, as companies get ready for business talks at the annual JP Morgan Healthcare Conference in January.

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Aerial view of Genentech's campus in South San Francisco [Credit: Getty]

Genen­tech sub­mits a plan to near­ly dou­ble its South San Fran­cis­co foot­print

The sign is still there, a quaint reminder of whitewashed concrete not 5 miles from Genentech’s sprawling, chrome-and-glass campus: South Francisco The Industrial City. 

The city keeps the old sign, first erected in 1923, as a tourist site and a kind of civic memento to the days it packed meat, milled lumber and burned enough steel to earn the moniker “Smokestack of the Peninsula.” But the real indication of where you are and how much has changed both in San Francisco and in the global economy since a couple researchers and investors rented out an empty warehouse 40 years ago comes in a far smaller blue sign, resembling a Rotary Club post, off the highway: South San Francisco, The Birthplace of Biotech.

A fa­vorite in Alex­ion’s C-suite is leav­ing, and some mighty sur­prised an­a­lysts aren’t the least bit hap­py about it

Analysts hate to lose a biotech CFO they’ve come to trust and admire — especially if they’re being blindsided by a surprise exit.

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Chemotherapy and radiotherapy are the current gladiators of cancer treatment, but they come with well-known limitations and side-effects. The emergence of immunotherapy — a ferocious new titan in oncologist’s toolbox — takes the brakes off the immune system to kill cancer cells with remarkable success in some cases, but the approach is not always effective. What makes certain forms of cancer so resilient? Scientists may have finally pieced together a tantalizing piece of the puzzle, and a new biotech is banking on a new approach to fill the gap.

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While No­var­tis ban­ish­es Zol­gens­ma scan­dal scars — Bio­gen goes on a Spin­raza 'of­fen­sive'

While Novartis painstakingly works to mop up the stench of the data manipulation scandal associated with its expensive gene therapy for spinal muscular atrophy (SMA) Zolgensma— rival Biogen is attempting to expand the use of its SMA therapy, Spinraza. 

The US drugmaker $BIIB secured US approval for Spinraza for use in the often fatal genetic disease in 2016. The approval covered a broad range of patients with infantile-onset (most likely to develop Type 1) SMA. 

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UP­DAT­ED: Speak­er Nan­cy Pelosi to un­veil bill for fed­er­al­ly ne­go­ti­at­ed drug prices

After months of buzz from both sides of the aisle, Speaker Nancy Pelosi will today introduce her plan to allow the federal government to negotiate prices for 250 prescription drugs, setting up a showdown with a pharmaceutical industry working overtime to prevent it.

The need to limit drug prices is a rare point of agreement between President Trump and Democrats, although the president has yet to comment on the proposal and will likely face pressure to back a more conservative option or no bill at all. Republican Senator Chuck Grassley is reportedly lobbying his fellow party members on a more modest proposal he negotiated with Democratic Senator Ron Wyden in July.