Can­cer tri­als aimed at 'sur­ro­gate' tar­gets miss big­ger mark — study

Find a ran­dom per­son on the street and ask them what a can­cer drug should do. What are the odds they don’t say “it should help pa­tients live health­i­er and longer”?

A con­flu­ence of forces have pushed clin­i­cal tri­als away from that seem­ing­ly cen­tral ques­tion, with de­vel­op­ers and pa­tient groups bet­ting on the promise that aim­ing at more sub­tle mea­sures can help bring need­ed ther­a­pies to mar­ket faster. But a new study from the British Med­ical Jour­nal sug­gests the con­ven­tion­al wis­dom may be right and that trend, among oth­ers, have led can­cer drugs to hit the mar­ket based off stud­ies that have a high risk of bias.

Re­searchers led by Lon­don School of Eco­nom­ics Pro­fes­sor Huseyin Naci tracked can­cer drug ap­provals by the Eu­ro­pean Med­ical As­so­ci­a­tion over three years from 2014 to 2016. Putting aside 13 tri­als not based on a ran­dom­ized con­trol mod­el — which have their own set of is­sues but can be use­ful for rare dis­eases — and two tri­als with­out pub­lished da­ta, they eval­u­at­ed 39 tri­als that formed the ba­sis of drug ap­provals in that pe­ri­od ac­cord­ing to a stan­dard cri­te­ria of bias and found: 19 (49%) were at high risk of bias and the ones that didn’t look at im­prov­ing sur­vival were more like­ly to be at risk. On­ly 10 tri­als pri­mar­i­ly looked at im­prov­ing sur­vival.

Among them, 20% of tri­als that looked at over­all sur­vival had a high risk of bias, com­pared to 55% of the rest.

Oth­er fac­tors be­sides end­point were at play in stud­ies at risk for bias, in­clud­ing miss­ing da­ta and red flags in how da­ta were mea­sured, such as the tri­al lack­ing a blind­ed as­sess­ment.

But in their dis­cus­sion of the re­sults, the au­thors fo­cused in part on the pauci­ty of tri­als that looked head-on at whether a drug will help pa­tients sur­vive, warn­ing that tri­als that look at oth­er “sur­ro­gate” end­points speed up de­vel­op­ment but might mis­lead pa­tients and bring drugs that don’t work. Eval­u­at­ing the study in a BMJ opin­ion col­umn, Bar­bara Mintzes and Agnes Vit­ry took sim­i­lar aim.

“Un­cer­tain­ty and ex­ag­ger­a­tion of the ev­i­dence that sup­ports ap­proval of can­cer drugs caus­es di­rect harm if pa­tients risk se­vere or fa­tal ad­verse ef­fects with­out like­ly ben­e­fit,” they wrote. “Or for­go more ef­fec­tive and safer treat­ments.”

The push to­ward these “sur­ro­gate” mea­sures has come from both de­vel­op­ers, ea­ger to get their treat­ments to mar­ket, and pa­tient groups hop­ing to se­cure ac­cess to new reme­dies as fast as pos­si­ble. Tar­get­ing over­all sur­vival on av­er­age takes about an ex­tra year, time many can­cer pa­tients don’t have.

A fed­er­al law, the 21st Cen­tu­ry Cures Act, that went in­to ef­fect in 2017 cod­i­fied that push. Yet da­ta on tri­als that avoid the cen­tral ques­tion of elon­gat­ing and im­prov­ing qual­i­ty of life have been mixed.

A 2018 JA­MA In­ter­nal Med­i­cine re­view of 52 ar­ti­cles cov­er­ing 38 tri­als on a to­tal of 14,000 pa­tients with 12 dif­fer­ent can­cers from 2000 through 2016 found no sig­nif­i­cant as­so­ci­a­tion be­tween pro­gres­sion-free sur­vival and health-re­lat­ed qual­i­ty of life.

The study al­so comes as one of many crit­i­cal­ly eval­u­at­ing ex­ist­ing sci­en­tif­ic lit­er­a­ture in the wake of the repli­ca­tion cri­sis that broke out most pub­licly in psy­chol­o­gy and has rip­pled across the sci­ences. In 2012 Am­gen’s head of re­search, Glenn Be­g­ley, pub­lished a pa­per in Na­ture re­veal­ing a 10-year com­pa­ny ef­fort to re­pro­duce 53 “land­mark” stud­ies in on­col­o­gy. They got pos­i­tive re­sults in 6.

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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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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Ted White, Verrica CEO

Ver­ri­ca hits an­oth­er bump in the road with CMO re­lat­ed let­ter from FDA

The FDA has rejected Verrica’s new drug application for VP-102 again, with the company pinning the CRL on problems at a CMO that it was partnered with, the company announced Monday.

The FDA didn’t raise issues that directly relate to the manufacturing of VP-102, the company said, but raised “general quality issues” at the CMO’s facility. There were also no clinical concerns, it said, or need to collect more data.

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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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).

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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