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.

Mer­ck is tak­ing the ax to its US op­er­a­tions, cut­ting 500 jobs in its lat­est re­or­ga­ni­za­tion

Merck is cutting 500 jobs in its US sales and headquarters commercial teams in its latest effort to find new ways to streamline the operation.

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Alice Shaw, Lung Cancer Foundation of America

Top ALK ex­pert and can­cer drug re­searcher Al­ice Shaw bids adieu to acad­e­mia, hel­lo to No­var­tis

Jay Bradner has recruited a marquee oncology drug researcher into the ranks of the Novartis Institutes for BioMedical Research. Alice Shaw is jumping from prestigious posts intertwined through Mass General, Harvard and Dana-Farber to take the lead of NIBR’s translational clinical oncology group.

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Mi­rati preps its first look at their KRAS G12C con­tender, and they have to clear a high bar for suc­cess

If you’re a big KRAS G12C fan, mark your calendars for October 28 at 4:20 pm EDT.

That’s when Mirati $MRTX will unveil its first peek at the early clinical data available on MRTX849 in presentations at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston.

Mirati has been experiencing the full effect of a rival’s initial success at targeting the G12C pocket found on KRAS, offering the biotech some support on the concept they’re after — and biotech fans a race to the top. Amgen made a big splash with its first positive snapshot on lung cancer, but deflated sky-high expectations as it proved harder to find similar benefits in other types of cancers.

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The FDA will hus­tle up an ex­pe­dit­ed re­view for As­traZeneca’s next shot at a block­buster can­cer drug fran­chise

AstraZeneca paid a hefty price to partner with Daiichi Sankyo on their experimental antibody drug conjugate for HER2 positive breast cancer. And they’ve been rewarded with a fast ride through the FDA, with a straight shot at creating another blockbuster oncology franchise.

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Sean Parker, AP

Sean Park­er helps cre­ate a CRISPRed cell ther­a­py 2.0 play — and he’s got a high-pro­file set of lead­ers on the team

You can rack up one more high-profile debut effort in the wave of activity forming around cell therapy 2.0. It’s another appealing Bay Area group that’s attracted some of the top hands in the business to a multi-year effort to create a breakthrough. And they have $85 million in hand to make that first big step to the clinic.

Today it’s Ken Drazan and the team at South San Francisco-based ArsenalBio that are coming from behind the curtain for a public bow, backed by billionaire Sean Parker and a collection of investors that includes Beth Seidenberg’s new venture investment operation based in LA.
Drazan — a J&J Innovation vet with a long record of entrepreneurial endeavors — exited the stage in 2018 when his last mission ended as he stepped aside as president of Grail. It wasn’t long, though, before he was helping out with a business plan for ArsenalBio that revolved around the work of a large group of interconnected scientists supported by the Parker Institute for Cancer Immunology.

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Med­ical an­i­ma­tion: Mak­ing it eas­i­er for the site and the pa­tient to un­der­stand

Medical animation has in recent years become an increasingly important tool for conveying niche information to a varied audience, particularly to those audiences without expertise in the specialist area. Science programmes today, for example, have moved from the piece-to-camera of the university professor explaining how a complex disease mechanism works, to actually showing the viewer first-hand what it might look like to shrink ourselves down to the size of an ant’s foot, and travel inside the human body to witness these processes in action. Effectively communicating a complex disease pathophysiology, or the novel mechanism of action of a new drug, can be complex. This is especially difficult when the audience domain knowledge is limited or non-existent. Medical animation can help with this communication challenge in several ways.
Improved accessibility to visualisation
Visualisation is a core component of our ability to understand a concept. Ask 10 people to visualise an apple, and each will come up with a slightly different image, some apples smaller than others, some more round, some with bites taken. Acceptable, you say, we can move on to the next part of the story. Now ask 10 people to visualise how HIV’s capsid protein gets arranged into the hexamers and pentamers that form the viral capsid that holds HIV’s genetic material. This request may pose a challenge even to someone with some virology knowledge, and it is that inability to effectively visualise what is going on that holds us back from fully understanding the rest of the story. So how does medical animation help us to overcome this visualisation challenge?

Hal Barron, GSK's president of R&D and CSO, speaks to Endpoints News founder and editor John Carroll in London at Endpoints' #UKBIO19 summit on October 8, 2019

[Video] Cel­e­brat­ing tri­al fail­ures, chang­ing the cul­ture and al­ly­ing with Cal­i­for­nia dream­ers: R&D chief Hal Bar­ron talks about a new era at GSK

Last week I had a chance to sit down with Hal Barron at Endpoints’ #UKBIO19 summit to discuss his views on R&D at GSK, a topic that has been central to his life since he took the top research post close to 2 years ago. During the conversation, Barron talked about changing the culture at GSK, a move that involves several new approaches — one of which involves celebrating their setbacks as they shift resources to the most promising programs in the pipeline. Barron also discussed his new alliances in the Bay Area — including his collaboration pact with Lyell, which we covered here — frankly assesses the pluses and minuses of the UK drug development scene, and talks about his plans for making GSK a much more effective drug developer.

This is one discussion you won’t want to miss. Insider and Enterprise subscribers can log-in to watch the video.

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Flu Virus (Source: CDC)

FDA ex­pands Xofluza ap­proval as Roche strug­gles to catch loom­ing flu mar­ket

As a potentially powerful flu season looms, so does a big test for Roche and its new flu drug, Xofluza. The Swiss giant just got a small boost in advance of that test as the FDA expanded Xofluza’s indication to include patients at high risk of developing flu-related complications.

Xofluza (baloxavir marboxil) was approved last October in the US, the first landmark flu drug approval in 20 years and a much-needed green light for a company that had watched its leading flu drug Tamiflu get eaten alive by generics. Like its predecessor, the pill offered a reduction in flu symptoms but not a cure.

EMA backs sev­en ther­a­pies, in­clud­ing Mer­ck­'s Ebo­la vac­cine

The first-ever Ebola vaccine is on the precipice of approval after the European Medicine’s Agency (EMA) backed the Merck product in this week’s roster of recommendations.

The drugmaker $MRK began developing the vaccine, christened Ervebo, during the West African outbreak that occurred between 2014 and 2016, killing more than 11,000.

The current outbreak in the Democratic Republic of Congo (DRC) has shown case fatality rates of approximately 67%, the agency estimated. Earlier this year, the WHO declared the outbreak — which so far has infected more than 3,000 people — a public health emergency of international concern.