FDA over­rides ad­comm opin­ions a fifth of the time, study finds — but why?

For drug­mak­ers, FDA ad­vi­so­ry pan­els are of­ten an ap­pre­hend­ed barom­e­ter of reg­u­la­tors’ fi­nal de­ci­sions. While the ex­perts’ en­dorse­ment or crit­i­cism of­ten trans­late di­rect­ly to fi­nal out­comes, the FDA some­times stun ob­servers by di­verg­ing from rec­om­men­da­tions.

A new pa­per out of Mil­bank Quar­ter­ly put a num­ber on that trend by an­a­lyz­ing 376 vot­ing meet­ings and sub­se­quent ac­tions from 2008 through 2015, con­firm­ing the gen­er­al im­pres­sion that reg­u­la­tors tend to agree with the ad­comms most of the time — with dis­cor­dances in on­ly 22% of the cas­es.

Most of the time the FDA opt­ed for a more re­stric­tive stance than the ex­perts. Among the 83 in­stances of dis­cor­dance, 75% end­ed with reg­u­la­tors push­ing for tougher de­ci­sions for the ap­pli­cants.

But per­haps the more im­por­tant ques­tion is, in what sit­u­a­tions do they dis­agree?

First, let’s set the scene: The ma­jor­i­ty of those meet­ings (63%) in­volved drugs, 21% were about bi­o­log­ics, and 16% con­cerned med­ical de­vices. The sub­jects ranged from ini­tial prod­uct ap­provals (72%), sup­ple­ment in­di­ca­tions (21%) to safe­ty ac­tions (7%). And the pe­ri­od cov­ered the tenure of three com­mis­sion­ers, An­drew von Es­chen­bach, Mar­garet Ham­burg and Robert Califf.

The re­searchers hy­poth­e­sized sev­er­al fac­tors that could pre­dict dis­cor­dances, in­clud­ing types of ac­tions, de­gree of con­sen­sus among pan­el mem­bers, pres­ence of ex­perts with con­flicts of in­ter­est, pub­lic opin­ion (as cap­tured by speak­ers and me­dia cov­er­age), and med­ical need (us­ing or­phan or oth­er sta­tus­es as a proxy).

They found that the types of ac­tions mat­tered — for in­stance, the FDA was more like­ly to dis­agree with ex­perts on safe­ty mat­ters — as did how much the ad­comm mem­bers agreed with each oth­er. Pres­ence of mem­bers with COI to de­clare, ad­vo­cates com­ing to the ad­comm meet­ing, cov­er­age in the New York Times, or spe­cial reg­u­la­to­ry des­ig­na­tions? Not so much.

Here’s their the­o­ry:

Al­though ad­vi­so­ry com­mit­tee mem­bers and FDA agency mem­bers may be broad­ly aligned in their goals, is­sues like the agency’s con­cerns about its rep­u­ta­tion may re­sult in dif­fer­ent pat­terns of de­ci­sion mak­ing. For ex­am­ple, the FDA has an in­cen­tive to avoid re­vers­ing ear­li­er de­ci­sions in­so­far as those re­ver­sals might dam­age its cred­i­bil­i­ty.

That would ex­plain why reg­u­la­tors are more in­clined to main­tain an ex­ist­ing prod­uct’s avail­abil­i­ty by tak­ing a less re­stric­tive stance on safe­ty is­sues, while draw­ing a firmer line over nov­el prod­ucts and new in­di­ca­tions.

The find­ings are in line with lit­er­a­ture cit­ed in the pa­per, which the re­searchers — Au­drey Zhang New York Uni­ver­si­ty to­geth­er with Ja­son Schwartz and Joseph Ross at Yale — say are less com­pre­hen­sive but sug­gest that reg­u­la­tors agree with ad­comms 60% to 87% of the time.

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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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.

Ronald Herb­st fol­lows Med­Im­mune ex­o­dus to Pyx­is CSO post; Jeff God­dard to suc­ceed CEO of AIT Bio­science

→ The outflow of top execs from MedImmune continues to fill the leadership ranks of smaller biotechs. The latest to take off is Ronald Herbst, the head of oncology research, who’s assuming the CSO post at Pyxis Oncology.  

Herbst was part of the old MedImmune organization AstraZeneca CEO Pascal Soriot restructured earlier this year, reorganizing the company and eliminating the storied subsidiary as a separate organization.

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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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UP­DAT­ED: J&J's Xarel­to, Amar­in's Vas­cepa are cost-ef­fec­tive, not bud­get friend­ly — ICER

ICER, an increasingly influential cost-effectiveness watchdog in the United States, has concluded in its review of treatments for cardiovascular disease that while the cost of J&J’s Xarelto and Amarin’s Vascepa meet its benchmark for value pricing — the two treatments will not likely treat as many patients as hoped without surpassing the annual budget threshold calculated by ICER for each therapy.

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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