When can RWE trans­late in­to cred­i­ble ev­i­dence? EMA of­fi­cials dis­cuss

Re­al-world ev­i­dence (RWE) may pro­vide an op­por­tu­ni­ty to learn more about a drug’s ben­e­fits and risks, but of­fi­cials from the EMA said in an ar­ti­cle pub­lished Tues­day in Clin­i­cal Phar­ma­col­o­gy & Ther­a­peu­tics that there will need to be ad­e­quate sta­tis­ti­cal meth­ods to ex­tract, an­a­lyze and in­ter­pret RWE be­fore they can trans­late in­to cred­i­ble ev­i­dence.

In or­der to en­sure that any new an­a­lyt­i­cal meth­ods are ac­cept­able for reg­u­la­tors, the EMA au­thors say they will re­quire test­ing and val­i­da­tion in near­ly the same way as a new med­i­cine is eval­u­at­ed: “prospec­tive­ly, well-con­trolled and ac­cord­ing to pre-agreed plan.”

They add: “The ul­ti­mate key to achiev­ing cred­i­bil­i­ty is to start with an open but ‘ag­nos­tic’ mind-set and sub­mit nov­el meth­ods to a fair, trans­par­ent and prospec­tive val­i­da­tion ex­er­cise; this can­not be done on­ly by dry runs with old prod­ucts. It is un­der­stand­able that drug de­vel­op­ers are wary of jeop­ar­dis­ing the de­vel­op­ment pro­grams for their val­ued new as­sets. How­ev­er, we em­pha­sise that if de­vel­op­ers want tri­al as­ses­sors to ac­cept nov­el meth­ods, they will have to ex­pose some of their ex­per­i­men­tal drugs to method­ol­o­gy de­vel­op­ment ex­er­cis­es.”

The of­fi­cials al­so note that an up­front agree­ment on a “fire­wall” is nec­es­sary to en­sure that an eval­u­a­tion of meth­ods will nei­ther jeop­ar­dize nor res­cue a prod­uct.

“We are aware that in­ter­est in con­duct­ing head-to-head RCTs [ran­dom­ized con­trolled tri­als] in the post-mar­ket­ing phase is of­ten lim­it­ed, but what is need­ed is at least sev­er­al RCTs com­par­ing two (or more) treat­ments that have been on the mar­ket for a suf­fi­cient pe­ri­od of time to en­able si­mul­ta­ne­ous RWD analy­sis. This would pro­vide an op­por­tu­ni­ty to ‘bolt-on’ a meth­ods eval­u­a­tion ex­er­cise by si­mul­ta­ne­ous­ly de­vel­op­ing the RCT pro­to­col and the pa­ra­me­ters of the RWD analy­sis which is to be con­duct­ed con­cur­rent­ly with the RCT but be­fore RCT re­sults be­come avail­able,” they ex­plain.

In a sec­tion on re­plac­ing RCTs with RWD analy­sis, the au­thors note: Prospec­tive­ly de­signed new RWD stud­ies to match the de­sign of planned RCTs “is fea­si­ble when both drugs have been in rou­tine use for a suf­fi­cient time. The con­cur­rent ap­proach avoids bias by match­ing the RCTs and RWD analy­ses as close­ly as pos­si­ble (e.g. for pa­tient char­ac­ter­is­tics, dose reg­i­mens), while avoid­ing the temp­ta­tion to trim RWD analy­sis to the RCT re­sults once they be­come avail­able. It al­so al­lows for sen­si­tiv­i­ty analy­ses to iden­ti­fy whether al­ter­na­tive de­signs or analy­ses could have im­proved agree­ment be­tween the de­signs.”

And while not­ing that any ef­forts in the RWE space are long-term projects that “will not come to fruition as a re­sult of short term ef­forts by in­di­vid­ual play­ers,” the EMA of­fi­cials al­so stress that the stakes are high for “over­com­ing method­ol­o­gy aver­sion and en­sur­ing that all stake­hold­ers ar­rive at a nu­anced view be­tween cat­e­gor­i­cal re­jec­tion and naïve adop­tion of nov­el meth­ods.”

RAPS: First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.


Zachary Brennan

managing editor, RAPS

A New Fron­tier: The In­ner Ear

What happens when a successful biotech venture capitalist is unexpectedly diagnosed with a chronic, life-disrupting vertigo disorder? Innovation in neurotology.

That venture capitalist was Jay Lichter, Ph.D., and after learning there was no FDA-approved drug treatment for his condition, Ménière’s disease, he decided to create a company to bring drug development to neurotology. Otonomy was founded in 2008 and is dedicated to finding new drug treatments for the hugely underserved community living with balance and hearing disorders. Helping patients like Jay has been the driving force behind Otonomy, a company heading into a transformative 2020 with three clinical trial readouts: Phase 3 in Ménière’s disease, Phase 2 in tinnitus, and Phase 1/2 in hearing loss. These catalysts, together with others in the field, highlight the emerging opportunity in neurotology.
Otonomy is leading the way in neurotology
Neurotology, or the treatment of inner ear neurological disorders, is a large and untapped market for drug developers: one in eight individuals in the U.S. have moderate-to-severe hearing loss, tinnitus or vertigo disorders such as Ménière’s disease.1 With no FDA-approved drug treatments available for these conditions, the burden on patients—including social anxiety, lower quality of life, reduced work productivity, and higher rates of depression—can be significant.2, 3, 4

Patrik Jonsson, the president of Lilly Bio-Medicines

Who knew? Der­mi­ra’s board kept watch as its stock price tracked Eli Lil­ly’s se­cret bid­ding on a $1.1B buy­out

In just 8 days, from December 6 to December 14, the stock jumped from $7.88 to $12.70 — just under the initial $13 bid. There was no hard news about the company that would explain a rise like that tracking closely to the bid offer, raising the obvious question of whether insider info has leaked out to traders.

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Ab­b­Vie do­nates $1M+ of the HIV drug that Chi­na is now rec­om­mend­ing for coro­n­avirus treat­ment

AbbVie is donating more than $1 million worth of an HIV drug to help combat the fast-spreading coronavirus outbreak in China, the company announced on Friday.

China’s National Health Commission has suggested Aluvia, a pill containing lopinavir and ritonavir, as one of two possible treatments for the symptoms of the virus currently known as 2019-nCoV in the absence of effective antiviral medications. The other part is nebulized alpha-interferon.

UP­DAT­ED: Ab­b­Vie and Al­ler­gan di­vesti­tures are in, and an old As­traZeneca drug comes home

When AbbVie announced their $63-billion Allergan acquisition last year, executives acknowledged the two companies would have to divest some drugs to satisfy regulators. The two main assets in discussion have now been sold off – and one of them is coming home.

AstraZeneca will acquire brazikumab, Allergan’s late-stage IL-23 candidate for Crohn’s disease and ulcerative colitis. The drug was originally developed by AstraZeneca’s defunct subsidiary MedImmune, in collaboration with Amgen. Allergan licensed it for $250 million upfront and $1.27 billion in milestones.

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As­traZeneca makes case for use of blood thin­ner Bril­in­ta in stroke pa­tients

AstraZeneca’s extravagant projections for its clot fighter Brilinta may have fizzled in the face of underwhelming trial data — but a new pivotal study is set to expand its use substantially.

On Monday, the British drugmaker said the drug, when taken in conjunction with aspirin, induced a statistically significant reduction in the risk of the primary composite endpoint of stroke and death, compared to aspirin alone, in 11,000 patients that have suffered minor acute ischaemic stroke or a high-risk transient ischemic attack (TIA).

Samantha Truex (file photo)

Bruce Booth and Saman­tha Truex's lat­est ven­ture aims just above Hu­mi­ra

In 2000, about a year after the first trial data on Humira came out, a Japanese team identified a new gene that appeared to prevent GI cancer in mice: gasdermin, they called it, after the particular proteins it expressed.

Over the next decade-and-a-half, researchers found five more genes in the same family – often identified as gasdermin A, B, C, D, E and F – and yet their purpose baffled scientists. Mutations in appeared to make mice bald (alopecia), but deleting it had no effect. Mutations in F and A were linked to deafness. Mutant E caused human cells to self-destruct.

“The exact biological function of these proteins remained unknown for more than 15 years,” three of the field’s top researchers wrote in a  Nature review in November.

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FDA’s golodirsen CRL: Sarep­ta’s Duchenne drugs are dan­ger­ous to pa­tients, of­fer­ing on­ly a small ben­e­fit. And where's that con­fir­ma­to­ry tri­al?

Back last summer, Sarepta CEO Doug Ingram told Duchenne MD families and investors that the FDA’s shock rejection of their second Duchenne MD drug golodirsen was due to some concerns regulators raised about the risk of infection and the possibility of kidney toxicity. But when pressed to release the letter for all to see, he declined, according to a report from BioPharmaDive, saying that kind of move “might not look like we’re being as respectful as we’d like to be.”

He went on to assure everyone that he hadn’t misrepresented the CRL.

But Ingram’s public remarks didn’t include everything in the letter, which — following the FDA’s surprise about-face and unexplained approval — has now been posted on the FDA’s website and broadly circulated on Twitter early Wednesday.

The CRL raises plenty of fresh questions about why the FDA abruptly decided to reverse itself and hand out an OK for a drug a senior regulator at the FDA believed — 5 months ago, when he wrote the letter — is dangerous to patients. It also puts the spotlight back on Sarepta $SRPT, which failed to launch a confirmatory study of eteplirsen, which was only approved after a heated internal controversy at the FDA. Ellis Unger, director of CDER’s Office of Drug Evaluation I, notes that study could have clarified quite a lot about the benefit and risks associated with their drugs — which can cost as much as a million dollars per patient per year, depending on weight.

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Aymeric Le Chatelier, Ipsen

A $1B-plus drug stum­bles in­to an­oth­er big PhI­II set­back — this time flunk­ing fu­til­i­ty test — as FDA hold re­mains in ef­fect for Ipsen

David Meek

At the time Ipsen stepped up last year with more than a billion dollars in cash to buy Clementia and a late-stage program for a rare bone disease that afflicts children, then CEO David Meek was confident that he had put the French biotech on a short path to a mid-2020 launch.

Instead of prepping a launch, though, the company was hit with a hold on the FDA’s concerns that a therapy designed to prevent overgrowth of bone for cases of fibrodysplasia ossificans progressiva might actually stunt children’s growth. So they ordered a halt to any treatments for kids 14 and under. Meek left soon after to run a startup in Boston. And today the Paris-based biotech is grappling with the independent monitoring committee’s decision that their Phase III had failed a futility test.

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Roche's check­point play­er Tecen­triq flops in an­oth­er blad­der can­cer sub­set

Just weeks after Merck’s star checkpoint inhibitor Keytruda secured FDA approval for a subset of bladder cancer patients, Swiss competitor Roche’s Tecentriq has failed in a pivotal bladder cancer study.

The 809-patient trial — IMvigor010 — tested the PD-L1 drug in patients with muscle-invasive urothelial cancer (MIUC) who had undergone surgery, and were at high risk for recurrence.

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