Robert Califf (Michael Brochstein/Sipa USA via AP Images)

Re­al world ev­i­dence: Lessons learned from an FDA pi­lot show the lim­its of em­u­lat­ing RCTs

On­ly about half of a se­lect group of clin­i­cal tri­als could be well-em­u­lat­ed with avail­able re­al world ev­i­dence, ac­cord­ing to the new­ly dis­cussed re­sults of an FDA pi­lot pro­gram.

The FDA-fund­ed pro­gram, known as RCT-DU­PLI­CATE, helped re­searchers from the Brigham and Women’s Hos­pi­tal in Boston try to eval­u­ate whether ran­dom­ized con­trolled tri­als can be du­pli­cat­ed with RWE across a range of ther­a­peu­tic ar­eas.

The ini­tia­tive is part of the FDA’s work, man­dat­ed by Con­gress in the 21st Cen­tu­ry Cures Act, on how it plans to eval­u­ate the use of RWE to as­sess the ef­fec­tive­ness of med­ical prod­ucts.

John Con­ca­to, as­so­ciate di­rec­tor for RWE an­a­lyt­ics in the FDA’s Of­fice of Med­ical Pol­i­cy, made clear at a Duke-Mar­go­lis event on the top­ic last week that the stan­dard for sub­stan­tial ev­i­dence re­mains un­changed. He al­so not­ed that seek­ing to em­u­late a hy­po­thet­i­cal RCT when de­sign­ing a non-in­ter­ven­tion­al study “is a fun­da­men­tal­ly dif­fer­ent task” than what the re­searchers did with RCT-DU­PLI­CATE.

In the case of RCT-DU­PLI­CATE, Shirley Wang, as­so­ciate pro­fes­sor of med­i­cine at Har­vard Med­ical School, ex­plained how the pro­gram sought to em­u­late 30 RCTs us­ing clin­i­cal prac­tice da­ta.

The re­searchers found that 50% of the se­lect­ed RCTs could be em­u­lat­ed close­ly re­gard­ing de­sign and analy­sis, and they saw com­pa­ra­ble treat­ment ef­fects. But RCT and RWE find­ings were more like­ly to di­verge when there were sub­stan­tive em­u­la­tion chal­lenges, which could be be­cause the data­base and RCTs are tar­get­ing dif­fer­ent ques­tions, or due to bias, or both.

Sub­stan­tive chal­lenges were seen in the re­searchers’ at­tempts to repli­cate stud­ies in os­teo­poro­sis, chron­ic kid­ney dis­ease, heart fail­ure, asth­ma and COPD, Wang said.

How­ev­er, oth­er tri­als that could be close­ly em­u­lat­ed dealt with atri­al fib­ril­la­tion, VTE and hy­per­ten­sion, where­as tri­als re­lat­ed to di­a­betes (8 tri­als) and an­tiplatelet ther­a­py (3 tri­als) saw vary­ing de­grees of chal­lenges.

“Data­base stud­ies can come to sim­i­lar con­clu­sions as RCTs when we are able to em­u­late them well. But it’s more chal­leng­ing to em­u­late tri­als that are de­signed with many con­straints to show ef­fects un­der dif­fer­ent con­di­tions,” Wang said, not­ing that it’s eas­i­er to em­u­late tri­als with more prag­mat­ic de­sign fea­tures.

“With da­ta that are fit-for-pur­pose and prop­er de­sign and analy­sis, non-ran­dom­ized RWE stud­ies can come to sim­i­lar con­clu­sions about a drug’s treat­ment ef­fect as ran­dom­ized tri­als,” Wang added.

Se­bas­t­ian Schneeweiss, pro­fes­sor of med­i­cine at Har­vard who al­so dis­cussed re­sults of the study last week, not­ed, “Most im­por­tant­ly, re­al-world ev­i­dence com­ple­ments ev­i­dence from ran­dom­ized tri­als and does not re­place it. The con­clu­sion of this demon­stra­tion project should not be that every RWE study needs to em­u­late an RCT. This would de­feat the val­ue of RWE in com­ple­ment with RCTs.”

The FDA-fund­ed Brigham Women’s re­search is still work­ing on em­u­lat­ing 7 RCTs that are on­go­ing.

Over­all, the FDA’s drug cen­ter has sup­port­ed more than 20 RWE demon­stra­tion pro­jec­tions, in­clud­ing ones re­lat­ed to im­prov­ing the use or qual­i­ty of RWD, as­sess­ing RWE study de­signs (e.g. RCT-DU­PLI­CATE), or eval­u­at­ing tools for spe­cif­ic pur­pos­es.

Back in 2018, the FDA al­so un­veiled its RWE frame­work, which has since been sup­ple­ment­ed with 4 new draft guid­ance doc­u­ments on EHRs and med­ical claims da­ta, da­ta stan­dards for RWD sub­mis­sions, as­sess­ing reg­istries to sup­port reg­u­la­to­ry de­ci­sions mak­ing, and us­ing RWD and RWE to sup­port reg­u­la­to­ry de­ci­sion-mak­ing.

But in ex­plain­ing how there are still mul­ti­ple ques­tion marks around the use of RWE, FDA’s Con­ca­to al­so high­light­ed an NE­JM ar­ti­cle from 2020, in which re­searchers from the Uni­ver­si­ty of Ox­ford wrote, “The re­place­ment of ran­dom­ized tri­als with non­ran­dom­ized ob­ser­va­tion­al analy­ses is a false so­lu­tion to the se­ri­ous prob­lem of en­sur­ing that pa­tients re­ceive treat­ments that are both safe and ef­fec­tive.”

Even FDA Com­mis­sion­er Rob Califf, who wasn’t com­mis­sion­er at the time, was on board.

Scoop: Boehringer qui­et­ly shut­ters a PhII for one of its top drugs — now un­der re­view

Boehringer Ingelheim has quietly shut down a small Phase II study for one of its lead drugs.

The private pharma player confirmed to Endpoints News that it had shuttered a study testing spesolimab as a therapy for Crohn’s patients suffering from bowel obstructions.

A spokesperson for the company tells Endpoints:

Taking into consideration the current therapeutic landscape and ongoing clinical development programs, Boehringer Ingelheim decided to discontinue our program in Crohn’s disease. It is important to note that this decision is not based on any safety findings in the clinical trials.

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State bat­tles over mifepri­s­tone ac­cess could tie the FDA to any post-Roe cross­roads

As more than a dozen states are now readying so-called “trigger” laws to kick into effect immediate abortion bans following the overturning of Roe v. Wade on Friday, these laws, in the works for more than a decade in some states, will likely kick off even more legal battles as states seek to restrict the use of prescription drug-based abortions.

Since Friday’s SCOTUS opinion to overturn Americans’ constitutional right to an abortion after almost 50 years, reproductive rights lawyers at Planned Parenthood and other organizations have already challenged these trigger laws in Utah and Louisiana. According to the Guttmacher Institute, other states with trigger laws that could take effect include Arkansas, Idaho, Kentucky, Mississippi, Missouri, North Dakota, Oklahoma, South Dakota, Tennessee, Texas, and Wyoming.

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No stranger to gene ther­a­py woes, Astel­las runs in­to an­oth­er safe­ty-re­lat­ed clin­i­cal hold

Astellas Pharma, which has been at the forefront of uncovering the risks associated with gene therapies delivered by adeno-associated viruses, must take another safety alarm head-on.

The FDA has slapped a clinical hold on Astellas’ Phase I/II trial of a gene therapy candidate for late-onset Pompe disease, after investigators flagged a serious case of peripheral sensory neuropathy.

It marks the latest in a streak of setbacks Astellas has encountered since making a splashy entry into the gene therapy space with its $3 billion buyout of Audentes. But the lead program, AT132 for the treatment of X-linked myotubular myopathy (XLMTM), had to be halted more than once after a total of four patients died in the trial — and the scientific community still doesn’t have all the answers of what caused the deaths.

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Albert Bourla, Pfizer CEO (Gian Ehrenzeller/Keystone via AP Images)

Up­dat­ing the Covid-19 vac­cine: FDA of­fers a qual­i­fied thumbs-up ahead of ad­comm

The FDA’s adcomm of outside vaccine experts will meet tomorrow to discuss how to protect the US from a likely coming wave of Omicron cases in the fall and winter, and whether to deploy vaccines that specifically target the Omicron variant.

While the data so far are limited, the FDA sounded an upbeat tone in the briefing documents on Pfizer/BioNTech’s candidates, released this weekend ahead of the VRBPAC meeting.

Alex­ion puts €65M for­ward to strength­en its po­si­tion on the Emer­ald Isle

Ireland has been on a roll in 2022, with several large pharma companies announcing multimillion-euro projects. Now AstraZeneca’s rare disease outfit Alexion is looking to get in on the action.

Alexion on Friday announced a €65 million ($68.8 million) investment in new and enhanced capabilities across two sites in the country, including at College Park in the Dublin suburb of Blanchardstown and the Monksland Industrial Park in the central Irish town of Athlone, according to the Industrial Development Agency of Ireland.

As court case looms, Bris­tol My­ers touts la­bel ex­pan­sion for Breyanzi

As Bristol Myers Squibb braces for a court battle over a costly delay — at least for Celgene shareholders — for its CAR-T lymphoma treatment Breyanzi, the pharma giant is touting a label expansion in the second-line setting.

Breyanzi, also known as liso-cel, snagged a win on Friday in adults with large B-cell lymphoma (LBCL) who: don’t respond to chemotherapy, or relapse within 12 months; don’t respond or relapse after 12 months; or are not eligible for hematopoietic stem cell transplant after chemo due to their age or comorbidities.

Deborah Dunsire, Lundbeck CEO

Af­ter a 5-year re­peat PhI­II so­journ, Lund­beck and Ot­su­ka say they're fi­nal­ly ready to pur­sue OK to use Rex­ul­ti against Alzheimer's ag­i­ta­tion

Five years after Lundbeck and their longtime collaborators at Otsuka turned up a mixed set of Phase III data for Rexulti as a treatment for Alzheimer’s dementia-related agitation, they’ve come through with a new pivotal trial success they believe will finally put them on the road to an approval at the FDA. And if they’re right, some analysts believe they’re a short step away from adding more than $500 million in annual sales for the drug, already approved in depression and schizophrenia.

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A Mer­ck part­ner is sucked in­to the fi­nan­cial quag­mire as key lender calls in a note

Another biotech standing on shaky financial legs has fallen victim to the bears.

Merck partner 4D Pharma has reported that a key lender, Oxford Finance, shoved the UK company into administration after calling in a $14 million loan they couldn’t immediately make good on. Trading in their stock was halted with a market cap that had fallen to a mere £30 million.

“Despite the very difficult prevailing market conditions,” 4D reported on Friday, the biotech had been making progress on finding some new financing and turned to Oxford with an alternative late on Thursday and then again Friday morning.

Members of the G7 from left to right: Prime Minister of Italy Mario Draghi, European Commission President Ursula von der Leyen, President Joe Biden, German Chancellor Olaf Scholz, British Prime Minister Boris Johnson, Canadian Prime Minister Justin Trudeau, Prime Minister of Japan Fumio Kishida, French President Emmanuel Macron and European Council President Charles Michel (AP Photo/Susan Walsh)

Biden and G7 na­tions of­fer funds for vac­cine and med­ical prod­uct man­u­fac­tur­ing project in Sene­gal

Amidst recently broader vaccine manufacturing initiatives from the EU and European companies, the G7 summit in the mountains of Bavaria has brought about some positive news for closing vaccine and medical product manufacturing gaps around the globe.

According to a statement from the White House, the G7 leaders have formally launched the partnership for global infrastructure, PGII. The effort will aim to mobilize hundreds of billions of dollars to deliver infrastructure projects in several sectors including the medical and pharmaceutical manufacturing space.