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.

M&A: a crit­i­cal dri­ver for sus­tain­able top-line growth in health­care

2021 saw a record $600B in healthcare M&A activity. In 2022, there is an anticipated slowdown in activity, however, M&A prospects remain strong in the medium to long-term. What are future growth drivers for the healthcare sector? Where might we see innovations that drive M&A? RBC’s Andrew Callaway, Global Head, Healthcare Investment Banking discusses with Vito Sperduto, Global Co-Head, M&A.

15 LGBTQ lead­ers in bio­phar­ma; Paul Stof­fels’ Gala­pa­gos re­vamp; As­traZeneca catch­es up in AT­TR; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

A return to in-person conferences also marks a return to on-the-ground reporting. My colleagues Beth Synder Bulik and Nicole DeFeudis were on-site at Cannes Lions, bringing live coverage of pharma’s presence at the ad festival — accompanied by photos from Clara Bui, our virtual producer, that bring you right to the scene. You can find a recap (and links to all the stories) below.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 144,300+ biopharma pros reading Endpoints daily — and it's free.

AstraZeneca's new Evusheld direct to consumer campaign aims to reach more immunocompromised patients.

As­traZeneca de­buts first con­sumer cam­paign for its Covid-19 pro­phy­lac­tic Evusheld — and a first for EUA drugs

AstraZeneca’s first consumer ad for Evusheld is also a first for drugs that have been granted emergency use authorizations during the pandemic.

The first DTC ad for a medicine under emergency approval, the Evusheld campaign launching this week aims to raise awareness among immunocompromised patients — and spur more use.

Evusheld nabbed emergency authorization in December, however, despite millions of immunocompromised people looking for a solution and now more widespread availability of the drug.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 144,300+ biopharma pros reading Endpoints daily — and it's free.

De­spite a slow start to the year for deals, PwC pre­dicts a flur­ry of ac­tiv­i­ty com­ing up

Despite whispers of a busy year for M&A, deal activity in the pharma space is actually down 30% on a semi-annualized basis, according to PwC’s latest report on deal activity. But don’t rule out larger deals in the second half of the year, the consultants said.

PwC pharmaceutical and life sciences consulting solutions leader Glenn Hunzinger expects to see Big Pharma companies picking up earlier stage companies to try and fill pipeline gaps ahead of a slew of big patent cliffs. Though a bear market continues to maul the biotech sector, Hunzinger said recent deals indicate that pharma companies are still paying above current trading prices.

FDA un­veils new draft guid­ance to help with oligonu­cleotide ther­a­peu­tics de­vel­op­ment

While oligonucleotides, a wide variety of synthetically modified RNA or RNA/DNA hybrids that bind to a target RNA sequence to alter RNA and/or protein expression, have been winning approvals in recent years (e.g. Novartis’ cholesterol drug Leqvio), the regulatory agency is offering new draft guidance for those looking to follow a similar path.

The non-binding guidance, titled “Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics Guidance for Industry” deals with pharmacokinetic, pharmacodynamic, and safety assessments required as part of oligonucleotide therapeutics R&D.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 144,300+ biopharma pros reading Endpoints daily — and it's free.

Abortion-rights protesters regroup and protest following Supreme Court's decision to overturn Roe v. Wade. (AP Photo/Gemunu Amarasinghe)

Fol­low­ing SCO­TUS de­ci­sion to over­turn abor­tion pro­tec­tions, AG Gar­land says states can't ban the abor­tion pill

Following the Supreme Court’s historic decision on Friday to overturn Americans’ constitutional right to an abortion after almost 50 years, Attorney General Merrick Garland sought to somewhat reassure women that states will not be able to ban the prescription drug sometimes used for abortions.

Following the decision, the New England Journal of Medicine also published an editorial strongly condemning the reversal, saying it “serves American families poorly, putting their health, safety, finances, and futures at risk.”

Joe Wiley, Amryt Pharma CEO

Am­ryt Phar­ma sub­mits a for­mal dis­pute res­o­lu­tion to the FDA over re­ject­ed skin dis­ease drug

The story of Amryt Pharma’s candidate for the genetic skin condition epidermolysis bullosa, or EB, will soon enter another chapter.

After the Irish drugmaker’s candidate, dubbed Oleogel-S10 and marketed as Filsuvez, was handed a CRL earlier this year, the company announced in a press release that it plans to submit a formal dispute resolution request for the company’s NDA for Oleogel-S10.

Sen. Thom Tillis (R-NC) (J. Scott Applewhite/AP Images)

Phar­ma-friend­ly sen­a­tor calls on FDA for a third time to show patent pro­tec­tions should­n't be blamed for high drug prices

North Carolina Republican Sen. Thom Tillis made a name for himself in the 2020 election cycle as the darling of the pharma industry, accepting hundreds of thousands in campaign contributions, even from the likes of Pfizer CEO Albert Bourla.

Those contributions have led Tillis to attempt to re-write patent laws in pharma’s favor, a move which failed to gain steam in 2019, and request for a third time since January that the FDA should help stop “the false narrative that patent protections are to blame for high drug prices.”

EMA signs off on 3 drugs re­cent­ly re­ject­ed by FDA, in­clud­ing Bio­Mar­in's new he­mo­phil­ia gene ther­a­py

The EMA’s human medicines committee on Friday recommended three new drugs for approval or conditional approval, even as their US counterparts have rejected these three for various reasons.

In a major move, CHMP offered a thumbs-up to a conditional marketing authorization for the first gene therapy to treat severe hemophilia A, although the agency cautioned that it’s so far unknown how long the effects of infusion will last.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 144,300+ biopharma pros reading Endpoints daily — and it's free.