In­no­va­tion in the clin­ic is pick­ing up steam. How adap­tive de­signs could pave the road to per­son­al­ized med­i­cine

Biotech Voices is a collection of exclusive opinion editorials from some of the leading voices in biopharma on the biggest industry questions today. Think you have a voice that should be heard? Reach out to senior editors Kyle Blankenship and Amber Tong.

Nor­mal­ly, when you hear about in­no­va­tion in R&D, the fo­cus is on the “R” and not the “D.” There’s a ten­den­cy to as­sume that lab-based sci­en­tists do the re­al­ly cre­ative re­search, where­as clin­i­cal de­vel­op­ment is a fair­ly straight­for­ward, check-the-box­es ac­tiv­i­ty.

There’s a ker­nel of truth in this oth­er­wise un­fair as­sump­tion. Just as the ba­sic de­sign of a car hasn’t changed much from the cars our grand­par­ents drove — gas and brake ped­als, four tires, and a steer­ing wheel — clin­i­cal tri­als still have time-hon­ored fea­tures like ran­dom­iza­tion, con­trol arms and blind­ing. What is chang­ing, though, is that we’ve be­gun to aug­ment well-es­tab­lished meth­ods with in­no­va­tions that promise to make drug de­vel­op­ment faster, less ex­pen­sive and more suc­cess­ful.

One big el­e­ment in this trans­for­ma­tion is broad­er use of adap­tive study de­signs. In con­ven­tion­al clin­i­cal tri­als, the study pro­to­col is carved in stone at the out­set, and you ex­e­cute that de­sign with no de­vi­a­tions from start to fin­ish. In adap­tive tri­als, you can build flex­i­bil­i­ty in­to the pro­to­col, which al­lows you to change key pa­ra­me­ters of the study in re­sponse to in­com­ing da­ta.

Adap­tive de­signs are typ­i­cal­ly em­ployed in Phase II tri­als, where re­sults from a small group of pa­tients are used to de­cide if a much larg­er Phase III study is war­rant­ed. “Adap­tive” doesn’t mean you can make any change that seems ad­van­ta­geous—the op­tions need to be spec­i­fied in ad­vance. But if the ear­ly da­ta con­form to pre-es­tab­lished cri­te­ria, you can al­ter the size or du­ra­tion of the study, drop or add dos­es to en­sure more pa­tients re­ceive the op­ti­mal dose, or bring in more of the types of pa­tients who seem to be re­spond­ing well to the test drug.

Adap­tive mod­i­fi­ca­tions don’t change the prop­er­ties of the drug mol­e­cule be­ing test­ed, but they im­prove the odds of test­ing it in the right pa­tients, at the right dose, for the right du­ra­tion to show its risks and ben­e­fits. Greater clar­i­ty can re­duce the risk of false-pos­i­tive or false-neg­a­tive re­sults. A false pos­i­tive — think­ing a drug works when it doesn’t — can lead a com­pa­ny to in­vest heav­i­ly in a large study that will ul­ti­mate­ly fail to de­liv­er what pa­tients need. A false neg­a­tive can cast doubt on the val­ue of a ther­a­py and ter­mi­nate de­vel­op­ment of an in­ves­ti­ga­tion­al drug with re­al ben­e­fits for pa­tients Ul­ti­mate­ly, adap­tive de­signs can al­low us to more read­i­ly achieve a per­son­al­ized med­i­cine, in which pa­tients most like­ly to ben­e­fit from a drug are the ones to re­ceive it.

The ba­sic idea of adap­tive clin­i­cal tri­al de­signs isn’t new — clin­i­cal sci­en­tists from acad­e­mia and in­dus­try have been study­ing this con­cept for two decades. But for much of that time, these meth­ods were seen as too un­proven and risky. Sev­er­al years ago, Am­gen de­cid­ed there was more risk in not adopt­ing these new ap­proach­es, which have the po­ten­tial to de­liv­er more suc­cess­ful stud­ies more quick­ly and with low­er de­vel­op­ment costs.

In con­ven­tion­al tri­als, this trio of pri­or­i­ties — cost, speed, and like­li­hood of suc­cess — in­volve trade-offs that make it hard to pur­sue all three goals si­mul­ta­ne­ous­ly. For ex­am­ple, to boost the like­li­hood of suc­cess, you nor­mal­ly need to col­lect more da­ta from more pa­tients, which trans­lates in­to added time and ex­pense. But im­ple­ment­ed cor­rect­ly, adap­tive de­signs can po­ten­tial­ly avoid these trade­offs and fa­cil­i­tate small­er and faster tri­als that re­veal a drug’s true po­ten­tial with more pre­ci­sion.

Two de­vel­op­ments are ac­cel­er­at­ing the trend to­ward adap­tive de­signs. First, the FDA is en­cour­ag­ing clin­i­cal in­no­va­tion and part­ner­ing with com­pa­nies that are will­ing to try new ap­proach­es. For ex­am­ple, Am­gen has an in­ves­ti­ga­tion­al ther­a­py for lu­pus, efavaleukin al­fa (for­mer­ly AMG 592), which is par­tic­i­pat­ing in the FDA’s Com­plex In­no­v­a­tive Tri­al De­sign (CID) Pi­lot Pro­gram. We plan to use an adap­tive de­sign to work to ze­ro in on the op­ti­mal dose and to en­sure more pa­tients re­ceive this op­ti­mal dose to in­crease the like­li­hood that the right dose is se­lect­ed for fu­ture stud­ies.

A re­lat­ed de­vel­op­ment has been greater ac­cess to re­al-world da­ta and ad­vances in com­pu­ta­tion­al meth­ods that use these da­ta to sim­u­late clin­i­cal tri­als. Sim­u­la­tions can’t pre­dict how a drug will per­form in an ac­tu­al clin­i­cal study, but they can show how dif­fer­ent study de­signs are ex­pect­ed to per­form un­der dif­fer­ent sce­nar­ios.

In de­sign­ing any tri­al, you need to make as­sump­tions about a whole range of vari­ables — the ef­fect size of the drug you are test­ing; how long it takes for this ef­fect to emerge; the re­sponse rate to the place­bo or com­para­tor drugs, etc. For our study in lu­pus pa­tients, we ran mil­lions of sim­u­la­tions, plug­ging in dif­fer­ent val­ues for these vari­ables and oth­ers, with the goal of find­ing the de­sign op­tions most like­ly to yield re­li­able re­sults.

In­no­v­a­tive de­signs ex­tend to tri­als where the drug it­self is the el­e­ment that is open to mod­i­fi­ca­tion. The COVID-19 pan­dem­ic has un­der­scored the im­por­tance of speed in drug de­vel­op­ment, and adap­tive plat­form tri­als pro­vide a way to rapid­ly test mul­ti­ple po­ten­tial ther­a­pies us­ing a sin­gle pro­to­col.

As part of the COVID R&D Al­liance, Am­gen is part­ner­ing with Take­da and UCB in the COM­MU­NI­TY study, which will ini­tial­ly test three po­ten­tial treat­ments for pa­tients hos­pi­tal­ized with COVID-19. The de­sign is ef­fi­cient be­cause it us­es same en­try cri­te­ria for all agents be­ing eval­u­at­ed, and it em­ploys a com­mon con­trol arm and a com­mon fu­til­i­ty bar to eval­u­ate for ef­fi­ca­cy. Test drugs can be dropped from the tri­al if they show lack of ef­fi­ca­cy, and new agents can be in­tro­duced quick­ly to take ad­van­tage of the es­tab­lished pro­to­col.

Am­gen is us­ing a sim­i­lar con­cept to in­ves­ti­gate so­tora­sib, a po­ten­tial new tar­get­ed ther­a­py for pa­tients with non-small cell lung can­cer who car­ry a mu­tat­ed gene known as KRAS G12C. Many of these pa­tients have failed to re­spond to stan­dard ther­a­pies, so there is an ur­gent need to eval­u­ate oth­er po­ten­tial treat­ment op­tions rapid­ly. To ac­cel­er­ate test­ing of so­tora­sib in com­bi­na­tion with oth­er can­cer ther­a­pies, we es­tab­lished a 10-arm mas­ter pro­to­col with a high­ly flex­i­ble de­sign. The goal is to de­tect any pos­i­tive ef­fi­ca­cy sig­nals as ear­ly as pos­si­ble, so that the most promis­ing com­bi­na­tions can be quick­ly iden­ti­fied and ex­pand­ed in­to larg­er stud­ies.

Clin­i­cal in­no­va­tion isn’t on­ly a smarter way to do drug de­vel­op­ment, it is bet­ter for pa­tients as well. The soon­er we can de­ter­mine whether an in­ves­ti­ga­tion­al ther­a­py or spe­cif­ic dose works or not, the soon­er we can ei­ther ad­vance that ther­a­py or stop test­ing it in pa­tients. Speed and clar­i­ty are im­por­tant in re­search, but even more im­por­tant to pa­tients search­ing for the right treat­ment for their dis­ease.

The Price of Re­lief: Ex­plor­ing So­lu­tions to the Ris­ing Costs of On­col­o­gy Drugs

In 2020, The National Cancer Institute estimated about 1.8 million new cases of cancer diagnosed in the United States, while the costs associated with treatment therapies continued to escalate. Given the current legislative climate on drug pricing, it’s never been more important to look at the evolution of drug pricing globally and control concerns of sustainable and affordable treatments in oncology.

Lat­est news on Pfiz­er's $3B+ JAK1 win; Pacts over M&A at #JPM22; 2021 by the num­bers; Bio­gen's Aduhelm reck­on­ing; The sto­ry of sotro­vimab; 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.

For those of you who attended #JPM22 in any shape or form, we hope you had a fruitful time. Regardless of how you spent the past hectic week, may your weekend be just what you need it to be.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 128,800+ biopharma pros reading Endpoints daily — and it's free.

A $3B+ peak sales win? Pfiz­er thinks so, as FDA of­fers a tardy green light to its JAK1 drug abroc­i­tinib

Back in the fall of 2020, newly crowned Pfizer chief Albert Bourla confidently put their JAK1 inhibitor abrocitinib at the top of the list of blockbuster drugs in the late-stage pipeline with a $3 billion-plus peak sales estimate.

Since then it’s been subjected to serious criticism for the safety warnings associated with the class, held back by a cautious FDA and questioned when researchers rolled out a top-line boast that their heavyweight contender had beaten the champ in the field of atopic dermatitis — Dupixent — in a head-to-head study.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 128,800+ biopharma pros reading Endpoints daily — and it's free.

Robert Califf, FDA commissioner nominee (Graeme Sloan/Sipa USA/Sipa via AP Images)

Rob Califf ad­vances as Biden's FDA nom­i­nee, with a close com­mit­tee vote

Rob Califf’s second confirmation process as FDA commissioner is already much more difficult than his near unanimous confirmation under the Obama administration.

The Senate Health Committee on Thursday voted 13-8 in favor of advancing Califf’s nomination to a full Senate vote. Several Democrats voted against Califf, including Sen. Bernie Sanders and Sen. Maggie Hassan. Several other Democrats who aren’t on the committee, like West Virginia’s Joe Manchin and Ed Markey of Massachusetts, also said Thursday that they would not vote for Califf. Markey, Hassan and Manchin all previously expressed reservations about the prospect of Janet Woodcock as an FDA commissioner nominee too.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 128,800+ biopharma pros reading Endpoints daily — and it's free.

Michel Vounatsos, Biogen CEO (World Economic Forum/Ciaran McCrickard)

Bio­gen vows to fight CM­S' draft cov­er­age de­ci­sion for Aduhelm be­fore April fi­nal­iza­tion

Biogen executives made clear in an investor call Thursday they are not preparing to run a new CMS-approved clinical trial for their controversial Alzheimer’s drug anytime soon.

As requested in a draft national coverage decision from CMS earlier this week, Biogen and other anti-amyloid drugs will need to show “a meaningful improvement in health outcomes” for Alzheimer’s patients in a randomized, placebo-controlled trial to get paid for their drugs, rather than just the reduction in amyloid plaques that won Aduhelm its accelerated approval in June.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 128,800+ biopharma pros reading Endpoints daily — and it's free.

CRO own­er pleads guilty to ob­struct­ing FDA in­ves­ti­ga­tion in­to fal­si­fied clin­i­cal tri­al da­ta

The co-owner of a Florida-based clinical research site pleaded guilty to lying to an FDA investigator during a 2017 inspection, revealing that she falsely portrayed part of a GlaxoSmithKline pediatric asthma study as legitimate, when in fact she knew that certain data had been falsified, the Department of Justice said Wednesday.

Three other employees — Yvelice Villaman Bencosme, Lisett Raventos and Maytee Lledo — previously pleaded guilty and were sentenced in connection with falsifying data associated with the trial at the CRO Unlimited Medical Research.

Susan Galbraith, AstraZeneca EVP, Oncology R&D

Can­cer pow­er­house As­traZeneca rolls the dice on a $75M cash bet on a buzzy up­start in the on­col­o­gy field

After establishing itself in the front ranks of cancer drug developers and marketers, AstraZeneca is putting its scientific shoulder — and a significant amount of cash — behind the wheel of a brash new upstart in the biotech world.

The pharma giant trumpeted news this morning that it is handing over $75 million upfront to ally itself with Scorpion Therapeutics, one of those biotechs that was newly birthed by some top scientific, venture and executive talent and bequeathed with a fortune by way of a bankroll to advance an only hazily explained drug platform. And they are still very much in the discovery and preclinical phase.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 128,800+ biopharma pros reading Endpoints daily — and it's free.

‘Skin­ny la­bels’ on gener­ics can save pa­tients mon­ey, re­search shows, but re­cent court de­ci­sions cloud fu­ture

New research shows how generic drug companies can successfully market a limited number of approved indications for a brand name drug, prior to coming to market for all of the indications. But several recent court decisions have created a layer of uncertainty around these so-called “skinny” labels.

While courts have generally allowed generic manufacturers to use their statutorily permitted skinny-label approvals, last summer, a federal circuit court found that Teva Pharmaceuticals was liable for inducing prescribers and patients to infringe GlaxoSmithKline’s patents through advertising and marketing practices that suggested Teva’s generic, with its skinny label, could be employed for the patented uses.

A patient in Alaska receiving an antibody infusion to prevent Covid hospitalizations in September. All but one of these treatments has been rendered useless by Omicron (Rick Bowmer/AP Images)

How a tiny Swiss lab and two old blood sam­ples cre­at­ed one of the on­ly ef­fec­tive drugs against Omi­cron (and why we have so lit­tle of it)

Exactly a decade before a novel coronavirus broke out in Wuhan, Davide Corti — a newly-minted immunologist with frameless glasses and a quick laugh — walked into a cramped lab on the top floor of an office building two hours outside Zurich. He had only enough money for two technicians and the ceiling was so low in parts that short stature was a job requirement, but Corti believed it’d be enough to test an idea he thought could change medicine.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.