Drug­mak­ers seek clar­i­ty on guid­ance on use of place­bo and blind­ing in on­col­o­gy tri­als

A half-dozen bio­phar­ma com­pa­nies are seek­ing fur­ther clar­i­ty from the FDA re­gard­ing draft guid­ance from Au­gust on us­ing a place­bo in cer­tain on­col­o­gy tri­als.

The draft fea­tures the FDA’s thoughts on the eth­i­cal chal­lenges of us­ing a place­bo in ran­dom­ized con­trolled clin­i­cal tri­als for ther­a­pies to treat hema­to­log­ic ma­lig­nan­cy and on­co­log­ic dis­ease. The draft al­so dis­cuss­es blind­ing and un­blind­ing, pa­tient re­port­ed out­comes (PROs) and prac­ti­cal and eth­i­cal con­cerns.

Com­ments

Roche’s Genen­tech said that it be­lieves the draft could be “fur­ther re­fined to ful­ly re­flect” the FDA’s in­creased recog­ni­tion of the val­ue of pa­tient in­put re­gard­ing their ex­pe­ri­ences with dis­ease and treat­ment.

“We urge the Agency to clar­i­fy that, al­though col­lec­tion of PROs from pa­tients blind­ed to treat­ment may be pre­ferred to re­move the risk of as­ses­sor bias, there are in­her­ent dif­fi­cul­ties in on­col­o­gy and hema­tol­ogy set­tings to de­sign tri­als as dou­ble-blind­ed stud­ies. For in­stance, when treat­ments are be­ing com­pared to ac­tive en­ti­ties with dif­fer­ing sched­ules or routes of ad­min­is­tra­tion, par­tic­u­lar­ly in­tra­venous (IV), ad­di­tion of place­bo is not eth­i­cal and blind­ing of the pa­tients not achiev­able.”

Mer­ck, mean­while, notes that the draft in­di­cates that a place­bo-con­trolled tri­al would be ap­pro­pri­ate in cir­cum­stances, such as where sur­veil­lance is stan­dard of care (SOC), or with cer­tain tri­al de­sign fea­tures, for ex­am­ple, if the tri­al us­es an add-on de­sign or when the end­point in­tend­ed to sup­port a la­bel­ing claim has a high de­gree of sub­jec­tiv­i­ty, such as with PROs. How­ev­er, Mer­ck cau­tions that the use of a place­bo con­trol “may raise prob­lems of ethics, ac­cept­abil­i­ty and fea­si­bil­i­ty in sub­se­quent tri­als or oth­er sce­nar­ios, and may not be ac­cept­able once some ben­e­fit has been shown.”

Mer­ck al­so says that it would be help­ful if the FDA could pro­vide ad­di­tion­al guid­ance on what a suit­able com­para­tor would be in sit­u­a­tions where there is no stan­dard of care (SOC) and a place­bo con­trol would be in­ap­pro­pri­ate.

“We al­so ask that FDA clar­i­fy when/which type of ex­ter­nal con­trols might be ad­e­quate to sub­stan­ti­ate the rel­e­vance of sin­gle-arm tri­al da­ta. For ex­am­ple, would re­al world ev­i­dence (RWE)-gen­er­at­ed his­tor­i­cal con­trols or mod­el-based meta-analy­ses of lit­er­a­ture be ac­cept­able, and in what sit­u­a­tions?” Mer­ck ques­tions.

Re­gen­eron al­so notes that the draft of­fers ad­vice on the im­pact of un­blind­ing on study de­sign, end­points and sta­tis­ti­cal analy­sis.

“Specif­i­cal­ly, if pa­tients are un­blind­ed and re­ceive al­ter­na­tive treat­ment up­on pro­gres­sion as sug­gest­ed in the draft guid­ance, eval­u­a­tion of over­all sur­vival (OS) may be con­found­ed by post-study treat­ments, and us­ing OS as a pri­ma­ry end­point may not be fea­si­ble. There­fore, we rec­om­mend that the Agency con­sid­er al­ter­na­tive pri­ma­ry end­points to sup­port reg­is­tra­tion for on­col­o­gy drugs and in­cor­po­rate these dis­cus­sions in the fi­nal ver­sion of this guid­ance,” Re­gen­eron said.

Bris­tol-My­ers Squibb, mean­while, said the draft is “a pos­i­tive step” in rec­om­mend­ing the use of place­bos in blind­ed ran­dom­ized con­trolled stud­ies for the treat­ment of hema­to­log­ic ma­lig­nan­cies and on­co­log­ic dis­eases, but the com­pa­ny called for the scope of the guid­ance to be re­fined to in­clude con­sid­er­a­tions for blind­ing in place­bo con­trol stud­ies on­ly.

“In cer­tain sec­tions of the pro­posed guid­ance, it is vague whether the rec­om­men­da­tions ap­ply to any blind­ed ran­dom­ized con­trolled study or just the ones that use place­bos,” B-MS says.

And As­traZeneca not­ed that the draft pro­vides guid­ance on the con­sid­er­a­tions for pa­tient and in­ves­ti­ga­tor blind­ing, but it does not ad­dress con­sid­er­a­tions for spon­sor-lev­el blind­ing of place­bo-con­trolled tri­als. “It would be help­ful if the Agency could pro­vide in­for­ma­tion to be con­sid­ered for main­te­nance of the spon­sor blind and/or un­blind­ing of the spon­sor,” the com­pa­ny says.

As pro­gres­sion-free sur­vival is a com­mon pri­ma­ry end­point in on­col­o­gy tri­als, As­traZeneca fur­ther says that the draft does not ad­dress con­cerns with bias in “some­what sub­jec­tive” end­points. “It would be help­ful for the FDA to pro­vide guid­ance on whether blind­ed cen­tral ad­ju­di­ca­tion is re­quired for end­points oth­er than over­all sur­vival,” the com­pa­ny adds.

Ab­b­Vie al­so sought more de­tail on the risks of un­blind­ing/run­ning open la­bel stud­ies, with de­scrip­tions on how po­ten­tial bi­as­es should be man­aged, “in­clud­ing how much bias is ac­cept­able.”


First pub­lished here. Reg­u­la­to­ry Fo­cus is the flag­ship on­line pub­li­ca­tion of the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety (RAPS), the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care and re­lat­ed prod­ucts, in­clud­ing med­ical de­vices, phar­ma­ceu­ti­cals, bi­o­log­ics and nu­tri­tion­al prod­ucts. Email news@raps.org for more in­for­ma­tion.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

Clay Siegall, Morphimmune CEO

Up­dat­ed: Ex-Seagen chief Clay Sie­gall emerges as CEO of pri­vate biotech

Clay Siegall will be back in the CEO seat, taking the helm of a private startup working on targeted cancer therapies.

It’s been almost a year since Siegall resigned from Seagen, the biotech he co-founded and led for more than 20 years, in the wake of domestic violence allegations by his then-wife. His eventual successor, David Epstein, sold the company to Pfizer in a $43 billion deal unveiled last week.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 163,600+ biopharma pros reading Endpoints daily — and it's free.

In­cyte hit by CRL on ex­tend­ed-re­lease JAK tablets, mud­dy­ing plans for Jakafi fran­chise ex­pan­sion

The FDA has rejected Incyte’s extended-release formulation of ruxolitinib tablets, in a surprise setback for the company’s plans to build on its blockbuster Jakafi franchise.

The ruxolitinib XR tablets are designed to be taken once a day, whereas Jakafi is indicated for twice daily dosage (although some patients can take it once daily).

According to Incyte, the FDA acknowledged in its complete response letter that the study submitted in the NDA “met its objective of bioequivalence based on area under the curve (AUC) parameters but identified additional requirements for approval.”

Zhi Hong, Brii Biosciences CEO

Brii Bio­sciences stops man­u­fac­tur­ing Covid-19 an­ti­body com­bo, plans to with­draw EUA re­quest

Brii Biosciences said it will stop manufacturing its Covid-19 antibody combination, sold in China, and is working to withdraw its emergency use authorization request in the US, which it started in October 2021.

The Beijing and North Carolina biotech commercially launched the treatment in China last July but is now axing the work and reverting resources to other “high-priority programs,” per a Friday update. The focus now is namely hepatitis B viral infection, postpartum depression and major depressive disorders.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 163,600+ biopharma pros reading Endpoints daily — and it's free.

FDA ad­vi­sors unan­i­mous­ly rec­om­mend ac­cel­er­at­ed ap­proval for Bio­gen's ALS drug

A panel of outside advisors to the FDA unanimously recommended that the agency grant accelerated approval to Biogen’s ALS drug tofersen despite the drug failing the primary goal of its Phase III study, an endorsement that could pave a path forward for the treatment.

By a 9-0 vote, members of the Peripheral and Central Nervous System Drugs Advisory Committee said there was sufficient evidence that tofersen’s effect on a certain protein associated with ALS is reasonably likely to predict a benefit for patients. But panelists stopped short of advocating for a full approval, voting 3-5 against (with one abstention) and largely citing the failed pivotal study.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 163,600+ biopharma pros reading Endpoints daily — and it's free.

Sergio Traversa, Relmada Therapeutics CEO

Rel­ma­da makes 'crit­i­cal changes' to PhI­II tri­al to try and save de­pres­sion drug

Relmada Therapeutics is making changes to its Phase III study of its lead drug for major depressive disorder, in an attempt to avoid problems with a prior trial that showed little difference between the drug and a placebo.

That failure in October wiped 80% from Relmada’s stock price, and was followed by another negative readout a few months later. In both cases, the company said that there had been trial sites that were associated with what it called surprising placebo effects that skewed the results compared with the drug, REL-1017.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 163,600+ biopharma pros reading Endpoints daily — and it's free.

Paul Song, NKGen Biotech CEO

NK cell ther­a­py-fo­cused biotech eyes SPAC deal

A small, Santa Ana-based biotech created in 2017 is looking to enter a SPAC deal as it lays out plans to begin trials in its lead cell therapy candidates and bring on new executives.

Graf Acquisition Corp. IV and NKGen Biotech announced Thursday, with few other details, that the two companies signed a non-binding letter of intent to “pursue a business combination.” Graf Acquisition II and III withdrew their IPOs last year.

Peter Hecht, Cyclerion Therapeutics CEO

Hard pressed for cash, Cy­cle­ri­on looks for help fund­ing rare dis­ease drug

Cyclerion Therapeutics may have the design of a Phase IIb study ready to go, but it’s scrambling for a way to fund it.

The company said in a press release that it’s “actively evaluating the best combination of capital, capabilities, and transactions available to it to advance the development of zagociguat,” its lead candidate for a rare, genetic mitochondrial disease known as MELAS.

In a separate SEC filing, Cyclerion once again flagged “substantial doubt about (its) ability to continue as a going concern.” As of the end of 2022, it had cash and cash equivalents of only $13.4 million.

Eu­ro­pean Com­mis­sion de­lays pro­pos­al for ma­jor changes to phar­ma leg­is­la­tion

The European Commission has once again delayed the release of its proposal for an overhaul of the continent’s pharmaceutical legislation.

The release, previously anticipated on March 29, will occur “slightly later” than expected due to the “very busy College agendas of the last few weeks,” a Commission spokesperson told Endpoints News via email.

While the agency hasn’t provided an updated timeline, the spokesperson said the agenda is “always indicative and adoption dates of Commission proposals may change any time, especially when these proposals concern reforms of complex legislations of major importance.”