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.


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.

Bio­mark­er 'roadmap­s' and the fu­ture of can­cer R&D; Cur­tain rais­es on #AS­CO22; Pfiz­er, No­var­tis tack­le drug ac­cess; 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.

While this was not a week for earth-shattering news, there were certainly a lot of interesting tidbits. If you found this recap helpful, please recommend it to your friends and colleagues. We’ll see you on the other side of the long weekend.

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Keep­ing pres­sure on Am­gen, Mi­rati draws mixed re­views on lat­est cut of KRAS da­ta

As the close runner-up to Amgen’s Lumakras in the KRAS race, any data cut from Mirati’s adagrasib continues to draw scrutiny from analysts. And the latest batch of numbers from ASCO is a decidedly mixed bag.

While a quick comparison suggests that adagrasib spurred slightly more responses and led to a longer overall survival than Lumakras among a group of non-small cell lung cancer patients, its duration of response appears shorter and the safety profile continues to spark concern.

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Ann is one of ViiV Healthcare's newest spokespeople as the retired school administrator speaks up about her HIV status.

GSK's Vi­iV de­buts next evo­lu­tion in HIV med Dova­to cam­paign with new spokes­peo­ple and new mes­sage

When Ann saw the first TV commercials for HIV medicine Dovato, she didn’t see herself represented. So the 74-year-old retired school administrator who’s been living with HIV since 1998, reached out to GSK’s ViiV Healthcare and asked why not?

Now Ann is one of three people starring in ViiV’s latest Dovato campaign called “Detect This.” The next-step evolution in the branded campaign plays on the word “detect” — often used in describing HIV status under control as undetectable — but in this case, uses the word as a directive for people to understand they can use fewer medicines.

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Switzer­land to de­stroy over 600,000 ex­pired dos­es of Mod­er­na Covid vac­cine

As concerns related to uptake and distribution continue to linger, Switzerland is among the first countries that plans to destroy hundreds of thousands of expired and unused Covid-19 vaccine doses.

The European country said it plans to destroy more than 600,000 doses of Moderna’s Spikevax Covid-19 vaccine as the doses have reached their expiration date.

However, Moderna CEO Stéphane Bancel told the World Economic Forum in Davos, Switzerland that he’s in the process of throwing 30 million doses in the garbage, exclaiming, “We have a big demand problem.”

Lina Khan, FTC chair (Graeme Jennings/Pool via AP Images)

Pile-on over PBMs con­tin­ues with FTC com­ments and a new bi­par­ti­san Sen­ate bill

More than 500 stakeholders sent comments to the FTC on whether the commission should look further into pharma middlemen, known as PBMs, with many of the commenters calling for more federal oversight.

Similar to the critical open comment period in a deadlocked FTC session last February, pharmacies and pharmacy groups are continuing to call out the lack of transparency among the top 3 PBMs, which control about 80% of the market.

Pharma brands are losing their shine with US consumers who are now thinking about the economy and inflation instead of Covid. (Credit: Shutterstock)

Phar­ma brands fade in an­nu­al Har­ris con­sumer vis­i­bil­i­ty poll: Mod­er­na drops off and Pfiz­er dips

As Covid-19 concerns are fading in the US, so is biopharma visibility. The annual Axios Harris Poll survey to determine and rank the 100 most top-of-mind brands in the US finds Moderna, which was No. 3 last year, not on the list at all for 2022, and Pfizer sinking 37 spots.

However, it’s not that Moderna or Pfizer did anything wrong, it’s just that Americans have moved on to other worries beyond Covid.

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HHS Secretary Xavier Becerra (Jacquelyn Martin/AP Images)

HHS fin­ish­es off Trump-era rule that would've erased ba­sic FDA regs with­out fre­quent re­views

HHS on Thursday finalized its decision to withdraw a rule, proposed just before former President Donald Trump left office, that would’ve caused thousands of HHS and FDA regulations to automatically expire if they weren’t reviewed within two years, and every 10 years thereafter.

The decision follows the filing of a lawsuit last March, in which several nonprofits alleged that the outgoing administration planted “a ticking timebomb” for HHS, essentially forcing it to devote an enormous amount of resources to the unprecedented and infeasible task of reviewing thousands of regulations regularly.

Tran­si­tion to new Eu­ro­pean clin­i­cal tri­als in­fo sys­tem starts slow­ly

At the end of January, the European Medicines Agency officially launched its new clinical trials info system (CTIS), although the migration to the new platform has only really just begun, and sponsors have until the end of January 2023 before all initial trial applications must be submitted through CTIS.

Overall, 56 clinical trial applications have been submitted in CTIS during the first 3 months since the launch of the system on Jan. 31, according to new data posted by the EMA. By comparison, about 4,000 new trials are authorized each year across Europe.

Vi­iV Health­care looks to make long-act­ing HIV pre­ven­tion shot ac­ces­si­ble in low- and mid­dle-in­come coun­tries

The Joint United Nations Programme on HIV and AIDS set a lofty goal back in 2019 to end the HIV epidemic by 2030. But according to the World Health Organization, infection rates are not falling rapidly enough to meet that target.

GSK’s ViiV Healthcare thinks it can help change that.

On Friday, ViiV announced that it’s in talks with the UN-backed Medicines Patent Pool (MPP) for patent rights to its cabotegravir long-acting HIV injectable for pre-exposure prophylaxis (PrEP) in low- and middle-income countries.