Need a place­bo con­trol group for your next can­cer drug study? On­ly in cer­tain cir­cum­stances, says FDA

Giv­en the eth­i­cal chal­lenges of us­ing a place­bo in ran­dom­ized con­trolled clin­i­cal tri­als for ther­a­pies to treat hema­to­log­ic ma­lig­nan­cy and on­co­log­ic dis­ease, the FDA rec­om­mends that a spon­sor use a place­bo-con­trolled de­sign on­ly in se­lect cir­cum­stances, ac­cord­ing to new draft guid­ance re­leased Thurs­day.

Such cir­cum­stances in­clude “where sur­veil­lance is stan­dard of care,” or with spe­cif­ic tri­al “de­sign fea­tures (e.g. if the tri­al us­es an add-on de­sign, when the end­point in­tend­ed to sup­port a la­bel­ing claim has a high de­gree of sub­jec­tiv­i­ty, such as pa­tient re­port­ed out­comes).”

And when con­sid­er­ing the use of a place­bo con­trol, the FDA says spon­sors should pro­vide a ra­tio­nale for the tri­al de­sign and a de­tailed de­scrip­tion in the pro­to­col and sta­tis­ti­cal analy­sis plan of the pro­pos­al for blind­ing and un­blind­ing.

“If a spon­sor in­tends to main­tain the treat­ment blind when dis­ease re­curs or pro­gress­es or a sus­pect­ed ad­verse event oc­curs, the in­formed con­sent doc­u­ment should spec­i­fy the risks and po­ten­tial dis­ad­van­tages of this ap­proach, and the pro­to­col should in­clude jus­ti­fi­ca­tion for the po­ten­tial added risk,” the three-page draft says.

The FDA al­so rec­om­mends that spon­sors un­blind a pa­tient “at the time of doc­u­ment­ed dis­ease re­cur­rence or pro­gres­sion to en­sure op­ti­mal pa­tient man­age­ment.”

Con­tin­ued blind­ing at the time of dis­ease pro­gres­sion or oc­cur­rence of se­ri­ous ad­verse events presents ad­di­tion­al chal­lenges, the FDA says.

For ex­am­ple, in a blind­ed im­munother­a­py tri­al, a pa­tient who de­vel­ops ad­verse events on the con­trol arm may re­ceive un­nec­es­sary treat­ments (e.g., im­muno­sup­pres­sive drug prod­ucts in­clud­ing a high dose of glu­co­cor­ti­coids, cy­clophos­phamide, in­ter­leukin-6 an­tag­o­nist, or in­flix­imab) for man­age­ment of ad­verse events in­cor­rect­ly at­trib­uted to the in­ves­ti­ga­tion­al drug prod­uct.

Main­tain­ing the blind af­ter dis­ease pro­gres­sion could al­so af­fect a pa­tient’s sub­se­quent ther­a­py.

The FDA al­so rec­om­mends un­blind­ing the pa­tient and in­ves­ti­ga­tor “when the pa­tient has an ad­verse event sus­pect­ed to be re­lat­ed to the in­ves­ti­ga­tion­al drug prod­uct and for which man­age­ment of the ad­verse event with one or more drug prod­ucts with sub­stan­tial tox­i­c­i­ty or in­va­sive pro­ce­dures is be­ing con­sid­ered. In such cas­es of un­blind­ing, the pa­tient should not be re­moved from the tri­al.”

In terms of the prac­ti­cal and eth­i­cal con­cerns re­lat­ed to us­ing place­bos in some on­col­o­gy tri­als, the FDA notes that in many cas­es, be­cause of the tox­i­c­i­ty of the ac­tive treat­ment, pa­tients and in­ves­ti­ga­tors may know if they are re­ceiv­ing a place­bo treat­ment.

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 for more in­for­ma­tion.


Zachary Brennan

managing editor, RAPS

John Hood [file photo]

UP­DATE: Cel­gene and the sci­en­tist who cham­pi­oned fe­dra­tinib's rise from Sanofi's R&D grave­yard win FDA OK

Six years after Sanofi gave it up for dead, the FDA has approved the myelofibrosis drug fedratinib, now owned by Celgene.

The drug will be sold as Inrebic, and will soon land in the portfolio at Bristol-Myers Squibb, which is finalizing a deal to acquire Celgene.

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Ab­b­Vie gets its FDA OK for JAK in­hibitor upadac­i­tinib, but don’t look for this one to hit ex­ecs’ lofty ex­pec­ta­tions

Another big drug approval came through on Friday afternoon as the FDA OK’d AbbVie’s upadacitinib — an oral JAK1 inhibitor that is hitting the rheumatoid arthritis market with a black box warning of serious malignancies, infections and thrombosis reflecting fears associated with the class.

It will be sold as Rinvoq — at a wholesale price of $59,000 a year — and will likely soon face competition from a drug that AbbVie once controlled, and spurned. Reuters reports that a 4-week supply of Humira, by comparison, is $5,174, adding up to about $67,000 a year.

UP­DAT­ED: AveX­is sci­en­tif­ic founder was axed — and No­var­tis names a new CSO in wake of an ethics scan­dal

Now at the center of a storm of controversy over its decision to keep its knowledge of manipulated data hidden from regulators during an FDA review, Novartis CEO Vas Narasimhan has found a longtime veteran in the ranks to head the scientific work underway at AveXis, where the incident occurred. And the scientific founder has hit the exit.

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The top 10 fran­chise drugs in bio­phar­ma his­to­ry will earn a to­tal of $1.4T (tril­lion) by 2024 — what does that tell us?

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ICER blasts FDA, PTC and Sarep­ta for high prices on DMD drugs Em­flaza, Ex­ondys 51

ICER has some strong words for PTC, Sarepta and the FDA as the US drug price watchdog concludes that as currently priced, their respective new treatments for Duchenne muscular dystrophy are decidedly not cost-effective.

The final report — which cements the conclusions of a draft issued in May — incorporates the opinion of a panel of 17 experts ICER convened in a public meeting last month. It also based its analysis of Emflaza (deflazacort) and Exondys 51 (eteplirsen) on updated annual costs of $81,400 and over $1 million, respectively, after citing “incorrect” lower numbers in the initial calculations.

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There’s nothing quite like a big patent win when it comes to burnishing your prospects in the pipeline. And for Amgen, which seems to have rescued Enbrel for a run to 2029, the cheering section on Wall Street is now fixed on AMG 510 and a key rival.

And it didn’t take much data to do it. 

There was the first snapshot of a handful of patients, with a 50% response rate. Then came word that Amgen researchers are also tracking responses in different cancers, at least one in colorectal cancer and appendiceal too. 

Bain's Or­ly Mis­han joins Pfiz­er's neu­ro spin­out Cerev­el; On­colyt­ic virus biotech taps Sil­la­Jen ex­ec He­le­na Chaye as CEO

→ Bain Capital is deploying one of its top investors to Cerevel Therapeutics, steering a $350 million-plus neuro play carved out of Pfizer. Orly Mishan — a co-founder and principal of Bain’s life sciences unit — was involved in the partnership that birthed the biotech spinout in the first place. As Cerevel’s first chief business officer, she is tasked with corporate development, program management as well as technical operations. 

UP­DAT­ED: Watch out Bay­er, Roche is com­ing for you with a dis­count price ri­val to the tu­mor ag­nos­tic drug you got from Loxo

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UP­DAT­ED: Sci­en­tist-CEO ac­cused of im­prop­er­ly us­ing con­fi­den­tial in­fo from uni­corn Alec­tor

The executive team at Alector $ALEC has a bone to pick with scientific co-founder Asa Abeliovich. Their latest quarterly rundown has this brief note buried inside:

On June 18, 2019, we initiated a confidential arbitration proceeding against Dr. Asa Abeliovich, our former consulting co-founder, related to alleged breaches of his consulting agreement and the improper use of our confidential information that he learned during the course of rendering services to us as our consulting Chief Scientific Officer/Chief Innovation Officer. We are in the early stage of this arbitration proceeding and are unable to assess or provide any assurances regarding its possible outcome.

There’s no explicit word in the filing on what kind of confidential info was involved, but the proceeding got started 2 days ahead of Abeliovich’s IPO.

Abeliovich, formerly a tenured associate professor at Columbia, is a top scientist in the field of neurodegeneration, which is where Alector is targeted. More recently, he’s also helped start up Prevail Therapeutics as the CEO, which raised $125 million in an IPO. And there he’s planning on working on new gene therapies that target genetically defined subpopulations of Parkinson’s disease. Followup programs target Gaucher disease, frontotemporal dementia and synucleinopathies.

But this time Abeliovich is the CEO rather than a founding scientist. And some of their pipeline overlaps with Alector’s.

Abeliovich and Prevail, though, aren’t taking this one lying down.

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