FDA drafts guid­ance on seam­less clin­i­cal tri­als for can­cer drug de­vel­op­ers

The FDA on Fri­day re­leased draft guid­ance to help spon­sors de­sign and con­duct first in hu­man (FIH) clin­i­cal tri­als that speed the clin­i­cal de­vel­op­ment of can­cer drugs through mul­ti­ple ex­pan­sion co­hort study de­signs.

The guid­ance pro­vides the FDA’s thoughts on the char­ac­ter­is­tics of drugs and bi­o­log­ics ap­pro­pri­ate­ly suit­ed for such an ex­pe­dit­ed plan, in­for­ma­tion to in­clude in such in­ves­ti­ga­tion­al new drug (IND) ap­pli­ca­tion sub­mis­sions, when to in­ter­act with the FDA and safe­guards to pro­tect pa­tients en­rolled in FIH ex­pan­sion co­hort stud­ies.

FDA Com­mis­sion­er Scott Got­tlieb ex­plained how the draft guid­ance dis­cuss­es ways spon­sors can com­press the tra­di­tion­al three phas­es of tri­als in­to one con­tin­u­ous tri­al, called an ex­pan­sion co­hort tri­al. “A lot of the time and cost of clin­i­cal de­vel­op­ment is spent wait­ing in be­tween the start and end of the phas­es of tri­als. Ex­pan­sion co­hort tri­als can bring ef­fi­cien­cy to drug de­vel­op­ment, po­ten­tial­ly re­duc­ing de­vel­op­ment costs and time,” he said.


Phase I clin­i­cal tri­als, which are ex­pect­ed to in­clude be­tween 20 and 80 pa­tients, are de­signed to de­ter­mine the me­tab­o­lism and phar­ma­co­log­ic ac­tions of an in­ves­ti­ga­tion­al drug, the side ef­fects as­so­ci­at­ed with in­creased dos­es, and, if pos­si­ble, to gain ear­ly ev­i­dence of ef­fec­tive­ness, ac­cord­ing to the FDA.

FIH mul­ti­ple ex­pan­sion co­hort tri­als, de­fined as tri­als with a sin­gle pro­to­col with an ini­tial dose-es­ca­la­tion phase that al­so con­tains three or more ad­di­tion­al pa­tient co­horts with co­hort-spe­cif­ic ob­jec­tives, are in­tend­ed to ex­pe­dite de­vel­op­ment by pro­ceed­ing from ini­tial de­ter­mi­na­tion of a po­ten­tial­ly ef­fec­tive dose to in­di­vid­ual co­horts that have tri­al ob­jec­tives typ­i­cal of Phase II tri­als (i.e., to es­ti­mate an­ti-tu­mor ac­tiv­i­ty), the FDA says.

The ob­jec­tives of these ex­pan­sion co­horts can in­clude “as­sess­ment of an­ti-tu­mor ac­tiv­i­ty in a dis­ease-spe­cif­ic set­ting, as­sess­ment of a rea­son­ably safe dose in spe­cif­ic pop­u­la­tions (e.g., pe­di­atric or el­der­ly pa­tients or pa­tients with or­gan im­pair­ment), eval­u­a­tion of al­ter­na­tive dos­es or sched­ules, es­tab­lish­ment of dose and sched­ule for the in­ves­ti­ga­tion­al drug ad­min­is­tered with an­oth­er on­col­o­gy drug, or eval­u­a­tion of the pre­dic­tive val­ue of a po­ten­tial bio­mark­er,” the draft says.

But chal­lenges are to be ex­pect­ed be­cause of the na­ture of these tri­als.

“Be­cause of the rapid en­roll­ment and evolv­ing na­ture of the in­for­ma­tion ob­tained in these tri­als, large num­bers of pa­tients are ex­posed to drugs with un­known ef­fi­ca­cy and min­i­mal­ly char­ac­ter­ized tox­i­c­i­ty pro­files,” the FDA ex­plains. “To mit­i­gate such risks and to pro­tect pa­tients, it is im­per­a­tive that spon­sors es­tab­lish an in­fra­struc­ture to stream­line tri­al lo­gis­tics, fa­cil­i­tate da­ta col­lec­tion, and in­cor­po­rate plans to rapid­ly as­sess emerg­ing da­ta in re­al time and to dis­sem­i­nate in­ter­im re­sults to in­ves­ti­ga­tors, in­sti­tu­tion­al re­view boards (IRBs), and reg­u­la­tors.”


FIH mul­ti­ple ex­pan­sion co­hort stud­ies pose unique chal­lenges and risks, ac­cord­ing to the FDA, in­clud­ing ex­pos­ing pa­tients across mul­ti­ple, si­mul­ta­ne­ous­ly ac­cru­ing, co­horts to po­ten­tial­ly sub­op­ti­mal or tox­ic dos­es of an in­ves­ti­ga­tion­al drug or ex­pos­ing more pa­tients than re­quired to achieve cer­tain ob­jec­tives.

“In­ef­fi­cient drug de­vel­op­ment based on pos­si­bly missed in­ter­pre­ta­tion of pre­lim­i­nary tri­al” was al­so cit­ed as a po­ten­tial chal­lenge in the draft.

To en­sure such stud­ies are worth the added risk, the FDA says, “The pa­tient pop­u­la­tion should be lim­it­ed to pa­tients with se­ri­ous dis­eases for which no cu­ra­tive ther­a­pies are avail­able.”

The 14-page draft guid­ance al­so fea­tures sec­tions on con­sid­er­a­tions based on co­hort ob­jec­tives, sta­tis­ti­cal and safe­ty con­sid­er­a­tions, as well as pro­to­col con­tent and com­mu­ni­ca­tions and in­ter­ac­tions with the FDA.

“Spon­sors should re­quest a pre-IND meet­ing to dis­cuss their plans to con­duct an FIH mul­ti­ple ex­pan­sion co­hort tri­al,” the draft says.

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. 

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Remarkable advances in cell and gene therapy over the last decade offer unprecedented therapeutic promise and bring new hope for many patients facing diseases once thought incurable. However, for cell and gene therapies to reach their full potential, researchers, manufacturers, life science companies, and academics will need to work together to solve the significant challenges facing the industry.

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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.

It’s always a bittersweet moment saying goodbye, but as Josh Sullivan goes off to new adventures we are grateful for the way he’s built up the Endpoints Manufacturing section — which the rest of the team will now carry forward. If you’re not already, this may be a good time to sign up for your weekly dose of drug manufacturing news. Thank you for reading and wish you a restful weekend.

Bay­er sounds re­treat from a $670 mil­lion CAR-T pact in the wake of a pa­tient death

Two months after Atara Biotherapeutics hit the hold button on its lead CAR-T 2.0 therapy following a patient death, putting the company under the watchful eye of the FDA, its Big Pharma partners at Bayer are bowing out of a $670 million global alliance. And the move is forcing a revamp of Atara’s pipeline plans, even as research execs vow to continue work on the two drugs allied with Bayer 18 months ago, which delivered a $60 million cash upfront.

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Sanofi and Re­gen­eron clear the fin­ish line in an in­flam­ma­to­ry esoph­a­gus dis­ease, leav­ing Take­da in the dust

With atopic dermatitis rivals breathing down Dupixent’s neck, Sanofi and Regeneron on Friday secured a first win in new territory in what Sanofi’s head of immunology and inflammation Naimish Patel called the fastest approval he’s ever seen.

The FDA approved Dupixent on Friday to treat patients 12 years and older with eosinophilic esophagitis (EoE), an inflammatory condition that causes swelling and scarring of the esophagus. The approval came just a couple months after regulators granted Dupixent priority review, and months ahead of its PDUFA date on Aug. 3.

Fu­ji­film con­tin­ues its biotech build­ing spree with new fa­cil­i­ty in Chi­na

A Japanese conglomerate is making a big play in China with the opening of a new facility, as it continues to expand.

Fujifilm Irvine Scientific has opened its new Innovation and Collaboration Center in Suzhou New District, China, an area in Jiangsu province specifically designated for technological and industrial development.

According to Fujifilm, the 12,000-square-foot site will be responsible for the company’s cell culture media optimization, analysis and design services. Cell culture media itself often requires customization of formulas and protocols to achieve the desired quantity and quality of therapeutic desired. Fujifilm Irvine Scientific is offering these services from its headquarters in California and Japan to its customers globally, as well as in China now.

Rob Etherington, Clene CEO

Mary­land of­fers loan to Clene de­spite ALS tri­al bumps

Even after Utah-based Clene failed to hit its primary endpoints for its ALS drug last year, the state of Maryland is putting its money at least behind Clene’s manufacturing facility.

The Maryland Board of Public Works has finalized a $3 million, 60-month loan facility with Clene Nanomedicine. The loan was provided by the state’s Neighborhood BusinessWorks program within the Maryland Department of Housing and Community Development.

Armon Sharei, SQZ founder and CEO

SQZ's out­side-the-box man­u­fac­tur­ing method slash­es pro­duc­tion time in ear­ly in study

At ASCO 2021 in June of last year, SQZ Biotech showcased a glimpse of its unorthodox cell therapy manufacturing tech. And on Wednesday, the Watertown, MA, company announced that its first-generation system showed comparable or better performance than a conventional clean-room-based manufacturing process.

The study was non-clinical. Clinical trials are expected by the first half of 2023.

SQZ’s device opens up a temporary window by cell-squeezing to deliver cargoes into cells. Its average processing time was less than six hours per batch, which is more than half the time than conventional methods. The company is planning to use the technology in its first red blood cell derived program for celiac disease. That IND is set to be submitted in the first half of 2023, the company said.

Bobby Sheng, Bora Pharmaceuticals CEO

With new ac­qui­si­tion, Bo­ra to ven­ture in­to bi­o­log­ics

Last week, Taiwan-based CDMO Bora Pharmaceuticals announced that it acquired Eden Biologics. Now, it says that purchase has helped established Bora Biologics, expanding into the biopharmaceutical market.

The acquisition of the company’s assets, which are located in the Hsinchu Biomedical Science Park in Taiwan, is helping Bora build its presence in the biopharma world by expanding production capacity of cell lines for the production of protein drugs. It will also improve the quality control and inspection specifications, as well as cell bank generation. The facility has four 500-liter bioreactors that have been approved by European and Taiwanese regulators.

Paul Chaplin, Bavarian Nordic president and CEO

With mon­key­pox cas­es ris­ing, one Eu­ro­pean coun­try is lock­ing down a small­pox vac­cine con­tract

As the global number of confirmed and suspected monkeypox cases continues to slowly climb, one country is trying to get a head start on potential vaccine stocking.

Bavarian Nordic signed a contract with an undisclosed European nation to supply its smallpox vaccine in response to new cases this month, the company announced Thursday morning. The continent saw its first monkeypox case confirmed about two weeks ago, with both the UK and Portugal seeing cases, according to the Washington Post.

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