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. 


Zachary Brennan

managing editor, RAPS

Oxitec biologist releases genetically modified mosquitoes in Piracicaba, Brazil in 2016 [credit: Getty Images]

In­trex­on unit push­es back against claims its GM mos­qui­toes are mak­ing dis­ease-friend­ly mu­tants

When the hysteria of Zika transmission sprang into the American zeitgeist a few years ago, UK-based Oxitec was already field-testing its male Aedes aegypti mosquito, crafted to possess a gene engineered to obliterate its progeny long before maturation.

But when a group of independent scientists evaluated the impact of the release of these genetically-modified mosquitoes in a trial conducted by Oxitec in Brazil between 2013 and 2015, they found that some of the offspring had managed to survive — prompting them to speculate what impact the survivors could have on disease transmission and/or insecticide resistance.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 60,000+ biopharma pros reading Endpoints daily — and it's free.

[via AP Images]

Pur­due threat­ens to walk away from set­tle­ment, asks to pay em­ploy­ees mil­lions in bonus­es

There are two updates on the lawsuit against Purdue Pharma over its role in fueling the opioid epidemic, as the Sackler family threatens to walk away from their pledge to pay out $3 billion if a bankruptcy judge does not stop outstanding state lawsuits against them. At the same time, the company has asked permission to pay millions in bonuses to select employees.

Purdue filed for chapter 11 bankruptcy this week as part of its signed resolution to over 2,000 lawsuits. The deal would see the Sackler family that owns Purdue give $3 billion from their personal wealth and the company turned into a trust committed to curbing and reversing overdoses.

As Nas­daq en­rolls the fi­nal batch of 2019 IPOs, how have the num­bers com­pared to past years?

IGM Biosciences’ upsized IPO haul, coming after SpringWorks’ sizable public debut, has revved up some momentum for the last rush of biotech IPOs in 2019.

With 39 new listings on the books and roughly two more months to go before winding down, Nasdaq’s head of healthcare listings Jordan Saxe sees the exchange marking 50 to 60 biopharma IPOs for the year.

“December 15 is usually the last possible day that companies will price,” he said, as companies get ready for business talks at the annual JP Morgan Healthcare Conference in January.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 60,000+ biopharma pros reading Endpoints daily — and it's free.

Aerial view of Genentech's campus in South San Francisco [Credit: Getty]

Genen­tech sub­mits a plan to near­ly dou­ble its South San Fran­cis­co foot­print

The sign is still there, a quaint reminder of whitewashed concrete not 5 miles from Genentech’s sprawling, chrome-and-glass campus: South Francisco The Industrial City. 

The city keeps the old sign, first erected in 1923, as a tourist site and a kind of civic memento to the days it packed meat, milled lumber and burned enough steel to earn the moniker “Smokestack of the Peninsula.” But the real indication of where you are and how much has changed both in San Francisco and in the global economy since a couple researchers and investors rented out an empty warehouse 40 years ago comes in a far smaller blue sign, resembling a Rotary Club post, off the highway: South San Francisco, The Birthplace of Biotech.

A fa­vorite in Alex­ion’s C-suite is leav­ing, and some mighty sur­prised an­a­lysts aren’t the least bit hap­py about it

Analysts hate to lose a biotech CFO they’ve come to trust and admire — especially if they’re being blindsided by a surprise exit.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 60,000+ biopharma pros reading Endpoints daily — and it's free.

David Grainger [file photo]

'Dis­con­nect the bas­tard­s' — one biotech's plan to break can­cer cell­s' uni­fied de­fens­es

Chemotherapy and radiotherapy are the current gladiators of cancer treatment, but they come with well-known limitations and side-effects. The emergence of immunotherapy — a ferocious new titan in oncologist’s toolbox — takes the brakes off the immune system to kill cancer cells with remarkable success in some cases, but the approach is not always effective. What makes certain forms of cancer so resilient? Scientists may have finally pieced together a tantalizing piece of the puzzle, and a new biotech is banking on a new approach to fill the gap.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 60,000+ biopharma pros reading Endpoints daily — and it's free.

While No­var­tis ban­ish­es Zol­gens­ma scan­dal scars — Bio­gen goes on a Spin­raza 'of­fen­sive'

While Novartis painstakingly works to mop up the stench of the data manipulation scandal associated with its expensive gene therapy for spinal muscular atrophy (SMA) Zolgensma— rival Biogen is attempting to expand the use of its SMA therapy, Spinraza. 

The US drugmaker $BIIB secured US approval for Spinraza for use in the often fatal genetic disease in 2016. The approval covered a broad range of patients with infantile-onset (most likely to develop Type 1) SMA. 

Jason Kelly. Mike Blake/Reuters via Adobe

Eye­ing big ther­a­peu­tic push, Gink­go bags $290M to build a cell pro­gram­ming em­pire

Ginkgo Bioworks is on a roll. Days after publicizing a plan to nurture new startups via partnerships with accelerators Y Combinator and Petri, the Boston biotech says it has raised another $290 million for its cell programming platform to reach further and wider.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 60,000+ biopharma pros reading Endpoints daily — and it's free.

UP­DAT­ED: Speak­er Nan­cy Pelosi to un­veil bill for fed­er­al­ly ne­go­ti­at­ed drug prices

After months of buzz from both sides of the aisle, Speaker Nancy Pelosi will today introduce her plan to allow the federal government to negotiate prices for 250 prescription drugs, setting up a showdown with a pharmaceutical industry working overtime to prevent it.

The need to limit drug prices is a rare point of agreement between President Trump and Democrats, although the president has yet to comment on the proposal and will likely face pressure to back a more conservative option or no bill at all. Republican Senator Chuck Grassley is reportedly lobbying his fellow party members on a more modest proposal he negotiated with Democratic Senator Ron Wyden in July.