Drug-drug in­ter­ac­tions: FDA is­sues guid­ance on clin­i­cal, in vit­ro stud­ies

The FDA on Thurs­day fi­nal­ized two guid­ances pro­vid­ing rec­om­men­da­tions to drug­mak­ers on eval­u­at­ing po­ten­tial drug-drug in­ter­ac­tions (DDIs) for new drugs through clin­i­cal and in vit­ro test­ing.

“To­geth­er, the two fi­nal guid­ances de­scribe a sys­tem­at­ic risk-based ap­proach to eval­u­a­tion and com­mu­ni­ca­tion of DDIs,” the FDA writes.

The two guid­ances fi­nal­ize draft ver­sions re­leased in 2017 and have been re­vised to clar­i­fy their scope, pro­vide ad­di­tion­al con­sid­er­a­tions for con­duct­ing prospec­tive stud­ies and to ex­plain “when DDI stud­ies are need­ed for drugs iden­ti­fied as trans­porter sub­strates from in vit­ro stud­ies.” Both guid­ances have been re­named from their draft ver­sions to re­flect an em­pha­sis on in­ves­ti­gat­ing the cy­tochrome P450 (CYP) en­zyme and trans­porter-me­di­at­ed drug in­ter­ac­tions.

The FDA ex­plains that DDIs are a crit­i­cal fac­tor in a drug’s over­all ben­e­fit-risk pro­file and stress­es that clin­i­cal­ly rel­e­vant DDIs should be iden­ti­fied dur­ing drug de­vel­op­ment, known at the time of ap­proval, in­clud­ed in la­bel­ing and mon­i­tored on an on­go­ing ba­sis.

“The con­comi­tant use of more than one med­ica­tion in a pa­tient is com­mon. Unan­tic­i­pat­ed, un­rec­og­nized, or mis­man­aged DDIs are an im­por­tant cause of mor­bid­i­ty and mor­tal­i­ty as­so­ci­at­ed with pre­scrip­tion drug use and have oc­ca­sion­al­ly been the ba­sis for with­draw­al of ap­proved drugs from the mar­ket. In some in­stances, un­der­stand­ing how to safe­ly man­age a DDI can al­low ap­proval of a drug that would oth­er­wise have an un­ac­cept­able lev­el of risk,” the FDA writes.

In Vit­ro Drug In­ter­ac­tion Stud­ies

The FDA’s 43-page guid­ance on in vit­ro drug in­ter­ac­tion stud­ies dis­cuss­es ap­proach­es to eval­u­ate the DDI po­ten­tial of in­ves­ti­ga­tion­al drugs and how those stud­ies can in­form clin­i­cal DDI stud­ies down the road.

The guid­ance ex­plains that “eval­u­at­ing the DDI po­ten­tial of an in­ves­ti­ga­tion­al new drug in­volves iden­ti­fy­ing the prin­ci­pal routes of the drug’s elim­i­na­tion; es­ti­mat­ing the con­tri­bu­tion of en­zymes and trans­porters to the drug’s dis­po­si­tion; and char­ac­ter­iz­ing the ef­fect of the drug on en­zymes and trans­porters.”

The re­sults of in vit­ro DDI stud­ies and phar­ma­co­ki­net­ic (PK) da­ta “pro­vide mech­a­nis­tic in­for­ma­tion that can in­form the need for and prop­er de­sign of po­ten­tial fu­ture clin­i­cal stud­ies.”

The guid­ance goes on to dis­cuss ap­proach­es to eval­u­at­ing me­tab­o­lism-me­di­at­ed and trans­porter-me­di­at­ed drug in­ter­ac­tions, as well as ap­proach­es to eval­u­ate the DDI po­ten­tial of metabo­lites.

Clin­i­cal Drug In­ter­ac­tion Stud­ies

In the 24-page fi­nal guid­ance on clin­i­cal drug in­ter­ac­tion stud­ies, the FDA ex­plains when DDI stud­ies should be con­duct­ed and pro­vides rec­om­men­da­tions for the de­sign, con­duct and in­ter­pre­ta­tion of those stud­ies.

Specif­i­cal­ly, the guid­ance dis­cuss­es dif­fer­ent DDI study de­signs and con­sid­er­a­tions for prospec­tive DDI stud­ies, CYP-me­di­at­ed in­ter­ac­tions, trans­porter-me­di­at­ed re­ac­tions and cock­tail study ap­proach­es. The guid­ance al­so dis­cuss­es oth­er fac­tors that could im­pact drug in­ter­ac­tions, such as pa­tient ge­net­ics, smok­ing and com­plex drug in­ter­ac­tions.

Ad­di­tion­al­ly, the guid­ance pro­vides rec­om­men­da­tions on what DDI in­for­ma­tion should be in­clud­ed in la­bel­ing and refers spon­sors to four oth­er rel­e­vant la­bel­ing guid­ances.

Fed­er­al Reg­is­ter No­tice

RAPS: First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.

Mi­no­ryx and Sper­o­genix ink an ex­clu­sive li­cense agree­ment to de­vel­op and com­mer­cial­ize lerigli­ta­zone in Chi­na

September 23, 2020 – Hong Kong, Beijing, Shanghai (China) and Mataró, Barcelona (Spain)  

Minoryx will receive an upfront and milestone payments of up to $78 million, as well as double digit royalties on annual net sales 

Sperogenix will receive exclusive rights to develop and commercialize leriglitazone for the treatment of X-linked adrenoleukodystrophy (X-ALD), a rare life-threatening neurological condition

FDA commissioner Stephen Hahn at the White House (AP Images)

Un­der fire, FDA to is­sue stricter guid­ance for Covid-19 vac­cine EUA this week — re­port

The FDA has been insisting for months that a Covid-19 vaccine had to be at least 50% effective – a measure of transparency meant to shore public trust in the agency and in a vaccine that had been brought forward at record speed and record political pressure. But now, with concerns of a Trump-driven authorization arriving before the election, the agency may be raising the bar.

The FDA is set to release new guidance that would raise safety and efficacy requirements for a vaccine EUA above earlier guidance and above the criteria used for convalescent plasma or hydroxychloroquine, The Washington Post reported. Experts say this significantly lowers the odds of an approval before the election on November 3, which Trump has promised despite vocal concerns from public health officials, and could help shore up public trust in the agency and any eventual vaccine.

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

Trump’s HHS claims ab­solute au­thor­i­ty over the FDA, clear­ing path to a vac­cine EUA

The top career staff at the FDA has vowed not to let politics overrule science when looking at vaccine data this fall. But Alex Azar, who happens to be their boss’s boss, apparently won’t even give them a chance to stand in the way.

In a new memorandum issued Tuesday last week, the HHS chief stripped the FDA and other health agencies under his purview of their rule making ability, asserting all such power “is reserved to the Secretary.” Sheila Kaplan of the New York Times first obtained and reported the details of the September 15 bulletin.

Vas Narasimhan (AP Images)

UP­DAT­ED: Still held down by clin­i­cal hold, No­var­tis' Zol­gens­ma falls fur­ther be­hind Bio­gen and Roche as FDA asks for a new piv­otal study

Last October, the FDA slowed down Novartis’ quest to extend its gene therapy to older spinal muscular atrophy patients by slapping a partial hold on intrathecal administration. Almost a year later, the hold is still there, and regulators are adding another hurdle required for regulatory submission: a new pivotal confirmatory study.

The new requirement — which departs significantly from Novartis’ prior expectations — will likely stretch the path to registration beyond 2021, when analysts were expecting a BLA submission. That could mean more time for Biogen to reap Spinraza revenues and Roche to ramp up sales of Evrysdi in the absence of a rival.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 90,400+ biopharma pros reading Endpoints daily — and it's free.

Scoop: ARCH’s Bob Nelsen is back­ing an mR­NA up­start that promis­es to up­end the en­tire man­u­fac­tur­ing side of the glob­al busi­ness

For the past 2 years, serial entrepreneur Igor Khandros relied on a small network of friends and close insiders to supply the first millions he needed to fund a secretive project to master a new approach to manufacturing mRNA therapies.

Right now, he says, he has a working “GMP-in-a-box” prototype for a new company he’s building — after launching 3 public companies — which plans to spread this contained, precise manufacturing tech around the world with a set of partners. He’s raised $60 million, recruited some prominent experts. And not coincidentally, he’s going semi-public with this just as a small group of pioneers appears to be on the threshold of ushering in the world’s first mRNA vaccines to fight a worldwide pandemic.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Isaac Veinbergs, Libra CEO

With $29M in Se­ries A, Boehringer-backed Li­bra looks to tack­le neu­rode­gen­er­a­tion through cel­lu­lar clean­ing

Can the natural process by which cells clean out toxic proteins be harnessed to create potential treatments for neurodegenerative disorders?

That’s the question Libra Therapeutics will be trying to answer, as the new biotech officially launched Wednesday morning with $29 million in Series A financing. The company has three preclinical programs at the ready, with its lead candidate targeting ALS and frontotemporal dementia. But CEO Isaac Veinbergs said he hopes to develop therapies for a wide range of diseases, including Parkinson’s, Alzheimer’s and Huntington’s.

Patrick Enright, Longitude co-founder (Longitude)

As its biotechs hit the pan­dem­ic ex­it, Lon­gi­tude rais­es $585M for new neu­ro, can­cer, ag­ing and or­phan-fo­cused fund

The years have been kind to Longitude Capital. This year, too.

A 2006 spinout of Pequot Capital, its founders started their new firm just four years before the parent company would go under amid insider trading allegations. Their first life sciences fund raised $325 million amid the financial crisis, they added a second for $385 million and then in, 2016, a third for $525 million. In the last few months, the pandemic biotech IPO boom netted several high-value exits from those funds, as Checkmate, Vaxcyte, Inozyme and Poseida all went public.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 90,400+ biopharma pros reading Endpoints daily — and it's free.

Gene Wang, Immetas co-founder and CEO (file photo)

Im­metas Ther­a­peu­tics nabs $11M Se­ries A to nar­row their bis­pe­cif­ic work tar­get­ing in­flam­ma­tion in age-re­lat­ed dis­eases

How does a biotech celebrate its two-year anniversary? For Immetas Therapeutics, it’s with an $11 million Series A round and a game plan to fight age-related disease.

Co-founders Gene Wang and David Sinclair came together years ago around the idea that inflammation is the ultimate process driving age-related illnesses, including cancer. The duo launched Immetas in 2018 and packed the staff with industry experts. Wang, who says he’s always had an entrepreneurial spirit, has held lead roles at Novartis, GSK, Bristol Myers Squibb and Merck. He’s worked on blockbuster drugs like Humira, Gardasil, Varubi and Zolinza. And now, he’s channeling that spirit as CEO.

#ES­MO20: Push­ing in­to front­line, Mer­ck and Bris­tol My­ers duke it out with new slate of GI can­cer da­ta

Having worked in parallel for years to move their respective PD-1 inhibitors up to the first-line treatment of gastrointestinal cancers, Merck and Bristol Myers Squibb finally have the data at ESMO for a showdown.

Comparing KEYNOTE-590 and CheckMate-649, of course, comes with the usual caveats. But a side-by-side look at the overall survival numbers also offer some perspective on a new frontier for the reigning checkpoint rivals, both of whom are claiming to have achieved a first.