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.

Big Phar­ma's Twit­ter ex­o­dus; Mer­ck wa­gers $1.35B on buy­out; $3.5M gene ther­a­py; 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.

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Paul Perreault, CSL Behring CEO

CSL lands FDA ap­proval for he­mo­phil­ia B gene ther­a­py, sets $3.5M list price

The FDA has approved the world’s first gene therapy for hemophilia B, ushering into the market a treatment that’s historic in both what it promises to do and how much it will cost.

CSL will be marketing the drug, Hemgenix, at a list price of $3.5 million — which sets a new record for the most expensive single-use gene therapy in the US.

In a statement provided to Endpoints News, the Australian company noted that the current costs of treating people with moderate to severe hemophilia B can be significant over a lifetime. By some estimates, healthcare systems could spend more than $20 million per person.

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Elon Musk (GDA via AP Images)

Biggest drug com­pa­nies halt­ed Twit­ter ad buys af­ter Lil­ly in­sulin spoof

Almost all of the drug industry’s biggest advertisers cut their spending on Twitter to zero or near-zero over the last two weeks amid worries about impersonation of their brands by pranksters and the future of the social media company.

Among 18 of the biggest pharmaceutical advertisers in the US market, 12 cut their Twitter ad spending to nothing for the week beginning Nov. 14, according to Pathmatics, which tracks data on prescription drug ad spending as well as general corporate advertising. The list of drugmakers cutting spending to zero includes Merck, AstraZeneca, Eli Lilly, Novartis, Pfizer and others.

Rob Davis, Merck CEO

Up­dat­ed: No Seagen here: 'Do more' means a small $1.35B pur­chase of Ima­go for Mer­ck

Merck is making an acquisition, the Big Pharma announced before Monday’s opening bell. No, Seagen is not entering the fold, as had been speculated for quarters.

Folding under Merck’s wings will be Pfizer-backed Imago BioSciences. For nearly a year, Merck CEO Rob Davis has been saying the pharma giant needs to “do more” on the business development front after its 2021 $11.5 billion acquisition of Acceleron.

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FDA preps for DMD drug gener­ics as Sarep­ta has yet to fin­ish its con­fir­ma­to­ry tri­al

The FDA typically releases guidance to help generic drug manufacturers develop new copycats of small molecule drugs, oftentimes in preparation for a brand name product’s patents or exclusivity to expire.

This week, FDA released such bioequivalence guidance for any generic drugmakers looking to take on Sarepta’s Duchenne muscular dystrophy (DMD) drug Exondys 51 (eteplirsen), even though the drug’s sponsor has yet to convert the accelerated approval to a full approval, showing clinical benefit.

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Roivant’s Der­ma­vant de­buts first-ever TV com­mer­cial for pso­ri­a­sis cream Vta­ma

Dermavant Sciences has been marketing its first product, psoriasis med Vtama, to dermatologists for months, but on Tuesday it rolled out its first consumer campaign. The debut DTC effort including a streaming TV commercial encourages patients to a “Topical Uprising” in a nod to Vtama being a topical cream.

In the new commercial, a swell of people discards scarves and jacket coverings, gathering in the street to converge on a pharmacy to demand a steroid-free prescription. A moment of levity follows when a pharmacist says, “You know you can just talk to your doctor, right?” The gathered crowds collectively says, “Oh.”

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Stanley Erck, Novavax CEO (Andrew Harnik/AP Images)

No­vavax pulls out of Covid-19 vac­cine al­liance with Gavi

Novavax is pulling out of its Covid-19 vaccine deal with Gavi, the Vaccine Alliance, a global partnership tasked with ensuring vaccine access in lower-income countries, following an alleged contract violation.

The Maryland-based company claimed on Friday that Gavi failed to purchase at least 350 million doses of its protein-based vaccine Nuvaxovid by the end of the year, per an advanced purchase agreement. Gavi, the World Health Organization and the Coalition for Epidemic Preparedness Innovations (CEPI) are co-leaders of COVAX, an effort to ensure that all participating countries, regardless of income levels, have access to vaccines.

Fu­ji­film to build $188M man­u­fac­tur­ing plant in North Car­oli­na’s re­search tri­an­gle

As the Japanese conglomerate Fujifilm continues to invest heavily in its CDMO arm, one of its manufacturing divisions is teeing up a major investment.

Fujifilm Irvine Scientific announced on Tuesday that parent Fujifilm is making a $188 million investment to build a cell culture media manufacturing site in the Research Triangle Park in North Carolina. The new site will mark Fujifilm Irvine’s fifth manufacturing site globally and its second in the US.

Days af­ter re­port­ing PhI­II fail­ure, GSK pulls BC­MA drug from US mar­ket — but it's not giv­ing up en­tire­ly yet

GSK is pulling its BCMA-targeting drug from the US market, ending a short, two-year run for a high-profile product that, among other things, was hailed for marking the pharma giant’s return to oncology.

The company is initiating the process for withdrawal at the request of the FDA, which in turn was based on the negative readout of a confirmatory Phase III trial earlier this month. In that trial, GSK’s Blenrep failed to extend progression-free survival over standard of care for patients with multiple myeloma who have received at least two prior lines of therapy.

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