Up­dat­ed: In­ter­change­able biosim­i­lars: FDA fi­nal­izes guid­ance

The FDA on Fri­day fi­nal­ized a long-await­ed guid­ance spelling out how biosim­i­lars can achieve an in­ter­change­able sta­tus, which means they may be sub­sti­tut­ed for the ref­er­ence bi­o­log­ic with­out a pre­scriber in­ter­ven­ing.

No in­ter­change­able biosim­i­lars have been ap­proved in the US yet, and the num­ber of com­pa­nies seek­ing ap­proval for an in­ter­change­able has re­mained at just one, with Boehringer In­gel­heim pub­licly dis­clos­ing that it’s be­gun an in­ter­change­abil­i­ty study for its adal­i­mum­ab (Hu­mi­ra) biosim­i­lar.

But for­mer FDA Com­mis­sion­er Scott Got­tlieb said last month that in­ter­change­able in­sulin prod­ucts are like­ly com­ing to the US in the next cou­ple of years. And fi­nal in­ter­change­abil­i­ty guid­ance will pro­vide spon­sors with more cer­tain­ty on how to de­vel­op in­ter­change­able prod­ucts.

Changes in Fi­nal Guid­ance

The fi­nal guid­ance is sev­en pages short­er than the draft and does not in­clude two ap­pen­dices that were in­clud­ed in the draft on com­par­a­tive use hu­man fac­tors stud­ies.

Com­menters on the draft took is­sue with terms that need­ed fur­ther clar­i­ty, such as “resid­ual un­cer­tain­ty” and “fin­ger­print-like,” which is used in the draft to de­scribe the sim­i­lar­i­ty be­tween the pro­posed in­ter­change­able prod­uct and the ref­er­ence prod­uct.

The fi­nal guid­ance, how­ev­er, no longer us­es the term “fin­ger­print-like” and where­as the draft in­cludes al­most 20 ref­er­ences to “resid­ual un­cer­tain­ty,” the fi­nal guid­ance in­cludes on­ly one. “The agency al­so con­sid­ered the nu­mer­ous com­ments on the draft in­ter­change­abil­i­ty guid­ance and made changes to pro­vide in­creased clar­i­ty to stake­hold­ers,” Act­ing Com­mis­sion­er Ned Sharp­less said.

Chris­tine Sim­mon

Chris­tine Sim­mon, ex­ec­u­tive di­rec­tor of the Biosim­i­lars Coun­cil, ap­plaud­ed the FDA’s “time­ly guid­ance on in­ter­change­abil­i­ty for biosim­i­lars, par­tic­u­lar­ly its stream­lined da­ta and study de­sign re­quire­ments that al­low flex­i­bil­i­ty and the use of glob­al com­para­tor prod­ucts to sup­port ap­pli­ca­tions.”

Com­pa­nies com­ment­ing on the draft al­so took is­sue with the re­quire­ment that they must use US-li­censed ref­er­ence prod­uct in a switch­ing study (or stud­ies). And the FDA has al­tered this re­quire­ment in the fi­nal guid­ance and re­named that sec­tion of the guid­ance.

“If a spon­sor seeks to use da­ta de­rived from a switch­ing study or stud­ies com­par­ing a pro­posed in­ter­change­able prod­uct with a non-U.S.-li­censed com­para­tor prod­uct as part of the demon­stra­tion that the pro­posed in­ter­change­able prod­uct meets the stan­dard de­scribed in sec­tion 351(k)(4)(B) of the PHS Act, the spon­sor should pro­vide ad­e­quate da­ta and in­for­ma­tion to es­tab­lish a ‘bridge’ be­tween the non-U.S.-li­censed com­para­tor and the U.S.-li­censed ref­er­ence prod­uct and there­by jus­ti­fy the rel­e­vance of the da­ta ob­tained us­ing the non-U.S.-li­censed com­para­tor to an eval­u­a­tion of whether the re­quire­ments of sec­tion 351(k)(4)(B) have been met,” the fi­nal guid­ance says, ex­plain­ing more about what the bridge would en­tail.

Oth­er­wise, most of the draft ver­sion was car­ried over in­to the fi­nal guid­ance, in­clud­ing the re­quire­ment that com­pa­nies use so-called “switch­ing stud­ies” to de­ter­mine whether al­ter­nat­ing be­tween a biosim­i­lar and its ref­er­ence prod­uct im­pacts the safe­ty or ef­fi­ca­cy of the treat­ment.

Bern­stein biotech an­a­lyst Ron­ny Gal added in a note to in­vestors: “The main added re­quire­ment is a 2-arm switch­ing tri­al where all pa­tients start on the ref­er­ence prod­uct. In one arm, the pa­tients will re­main on the ref­er­ence prod­uct through­out. On the oth­er, they will switch back and forth twice, end­ing on the biosim­i­lar prod­uct. Crit­i­cal­ly, the main com­par­i­son is on PK/PD mark­ers, not ef­fi­ca­cy mark­ers (which FDA con­sid­ers less sen­si­tive). This will ma­te­ri­al­ly low­er costs of do­ing these tri­als.”

He al­so said he ex­pects this guid­ance will en­able in­sulin in­ter­change­ables and al­low for in­ter­change­able ver­sions of “some of the eas­i­er an­ti­bod­ies to repli­cate like Eylea.”

Con­sid­er­a­tions in Demon­strat­ing In­ter­change­abil­i­ty With a Ref­er­ence Prod­uct: Guid­ance for In­dus­try

Ed­i­tor’s Note: Up­dat­ed with com­ment from Bern­stein’s Gal.


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.

Author

Zachary Brennan

managing editor, RAPS

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HDV is a single-stranded, circular RNA virus that requires the envelope protein (HBsAg) of the hepatitis B virus (HBV) for its own assembly. As a result, hepatitis delta virus (HDV) infection occurs only as a co-infection in individuals infected with HBV. However, HDV/HBV co-infections lead to more serious liver disease than HBV infection alone. HDV is associated with faster progression to liver fibrosis (progressing to cirrhosis in about 80% of individuals in 5-10 years), increased risk of liver cancer, and early decompensated cirrhosis and liver failure.
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Democratic presidential candidate, U.S. Sen. Elizabeth Warren (D-MA) speaks during the Nevada Democrats' "First in the West" event at Bellagio Resort & Casino on November 17, 2019 in Las Vegas, Nevada (Getty Images)

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Left to right: Arthur Pappas, Robert Nelsen, Peter Kolchinsky Doug Cole and David Beier

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