San­doz rais­es ques­tions with FDA draft guid­ance on sta­tis­ti­cal ap­proach­es for biosim­i­lars

Mar­tin Schi­estl, chief sci­ence of­fi­cer at No­var­tis’ San­doz, on Tues­day ex­plained how the FDA’s draft guid­ance on sta­tis­ti­cal ap­proach­es to eval­u­ate an­a­lyt­i­cal sim­i­lar­i­ty pos­es risks that could end up caus­ing true biosim­i­lars to be re­ject­ed ran­dom­ly.

Mar­tin Schi­estl, San­doz

Schi­estl told at­ten­dees of DIA’s biosim­i­lars con­fer­ence in Bethes­da, MD, that the prob­lem is re­lat­ed to equiv­a­lence test­ing, which FDA says in the draft, “is typ­i­cal­ly rec­om­mend­ed for qual­i­ty at­trib­ut­es with the high­est risk rank­ing and should gen­er­al­ly in­clude as­say(s) that eval­u­ate clin­i­cal­ly rel­e­vant mech­a­nism(s) of ac­tion of the prod­uct for each in­di­ca­tion for which ap­proval is sought.”

The draft, re­leased about a month ago, al­so notes: “De­ter­min­ing an ap­pro­pri­ate mar­gin is a crit­i­cal but chal­leng­ing step for equiv­a­lence test­ing in any set­ting. Ide­al­ly, it would be pos­si­ble to es­tab­lish and pre-spec­i­fy a bi­o­log­i­cal­ly or clin­i­cal­ly mean­ing­ful equiv­a­lence mar­gin based on sci­en­tif­ic knowl­edge or past ex­pe­ri­ence. Of­ten, how­ev­er, such a mar­gin is not read­i­ly avail­able for every qual­i­ty at­tribute deemed im­por­tant enough for Tier 1 test­ing in a biosim­i­lar de­vel­op­ment pro­gram. With this lim­i­ta­tion, FDA cur­rent­ly rec­om­mends use of an equiv­a­lence mar­gin that is a func­tion of the ref­er­ence prod­uct’s vari­abil­i­ty for the at­tribute be­ing test­ed.”

But Schi­estl not­ed that mon­i­tor­ing the mean is use­ful in process de­vel­op­ment and post ap­proval process mon­i­tor­ing.

How­ev­er, for lot re­lease de­ci­sions, “Com­pli­ance with a pre­set mean is an im­pos­si­ble cri­te­ria.”

He added, “Strict ad­her­ence to equiv­a­lence test­ing for Tier 1 at­trib­ut­es makes biosim­i­lar de­vel­op­ment a gam­ble. Jus­ti­fi­ca­tions which may over­rule a failed equiv­a­lence test should be added in the guid­ance.”

Such jus­ti­fi­ca­tions may in­clude a sci­en­tif­ic un­der­stand­ing of a vari­a­tion and an “in­con­sis­tent mean of the ref­er­ence prod­uct which might be caused by in­her­ent process fluc­tu­a­tions with­in ac­cept­able ranges, man­u­fac­tur­ing changes or move­ments with­in a de­sign space,” Schi­estl added.

The draft guid­ance is still open for com­ments, which can be made un­til 21 No­vem­ber here.


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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