EMA opens con­sul­ta­tion on guide­line for ad­vanced ther­a­pies in clin­i­cal tri­als

The EMA on Thurs­day opened for con­sul­ta­tion a new guide­line on the struc­ture and da­ta re­quire­ments for a clin­i­cal tri­al ap­pli­ca­tion for ex­plorato­ry and con­fir­ma­to­ry tri­als with ad­vanced ther­a­py in­ves­ti­ga­tion­al med­i­c­i­nal prod­ucts (ATIMPs).

The 53-page guide­line ad­dress­es de­vel­op­ment, man­u­fac­tur­ing and qual­i­ty con­trol, fea­tur­ing sec­tions on qual­i­ty doc­u­men­ta­tion (in­clud­ing parts on the ac­tive sub­stance and the in­ves­ti­ga­tion­al med­i­c­i­nal prod­uct), non-clin­i­cal doc­u­men­ta­tion and clin­i­cal doc­u­men­ta­tion.


Ac­cord­ing to the guide­line, ad­vanced ther­a­py med­i­c­i­nal prod­ucts (ATMPs) in­clude gene ther­a­py, so­mat­ic cell ther­a­py med­i­c­i­nal prod­ucts and tis­sue en­gi­neered prod­ucts.

“In gen­er­al, the de­vel­op­ment of an ATMP should fol­low the same gen­er­al prin­ci­ples as oth­er med­i­c­i­nal prod­ucts,” the EMA says. “How­ev­er, it is ac­knowl­edged that the dis­tinc­tive char­ac­ter­is­tics and fea­tures of ATMPs are ex­pect­ed to have an im­pact on prod­uct de­vel­op­ment.”

The EMA ad­vo­cates for a risk-based ap­proach in de­ter­min­ing the con­tent of an in­ves­ti­ga­tion­al med­i­c­i­nal prod­uct dossier (IM­PD), with ap­pli­cants per­form­ing an ini­tial risk analy­sis based on ex­ist­ing knowl­edge on the type of prod­uct and its in­tend­ed use.

“As­pects to be tak­en in­to con­sid­er­a­tion in­clude the ori­gin of the cells, the type of vec­tor and/or the method used for the ge­net­ic mod­i­fi­ca­tion, the man­u­fac­tur­ing process, the non-cel­lu­lar com­po­nents and the spe­cif­ic ther­a­peu­tic use as ap­plic­a­ble,” the guide­line says.

And the EMA warns that an im­ma­ture qual­i­ty de­vel­op­ment “may com­pro­mise the use of the study in the con­text of a mar­ket­ing au­tho­ri­sa­tion ap­pli­ca­tion (e.g. if the prod­uct has not been ad­e­quate­ly char­ac­terised). A weak qual­i­ty sys­tem may al­so com­pro­mise the ap­proval of the clin­i­cal tri­al if the safe­ty of tri­al sub­jects is at risk.”


In ex­plain­ing the de­vel­op­ment of such ATMP prod­ucts, the guide­line says that clin­i­cal tri­al phas­es “are usu­al­ly not as clear-cut as they might be for oth­er prod­uct types,” and ex­plorato­ry tri­als, in­clud­ing first-in-hu­man tri­als, are the main fo­cus of the guid­ance.

For con­fir­ma­to­ry tri­als, which are per­formed to ob­tain piv­otal da­ta for a mar­ket­ing au­tho­riza­tion ap­pli­ca­tion (MAA), the guid­ance says de­vel­op­ers should al­so take in­to con­sid­er­a­tion ex­ist­ing rel­e­vant guide­lines out­lin­ing MAA re­quire­ments.

Un­der qual­i­ty doc­u­men­ta­tion, the guide­line notes that the IM­PD should be di­vid­ed in­to a drug sub­stance (DS) and a drug prod­uct (DP) sec­tion. “For cer­tain ATIMPs, the start­ing ma­te­r­i­al, the ac­tive sub­stance and the fin­ished prod­uct can be close­ly re­lat­ed or near­ly iden­ti­cal. The ac­tive sub­stance, any in­ter­me­di­ate and the fi­nal prod­uct should be iden­ti­fied, if pos­si­ble. In those cas­es where the ATIMPs pro­duc­tion is a con­tin­u­ous process, it is not nec­es­sary to re­peat the in­for­ma­tion that was al­ready pro­vid­ed in the DS part, in­to the DP sec­tion.”

Un­der the ac­tive sub­stance sec­tion, the guide­line says the pro­posed mech­a­nism of ac­tion “should be pre­sent­ed and form the ba­sis for the de­f­i­n­i­tion of the rel­e­vant prop­er­ties of the ac­tive sub­stance in­clud­ing bi­o­log­i­cal ac­tiv­i­ty (i.e. the spe­cif­ic abil­i­ty or ca­pac­i­ty of a prod­uct to achieve a de­fined bi­o­log­i­cal ef­fect).”

As far as the ATIMP man­u­fac­tur­ing process and process con­trols, the guide­line rec­om­mends care­ful de­sign and con­cise, step-by-step de­scrip­tions. “The suit­abil­i­ty of the con­trols for the in­tend­ed pur­pose needs to be proven,” the EMA says.

But it’s the non-clin­i­cal de­vel­op­ment that is re­al­ly unique for ATMPs, es­pe­cial­ly as the EMA says “po­ten­tial flex­i­bil­i­ty can be ap­plied.”

“The non-clin­i­cal de­vel­op­ment path­way for ATMPs may be sig­nif­i­cant­ly dif­fer­ent from the one for oth­er med­i­c­i­nal prod­ucts in­clud­ing the tim­ing of stud­ies. The se­quen­tial non-clin­i­cal de­vel­op­ment in which the amount of da­ta re­quired and the du­ra­tion of dos­ing in­crease by the phase of clin­i­cal de­vel­op­ment and by the num­ber of pa­tients, is not gen­er­al­ly ap­plic­a­ble for ATMPs,” the guide­line ad­vis­es.

In­stead, in many cas­es, the guide­line says, most non-clin­i­cal da­ta may need to be avail­able be­fore hu­man ex­po­sure.

“In gen­er­al, the non-clin­i­cal da­ta sup­port­ing the safe use of an ATMP in hu­mans should pro­vide in­for­ma­tion for the es­ti­ma­tion of the safe and bi­o­log­i­cal­ly ef­fec­tive dose(s) to be used in clin­i­cal tri­als, sup­port the fea­si­bil­i­ty of the ad­min­is­tra­tion route and the ap­pro­pri­ate ap­pli­ca­tion pro­ce­dure, iden­ti­fy safe­ty con­cerns and tar­get or­gans for po­ten­tial tox­i­c­i­ty and iden­ti­fy safe­ty pa­ra­me­ters to be fol­lowed in the clin­i­cal tri­als,” the guide­line says.

As for clin­i­cal doc­u­men­ta­tion, the guide­line al­so notes that the dis­tinc­tive char­ac­ter­is­tics and fea­tures of ATMPs are ex­pect­ed to have an im­pact on the tri­al de­sign, specif­i­cal­ly with re­gard to ear­ly phase tri­als and dose se­lec­tion, phar­ma­co­dy­nam­ics and phar­ma­co­ki­net­ics/biodis­tri­b­u­tion, while the gen­er­al prin­ci­ples in late phase tri­als to demon­strate ef­fi­ca­cy and safe­ty in the spe­cif­ic ther­a­peu­tic area are less af­fect­ed and are es­sen­tial­ly the same as for oth­er prod­ucts.

Com­ments on the con­sul­ta­tion are due by 1 Au­gust.

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.

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