Dr. Gabriel Kremmidiotis, Chief Scientific Officer (left) heads up the biotech ClinicReady team of scientific and medical affairs specialists with a 20-year track record. Dr. Jorgen Mould Avance Clinical Scientific Affairs Specialist (right) and Yvonne Lungershausen, Avance Clinical’s CEO.

How Clini­cReady by Aus­tralian CRO Avance Clin­i­cal de­liv­ers pre­clin­i­cal project man­age­ment and sci­en­tif­ic and reg­u­la­to­ry ad­vice to get biotechs in­to clin­ic faster

Avance Clin­i­cal has formed a ded­i­cat­ed sci­en­tif­ic and reg­u­la­to­ry af­fairs ser­vice, Clini­cReady by Avance Clin­i­cal, in re­sponse to in­creased de­mand from biotechs for pre­clin­i­cal study man­age­ment and sci­en­tif­ic and reg­u­la­to­ry ad­vice to take their prod­ucts to first-in-hu­man tri­als.

The high­ly re­gard­ed Avance Clin­i­cal sci­en­tif­ic and reg­u­la­to­ry team, which has been ad­vis­ing biotech clients on their drug de­vel­op­ment for more than 20 years, is now a ded­i­cat­ed Clini­cReady ser­vice un­der the Avance Clin­i­cal ban­ner.

Yvonne Lunger­shausen, Avance Clin­i­cal’s CEO


Avance Clin­i­cal is an Aus­tralian owned Con­tract Re­search Or­gan­i­sa­tion (CRO) that has been pro­vid­ing high-qual­i­ty clin­i­cal re­search ser­vices to the lo­cal and in­ter­na­tion­al drug de­vel­op­ment in­dus­try for over 20 years. Avance Clin­i­cal spe­cialis­es in work­ing with biotech­nol­o­gy com­pa­nies to ex­e­cute ear­ly phase clin­i­cal tri­als.

“With our two decades of CRO ex­pe­ri­ence we have be­come acute­ly aware of the im­por­tance of ad­vis­ing clients ear­li­er in the de­vel­op­ment process, pri­or to them com­menc­ing pre­clin­i­cal safe­ty and tox­i­col­o­gy ac­tiv­i­ties, so they con­duct an ap­pro­pri­ate­ly bal­anced set of pre­clin­i­cal stud­ies to get the right da­ta re­quired for ap­proval of their first-in-hu­man study in Aus­tralia,” said Yvonne Lunge­shausen, Avance Clin­i­cal’s CEO.



The Clini­cReady Team

Avance Clin­i­cal’s Clini­cReady team of sci­en­tif­ic and med­ical af­fairs spe­cial­ists com­prise PhD qual­i­fied in­di­vid­u­als with decades of ex­pe­ri­ence in in­dus­try and aca­d­e­m­ic re­search. They pro­vide clients with sci­en­tif­ic, reg­u­la­to­ry and med­ical writ­ing ser­vices, prepa­ra­tion of in­ves­ti­ga­tor brochures, clin­i­cal tri­al de­signs, study pro­to­cols, and pa­tient in­for­ma­tion and con­sent forms as well as clin­i­cal tri­al da­ta and clin­i­cal study re­ports.

Ben Ed­wards, Avance Clin­i­cal’s Chief Strat­e­gy Of­fi­cer

“Many of our clients are biotechs look­ing to get in­vestor sup­port to progress their project to demon­stra­tion of ear­ly Proof of Con­cept (POC) which will en­able them to ac­cess re­turn on their in­vest­ment through a li­cens­ing deal to Phar­ma. This sce­nario al­so en­sures high prob­a­bil­i­ty of suc­cess in bring­ing promis­ing treat­ments to the mar­ket and avail­able to the pa­tient pop­u­la­tion,” com­ment­ed Ben Ed­wards, Avance Clin­i­cal’s Chief Strat­e­gy Of­fi­cer.

Avance Clin­i­cal has cre­at­ed the Clini­cReady by Avance Clin­i­cal range of ser­vices in re­sponse to de­mand from biotechs for ex­per­tise in pre­clin­i­cal study man­age­ment and sci­en­tif­ic and reg­u­la­to­ry ad­vice to take their prod­ucts to first-in-hu­man tri­als.

Jor­gen Mould PhD,
BSc (Hons) Avance Clin­i­cal’s Sci­en­tif­ic Af­fairs Spe­cial­ist

“In or­der to ex­pand our range of ser­vices to cater for the pre­clin­i­cal re­search man­age­ment needs of small biotech­nol­o­gy en­ter­pris­es and as­sist them in bring­ing their prod­ucts to clin­i­cal tri­als we have re­cent­ly an­nounced the ad­di­tion of Dr Jor­gen Mould to our Clini­cReady sci­en­tif­ic and med­ical af­fairs team,” com­ment­ed Yvonne Lunger­shausen.

Dr Jor­gen Mould joined Avance Clin­i­cal in the role of Sci­en­tif­ic Af­fairs Spe­cial­ist. He has over 20 years of ex­pe­ri­ence in the med­ical in­dus­try spe­cial­is­ing in drug dis­cov­ery and clin­i­cal de­vel­op­ment. With depth of ther­a­peu­tic ex­per­tise in neu­ro­bi­ol­o­gy and in­flam­ma­tion, Jor­gen has man­aged the progress of sev­er­al projects through pre­clin­i­cal de­vel­op­ment to pro­gres­sion to first-in-hu­man tri­als and is unique­ly po­si­tioned to as­sist Avance Clin­i­cal’s clients with man­age­ment of reg­u­la­to­ry ap­proval and bring­ing promis­ing pre­clin­i­cal prod­ucts to the clin­ic.

“Hav­ing spent sev­er­al years tak­ing prod­ucts to the clin­ic in the biotech­nol­o­gy sec­tor, I am re­al­ly look­ing for­ward to the op­por­tu­ni­ty of shar­ing my ex­pe­ri­ence with Avance Clin­i­cal’s clients in a way that ex­pe­dites ac­cess to the clin­i­cal tri­al test­ing for their pre­clin­i­cal as­sets,” com­ment­ed Dr Jor­gen Mould.

From Dis­cov­ery to Proof of Con­cept with Avance Clin­i­cal

The Clini­cReady range of ser­vices con­sti­tutes a nat­ur­al pro­gres­sion in Avance Clin­i­cal’s role as the pre­mier provider of ear­ly drug de­vel­op­ment sup­port to the biotech­nol­o­gy sec­tor. The com­pa­ny recog­nis­es the ma­jor chal­lenges faced by small biotech­nol­o­gy com­pa­nies, par­tic­u­lar­ly start-up com­pa­nies who seek to dri­ve their nov­el ther­a­peu­tics to demon­stra­tion of safe­ty and pre­lim­i­nary clin­i­cal Proof of Con­cept. Start-up com­pa­nies of­ten need to lever­age de­vel­op­ment of their prod­ucts with­out the time and cost bur­den as­so­ci­at­ed with hir­ing staff and ac­cess­ing ap­pro­pri­ate ex­per­tise. With Clini­cReady, Avance Clin­i­cal’s team can act as a sur­ro­gate drug de­vel­op­ment de­part­ment for start-up com­pa­nies who are look­ing to ben­e­fit from a vir­tu­al mod­el of op­er­a­tional­i­sa­tion and ex­e­cu­tion from the ear­ly stages of drug can­di­date dis­cov­ery to demon­stra­tion of pre­lim­i­nary clin­i­cal POC.

With Clini­cReady, Avance Clin­i­cal’s team can act as a sur­ro­gate drug de­vel­op­ment de­part­ment for start-up com­pa­nies

Clini­cReady en­ables Avance Clin­i­cal to fur­ther dif­fer­en­ti­ate it­self from oth­er clin­i­cal CROs by firm­ly em­bed­ding its range of ser­vices in the ear­ly drug de­vel­op­ment space in­cor­po­rat­ing both pre­clin­i­cal and clin­i­cal as­pects. Avance Clin­i­cal’s mod­el is of a trans­la­tion­al CRO help­ing biotech com­pa­nies to progress lab­o­ra­to­ry re­search dis­cov­er­ies to ear­ly clin­i­cal proof of con­cept and ef­fec­tive­ly trans­lat­ing pre­clin­i­cal mol­e­cules to promis­ing clin­i­cal ther­a­peu­tics.

Clini­cReady by Avance of­fers the fol­low­ing ser­vices:

  • Prepa­ra­tion of Drug De­vel­op­ment Plans (from dis­cov­ery to phase II proof of Con­cept)
  • Pro­gram gap analy­sis with par­tic­u­lar em­pha­sis on pre­clin­i­cal study plans
  • Pre­clin­i­cal ven­dor se­lec­tion and man­age­ment
  • Sci­en­tif­ic Ad­vice on trans­la­tion­al as­pects with em­pha­sis on at­tain­ing ev­i­dence of phar­ma­co­log­i­cal ef­fect ear­ly in clin­i­cal de­vel­op­ment
  • Ther­a­peu­tic Area Ad­vice with par­tic­u­lar em­pha­sis on prod­uct dif­fer­en­ti­a­tion and po­si­tion­ing with­in ex­ist­ing and evolv­ing ther­a­peu­tic par­a­digms
  • Chem­istry Man­u­fac­tur­ing Con­trols (CMC) and In­ves­ti­ga­tion­al prod­uct man­age­ment Ad­vice
  • Prepa­ra­tion of In­ves­ti­ga­tor’s Brochure
  • Reg­u­la­to­ry agency sub­mis­sion and Hu­man Re­search Ethics ap­proval sup­port

The Aus­tralian Land­scape – Pre­clin­i­cal Stud­ies to En­able Drug Can­di­date Progress to Clin­i­cal In­ves­ti­ga­tion

Promis­ing drug can­di­dates show­ing ear­ly proof of con­cept in an­i­mal mod­els of hu­man dis­ease need to be fur­ther eval­u­at­ed for safe­ty be­fore they can progress in­to hu­man tri­als. First-in-hu­man tri­als have the great­est el­e­ment of risk in re­la­tion to drug safe­ty. Pri­or to eval­u­at­ing nov­el ther­a­peu­tics in hu­mans, it is crit­i­cal to ob­tain ap­pro­pri­ate pre­clin­i­cal da­ta which in­forms the po­ten­tial risks and de­fines dose lev­els and dos­ing reg­i­mens to de­ter­mine an ac­cept­able risk/ben­e­fit pro­file.

In re­la­tion to pre­clin­i­cal da­ta re­quire­ments, the Ther­a­peu­tic Goods Ad­min­is­tra­tion (TGA) in Aus­tralia rec­om­mends a num­ber of ICH and EMA guide­line doc­u­ments for the Aus­tralian equiv­a­lent of IRBs, the Hu­man Re­search Ethics Com­mit­tees (HREC), to take in­to con­sid­er­a­tion when re­view­ing ap­pli­ca­tions for the con­duct of clin­i­cal tri­als in Aus­tralia.

The pri­ma­ry ob­jec­tives of pre­clin­i­cal stud­ies should aim to:

  1. Es­tab­lish a proof of con­cept to pro­vide a ra­tio­nale for the tar­get ther­a­peu­tic in­di­ca­tion
  2. Ob­tain in­for­ma­tion re­quired to guide dos­ing in hu­man stud­ies
  3. Iden­ti­fy tar­get or­gans/tis­sues or phys­i­o­log­i­cal process­es which are like­ly to dri­ve ad­verse events
  4. In­form on safe­ty pa­ra­me­ters that should be mon­i­tored in the hu­man tri­al
  5. Es­tab­lish a risk/ben­e­fit pro­file of the in­tend­ed ther­a­py.

As hu­man safe­ty is the key con­cern in ear­ly phase tri­als, piv­otal pre­clin­i­cal safe­ty and tox­i­col­o­gy stud­ies should com­ply with Good Lab­o­ra­to­ry Prac­tice (GLP) stan­dards. A typ­i­cal set of pre­clin­i­cal stud­ies which would cap­ture the nec­es­sary in­for­ma­tion to de­fine the dos­ing pa­ra­me­ters and risk/ben­e­fit pro­file of a drug can­di­date pri­or to en­ter­ing the clin­ic in­cludes (but is not lim­it­ed to) the fol­low­ing:

Pri­ma­ry Phar­ma­col­o­gy (non-GLP)

  • In vit­ro da­ta demon­strat­ing the ac­tiv­i­ty of the drug on the ther­a­peu­tic tar­get (cell-based as­says, en­zyme as­says, tar­get bind­ing)
  • In vi­vo da­ta show­ing ac­tiv­i­ty in dis­ease rel­e­vant an­i­mal mod­els
  • Phar­ma­co­ki­net­ic da­ta en­abling ef­fi­ca­cy-to-ex­po­sure cor­re­la­tion

Safe­ty Phar­ma­col­o­gy

  • In vit­ro off Tar­get screen (pro­tein class, com­mon safe­ty re­cep­tor pan­el) (non-GLP)
  • In vit­ro hERG in­hi­bi­tion, to ex­clude car­diac li­a­bil­i­ty (GLP)
  • Cen­tral ner­vous sys­tem safe­ty phar­ma­col­o­gy, in vi­vo (GLP)
  • Res­pi­ra­to­ry sys­tem safe­ty phar­ma­col­o­gy, in vi­vo (GLP)
  • Car­dio­vas­cu­lar sys­tem safe­ty phar­ma­col­o­gy, in vi­vo (GLP)

Tox­i­col­o­gy

  • 7-day dose range find­ing tox­i­c­i­ty study in male and fe­male rats (non-GLP)
  • 28-day re­peat dose tox­i­c­i­ty and tox­i­co­ki­net­ic study in male and fe­male rats (GLP)
  • 7-day dose range find­ing tox­i­c­i­ty study in male and fe­male dogs or oth­er non-ro­dent species (non-GLP)
  • 28-day re­peat dose tox­i­c­i­ty and tox­i­co­ki­net­ic study in male and fe­male dogs or oth­er non-ro­dent species (GLP)

Me­tab­o­lism

  • Plas­ma pro­tein bind­ing in rat, dog, and hu­man plas­ma (non-GLP)
  • Mi­cro­so­mal sta­bil­i­ty in rat, dog, and hu­man mi­cro­somes (non-GLP)
  • He­pa­to­cyte sta­bil­i­ty in rat, dog, and hu­man he­pa­to­cytes (non-GLP)
  • CYP450 in­hi­bi­tion/in­duc­tion (non-GLP)

Geno­tox­i­c­i­ty

  • Bac­te­r­i­al re­verse mu­ta­tion as­say (GLP)
  • In vit­ro mam­malian chro­mo­so­mal aber­ra­tion as­say in hu­man pe­riph­er­al blood lym­pho­cytes (GLP)
  • Mam­malian mi­cronu­cle­us as­say in rats with flow cy­to­met­ric analy­sis in pe­riph­er­al blood retic­u­lo­cytes (GLP)

It is im­por­tant to note that the pre­clin­i­cal GLP tox­i­col­o­gy stud­ies in two species (e.g. rat, dog) are of cen­tral sig­nif­i­cance to defin­ing the key pa­ra­me­ters of a First-in-Hu­man tri­al. The pre­clin­i­cal tox­i­col­o­gy stud­ies should be ad­e­quate to iden­ti­fy and char­ac­ter­ize po­ten­tial tox­ic ef­fects of the drug can­di­date to al­low in­ves­ti­ga­tors to con­clude that it is rea­son­ably safe to pro­ceed to clin­i­cal in­ves­ti­ga­tion. As­pects to be con­sid­ered in de­sign­ing an­i­mal tox­i­col­o­gy stud­ies in­clude the choice of rel­e­vant an­i­mal species and strain, dos­ing sched­ule and route of ad­min­is­tra­tion, as well as tim­ing of drug ad­min­is­tra­tion and eval­u­a­tion of end­points (e.g. sam­pling for clin­i­cal chem­istry). The tox­i­col­o­gy study du­ra­tion and num­ber of dos­es of test drug ad­min­is­tered to an­i­mals should be equiv­a­lent to or ex­ceed that used for the clin­i­cal study.

Gain­ing Ap­proval to Con­duct Clin­i­cal Tri­als in Aus­tralia

There are two al­ter­na­tive schemes to gain­ing ap­proval to con­duct a clin­i­cal tri­al in Aus­tralia.

In Aus­tralia, the ma­jor­i­ty (>90%) of clin­i­cal tri­als can be sub­mit­ted via the CTN scheme where­by pre­clin­i­cal da­ta sum­marised in an In­ves­ti­ga­tor Brochure are re­viewed by an HREC who then no­ti­fies the TGA of the out­come. This pro­vides an op­por­tu­ni­ty to con­duct ear­ly phase tri­als in Aus­tralia whilst prepar­ing doc­u­men­ta­tion re­quired for an IND sub­mis­sion to the FDA


Watch our Clini­cReady we­bi­nar here: https://www.biospec­tru­ma­sia.com/avance-clin­i­cal

AUTHOR

Gabriel Kremmidiotis

Chief Scientific Officer, Avance Clinical