ICH E17 General principle n planning and design f Multi-Reginal Clinical Trials January 14th, 2017 Internatinal Cuncil fr Harmnisatin f Technical Requirements fr Pharmaceuticals fr Human Use Legal Ntice This presentatin is prtected by cpyright and may be used, reprduced, incrprated int ther wrks, adapted, mdified, translated r distributed under a public license prvided that ICH's cpyright in the presentatin is acknwledged at all times. In case f any adaptin, mdificatin r translatin f the presentatin, reasnable steps must be taken t clearly label, demarcate r therwise identify that changes were made t r based n the riginal presentatin. Any impressin that the adaptin, mdificatin r translatin f the riginal presentatin is endrsed r spnsred by the ICH must be avided The presentatin is prvided "as is" withut warranty f any kind. In n event shall the ICH r the authrs f the riginal presentatin be liable fr any claim, damages r ther liability arising frm the use f the presentatin The abve-mentined permissins d nt apply t cntent supplied by third parties. Therefre, fr dcuments where the cpyright vests in a third party, permissin fr reprductin must be btained frm this cpyright hlder. 2 1
ICH HARMONISED TRIPARTITE GUIDELINE General Principles fr Planning and Design f Multi-Reginal Clinical Trials E17 (FINAL) Nvember 16 th, 2017 ICH E17 Guideline Started in June 2014 Draft in June 2016 Finalised in Nvember 2017 3 Table f Cntents (E17 final) 4 2
1.1 Objectives f the Guideline With the increasing glbalisatin f drug develpment, it has becme imprtant that data frm multi-reginal clinical trials (MRCTs) can be accepted by regulatry authrities acrss regins and cuntries as the primary surce f evidence, t supprt marketing apprval f drugs (medicinal prducts) The purpse f this guideline is t describe general principles fr the planning and design f MRCTs with the aim f increasing the acceptability f MRCTs in glbal regulatry submissins The guideline addresses strategic prgramme issues as well as issues that are specific t the planning and design f cnfirmatry MRCTs, and it shuld be used tgether with ther ICH Guidelines, including E5, E6, E8, E9, E10, and E18. 5 1.3 Scpe f the Guideline MRCT is defined in the present guideline as a clinical trial cnducted in mre than ne regin under a single prtcl. In this cntext, a regin may refer t a gegraphical regin, cuntry r regulatry regin (see Sectin 3. Glssary) The primary fcus f this guideline is n MRCTs designed t prvide data that will be submitted t multiple regulatry authrities fr drug apprval (including apprval f additinal indicatins, new frmulatins and new dsing regimens) and fr studies cnducted t satisfy pst-marketing requirements Certain aspects f this guideline may als be relevant t studies cnducted early in clinical develpment r in later phases. The present guideline mainly cvers drugs including bilgical prducts, althugh sme sectins may nt be applicable t all develpment prgrammes (e.g., pharmackinetics (PK) nt used fr preventive vaccine dse-finding). 6 3
2.1.1 The Value f MRCTs in Drug Develpment 7 1.4 Basic Principles 8 4
1.4 Basic Principles (1) 1. Strategic use f MRCTs in drug develpment prgrammes, prperly designed and executed accrding t this guideline, can increase efficiency f drug develpment. MRCTs may enable simultaneus submissin f marketing authrisatin applicatins and supprt regulatry decisin-making in multiple regins, allwing earlier access t new drugs wrldwide. Althugh MRCTs may generally becme the preferred ptin fr investigating a new drug fr which regulatry submissin is planned in multiple regins, the ptential fr reginal differences t impact the interpretability f study results shuld be carefully cnsidered. 2. The intrinsic and extrinsic factrs imprtant t the drug develpment prgramme, shuld be identified early. The ptential impact f these factrs culd be examined in the explratry phases befre the design f cnfirmatry MRCTs. Infrmatin abut them shuld als be cllected during the cnfirmatry trial fr evaluatin f their impact n treatment effects. 9 1.4 Basic Principles (2) 3. MRCTs are planned under the assumptin that the treatment effect applies t the entire target ppulatin, particularly t the regins included in the trial. Strategic allcatin f the sample size t regins allws an evaluatin f the extent t which this assumptin hlds. 4. Pre-specified pling f regins r subppulatins, based n established knwledge abut similarities, may help prvide flexibility in sample size allcatin t regins, facilitate the assessment f cnsistency in treatment effects acrss regins, and supprt regulatry decisin-making. 5. A single primary analysis apprach fr hypthesis testing and estimatin f the verall treatment effect shuld be planned s that it will be acceptable t all cncerned regulatry authrities. A structured explratin t examine the cnsistency f treatment effects acrss regins and subppulatins shuld be planned. 10 5
1.4 Basic Principles (3) 6. In light f diverse reginal practices, ensuring high quality f study design and cnduct in accrdance with ICH E6 in all regins is f paramunt imprtance t ensure the study results are interpretable. Careful attentin t quality during trial planning, investigatr training, and trial mnitring will help achieve cnsistently high trial quality required fr a successful MRCT. 7. Efficient cmmunicatin amng spnsrs and regulatry authrities is encuraged at the planning stage f MRCTs, with the gal f btaining acceptance f a glbal apprach t study design acrss the different regulatry regins. 11 Majr pints described in Sectin 2 12 6
2.2.1 Pre-cnsideratin f Reginal Variability and its Ptential Impact n Efficacy and Safety At the planning stage, reginal variability, the extent t which it can be explained by intrinsic and extrinsic factrs, and its ptential t influence the study results, shuld be carefully cnsidered in determining the rle MRCTs can play in the drug develpment strategy The intrinsic and extrinsic factrs imprtant t the drug develpment prgramme, shuld be identified during the planning stage f an MRCT. 13 2.2.1 Pre-cnsideratin f Reginal Variability and its Ptential Impact n Efficacy and Safety Figure 2 illustrates the way in which intrinsic and/r extrinsic factrs such as disease severity (Figure 2a) r ethnicity (Figure 2b) may manifest as reginal differences in treatment respnse. 14 7
2.2.2 Subject Selectin In MRCTs, subject selectin shuld be carefully cnsidered t better understand and pssibly mitigate ptential surces f reginal variability and their impact n trial results Clear and specific inclusin and exclusin criteria, that are acceptable and can be applied acrss regins, shuld be included in the prtcl T harmnise subject selectin, unifrm classificatin and criteria fr diagnsis f the disease r definitin f the at-risk ppulatin shuld be implemented, such as the use f relevant guidelines fr disease definitins. 15 2.2.3 Selectin f Dses fr Use in Cnfirmatry MRCTs It is imprtant t execute well-planned early develpment prgrammes that include PK and/r PK-PD studies f applicable parameters, in rder t identify reginal differences which may impact dse selectin The dse regimens in cnfirmatry MRCTs (based n data frm studies mentined abve) shuld in principle be the same in all participating ethnic ppulatin If earlier trial data shw a clear difference in dse-respnse and/r expsure-respnse relatinships fr an ethnic ppulatin, it may be apprpriate t use a different dsing regimen, prvided that the regimen is expected t prduce similar therapeutic effects with an acceptable safety margin, and prvided it is scientifically justified in the study prtcl. Prspective careful planning f assessment strategies where different dses are used shuld be tailred t each case and described in the analysis plans. 16 8
2.2.4 Chice f Endpints The primary endpint shuld be relevant t the target ppulatin. In MRCTs, this relevance needs t be cnsidered fr all regins in the trial and with respect t the varius drug, disease and ppulatin characteristics represented in thse regins An ideal clinical trial endpint is ne that is clinically relevant, accepted in medical practice (e.g., by regulatry guidance r prfessinal sciety guidelines) and sufficiently sensitive and specific t detect the anticipated effect f the treatment The primary endpint, whether efficacy r safety, shuld satisfy these criteria as well as being acceptable t all cncerned regulatry authrities, t ensure that interpretatin f the success r failure f the MRCT is cnsistent acrss regins and amng regulatry authrities The primary endpint f MRCTs shuld be ne fr which experience is already available in the participating regins. 17 2.2.5 Sample Size Planning The key cnsideratin fr sample size planning, is ensuring sufficient sample size t be able t evaluate the verall treatment effect, under the assumptin that the treatment effect applies t the entire target ppulatin, particularly t the regins included in the trial Tw additinal factrs are particularly imprtant in the MRCT setting; (i) the size f the treatment effect that is cnsidered clinically relevant t all regins in the trial, and (ii) the expected variability f the primary utcme variables based n cmbining data acrss regins. 18 9
2.2.5 Sample Size Planning The MRCT shuld be planned t include an evaluatin f the cnsistency f treatment effects amng regins, where cnsistency is defined as a lack f clinically relevant differences If clinically relevant differences amng regins are bserved, then the MRCT prvides a unique pprtunity fr additinal learning abut the factrs that may explain these differences Reginal allcatin shuld have a scientific basis (rather than arbitrary targets), shuld supprt the evaluatin f cnsistency and shuld prvide the infrmatin needed t supprt regulatry decisins. 19 2.2.5 Sample Size Planning 1 Prprtinal Allcatin: Allcatin f subjects t regins in prprtin t size f regin and disease prevalence. Five examples fr sample size allcatin t regin 2 4 3 Equal Allcatin: Allcatin f equal numbers f subjects t each regin. Preservatin f Effect: Allcatin f subjects t ne r mre regins based n preserving sme specified prprtin f the verall treatment effect. Lcal Significance: Allcatin f a sufficient number f subjects t be able t achieve significant results within each regin. A balance between #1 and #2 is recmmended t ensure that recruitment is feasible and able t be cmpleted in a timely fashin, but als t prvide sufficient infrmatin t evaluate the drug in its reginal cntext. 5 Fixed Minimum Number: Allcatin f a fixed minimum number f subjects t a regin. 20 10
2.2.5 Sample Size Planning Pled regins: Pled Regins and Subppulatins Pling sme gegraphical regins, cuntries r regulatry regins at the planning stage, if subjects in thse regins are thught t be similar enugh with respect t intrinsic and/r extrinsic factrs relevant t the disease and/r drug under study. Pled subppulatins: Pling a subset f the subjects frm a particular regin with similarly defined subsets frm ther regins whse members share ne r mre intrinsic r extrinsic factrs imprtant fr the drug develpment prgramme at the planning stage. Pled subppulatins is assumed as ethnicity-related subgrup particular imprtant in the MRCT setting. 21 2.2.5 Sample Size Planning Pled Regins and Subppulatins Pre-specified pling f regins r subppulatins may help prvide flexibility in sample size allcatin t regins, facilitate the assessment f cnsistency in treatment effects acrss regins, and supprt regulatry decisin-making. The pling strategy shuld be justified based n the distributin f the intrinsic and extrinsic factrs knwn t affect the treatment respnse, and the disease under investigatin and similarity f thse factrs acrss regins. Fr example, pling Canada and the United States int a Nrth American regin is ften justified because f similar medical practices and similar use f cncmitant medicatins. Pling strategies shuld be specified in the study prtcl and statistical analysis plan, if applicable. 22 11
2.2.6 Cllecting and Handling f Efficacy and Safety Infrmatin Adherence t GCP is critical fr any clinical trial t meet its stated bjectives and is particularly imprtant in an MRCT, because f the crdinatin required t cnduct a trial in diverse gegraphic regins. Methds f cllecting and handling efficacy and safety infrmatin shuld be standardised acrss participating regins. It is als imprtant t prvide standardised training fr investigatrs and study persnnel in each regin befre initiating the trial in that regin t ensure that the trial bjectives are met thrugh standardised implementatin f the study prtcl. 23 2.2.7. Statistical Analysis Planning The analysis strategy shuld be planned t enable the qualitative and/r quantitative evaluatin f benefit/risk acrss regins r imprtant subppulatins represented in the MRCT. In planning an MRCT, the primary analysis strategy shuld carefully cnsider (1) the target ppulatin, (2) the endpints/variables f primary interest (3) the relevant intrinsic and extrinsic factrs in the multi-reginal, multi-subppulatin cntext (4) the ppulatin-level summary f data required t describe the treatment effect. Fr mst MRCTs, the primary analysis will crrespnd t a test f the hypthesis abut the treatment effect and the estimatin f that effect, cnsidering data frm all regins and subppulatins included in the trial. 24 12
2.2.7. Statistical Analysis Planning The statistical analysis strategy shuld include the evaluatin f the cnsistency f treatment effects acrss regins and subppulatins Graphical displays Mdel-based estimatin Descriptive summaries MRCT data Test f treatment by regin interactin Internal cnsistency within the MRCT (amng endpints) Cnsistency with external data (the ther trial results) The evaluatin f reginal cnsistency is nt cnsidered a cnfirmatry exercise but rather a gateway fr further explratin. 25 2.2.7. Statistical Analysis Planning In case f clinically relevant differences in treatment effects amng regins, a structured explratin f these differences shuld be planned. Factrs knwn a priri t vary amng regins (e.g., disease severity, race, ther subject characteristics) and hypthesized t be prgnstic r predictive shuld be planned fr and evaluated in the analysis mdel Unexpected reginal differences may be bserved, and pst-hc analyses shuld be used fr further investigatin. Factrs knwn t be prgnstic fr the disease wuld be examined first Reginal differences may require further pst-hc investigatin t either identify plausible reasns fr the differences r t better understand the bserved hetergeneity. In sme cases, additinal data, including data frm ther clinical trials, r supprtive evidence frm ther surces, may be needed t understand the reginal differences bserved These eventualities shuld be carefully cnsidered at the planning stage. 26 13
2.2.8. Selectin f Cmparatrs The chice f cntrl grups shuld be cnsidered in the cntext f the available standard therapies, the adequacy f the evidence t supprt the chsen design, and ethical cnsideratins. Cmparatrs in MRCTs shuld in principle be the same in all participating regins. The justificatin (including safety cnsideratins) fr the use f an unapprved drug shuld therefre be described in the prtcl based n scientific infrmatin, treatment guidelines and ther relevant dcuments. 27 2.2.9. Handling Cncmitant Medicatins In general, drugs used cncmitantly with the investigatinal drug shuld be the same thrughut the regins t the extent pssible, but there may be sme differences in the drugs and/r dses actually used due t variatins in medical practices. This culd be acceptable if nt expected t substantially impact trial results. In circumstances where apprved drugs are cmbined with an investigatinal drug, the same dsage regimen in all regins shuld generally be applied. If required by prtcl, cncmitant medicatins that are nt apprved in a regin shuld have their use justified based n scientific infrmatin, treatment guidelines and ther relevant dcuments. 28 14
Impacts f E17 guideline Earlier access t innvative therapies Synchrnize clinical drug develpment acrss different regins Avid duplicatin Reduce the need fr regin specific studies and bridging studies Prmte internatinal harmnizatin A glbally harmnized apprach t drug develpment shuld be cnsidered first Prvide better evidences fr drug apprval in each regin Incrprate latest knwledge and experience frm regins int ne trial Develp an infrastructure fr glbal drug develpment Cnducting high quality MRCTs is a valuable investment in mdern drug develpment 29 Thank Yu! Internatinal Cnference n Harmnisatin f Technical Requirements fr Registratin f Pharmaceuticals fr Human Use 15