BIOMARKERS RELATED TO DRUG OR BIOTECHNOLOGY PRODUCT DEVELOPMENT: CONTEXT, STRUCTURE AND FORMAT OF QUALIFICATION SUBMISSIONS E16

Transcription

1 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE BIOMARKERS RELATED TO DRUG OR BIOTECHNOLOGY PRODUCT DEVELOPMENT: CONTEXT, STRUCTURE AND FORMAT OF QUALIFICATION SUBMISSIONS E16 Current Step 4 versin dated 20 August 2010 This Guideline has been develped by the apprpriate ICH Expert Wrking Grup and has been subject t cnsultatin by the regulatry parties, in accrdance with the ICH Prcess. At Step 4 f the Prcess the final draft is recmmended fr adptin t the regulatry bdies f the Eurpean Unin, Japan and USA.

2 E16 Dcument Histry Cde Histry Date E16 Apprval by the Steering Cmmittee under Step 2 and release fr public cnsultatin. 10 June 2009 Current Step 4 versin Cde Histry Date E16 Apprval by the Steering Cmmittee under Step 4 and recmmendatin fr adptin t the three ICH regulatry bdies. 20 August 2010

3 BIOMARKERS RELATED TO DRUG OR BIOTECHNOLOGY PRODUCT DEVELOPMENT: CONTEXT, STRUCTURE AND FORMAT OF QUALIFICATION SUBMISSIONS ICH Harmnised Tripartite Guideline Having reached Step 4 f the ICH Prcess n 20 August 2010, this guideline is recmmended fr adptin t the three regulatry parties t ICH TABLE OF CONTENTS 1. INTRODUCTION Backgrund Objectives Scpe General Principles STRUCTURE OF BIOMARKER QUALIFICATION SUBMISSIONS Sectin 1: Reginal Administrative Infrmatin Sectin 2: Summaries Bimarker Qualificatin Overview Data Summaries (Analytical, Nnclinical, Clinical; as apprpriate) Sectin 3: Quality Sectins 4 (Nnclinical) and 5 (Clinical) ABBREVIATIONS... 9 i

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5 BIOMARKERS RELATED TO DRUG OR BIOTECHNOLOGY PRODUCT DEVELOPMENT: CONTEXT, STRUCTURE AND FORMAT OF QUALIFICATION SUBMISSIONS 1. INTRODUCTION 1.1 Backgrund The use f bimarkers has the ptential t facilitate the availability f safer and mre effective drug r bitechnlgy prducts, t guide dse selectin and t enhance their benefit-risk prfile. This guideline is based n previus experiences with submissins cntaining bimarker data in the varius regins. These submissins have been either stand-alne bimarker qualificatin applicatins r a cmpnent f medicinal prductrelated regulatry prcess marketing applicatins (NDAs / BLAs / MAAs). The develpment f a cnsistent frmat fr submissin f bimarker data will facilitate easy review and exchange f assessments between regins. 1.2 Objectives The guideline describes recmmendatins regarding cntext, structure and frmat f regulatry submissins fr qualificatin f genmic bimarkers (as defined in ICH E15 1 ). Qualificatin is a cnclusin that, within the stated cntext f use, the results f assessment with a bimarker can be relied upn t adequately reflect a bilgical prcess, respnse r event, and supprt use f the bimarker during drug r bitechnlgy prduct develpment, ranging frm discvery thrugh pst-apprval. A bimarker qualificatin applicatin might be submitted t regulatry authrities if the bimarker directly r indirectly helps in regulatry decisin-making. The bjective f the guideline is t create a harmnized recmmended structure fr bimarker qualificatin applicatins that will fster cnsistency f applicatins acrss regins and facilitate discussins with and amng regulatry authrities. It will als reduce the burden n spnsrs as a harmnized frmat will be recmmended fr use acrss all ICH regulatry regins. It is als expected that the prpsed dcument frmat will facilitate incrpratin f bimarker data int specific prduct-related applicatins. Bimarker qualificatin can take place at any time during drug r bitechnlgy prduct develpment, ranging frm discvery thrugh pst-apprval. Fr thse instances where it is apprpriate, general guidance fr inclusin f bimarker qualificatin data int the Cmmn Technical Dcument fr the Registratin f Pharmaceuticals fr Human Use (CTD) frmat marketing authrizatin applicatins is prvided in this dcument. The use f the CTD frmat wuld be cnsidered apprpriate when bimarker data are submitted as part f an NDA, a BLA, a MAA, ther pst-apprval regulatry prcedures r upn request by the regulatry authrities. 1.3 Scpe The scpe f this guideline is the cntext, structure, and frmat f qualificatin submissins fr clinical and nnclinical genmic bimarkers related t develpment f drug r bitechnlgy prducts including translatinal medicine appraches, pharmackinetics, pharmacdynamics, efficacy and safety aspects. A qualificatin submissin can include data and claims fr a single genmic bimarker, r fr multiple 1 ICH E15 defines a genmic bimarker as a measurable DNA and/r RNA characteristic that is an indicatr f nrmal bilgic prcesses, pathgenic prcesses, and/r respnse t therapeutic r ther interventins. 1

6 Bimarkers Related t Drug r Bitechnlgy Prduct Develpment: Cntext, Structure and Frmat f Qualificatin Submissins genmic bimarkers used as classifiers. While this guideline des nt explicitly cver nn-genmic bimarkers, the principles described in this dcument are applicable t a variety f bimarker categries (e.g., genmics, prtemics, imaging) and ther qualificatin cntexts assciated with drug r bitechnlgy prduct develpment. A qualificatin submissin fr a cmbinatin f bimarkers (e.g., genmic tgether with nn-genmic bimarkers) is als pssible. Unless therwise specified, we will use the generic term bimarker thrughut the remainder f this dcument. The guideline als cvers the submissin f data relevant t the validatin f new analytical appraches t imprve the evaluatin f current bimarkers. This guideline des nt address either the qualificatin prcess r the evidentiary standards fr a bimarker t be qualified by regulatry authrities. 1.4 General Principles The prpsed cntext f use f a bimarker crrespnds t the data supprting its qualificatin. The prpsed cntext f use shuld be clearly detailed in the submissin package. Reference shuld be made t the specific use f the bimarker in drug r bitechnlgy prduct develpment. The cntext f use f a bimarker in a bimarker qualificatin can be narrw r brad: the bimarker(s) might be useful fr nly a single drug r bitechnlgy prduct, r fr several drug r bitechnlgy prducts in a drug class, r even acrss several drug classes. The structure f the submissin shuld be cnsistent regardless f the cntext prpsed, and flexible enugh t deal with the specific attributes f each submissin. In additin, use f the recmmended structure shuld facilitate submissin and review f future bimarker qualificatin submissins expanding the use f the bimarker t new cntexts, as wuld be the case e.g., if a nnclinical cntext f use expands t a clinical cntext f use. The frmat f the data fr qualifying a bimarker can vary significantly depending n the cntext. It is therefre nly pssible t prvide general guidelines n data frmat fr a bimarker qualificatin submissin. The frmat shuld supprt an evaluatin f the data and can include reprts, tabulatins, and raw data (if requested by regulatry authrities accrding t the relevant practices in place). Data frmat shuld be cnsistent with the methdlgy and platfrm used fr analysing the bimarker in questin. Reference t standards and / r accepted methds used shuld be described as applicable. The dssier structure described in this guideline is intended fr bimarker qualificatin submissins after sufficient supprting data have been generated. Hwever, this structure can als be cnsidered fr submissins intended t btain scientific advice frm regulatry authrities befre r during the generatin f the bimarker data intended t supprt qualificatin. The recmmended bimarker qualificatin submissin is aligned with the CTD frmat t facilitate submissin and review. The prpsed verall rganizatin f the bimarker qualificatin submissin described herein crrespnds t the CTD frmat, which cnsists f 5 parts (Mdules 1-5). The sectins f the bimarker qualificatin submissin and their crrespnding CTD sectins are as fllws: ICH E-16 Sectin 1 (Reginal Administrative Infrmatin) crrespnds t CTD Mdule 1 with specific infrmatin n the qualificatin prcedures; Sectin 2 (Summaries) crrespnds t CTD Mdule 2; Sectin 3 (Quality Reprts) crrespnds t CTD Mdule 3; Sectin 4 (Nnclinical Study Reprts) crrespnds t Mdule 4; and Sectin 5 (Clinical Study Reprts) crrespnds t Mdule 5. Mre details are described in the ICH M4 and ther relevant guidelines. Applicants wh wish t submit in accrdance with the Electrnic Cmmn Technical 2

7 Bimarkers Related t Drug r Bitechnlgy Prduct Develpment: Cntext, Structure and Frmat f Qualificatin Submissins Dcument (ectd) frmat shuld als cnsult the ICH M2 guideline (Electrnic Standards fr Transmissin f Regulatry Infrmatin) and ther relevant guidelines, as well as natinal and reginal laws, regulatins, and recmmendatins. T facilitate the integratin f bimarkers in glbal drug r bitechnlgy prduct develpment it is recmmended that qualificatin submissins be submitted simultaneusly t pertinent regulatry authrities. It shuld be nted that, if a bimarker has already been endrsed as qualified by a regulatry authrity, bimarker data generated within the qualified cntext f use d nt need t be re-submitted t the authrity fr re-qualificatin in an NDA / BLA / MAA. It wuld be apprpriate t simply prvide a cpy f the assessment reprt f the authrity in the NDA / BLA / MAA r ther relevant regulatry prcedure. 2. STRUCTURE OF BIOMARKER QUALIFICATION SUBMISSIONS The bimarker qualificatin submissin shuld include the fllwing sectins: Sectin 1: Reginal Administrative Infrmatin Sectin 2: Summaries Bimarker Qualificatin Overview Intrductin, prpsed cntext f use, high-level data descriptin, integrated critical appraisal f the data / methds, additinal data needed frm nging r planned studies, and justificatin fr the prpsed cntext f use. Overall Summaries f the fllwing (if apprpriate): Analytical Assay Data Nnclinical Bimarker Data Clinical Bimarker Data If included in an NDA / BLA / MAA, the cntents in the Sectin 2 shuld be cnverted int chapters in the apprpriate CTD Mdule 2 such as Overview(s) and / r Overall Summary(ies). Sectin 3: Quality Reprts Structural, manufacturing and quality characteristics f investigatinal drug(s) fr the bimarker qualificatin studies (as applicable) Such infrmatin is nt expected t be included in a stand-alne bimarker qualificatin submissin, independent frm an NDA, BLA r MAA. Sectin 4: Nnclinical Reprts Analytical assay develpment reprts 2 Analytical assay validatin reprts 2 Nnclinical study reprts (in vitr) Nnclinical study reprts (in viv, specify species) Sectin 5: Clinical Reprts Analytical Assay develpment reprts 3 Analytical assay validatin reprts 3 2 Crrespnds t CTD Mdule 4 Sectin 4.2 r Crrespnds t CTD Mdule 5 Sectin 5.3 3

8 Bimarkers Related t Drug r Bitechnlgy Prduct Develpment: Cntext, Structure and Frmat f Qualificatin Submissins Clinical pharmaclgy study reprts Clinical efficacy and / r safety study reprts The recmmended cntent f these sectins is explained in mre detail belw. 2.1 Sectin 1: Reginal Administrative Infrmatin 4 This sectin shuld cntain dcuments specific t each regin, fr example applicatin frms and / r cver letter. The cntent and frmat f this sectin can be specified by the relevant regulatry authrities. 2.2 Sectin 2: Summaries 5 By analgy t the CTD structure, bimarker qualificatin submissins shuld cntain a Bimarker Overview t discuss and interpret the strengths and limitatins f the submitted data. It shuld be supprted by the separate technical, preclinical and clinical Data Summaries which shuld present the study data as a detailed factual summarisatin in text, tables and figures Bimarker Qualificatin Overview Intrductin This sectin shuld be cncise. It can include a descriptin f the disease and / r experimental setting, the definitin f the bimarker (e.g., in the case f genmic bimarkers, whether a SNP, CNV r differential gene expressin signature) and a ratinale fr the bimarker s use in drug r bitechnlgy prduct develpment, frm discvery thrugh pst-apprval. It shuld: Summarize the key characteristics f the bimarker, including: strengths and limitatins (e.g., cmparisn with relevant standard methds where available, presence / absence f infrmatin n pertinent species / ppulatin); whether it is a single r cmpsite bimarker; if it is a cmpsite bimarker, its cmpnent markers and the prcess thrugh which these were selected shuld be defined; bjective and design f the studies supprting its use, such as prspective versus retrspective study design, study cmparatrs and sample size. A summary f the prpsed cntext f use f the bimarker shuld be prvided in this sectin. Mre details, including the full cntext f bimarker use, shuld be described in the next sectin Cntext f Use The elements describing the cntext f use fr a bimarker shuld include (i) the general area, (ii) the specific bimarker use, and (iii) the critical parameters which define when and hw the bimarker shuld be used. The cntext f use can be limited t use in drug r bitechnlgy prduct develpment. It is expected that a bimarker prpsed fr qualificatin wuld facilitate drug r bitechnlgy prduct develpment prgram(s) r drug r bitechnlgy prduct use and culd ffer an imprvement ver currently available bimarkers r safety r efficacy endpint assessments. 4 Crrespnds t CTD Mdule 1 5 Crrespnds t CTD Mdule 2 4

9 Bimarkers Related t Drug r Bitechnlgy Prduct Develpment: Cntext, Structure and Frmat f Qualificatin Submissins The prpsed cntext f use fr a bimarker shuld be supprted by data that are available in the initial qualificatin dssier submissin. If the reviewing authrity identifies an incnsistency between the prpsed cntext and the data, additinal data can be prvided during the qualificatin prcesses, if the authrity agrees. The cntext f use can be described accrding t the fllwing taxnmy (see examples belw): General Area (including, but nt limited t): Nnclinical / Clinical Pharmaclgy Txiclgy Efficacy Safety Disease Specific Bimarker Use(s) Bimarkers can be used fr a wide range f purpses, including, but nt limited t, the fllwing examples: Patient / clinical trial subject selectin Inclusin / exclusin criteria Trial enrichment r stratificatin Assessment f disease state and / r prgnsis Assessment f mechanism f actin Mechanism f pharmaclgical mde f actin Mechanism f therapeutic effect Mechanism f txicity / adverse reactin Dse ptimizatin N bserved effect level (NOEL) in animal mdels N bserved adverse effect level (NOAEL) in animal mdels Algrithm-based dse determinatin (quantitative algrithmic dsing) Determinatin f likely dse range Drug respnse mnitring Mnitring drug safety Mnitring drug efficacy Efficacy maximizatin Indicating / predicting drug efficacy Txicity/Adverse reactins minimizatin Indicating / predicting txicity / adverse reactins Detecting / mnitring nset / reversibility f txicity / adverse reactins Critical Parameters f Cntext f Use (including, but nt limited t): Drug r bitechnlgy prduct-specific use/ drug class-specific use / use nt linked t specific drug r bitechnlgy prducts r drug classes Disease diagnsis and phentypes, prgnsis, r stage Sample cllectin Assay specificatins 5

10 Bimarkers Related t Drug r Bitechnlgy Prduct Develpment: Cntext, Structure and Frmat f Qualificatin Submissins Tissue r physilgical / pathlgical prcess Species Demgraphics, including ancestry and / r gegraphic rigin Envirnmental factrs Examples f Cntext f Use fr Bimarkers A bimarker measurement culd apply t mre than ne cntext f use, depending n the general area and / r specific use within a single submissin, as shwn in the fllwing examples f genmic bimarkers. While hypthetical examples fr genmic bimarkers are depicted here, the principles fr cntext descriptin are applicable fr all types f bimarkers submitted fr qualificatin. i) Nnclinical Safety Messenger RNA levels f kidney injury mlecule 1 (Kim-1) and clusterin (Clu) can be included as genmic bimarkers f drug r bitechnlgy-induced acute renal tubular txicity in rat txiclgy studies. The cntext f the submissin in the bimarker qualificatin applicatin wuld be defined as fllws: General Area: Nnclinical safety and txiclgy Specific Bimarker Use: assessment f mechanism f txicity and dse ptimizatin (NOAEL) in animal mdels Critical Parameters f Cntext f Use: Drug r bitechnlgy prduct-specific use: n Assay specificatins: mrna Tissue r physilgical / pathlgical prcess addressed: kidney Species: Rattus nrvegicus ii) Clinical Pharmaclgy / Drug Metablism CYP2C9 genetic plymrphism prduces pr metablizer (PM) and extensive metablizer phentypes and differences in Drug A expsure. Plasma levels f Drug A in patients / clinical trial subjects wh are knwn t be CYP2C9 PMs are increased due t reduced metablic clearance. Cntext f the submissin in the bimarker qualificatin applicatin wuld be defined as fllws: General Area: Clinical Pharmaclgy / Drug Metablism and Safety Specific Bimarker Use: patient / clinical trial subject selectin (inclusin / exclusin criteria, trial enrichment r stratificatin), dse ptimizatin in individual patients and predicting adverse reactins / risk minimizatin Critical Parameters f Cntext f Use: Drug r bitechnlgy prduct-specific use: Drug A Assay specificatins: Gentyping Species: Hm sapiens Demgraphics including ancestry and / r gegraphy: ppulatinspecific allele frequency iii) Clinical Safety The HLA-B*1502 allele is assciated with an increased risk f the develpment f Stevens-Jhnsn Syndrme fllwing administratin f Drug B in Han-Chinese. General Area: clinical safety 6

11 Bimarkers Related t Drug r Bitechnlgy Prduct Develpment: Cntext, Structure and Frmat f Qualificatin Submissins Specific Bimarker Use: patient selectin (inclusin / exclusin criteria), predicted safety and mechanism f adverse reactin / txicity Critical Parameters fr Cntext f Use: Drug r bitechnlgy prduct-specific use: Drug B Assay specificatins: Gentyping Species: Hm sapiens Demgraphics including ancestry and / r gegraphic rigin: Han-Chinese Summary f Methdlgy and Results This sectin shuld prvide a high level summary f methds and results acrss studies, using tabular representatins and figures as applicable. The review shuld be fllwed by a critical assessment and appraisal f verall results, including discussin and interpretatin f the findings with regard t the prpsed cntext. It shuld present and discuss the strengths and limitatins f the bimarker qualificatin prgram and study results, analyze the benefits f the bimarker fr its cntext, and describe hw the study results supprt its use in the prpsed cntext. Imprtant bservatins regarding the surce f data, identified deficiencies, a brief verview f hw they relate t the prpsed cntext and hw they culd be addressed in future submissins shuld be included. Additinally, key tpics identified fr discussin shuld be mentined Cnclusin The Cnclusin shuld: Prvide an assessment f expected benefits fr the applicatin f the bimarker based upn results f relevant studies, including interpretatin f hw the bimarker perfrmance supprts its use in the prpsed cntext; Address issues encuntered during the bimarker qualificatin studies, explaining hw they have been evaluated and reslved; Identify unreslved issues, and explain why they shuld nt be cnsidered barriers t qualificatin fr the prpsed cntext f use and / r describe plans t reslve them, if applicable Data Summaries (Analytical, Nnclinical, Clinical; as apprpriate) The Data Summaries shuld include a detailed factual summarisatin f infrmatin frm the analytical (assay develpment) r any additinal technical infrmatin, nnclinical r clinical studies (as apprpriate), including integrated analysis f the bimarker qualificatin studies and individual study synpses. These shuld prvide results acrss studies, using tabular representatins r figures as applicable. T achieve these bjectives, this sectin shuld: Describe and explain the verall apprach t the bimarker qualificatin prgram including 1) methds and relevant aspects f study design, 2) technical and bilgical replicatin, and 3) statistical analysis, including hypthesis statements, endpints and justificatin fr sample size. Describe the ratinale fr the selectin f the ppulatin sample studied in the bimarker qualificatin and discuss cnstraints derived frm this selectin, such as thse assciated with ethnicity r disease state; Cntain criteria fr determining sample suitability (e.g., type, amunt and / r age f specimen, DNA yield, etc.); 7

12 Bimarkers Related t Drug r Bitechnlgy Prduct Develpment: Cntext, Structure and Frmat f Qualificatin Submissins Describe the analytical perfrmance characteristics f the assay (e.g., fr in vitr assays, accuracy, precisin, and ther standard parameters) including any specific recmmendatins where applicable n sample handling, strage, and quality requirements; Describe the results supprting the nnclinical / clinical use f the bimarker (e.g., retrspective / prspective crrelatin with phentype / utcme). The use f graphs and tables in the bdy f the text is encuraged t facilitate the regulatry review prcess. It is suggested that material presented fully elsewhere nt be repeated in this sectin; rather, apprpriate crss-references t mre detailed presentatins prvided elsewhere in the study reprts and ther dcuments (Sectin 4 and 5) are encuraged Individual Study Synpses This sectin shuld prvide synpses f the individual studies included in the qualificatin dssier. Where the submissin is based primarily n scientific publicatins, abstracts and key tables taken frm the scientific publicatins can be used fr this sectin. These shuld summarize infrmatin btained frm each f the studies fr which reprts and / r manuscripts have been included in Sectins 4 and 5. The length f these sectins can vary accrding t the infrmatin t be cnveyed. 2.3 Sectin 3: Quality 6 Drug r bitechnlgy prduct quality and manufacturing data wuld nt be expected in a stand alne bimarker qualificatin submissin independent frm an NDA, BLA r MAA. 2.4 Sectins 4 7 (Nnclinical) and 5 8 (Clinical) In these sectins, full study reprts fr bimarker qualificatin shuld be prvided, and raw data made available t the regulatry authrities upn request. Infrmatin n cmpliance with Gd Clinical Practices (GCP) can be included in these sectins. The study reprts can fllw relevant ICH guidelines (e.g., E3, E15, M4E, M4S) where apprpriate fr their preparatin. Within the study reprts, the apprpriate frmat f the data will depend n the characteristics f the bimarker measured (e.g., fr genmic bimarkers, SNPs and / r CNV) and the methdlgy used (e.g., fr genmic bimarkers, micrarray and / r Plymerase Chain Reactin). Regardless f the bimarker investigated r technlgy used, the ratinale fr selectin f the ppulatin sample (e.g., species, age, sex) and f ther variables related t the phentype studied shuld be clearly described. Study reprts used t generate the bimarker qualificatin data shuld specify critical variables including, but nt limited t, the fllwing examples: The number and classificatin f patients / clinical trial subjects wh participated in the bimarker study, and the number and classificatin f patients / clinical trial subjects with assessable bimarker data; Perfrmance characteristics f the bimarker test used, based n retrspective and / r prspective crrelatin with nnclinical and / r clinical endpint data. These reprts shuld include a descriptin f the methds and study designs as well as the results f any functinal studies perfrmed; 6 Crrespnds t CTD Mdule 3 7 Crrespnds t CTD Mdule 4 8 Crrespnds t CTD Mdule 5 8

13 Bimarkers Related t Drug r Bitechnlgy Prduct Develpment: Cntext, Structure and Frmat f Qualificatin Submissins Variables that might bth impact n the validity f the assay chsen and cntribute t interpretatin f results: Hardware r platfrm used; Current internatinally recgnized standards fr the chsen technlgy; Clinical variables that might cntribute t interpretatin f results such as fd, exercise, measurement schedule; Methds and sftware used fr analyses f raw data. As an example, in the case f genmic bimarkers, additinal critical parameters culd als include: Criteria fr determining sample quality (e.g., age f specimen, DNA yield, etc.); Methds used fr determinatin f gene expressin r DNA sequence and ther structural characteristics including mdified DNA bases (e.g., epigenetic marks such as 5-methylcytsine); Criteria used fr selectin f candidate genes, if this is the chsen apprach (candidate by psitin, by functin, based n expressin prfiling data); Results f analyses f genmic bimarkers, all f which shuld be described, as applicable, t current internatinally recgnized standards. Cpies f ther dcuments supprting the bimarker qualificatin submissin shuld be prvided in Sectin 4 fr nnclinical infrmatin r Sectin 5 fr clinical infrmatin. This includes, but is nt limited t, cpies f reference material relating t Sectins 2, 4 and 5. This reference material can include, but is nt limited t, the fllwing: Published articles in peer-reviewed jurnals (including meta-analyses); Expert statements regarding the utility f the bimarker(s) issued by academic r cmmercial institutins, patient rganizatins, public-private cnsrtia, and medical practice versight bards prviding guidance n such utility; Evaluatin reprts r ther relevant dcuments as issued by regulatry authrities (e.g., reprt f relevant scientific advice etc.); Manufacturer s technical descriptin f cmmercially available bimarker assays (if apprpriate). 3. ABBREVIATIONS BLA CNV DNA MAA NDA NOAEL NOEL PM RNA SNPs Bilgics License Applicatin (FDA) Cpy Number Variatin Dexyribnucleic Acid Market Authrizatin Applicatin (EMA) New Drug Applicatin (FDA) and Japanese New Drug Applicatin (MHLW/PMDA) N Observed Adverse Effect Level N Observed Effect Level Pr Metablizer Ribnucleic Acid Single Nucletide Plymrphisms 9