Guidance for Industry 
 
E16 Biomarkers Related to 
Drug or Biotechnology 
Product Development:  
Context, Structure, and 
Format of Qualification 
Submissions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
August 2011 
ICH 
 
   
Guidance for Industry 
 
E16 Biomarkers Related to 
Drug or Biotechnology 
Product Development:  
Context, Structure, and 
Format of Qualification 
Submissions
 
 
Additional copies are available from: 
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http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm   
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
August 2011 
ICH 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION (1, 1.2)................................................................................................1 
A.  Objectives (1.2)...............................................................................................................................2 
B.  Background (1.1)............................................................................................................................2 
C.  Scope (1.3).......................................................................................................................................2 
II.  GENERAL PRINCIPLES (1.4).......................................................................................3 
III.  STRUCTURE OF BIOMARKER QUALIFICATION SUBMISSIONS (2)...............4 
A.  Section 1:  Regional Administrative Information (2.1)..............................................................5 
B.  Section 2:  Summaries (2.2)...........................................................................................................5 
1. Biomarker Qualification Overview (2.2.1)......................................................................................5 
2. Data Summaries (Analytical, Nonclinical, Clinical; as appropriate) (2.2.2)..................................9 
C.  Section 3: Quality (2.3)................................................................................................................10 
D.  Sections 4 (Nonclinical) and 5 (Clinical) (2.4)............................................................................10 
IV.  ABBREVIATIONS (3)...................................................................................................12 
 
  i Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
 
E16 Biomarkers Related to Drug or Biotechnology Product 
Development:  Context, Structure, and Format of Qualification 
Submissions  
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
I.  INTRODUCTION (1, 1.2)2 
 
The guidance describes recommendations regarding context, structure and format of regulatory 
submissions for qualification of genomic biomarkers (as defined in ICH E15 3). Qualification is 
a conclusion that, within the stated context of use, the results of assessment with a biomarker can 
be relied upon to adequately reflect a biological process, response, or event, and support use of 
the biomarker during drug or biotechnology product development, ranging from discovery 
through postapproval. A biomarker qualification application might be submitted to regulatory 
authorities if the biomarker directly or indirectly helps in regulatory decision-making.  
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
                                                 
1 This guidance was developed within the Efficacy Working Group of the International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been 
subject to consultation by the regulatory parties, in accordance with the ICH process.  This document has been 
endorsed by the ICH Steering Committee at Step 4 of the ICH process, August 2010.  At Step 4 of the process, the 
final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United 
States. 
2 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering Committee at 
Step 4 of the ICH process, August 2010. 
 
3 ICH E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories defines a genomic biomarker as a measurable DNA and/or RNA characteristic that is an 
indicator of normal biologic processes, pathogenic processes, and/or response to therapeutic or other interventions. 
  1 Contains Nonbinding Recommendations 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
 
A.  Objectives (1.2) 
 
The objective of the guidance is to create a harmonized recommended structure for biomarker 
qualification applications that will foster consistency of applications across regions and facilitate 
discussions with and among regulatory authorities. It will also reduce the burden on sponsors as 
a harmonized format will be recommended for use across all ICH regulatory regions.  It is also 
expected that the proposed document format will facilitate incorporation of biomarker data into 
specific product-related applications. Biomarker qualification can take place at any time during 
drug or biotechnology product development, ranging from discovery through postapproval. For 
those instances where it is appropriate, general guidance for inclusion of biomarker qualification 
data into the Common Technical Document for the Registration of Pharmaceuticals for Human 
Use (CTD) format for marketing authorization applications is provided in this document. The use 
of the CTD format would be considered appropriate when biomarker data are submitted as part 
of a new drug application (NDA), a biologics license application (BLA), a market authorization 
application (MAA), or other postapproval regulatory procedures, or upon request by the 
regulatory authorities. 
 
B.  Background (1.1) 
 
The use of biomarkers has the potential to facilitate the availability of safer and more effective 
drug or biotechnology products, to guide dose selection, and to enhance their benefit-risk profile. 
This guidance is based on previous experiences with submissions containing biomarker data in 
the various regions. These submissions have been either stand-alone biomarker qualification 
applications or a component of medicinal product-related regulatory process marketing 
applications (NDAs/BLAs/MAAs). The development of a consistent format for submission of 
biomarker data will facilitate easy review and exchange of assessments between regions. 
 
C.  Scope (1.3) 
  
The scope of this guidance is the context, structure, and format of qualification submissions for 
clinical and nonclinical genomic biomarkers related to development of drug or biotechnology 
products including translational medicine approaches, pharmacokinetics, pharmacodynamics, 
and efficacy and safety aspects. A qualification submission can include data and claims for a 
single genomic biomarker, or for multiple genomic biomarkers used as classifiers. While this 
guidance does not explicitly cover nongenomic biomarkers, the principles described in this 
document are applicable to a variety of biomarker categories (e.g., genomics, proteomics, 
imaging) and other qualification contexts associated with drug or biotechnology product 
development. A qualification submission for a combination of biomarkers (e.g., genomic 
together with nongenomic biomarkers) is also possible. Unless otherwise specified, we will use 
the generic term biomarker throughout the remainder of this document. 
 
  2 Contains Nonbinding Recommendations 
The guidance also covers the submission of data relevant to the validation of new analytical 
approaches to improve the evaluation of current biomarkers. This guidance does not address 
either the qualification process or the evidentiary standards for a biomarker to be qualified by 
regulatory authorities. 
 
 
II.  GENERAL PRINCIPLES (1.4) 
 
The proposed context of use of a biomarker corresponds to the data supporting its qualification. 
The proposed context of use should be clearly detailed in the submission package. Reference 
should be made to the specific use of the biomarker in drug or biotechnology product 
development. The context of use of a biomarker in a biomarker qualification can be narrow or 
broad: the biomarker(s) might be useful for only a single drug or biotechnology product, for 
several drug or biotechnology products in a drug class, or even across several drug classes. 
 
The structure of the submission should be consistent, regardless of the context proposed, and 
flexible enough to deal with the specific attributes of each submission. In addition, use of the 
recommended structure should facilitate submission and review of future biomarker qualification 
submissions expanding the use of the biomarker to new contexts, as would be the case, e.g., if a 
nonclinical context of use expands to a clinical context of use. 
 
The format of the data for qualifying a biomarker can vary significantly depending on the 
context. It is therefore only possible to provide general guidelines on data format for a biomarker 
qualification submission. The format should support an evaluation of the data and can include 
reports, tabulations, and raw data (if requested by regulatory authorities according to the relevant 
practices in place). Data format should be consistent with the methodology and platform used for 
analyzing the biomarker in question. Reference to standards and/or accepted methods used 
should be described as applicable.  
 
The dossier structure described in this guidance is intended for biomarker qualification 
submissions after sufficient supporting data have been generated. However, this structure can 
also be considered for submissions intended to obtain scientific advice from regulatory 
authorities before or during the generation of the biomarker data intended to support 
qualification. 
 
The recommended biomarker qualification submission is aligned with the CTD format to 
facilitate submission and review. The proposed overall organization of the biomarker 
qualification submission described herein corresponds to the CTD format, which consists of five 
parts (Modules 1-5). The sections of the biomarker qualification submission and their 
corresponding CTD sections are as follows:  
  ICH E16 Section 1 (Regional Administrative Information) corresponds to CTD Module 1 
with specific information on the qualification procedures;  
  Section 2 (Summaries) corresponds to CTD Module 2;  
  Section 3 (Quality Reports) corresponds to CTD Module 3;  
  3 Contains Nonbinding Recommendations 
  Section 4 (Nonclinical Study Reports) corresponds to Module 4; and  
  Section 5 (Clinical Study Reports) corresponds to Module 5.  
More details are described in the ICH M4 and other relevant guidances. Applicants who wish to 
submit in accordance with the Electronic Common Technical Document (eCTD) format should 
also consult the ICH M2 guidance (Electronic Standards for Transmission of Regulatory 
Information) and other relevant guidances, as well as national and regional laws, regulations, and 
recommendations. 
  
To facilitate the integration of biomarkers in global drug or biotechnology product development 
it is recommended that qualification submissions be submitted simultaneously to pertinent 
regulatory authorities. It should be noted that if a biomarker has already been endorsed as 
qualified by a regulatory authority, biomarker data generated within the qualified context of use 
do not need to be re-submitted to the authority for re-qualification in an NDA/BLA/MAA. It 
would be appropriate to simply provide a copy of the assessment report of the authority in the 
NDA/BLA/MAA or other relevant regulatory procedure. 
 
III.  STRUCTURE OF BIOMARKER QUALIFICATION SUBMISSIONS (2) 
 
The biomarker qualification submission should include the following sections: 
 
Section 1:  Regional Administrative Information 
 
Section 2:   Summaries 
 
  Biomarker Qualification Overview 
 
Introduction, proposed context of use, high-level data description, integrated critical appraisal of 
the data/methods, additional data needed from ongoing or planned studies, and justification for 
the proposed context of use. 
 
  Overall Summaries of the following (if appropriate): 
o  Analytical Assay Data  
o  Nonclinical Biomarker Data  
o  Clinical Biomarker Data 
 
If included in an NDA/BLA/MAA, the contents in Section 2 should be converted into chapters in 
the appropriate CTD Module 2 such as Overview(s) and/or Overall Summary(ies). 
 
Section 3:  Quality Reports 
 
  Structural, manufacturing, and quality characteristics of investigational drug(s) for the 
biomarker qualification studies (as applicable). 
 
  4 Contains Nonbinding Recommendations 
Such information is not expected to be included in a stand-alone biomarker qualification 
submission, independent from an NDA, BLA, or MAA. 
 
Section 4:  Nonclinical Reports 
 
  Analytical assay development reports4 
  Analytical assay validation reports2 
  Nonclinical study reports (in vitro) 
  Nonclinical study reports (in vivo, specify species) 
 
Section 5:  Clinical Reports 
 
  Analytical assay development reports5 
  Analytical assay validation reports3 
  Clinical pharmacology study reports  
  Clinical efficacy and/or safety study reports 
 
The recommended content of these sections is explained in more detail below. 
 
A.  Section 1:  Regional Administrative Information6 (2.1) 
 
This section should contain documents specific to each region, for example application forms 
and/or cover letter. The content and format of this section can be specified by the relevant 
regulatory authorities. 
 
B.  Section 2:  Summaries7 (2.2) 
 
By analogy to the CTD structure, biomarker qualification submissions should contain a 
Biomarker Overview to discuss and interpret the strengths and limitations of the submitted data.  
It should be supported by the separate technical, preclinical and clinical data summaries, which 
should present the study data as a detailed factual summarization in text, tables and figures. 
 
1.  Biomarker Qualification Overview (2.2.1) 
 
a.  Introduction (2.2.1.1) 
 
                                                 
4 Corresponds to CTD Module 4 section 4.2 or 4.3 
 
5 Corresponds to CTD Module 5 section 5.3 
 
6 Corresponds to CTD Module 1 
 
7 Corresponds to CTD Module 2 
  5 Contains Nonbinding Recommendations 
This section should be concise. It can include a description of the disease and/or experimental 
setting, the definition of the biomarker (e.g., in the case of genomic biomarkers, whether a single 
nucleotide polymorphism (SNP), copy number variation (CNV), or differential gene expression 
signature) and a rationale for the biomarkers use in drug or biotechnology product development, 
from discovery through postapproval. 
 
It should summarize the key characteristics of the biomarker, including; 
  strengths and limitations (e.g., comparison with relevant standard methods where 
available, presence/absence of information on pertinent species/population) 
  whether it is a single or composite biomarker; if it is a composite biomarker, its 
component markers and the process through which these were selected should be defined 
  objective and design of the studies supporting its use, such as prospective versus 
retrospective study design, study comparators and sample size 
 
A summary of the proposed context of use of the biomarker should be provided in this section. 
More details, including the full context of biomarker use, should be described in the next section. 
 
 
b.  Context of Use (2.2.1.2) 
 
The elements describing the context of use for a biomarker should include (1) the general area, 
(2) the specific biomarker use, and (3) the critical parameters that define when and how the 
biomarker should be used. The context of use can be limited to use in drug or biotechnology 
product development. It is expected that a biomarker proposed for qualification would facilitate 
drug or biotechnology product development program(s) or drug or biotechnology product use 
and could offer an improvement over currently available biomarkers or safety or efficacy 
endpoint assessments. 
 
The proposed context of use for a biomarker should be supported by data that are available in the 
initial qualification dossier submission. If the reviewing authority identifies an inconsistency 
between the proposed context and the data, additional data can be provided during the 
qualification processes, if the authority agrees.  
 
The context of use can be described according to the following taxonomy (see examples 
below): 
 
General Area (including, but not limited to) 
Nonclinical/Clinical 
  Pharmacology 
  Toxicology 
  Efficacy 
  Safety 
  Disease 
 
  6 Contains Nonbinding Recommendations 
Specific Biomarker Use(s) Biomarkers can be used for a wide range of purposes, including, but 
not limited to, the following examples: 
  Patient/clinical trial subject selection 
o  Inclusion/exclusion criteria 
o  Trial enrichment or stratification 
  Assessment of disease state and/or prognosis 
  Assessment of mechanism of action 
o  Mechanism of pharmacological mode of action  
o  Mechanism of therapeutic effect 
o  Mechanism of toxicity/adverse reaction 
  Dose optimization 
o  No observed effect level (NOEL) in animal models 
o  No observed adverse effect level (NOAEL) in animal models 
o  Algorithm-based dose determination (quantitative algorithmic dosing) 
o  Determination of likely dose range 
  Drug response monitoring 
o  Monitoring drug safety 
o  Monitoring drug efficacy 
  Efficacy maximization 
o  Indicating/predicting drug efficacy 
  Toxicity/adverse reactions minimization 
o  Indicating/predicting toxicity/adverse reactions 
o  Detecting/monitoring onset/reversibility of toxicity/adverse reactions 
 
Critical Parameters of Context of Use (including, but not limited to) 
  Drug or biotechnology product-specific use/drug class-specific use/use not linked to 
specific drug or biotechnology products or drug classes 
  Disease diagnosis and phenotypes, prognosis, or stage 
  Sample collection 
  Assay specifications 
  Tissue or physiological/pathological process 
  Species 
  Demographics, including ancestry and/or geographic origin 
  Environmental factors 
 
Examples of Context of Use for Biomarkers 
 
A biomarker measurement could apply to more than one context of use, depending on the 
general area and/or specific use within a single submission, as shown in the following examples 
of genomic biomarkers. While hypothetical examples for genomic biomarkers are depicted here, 
the principles for context description are applicable for all types of biomarkers submitted for 
qualification. 
 
 
  7 Contains Nonbinding Recommendations 
(i) Nonclinical Safety  
Messenger RNA levels of kidney injury molecule 1 (Kim-1) and clusterin (Clu) can be 
included as genomic biomarkers of drug or biotechnology-induced acute renal tubular 
toxicity in rat toxicology studies. The context of the submission in the biomarker 
qualification application would be defined as follows: 
  General Area:  nonclinical safety and toxicology 
  Specific Biomarker Use:  assessment of mechanism of toxicity and dose 
optimization (NOAEL) in animal models 
  Critical Parameters of Context of Use: 
o  Drug or biotechnology product-specific use:  no 
o  Assay specifications:  mRNA 
o  Tissue or physiological/pathological process addressed:  kidney  
o  Species:  Rattus norvegicus 
 
(ii) Clinical Pharmacology/Drug Metabolism 
CYP2C9 genetic polymorphism produces poor metabolizer (PM) and extensive 
metabolizer phenotypes and differences in Drug A exposure. Plasma levels of Drug A in 
patients/clinical trial subjects who are known to be CYP2C9 PMs are increased due to 
reduced metabolic clearance. Context of the submission in the biomarker qualification 
application would be defined as follows: 
  General Area: Clinical Pharmacology/Drug Metabolism and Safety 
  Specific Biomarker Use: patient/clinical trial subject selection 
(inclusion/exclusion criteria, trial enrichment or stratification), dose optimization 
in individual patients and predicting adverse reactions/risk minimization 
  Critical Parameters of Context of Use: 
o  Drug or biotechnology product-specific use:  Drug A 
o  Assay specifications:  Genotyping 
o  Species:  Homo sapiens 
o  Demographics including ancestry and/or geography:  population-specific 
allele frequency  
 
(iii) Clinical Safety 
The HLA-B*1502 allele is associated with an increased risk of the development of 
Stevens-Johnson Syndrome following administration of Drug B in Han-Chinese. 
  General Area:  clinical safety. 
  Specific Biomarker Use:  patient selection (inclusion/exclusion criteria), predicted 
safety and mechanism of adverse reaction/toxicity 
  Critical Parameters for Context of Use: 
o  Drug or biotechnology product-specific use:  Drug B 
o  Assay specifications:  Genotyping  
o  Species:  Homo sapiens 
o  Demographics including ancestry and/or geographic origin:  Han-Chinese 
 
  8 Contains Nonbinding Recommendations 
c.  Summary of Methodology and Results (2.2.1.3) 
   
This section should provide a high level summary of methods and results across studies, using 
tabular representations and figures as applicable. The review should be followed by a critical 
assessment and appraisal of overall results, including discussion and interpretation of the 
findings with regard to the proposed context. It should present and discuss the strengths and 
limitations of the biomarker qualification program and study results, analyze the benefits of the 
biomarker for its context, and describe how the study results support its use in the proposed 
context. 
 
Important observations regarding the source of data, identified deficiencies, and a brief overview 
of how they relate to the proposed context and how they could be addressed in future 
submissions should be included. Additionally, key topics identified for discussion should be 
mentioned. 
 
d.  Conclusion (2.2.1.4) 
 
The conclusion should: 
 
  Provide an assessment of expected benefits for the application of the biomarker based 
upon results of relevant studies, including interpretation of how the biomarker 
performance supports its use in the proposed context; 
  Address issues encountered during the biomarker qualification studies, explaining how 
they have been evaluated and resolved; 
  Identify unresolved issues, and explain why they should not be considered barriers to 
qualification for the proposed context of use and/or describe plans to resolve them, if 
applicable. 
 
2.  Data Summaries (Analytical, Nonclinical, Clinical; as appropriate) (2.2.2) 
 
The data summaries should include a detailed factual summarization of information from the 
analytical (assay development) or any additional technical information, nonclinical or clinical 
studies (as appropriate), including integrated analysis of the biomarker qualification studies and 
individual study synopses.  These should provide results across studies, using tabular 
representations or figures as applicable.  
 
To achieve these objectives, this section should: 
  Describe and explain the overall approach to the biomarker qualification program 
including (1) methods and relevant aspects of study design, (2) technical and biological 
replication, and (3) statistical analysis, including hypothesis statements, endpoints, and 
justification for sample size. Describe the rationale for the selection of the population 
sample studied in the biomarker qualification and discuss constraints derived from this 
selection, such as those associated with ethnicity or disease state; 
  Contain criteria for determining sample suitability (e.g., type, amount and/or age of 
specimen, DNA yield); 
  9 Contains Nonbinding Recommendations 
  Describe the analytical performance characteristics of the assay (e.g., for in vitro assays, 
accuracy, precision, and other standard parameters) including any specific 
recommendations where applicable on sample handling, storage, and quality 
requirements; 
  Describe the results supporting the nonclinical/clinical use of the biomarker (e.g., 
retrospective/prospective correlation with phenotype/outcome). 
 
The use of graphs and tables in the body of the text is encouraged to facilitate the regulatory 
review process. It is suggested that material presented fully elsewhere not be repeated in this 
section; rather, appropriate cross-references to more detailed presentations provided elsewhere in 
the study reports and other documents (Section 4 and 5) are encouraged. 
 
  Individual study synopses (2.2.2.1) 
 
This section should provide synopses of the individual studies included in the qualification 
dossier. Where the submission is based primarily on scientific publications, abstracts and key 
tables taken from the scientific publications can be used for this section; these should summarize 
information obtained from each of the studies for which reports and/or manuscripts have been 
included in Sections 4 and 5. The length of these sections can vary according to the information 
to be conveyed. 
 
C.  Section 3: Quality8 (2.3) 
 
Drug or biotechnology product quality and manufacturing data would not be expected in a stand 
alone biomarker qualification submission independent from an NDA, BLA, or MAA. 
 
D.  Sections 49 (Nonclinical) and 510 (Clinical) (2.4) 
 
In these sections, full study reports for biomarker qualification should be provided, and raw data 
made available to the regulatory authorities upon request. Information on compliance with Good 
Clinical Practices (GCP) can be included in these sections. The study reports can follow relevant 
ICH guidances (e.g., E3, E15, M4E, M4S)11 where appropriate for their preparation. Within the 
study reports, the appropriate format of the data will depend on the characteristics of the 
biomarker measured (e.g., for genomic biomarkers, SNPs, and/or CNV) and the methodology 
used (e.g., for genomic biomarkers, microarray and/or Polymerase Chain Reaction).  
 
                                                 
8 Corresponds to CTD Module 3 
 
9 Corresponds to CTD Module 4 
 
10 Corresponds to CTD Module 5 
 
11 ICH E3 Structure and Content of Clinical Study Reports; E15 (see note 4); M4E The CTD  Efficacy; M4S The 
CTD  Safety. 
 
  10 Contains Nonbinding Recommendations 
Regardless of the biomarker investigated or technology used, the rationale for selection of the 
population sample (e.g., species, age, sex) and of other variables related to the phenotype studied 
should be clearly described. Study reports used to generate the biomarker qualification data 
should specify critical variables including, but not limited to, the following examples: 
  The number and classification of patients/clinical trial subjects who participated in the 
biomarker study, and the number and classification of patients/clinical trial subjects with 
assessable biomarker data. 
  Performance characteristics of the biomarker test used, based on retrospective and/or 
prospective correlation with nonclinical and/or clinical endpoint data. These reports 
should include a description of the methods and study designs as well as the results of 
any functional studies performed. 
  Variables that might both impact on the validity of the assay chosen and contribute to 
interpretation of results: 
o  Hardware or platform used 
o  Current internationally recognized standards for the chosen technology 
o  Clinical variables that might contribute to interpretation of results such as food, 
exercise, measurement schedule 
  Methods and software used for analyses of raw data. 
 
As an example, in the case of genomic biomarkers, additional critical parameters could also 
include:  
  Criteria for determining sample quality (e.g., age of specimen, DNA yield) 
  Methods used for determination of gene expression or DNA sequence and other structural 
characteristics including modified DNA bases (e.g., epigenetic marks such as 5-
methylcytosine) 
  Criteria used for selection of candidate genes, if this is the chosen approach (candidate by 
position, by function, based on expression profiling data) 
  Results of analyses of genomic biomarkers, all of which should be described, as 
applicable, to current internationally recognized standards 
 
Copies of other documents supporting the biomarker qualification submission should be 
provided in Section 4 for nonclinical information or Section 5 for clinical information. This 
includes, but is not limited to, copies of reference material relating to Sections 2, 4, and 5. This 
reference material can include, but is not limited to, the following: 
  Published articles in peer-reviewed journals (including meta-analyses)  
  Expert statements regarding the utility of the biomarker(s) issued by academic or 
commercial institutions, patient organizations, public-private consortia, and medical 
practice oversight boards providing guidance on such utility 
  Evaluation reports or other relevant documents as issued by regulatory authorities (e.g., 
report of relevant scientific advice) 
  Manufacturers technical description of commercially available biomarker assays (if 
appropriate) 
 
  11 Contains Nonbinding Recommendations 
IV.  ABBREVIATIONS (3) 
 
BLA   biologics license application (FDA) 
CNV    copy number variation 
DNA    deoxyribonucleic acid 
MAA   market authorization application (EMA) 
NDA    new drug application (FDA) and Japanese new drug application (MHLW/PMDA) 
NOAEL  no observed adverse effect level 
NOEL  no observed effect level 
PM    poor metabolizer 
RNA    ribonucleic acid 
SNPs   single nucleotide polymorphisms 
 
  12