Guidance for Industry 

E15 Definitions for 

Genomic Biomarkers, 

Pharmacogenomics, 

Pharmacogenetics, Genomic 

Data and Sample Coding 

Categories 

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) 

April 2008 

ICH 
 Guidance for Industry 

E15 Definitions for 

Genomic Biomarkers, 

Pharmacogenomics, 

Pharmacogenetics, Genomic 

Data and Sample Coding 

Categories 

Additional copies are available from: 

Office of Training and Communication 

Division of Drug Information

Center for Drug Evaluation and Research

Food and Drug Administration 

10903 New Hampshire Ave.,Bldg. 51, Room 2201

Silver Spring, MD 20993-0002

(Tel) 301-796-3400

 http://www.fda.gov/cder/guidance/index.htm 

Office of Communication, Training and

Manufacturers Assistance, HFM-40  

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Rockville, MD 20852-1448 

(Tel) 1-800-835-4709 or 301-827-1800 

 http://www.fda.gov/cber/guidelines.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) 

April 2008 

ICH 
 TABLE OF CONTENTS 

I.  INTRODUCTION (1, 1.1, 1.3)......................................................................................... 1

II.  BACKGROUND (1.2)....................................................................................................... 2

III.  GUIDANCE (2) ................................................................................................................. 2

A.  Genomic Biomarker (2.1)..............................................................................................................2

1. Definition (2.1.1)..............................................................................................................................2

2. Additional Information (2.1.2).........................................................................................................2

B.  Pharmacogenomics and Pharmacogenetics (2.2)........................................................................3

1. Definitions (2.2.1) ............................................................................................................................3

2. Additional Information (2.2.2).........................................................................................................4

C.  Categories for Genomic Data and Samples Coding (2.3)...........................................................4

1. Identified Data and Samples (2.3.1)................................................................................................4

2. Coded Data and Samples (2.3.2).....................................................................................................4

3. Anonymized Data and Samples (2.3.3)............................................................................................5

4. Anonymous Data and Samples (2.3.4).............................................................................................6

5. Additional Information (2.3.5).........................................................................................................6

Table 1: Summary of Genomic Data and Sample Coding Categories..............................................7

i  Contains Nonbinding Recommendations 
1

Guidance for Industry
E15 Definitions for Genomic Biomarkers, Pharmacogenomics, 

Pharmacogenetics, Genomic Data and Sample Coding Categories  

This guidance represents the Food and Drug Administration's (FDA's) 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, 1.1, 1.3)2 
This guidance contains definitions of key terms in the discipline of pharmacogenomics and 
pharmacogenetics, namely genomic biomarkers, pharmacogenomics, pharmacogenetics, and 
genomic data and sample coding categories.  In the effort to develop harmonized approaches to 
drug regulation, it is important to ensure that consistent definitions of terminology are being 
applied across all constituents of the International Conference on Harmonisation (ICH).  This 
guidance on definitions is intended to facilitate the integration of the discipline of 
pharmacogenomics and pharmacogenetics into global drug development and approval processes.  
As new scientific knowledge in the discipline of pharmacogenomics and pharmacogenetics 
emerges, the current guidance will be reviewed and expanded if appropriate. 
The validation and qualification processes for genomic biomarkers, evidence for their intended 
use, and acceptance criteria across ICH regions are outside of the scope of this guidance.  
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's 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 Expert Working Group (Efficacy) 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, November 2007.  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, November 2007. 
1
 Contains Nonbinding Recommendations 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
II.  BACKGROUND (1.2) 
Pharmacogenomics and pharmacogenetics have the potential to improve the discovery, 
development, and use of medicines.  Each of the ICH regions has published specific 
pharmacogenomic and pharmacogenetic guidelines, or concept papers, and is in the process of 
developing others. However, the lack of consistently applied definitions for commonly used 
terminology raises the potential for either conflicting use of terms in regulatory documentation 
and guidelines or inconsistent interpretation by regulatory authorities, ethics committees, and 
sponsor companies. 
III.  GUIDANCE (2) 
Definitions of a genomic biomarker, pharmacogenomics, pharmacogenetics, and genomic data 
and sample coding categories are detailed below.  The definition of what constitutes a genomic 
biomarker is key to understanding the definitions of pharmacogenomics and pharmacogenetics 
and is therefore introduced in this guidance first.  Additional information useful to an 
understanding of aspects covered by each of the definitions is also provided.  Some of the 
principles described in this guidance might be applicable to proteomics, metabolomics, and other 
related disciplines. 
A.  Genomic Biomarker (2.1) 
1.  Definition (2.1.1) 
A genomic biomarker is defined as follows: 
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. 
2.  Additional Information (2.1.2) 
a.  A genomic biomarker could, for example, be a measurement of: 
  The expression of a gene 
  The function of a gene 
  The regulation of a gene 
2
 Contains Nonbinding Recommendations 
b. 	 A genomic biomarker can consist of one or more deoxyribonucleic acid (DNA) 
and/or ribonucleic acid (RNA) characteristics. 
c. 	 DNA characteristics include, but are not limited to: 
	 Single nucleotide polymorphisms (SNPs) 
	 Variability of short sequence repeats 
	 Haplotypes 
	 DNA modifications, e.g., methylation 
	 Deletions or insertions of (a) single nucleotide(s) 
	 Copy number variations 
	 Cytogenetic rearrangements, e.g., translocations, duplications, deletions, or 
inversions 
d. 	 RNA characteristics include, but are not limited to: 
	 RNA sequences 
	 RNA expression levels 
	 RNA processing, e.g., splicing and editing  
	 microRNA levels 
e. 	 The definition of a genomic biomarker is not limited to human samples, but 
includes samples from viruses and infectious agents as well as animal samples, 
i.e., for the application of genomic biomarkers to nonclinical and/or toxicological 
studies. 
f. 	 The definition of a genomic biomarker does not include the measurement and 
characterization of proteins or low molecular weight metabolites. 
B. 	 Pharmacogenomics and Pharmacogenetics (2.2) 
1.  	Definitions (2.2.1) 
a.  	Pharmacogenomics (2.2.1.1)  

Pharmacogenomics (PGx) is defined as: 

The study of variations of DNA and RNA characteristics as related to drug 
response. 
b.  	Pharmacogenetics (2.2.1.2) 
Pharmacogenetics (PGt) is a subset of pharmacogenomics (PGx) and is defined 
as: 
The study of variations in DNA sequence as related to drug response. 
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 Contains Nonbinding Recommendations 
2. 	 Additional Information (2.2.2) 
a.  	The term drug should be considered synonymous with investigational (medicinal) 
product, medicinal product, medicine, and pharmaceutical product (including 
vaccines and other biological products).  
b. 	 PGx and PGt are applicable to activities such as drug discovery, drug 
development, and clinical practice. 
c. 	 Drug response includes the processes of drug absorption and disposition (e.g., 
pharmacokinetics (PK)), and drug effects (e.g., pharmacodynamics (PD), drug 
efficacy, and adverse effects of drugs). 
d. 	 The definitions of PGx and PGt do not include other disciplines such as 
proteomics and metabolomics. 
C. 	 Categories for Genomic Data and Samples Coding (2.3) 
PGx and PGt research depends on the use of biological samples to generate data.  A harmonized 
definition for the coding of these samples and their associated data will facilitate use in research 
and development of new medicines.   
There are four general categories of coding:  identified, coded, anonymized, and anonymous.  
Coded data or samples can be single or double coded.   
The implications of using a specific data and sample coding category should be considered in the 
design of PGx and PGt research studies. 
Some implications are highlighted in this section and summarized in Table 1.  
1. 	 Identified Data and Samples (2.3.1) 
Identified data and samples are labeled with personal identifiers such as name or identification 
numbers (e.g., social security or national insurance number).  As the samples and associated data 
are directly traceable back to the subject, it is possible to undertake actions such as sample 
withdrawal or the return of individual results in accordance with the subjects request.  The use 
of identified data and samples allows for clinical monitoring, subject follow-up, and the addition 
of new data from the subject.  Identified data and samples offer privacy protection comparable to 
that of general health care confidentiality in everyday medical practice.  Identified data and 
samples are generally not considered appropriate for purposes of clinical trials in drug 
development. 
2. 	 Coded Data and Samples (2.3.2) 
Coded data and samples are labeled with at least one specific code and do not carry any personal 
identifiers. 
4
 Contains Nonbinding Recommendations 
a.  Single-Coded Data and Samples (2.3.2.1) 
Single-coded data and samples are usually labeled with a single specific code and do not 
carry any personal identifiers. It is possible to trace the data or samples back to a given 
individual with the use of a single coding key.  In general, the clinical investigator is 
responsible for maintaining the coding key.  As the samples and associated data are indirectly 
traceable back to the subject via the coding key, it is possible to undertake actions such as 
sample withdrawal or the return of individual results in accordance with the subjects request.  
The use of single-coded data and samples allows for clinical monitoring, subject follow-up, 
or the addition of new data from the subject.  Single coding is the current standard used in 
clinical research and offers additional safeguards to the subjects identifiers compared to the 
general health care confidentiality and privacy protection in everyday medical practice.  
b.  Double-Coded Data and Samples (2.3.2.2) 
Double-coded data and samples are initially labeled with a single specific code and do not 
carry any personal identifiers. The data and samples are then relabeled with a second code, 
which is linked to the first code via a second coding key.  It is possible to trace the data or 
samples back to the individual by the use of both coding keys.  In general, the clinical 
investigator is responsible for maintaining the first coding key and does not have access to 
the second coding key. As the samples and associated data can very indirectly be traced back 
to the subject via the use of both coding keys, it may be possible to undertake actions such as 
sample withdrawal, or the return of individual results in accordance with the subjects 
request. However, additional electronic or technical processes may be added to further limit 
the ability to trace back from a genotype result to an individual subject (for example, a 
specific computer process that allows new subject data to be added but prevents the 
reconnection of the genotype data back to the individual subject identifier).  The use of 
double-coded data and samples allows for clinical monitoring, subject follow-up, or the 
addition of new data from the subject. The use of the second code provides additional 
confidentiality and privacy protection for subjects over the use of a single code.  Access to 
both coding keys is needed to link any data or samples back to a subject identifier. 
3.  Anonymized Data and Samples (2.3.3) 
Anonymized data and samples are initially single or double coded but where the link between the 
subjects identifiers and the unique code(s) is subsequently deleted.  Once the link has been 
deleted, it is no longer possible to trace the data and samples back to individual subjects through 
the coding key(s). Anonymization is intended to prevent subject re-identification.  As 
anonymized samples and associated data are not traceable back to the subject, it is not possible to 
undertake actions such as sample withdrawal, or the return of individual results, even at the 
subjects request. The use of anonymized data and samples does not allow for clinical 
monitoring, subject follow-up, or the addition of new data from the subject.  The deletion of the 
coding key(s) linking the data and samples to a given subjects identifiers provides additional 
confidentiality and privacy protection over coded data and samples, as it prevents subject re-
identification through the use of the coding key(s). 
5
 Contains Nonbinding Recommendations 
4.  Anonymous Data and Samples (2.3.4) 
Anonymous data and samples are never labeled with personal identifiers when originally 
collected, neither is a coding key generated. Therefore, there is no potential to trace back 
genomic data and samples to individual subjects.  In some instances, only limited clinical data 
can be associated with anonymous samples (e.g., samples from subjects with diabetes, male, age 
50-55, cholesterol>240 mg/dl).  As anonymous samples and associated data are not traceable 
back to subjects, it is not possible to undertake actions such as sample withdrawal, or the return 
of individual results, even at the subjects request.  The use of anonymous data and samples does 
not allow for clinical monitoring, subject follow-up, or the addition of new data. 
5.  Additional Information (2.3.5) 
The use of a specific coding category in relation to obtaining informed consent from subjects is 
not within the focus of this guidance and is not addressed in this guidance.    
The conditions under which the genomic data can be linked back to a subjects personal 
identifiers for any purpose, including the return of genomic data to the subject, should be 
described in research related documents, e.g., the informed consent document.  
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 Contains Nonbinding Recommendations 
Table 1: Summary of Genomic Data and Sample Coding Categories 
Traceability Back to the  Ability to Perform  Extent of Subjects 
Sample Coding  Link Between Subjects 
Subject  Clinical Monitoring,  Confidentiality and Privacy 
Category  Personal Identifiers And 
(Actions possible, including  Subject Follow-up, or  Protection 
Genomic Biomarker Data 
e.g., sample withdrawal or  Addition of New Data 
return of individual genomic 
results at  subjects request) 
Identified  Yes (direct)  Yes  Yes  Similar to general health care 
Allows for subjects to be  confidentiality and privacy 
identified 
Coded  Single  Yes (indirectly)  Yes  Yes  Standard for clinical research 
Allows for subjects to be 
identified (via single, specific 
coding key) 
Double  Yes (very indirectly)  Yes  Yes  Added privacy and 
Allows for subjects to be  confidentiality protection over 
identified (via the two specific  single code 
coding keys) 
Anonymized  No  No  No  Genomic data and samples no 
Does not allow for subjects to  longer linked to subject as 
be re-identified as coding  coding key(s) have been deleted 
key(s) have been deleted 
Anonymous  No  No  No  Genomic data and samples 
Identifiers never collected and  never linked to subject 
coding keys never applied 
Does not allow for subjects to 
be identified 
7