E15
1 INTRODUCTION
1.1 Objective of the Guideline
The International Conference on Harmonization (ICH) must make sure that all of its members are using the same definitions of terms in order to create standardized approaches to drug control. The integration of the fields of pharmacogenomics and pharmacogenetics into global drug development and approval procedures will be made easier by an agreement on definitions.
1.2 Background
The fields of pharmacogenomics and pharmacogenetics have promise for enhancing discovery, development, and use of medicines. Every ICH region has released its own concept papers, or pharmacogenomic and pharmacogenetic guidelines, and is working on more. The absence of uniformly applied definitions for widely used phrases, however, increases the possibility of either conflicting term usage in regulatory documents and guidelines or inconsistent interpretation by sponsor corporations, ethics committees, and regulatory bodies.
1.3 Scope of the Guideline
Key words in the fields of pharmacogenomics and pharmacogenetics, including genomic biomarkers, pharmacogenomics, pharmacogenetics, and genomic data and sample coding categories, are defined in this guidance. This guideline does not cover genetic biomarker validation and qualification procedures, data supporting their intended use, or acceptability criteria across ICH regions. We will review and, if necessary, update the current guidance as new scientific information in the fields of pharmacogenomics and pharmacogenetics becomes available.
2. GUIDELINE
Below are definitions of pharmacogenomics, pharmacogenetics, genomic data and sample coding categories, and genomic biomarker. This guideline begins with defining what a genomic biomarker is, as this is essential to comprehending the meanings of pharmacogenomics and pharmacogenetics. Additional details that are helpful in comprehending the topics addressed by each definition are also given. In proteomics, metabalomics, and other related fields, some of the principles outlined in this guideline may be relevant.
1. INTRODUCTION
1.1 Objective of the Guideline
In order to develop harmonised 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). An agreement on definitions will facilitate the integration of the discipline of pharmacogenomics and pharmacogenetics into global drug development and approval processes.
1.2 Background
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 to 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.
1.3 Scope of the Guideline
This guideline contains definitions of key terms in the discipline of pharmacogenomics and pharmacogenetics, namely genomic biomarkers, pharmacogenomics, pharmacogenetics and genomic data and sample coding categories. 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 guideline. As new scientific knowledge in the discipline of pharmacogenomics and pharmacogenetics emerges, the current guideline will be reviewed and expanded if appropriate.
2. GUIDELINE
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 guideline 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 guideline might be applicable to proteomics, metabalomics and other related disciplines.
2.1 Genomic Biomarker
2.1.1 Definition
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.
2.1.2 Additional Information
1. 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. A genomic biomarker can consist of one or more deoxyribonucleic acid (DNA) and/or ribonucleic acid (RNA) characteristics.
3. 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.
4. RNA characteristics include, but are not limited to:
- RNA sequences;
- RNA expression levels;
- RNA processing, e.g., splicing and editing;
- microRNA levels.
5. 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 non-clinical and/or toxicological studies.
6. The definition of a genomic biomarker does not include the measurement and characterisation of proteins or low molecular weight metabolites.
2.2 Pharmacogenomics and Pharmacogenetics
2.2.1 Definitions
2.2.1.1 Pharmacogenomics
Pharmacogenomics (PGx) is defined as:
The study of variations of DNA and RNA characteristics as related to drug response.
2.2.1.2 Pharmacogenetics
Pharmacogenetics (PGt) is a subset of pharmacogenomics (PGx) and is defined as:
The study of variations in DNA sequence as related to drug response.
2.2.2 Additional Information
- The term drug should be considered synonymous with investigational (medicinal) product, medicinal product, medicine and pharmaceutical product (including vaccines and other biological products).
- PGx and PGt are applicable to activities such as drug discovery, drug development, and clinical practice.
- 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).
- The definitions of PGx and PGt do not include other disciplines such as proteomics and metabalomics.
2.3 Categories for Genomic Data and Samples Coding
PGx and PGt research depends on the use of biological samples to generate data. A harmonised 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, anonymised 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 summarised in Table 1.
2.3.1 IdentifiedData and Samples
Identification numbers (e.g., social security or national insurance number) or personal identifiers like names are used to label identified data and samples. Since the subject can be directly linked to the samples and related data, actions like sample withdrawal or the return of specific results can be taken at the subject’s request. The addition of additional data from the subject, clinical monitoring, and subject follow-up are all made possible by the utilization of identifying data and samples. Similar to the confidentiality of general healthcare in routine medical practice, identified data and samples provide privacy protection. In general, identified data and samples are not thought to be suitable for use in clinical trials during the course of drug development.
2.3.2 Coded Data and Samples
Coded data and samples are labelled with at least one specific code and do not carry any personal identifiers.
2.3.2.1 Single Coded Data and Samples
Typically, single-coded data and samples are identified by a single, unique code and lack any personal identifiers. With just one coding key, it is feasible to link the data or samples to a specific person. Generally speaking, the coding key must be kept up to date by the clinical investigator. Since the coding key allows for indirect traceability of the samples and related data back to the subject, activities like sample withdrawal or the return of specific results at the subject’s request are feasible. Clinical monitoring, subject follow-up, and the insertion of fresh data from the patient are all made possible by the use of single coded data and samples.The current standard for clinical research is single coding, which provides more protection for the subjects’ identifiers than the usual healthcare confidentiality and privacy protections found in routine medical practice.
2.3.2.2 Double Coded Data and Samples
Double coded data and samples are labeled with a single code without personal identifiers, and then relabelled with a second code linked to the first code via a second coding key. This allows for indirect traceback to the individual, allowing actions like sample withdrawal or individual results return. However, additional electronic or technical processes may limit traceability. Double coded data and samples enable clinical monitoring, subject follow-up, and new data addition, providing additional confidentiality and privacy protection. Access to both coding keys is required.
2.3.3 Anonymised Data and Samples
Anonymised data and samples are initially coded but deleted to prevent subject re-identification. This prevents actions like sample withdrawal or return of results, and does not allow for clinical monitoring or subject follow-up. The deletion of coding keys provides additional confidentiality and privacy protection, preventing subject re-identification through the coding key(s).
2.3.4 Anonymous Data and Samples
Anonymous data and samples lack personal identifiers and coding keys, making it impossible to trace genomic data to individual subjects. Limited clinical data can be associated with anonymous samples, and actions like sample withdrawal or results return are not possible.
2.3.5 Additional Information
This guideline is not intended to address the use of a particular coding category in connection with gaining subjects’ informed permission.
Research-related documentation, such as the informed consent document, should outline the circumstances in which the genetic data can be connected to a subject’s personal identifiers for any reason, including returning the genomic data to the subject.
Reference:
https://database.ich.org/sites/default/files/E15_Guideline.pdf
Dr Subramanian S Iyer
