E16
1 INTRODUCTION
1.1 Background
Biomarkers can be used to guide dose selection, improve the benefit-risk balance, and make safer and more effective pharmaceutical or biotechnology treatments more readily available. Previous experiences with submissions comprising biomarker data in the various regions served as the basis for this recommendation. These submissions have either been part of regulatory process marketing applications (NDAs, BLAs, and MAAs) related to medicinal products or stand-alone biomarker qualifying applications. The creation of a uniform framework for biomarker data input will make it simpler to examine and share evaluations across regions.
1.2 Objectives
The guideline outlines recommendations for the context, structure, and format of regulatory submissions for the qualification of genomic biomarkers, as defined in ICH E151. Biomarker qualification establishes that assessment results can reliably reflect biological processes and support drug development. Applications can be submitted to regulatory authorities when biomarkers aid in decision-making. The guideline aims to harmonize the structure of biomarker qualification applications to ensure consistency across regions, easing the burden on sponsors and facilitating discussions with regulatory bodies. It includes guidance for incorporating biomarker qualification data into the Common Technical Document (CTD) format for marketing authorization applications, applicable during any phase of drug development.
1.3 Scope
The guideline outlines the context, structure, and format for qualification submissions of genomic biomarkers relevant to drug or biotechnology product development, including translational medicine, pharmacokinetics, pharmacodynamics, and safety. It addresses submissions for single or multiple genomic biomarkers while noting that the principles apply to various biomarker categories, including non-genomic types, and allows for their combination. The term “biomarker” will be used generically throughout the document.
The guideline also covers the submission of data relevant to the validation of new analytical approaches to improve the evaluation of current biomarkers. This guideline does not address either the qualification process or the evidentiary standards for a biomarker to be qualified by regulatory authorities.
1.4 General Principles
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, or 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 analysing the biomarker in question. Reference to standards and / or accepted methods used should be described as applicable.
The dossier structure described in this guideline 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.
Document (eCTD) format should also consult the ICH M2 guideline (Electronic Standards for Transmission of Regulatory Information) and other relevant guidelines, as well as national and regional laws, regulations, and recommendations.Each section of the submission aligns with CTD sections:ICH E-16 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; Section 4 (Nonclinical Study Reports) corresponds to Module 4; and Section 5 (Clinical Study Reports) corresponds to Module 5.
To integrate biomarkers in drug or biotechnology development, it is recommended that qualification submissions be made simultaneously to relevant regulatory authorities. If a biomarker is already qualified, data generated in that context does not need resubmission for re-qualification in an NDA/BLA/MAA; instead, a copy of the authority’s assessment report should be included in the relevant regulatory submission.
2. STRUCTURE OF BIOMARKER QUALIFICATION SUBMISSIONS
The biomarker qualification submission should include the following sections:
Section 1: Regional Administrative Information
Section 2: Summaries
• Biomarker Qualification Overview
An introduction, a high-level explanation of the data, an integrated critical evaluation of the data and techniques, the need for further data from existing or prospective investigations, and a rationale for the proposed context of use are all included.
• Overall Summaries of the following (if appropriate):
oAnalytical Assay Data
o Nonclinical Biomarker Data
o Clinical Biomarker Data
The contents of Section 2 should be converted into chapters in the relevant CTD Module 2, such as Overview(s) and/or Overall Summary(ies), if they are included in an NDA, BL, or MAA.
Section 3: Quality Reports
• Structural, manufacturing and quality characteristics of investigational drug(s) for the biomarker qualification studies (as applicable)
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 reports
• Analytical assay validation reports
• Nonclinical study reports (in vitro)
• Nonclinical study reports (in vivo, specify species)
Section 5: Clinical Reports
•Analytical Assay development reports
•Analytical assay validation reports
• Clinical pharmacology study reports
• Clinical efficacy and / or safety study reports
Below is a more detailed explanation of the suggested material for these sections.
2.1 Section 1: Regional Administrative Information
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.
2.2 Section 2: Summaries
Biomarker qualification submissions should include a Biomarker Overview to discuss and analyze the advantages and disadvantages of the supplied data, similar to the CTD structure. It should be backed up by distinct technical, preclinical, and clinical data summaries that provide a thorough factual summary of the study data in text, tables, and figures.
2.2.1 Biomarker Qualification Overview
2.2.1.1 Introduction
This section emphasizes the need for a concise description of the disease and experimental setting, a definition of the biomarker (including its type, such as SNP, CNV, or differential gene expression signature), and a rationale for the biomarker’s application in drug or biotechnology product development, spanning from discovery to post-approval.
It should summarize the key characteristics of the biomarker, including:
o strengths and limitations (e.g., comparison with relevant standard methods where available, presence / absence of information on pertinent species / population);
o 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;
o objective and design of the studies supporting its use, such as prospective versus retrospective study design, study comparators and sample size.
This section should include an overview of the suggested biomarker use setting. The following section should provide more information, including the complete context of biomarker use.
2.2.1.2 Context of Use
The elements describing the context of use for a biomarker should include (i) the general area, (ii) the specific biomarker use, and (iii) the critical parameters which 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 following taxonomy can be employed to describe the context of use (see examples below):
General Area (including, but not limited to):
Nonclinical / Clinical
• Pharmacology
• Toxicology
• Efficacy
• Safety
• Disease
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
The entire text of E16 could not be presented in this article due to space constraints. To properly grasp this Guideline on Biomarkers(E16), it is advised that you read the entire guideline. The link is provided below.
Reference:
https://database.ich.org/sites/default/files/E16_Guideline.pdf
–Dr Subramanian S Iyer
