Imagine a pharmaceutical company about to launch a new drug. Clinical trials have shown promising results, but the real test lies in how this drug will perform in the hands of thousands—or even millions—of patients in the real world. Will it be as effective? Will unexpected safety issues arise? The answers to these questions often lie in pharmaco-epidemiological studies where real-world data (RWD) is analyzed to assess the safety of medicines. This blog covers key aspects for sponsors to consider when designing effective pharmaco-epidemiological studies with ICHs M14.
Facilitating global harmonization with ICHs M14
Each regulatory agency across different countries asks the company to conduct separate studies, each with its own set of rules and methods. The result? Duplicated efforts, delayed access to vital medicines, and millions in wasted resources. The International Council for Harmonisation (ICH) developed the M14 guideline as a solution—designed to bring harmony to the way pharmaco-epidemiological studies are conducted globally.
ICHs M14 was released as a Step 2 document for public consultation in May 2024. The document aims to harmonize approaches across regulatory jurisdictions, ensuring that studies meet high standards of reliability, relevance, and transparency. Through this new guideline, ICH aims to streamline the design and conduct of these studies, ensuring that robust, reliable evidence is generated using RWD that can answer critical safety questions across borders. With ICH M14, pharmaceutical companies can focus on what truly matters: generating high-quality data to ensure medicines are safe, while avoiding unnecessary duplication of efforts.
Principles of ICHs M14
The ICH’s M14 guideline, “General Principles on Plan, Design and Analysis of Pharmaco-epidemiological Studies That Utilize Real-World Data for Safety Assessment of Medicines” is built around creating high-quality, fit-for-purpose pharmaco-epidemiological studies that answer specific regulatory safety questions. The focus is on non-interventional observational studies, encompassing drugs, vaccines, and biological products, and ensuring the use of robust real-world data (RWD). The guideline emphasizes an iterative process for study design, addressing study limitations and ensuring that the evidence generated can adequately support regulatory decision-making.
Key principles of the ICHs M14 guideline include:
- Defining a clear research question that guides the study’s purpose and hypotheses.
- Establishing a reliable study population, exposures, outcomes, and covariates with an emphasis on representativeness and minimizing bias.
- Selection of an appropriate data source tailored to the study’s needs, ensuring that RWD is relevant and fit-for-purpose.
Framework for Generating Evidence with Real-World Data
ICH M14 introduces a structured framework for generating adequate evidence using RWD, focusing on addressing safety-related regulatory questions. The guideline acknowledges that the success of these studies heavily relies on the quality of the data and the methodological soundness applied in the study’s design and analysis.
The process begins with formulating a precise research question and conducting feasibility assessments to ensure that the selected data source is appropriate for the study’s scope. This process helps to verify that the data captures the necessary population with adequate follow-up and statistical precision to provide meaningful insights.
Initial Design and Feasibility Assessments
The design phase under ICHs M14 starts with formulating a concise research question that addresses the study’s objectives. Feasibility assessments are crucial to identify suitable data sources and determine the statistical precision of the study. This involves an iterative process of narrowing down data sources to ensure that the appropriate population is captured with adequate follow-up, and sufficient data is available to support study conclusions.
Should secondary data sources fail to meet the study’s needs, primary data collection is considered a viable alternative. The feasibility assessments, particularly regarding the availability and completeness of key data, inform subsequent design decisions, ensuring that the chosen approach aligns with regulatory requirements.
Protocol Development
The ICHs M14 outlines a detailed approach to protocol development, involving a multidisciplinary team to ensure the study’s rigor. The protocol must include:
- Study design selection, such as cohort or case-control studies.
- Comparator population identification, which is essential for generating valid comparisons.
- Defining exposures, outcomes, and covariates with clear operational definitions to ensure the extraction of complete and accurate data from RWD.
A critical part of protocol development under M14 involves identifying potential sources of bias, such as selection bias or confounding variables. Plans to control or mitigate these biases must be embedded in the study design, with ongoing evaluations to ensure these controls are effective.
Data Management and Quality Assurance
ICH M14 emphasizes robust data management and quality control. Before study initiation, management plans should be in place to ensure data integrity, transparency, and consistency between researchers and data holders. This is crucial for maintaining the reliability of analytic datasets used in regulatory submissions. Data holders and researchers must collaborate closely to align data strengths, limitations, and the necessary quality standards for regulatory acceptance.
Analysis Strategy
A thorough analytic strategy is a cornerstone of the M14 guideline. The analysis must be pre-specified, including both descriptive and inferential approaches that address the study’s objectives. Key considerations for analysis include:
- Controlling for bias and confounding through robust statistical methods.
- Subgroup and sensitivity analyses to test the robustness of findings.
- Handling of missing data and evaluating the representativeness of the study population.
The use of quantitative bias analysis is encouraged to help interpret study results and assess their validity.
Reporting and Submission Requirements
Adverse events and drug reactions identified in the study must be reported to regulatory authorities, with specific submission requirements varying across regions. The M14 guideline refers to researchers other ICH guidelines, such as ICH E2D, for guidance on post-approval safety data management.
ICH M14 encourages researchers to use existing frameworks like ISPE/ISPOR’s HARPER (Harmonized Protocol Template to Enhance Reproducibility) when preparing study documents for submission to regulatory bodies.
Communication and Dissemination
The guideline encourages making study materials publicly available, such as through public registers, to promote scientific exchange and increase reproducibility. This includes making protocols and statistical analysis plans available before study initiation and ensuring study results are communicated clearly to participants and the public, even when results are negative or inconclusive.
Conclusion
The guideline provides a harmonized framework for the design and conduct of pharmaco-epidemiological studies that utilize RWD for safety assessment. By offering clear guidance on key aspects such as study design, data management, and analysis, M14 promotes the generation of high-quality evidence that can support regulatory decision-making across multiple jurisdictions. This harmonization is expected to reduce the need for duplicative studies, improve transparency, and increase the efficiency of regulatory reviews, benefiting both regulators and the pharmaceutical industry.
Don’t let the complexities of regulatory submissions hold you back. Reach out to DDReg today for expert, personalized guidance on your application and to learn more about how we can assist you in harnessing the power of RWD to support your regulatory objectives. Missed out on our last blog? Read more from our experts here: Expediting Access to Cell and Gene Therapy Products