Managing Drug Safety in the EU: From Clinical Development to Marketing Authorisation Submission
in collaboration with…
Scendea Authors:
Dr Maria Beatrice Panico
Head of Clinical & Principal Consultant
Ellen Wilkinson
Senior Consultant
Signal Pharma Experts Authors:
Catherine Kenny
Managing Partner, Co-Founder
Carly Gould
Managing Partner, Co-Founder
Introduction
Patient safety is at the centre of drug development and monitoring the safety profile of a drug from the first patient dose through to market and beyond is a key activity for all drug developers.
In this paper we summarise the key regulatory documents where safety is addressed during clinical development, plus the European Union (EU) regulatory requirements for safety reporting. We will also explore considerations for patient safety monitoring whilst preparing for marketing authorisation in the EU.
Key regulatory documents addressing safety during development
The Protocol
The European Medicines Agency (EMA) Guideline for Good Clinical Practice (GCP) E6(R2) describes the responsibilities of all those involved in the conduct of a clinical study to ensure the protection of trial subjects, and compliance with the principles of the Declaration of Helsinki (European Medicines Agency, 2016) (World Medical Association, 2013). The guidance includes considerations for the assessment of patient safety and the benefit-risk profile throughout clinical development. In particular, it provides detailed information on the content and format of the clinical protocol and Investigator’s Brochure (IB).
Subject safety is carefully considered throughout a clinical trial protocol, from ensuring robust dose justification [particularly when moving from nonclinical studies to first in human (FIH) trial], to selecting appropriate eligibility criteria and implementing an adequate safety monitoring plan throughout study conduct. When authoring a clinical study protocol for studies conducted in International Council for Harmonisation (ICH) regions, Scendea recommends that Sponsors consider the ICH M11 Clinical Electronic Structured Harmonised Protocol Template which provides a comprehensive overview of the standardised content required across all ICH regions (European Medicines Agency, 2022a).
When developing a protocol, Sponsors should include a description and schedule of the safety assessments and procedures to be undertaken during the study including, but not limited to, physical examinations, vital signs, electrocardiograms, clinical laboratory assessments and, if deemed appropriate, behavioural risk monitoring. Additionally, the Sponsor’s plan for management of adverse events (AEs), serious AEs (SAEs), AEs of special interest (AESI) and Suspected Unexpected Serious Adverse Reactions (SUSARs) should be documented.
This will include the definitions of such events, the periodicity and methods for collection, identification, recording, reporting and follow-up of these AEs. Sponsors should also consider how they plan to analyse safety data throughout trial conduct and include this information in the statistical analysis section.
The developing safety profile of a study drug should continue to be reviewed throughout the conduct of a clinical trial. When planning a clinical trial, the Sponsor should consider whether it would be appropriate to appoint a Data Monitoring Committee (DMC). DMCs, also known as Data Safety Monitoring Committees (DSMCs), consist of independent experts tasked with periodic review of newly available safety data in order to provide recommendations on study modification, continuation or termination. For example, in long-term trials in life-threatening indications, paediatric populations or in trials with high risk investigational medicinal products or requiring interim analyses, a DMC could be beneficial or indicated due to ethical considerations. If a DMC is appointed the Sponsor should include in the protocol or in a DMC charter a description of the responsibilities of the committee, the timing of the meetings and which data is to be evaluated.
It is the responsibility of the Sponsor to keep the protocol up to date throughout the clinical trial. If the Sponsor wants to introduce modifications that will have a substantial impact on the safety or rights of subjects and/or the reliability and robustness of the data generated, permission to implement these changes should be sought from the relevant regulatory authorities.
The Investigator’s Brochure (IB)
As previously mentioned the EMA Guideline for GCP E6(R2) also provides detailed guidance on the content and format of the IB (European Medicines Agency, 2016). The IB summarises all available clinical and nonclinical data pertaining to an investigational product. The document provides investigators and regulators with an overview of the developing safety profile of a medicinal product and supports the assessment of the benefit-risk balance of a proposed clinical trial. The IB should be reviewed annually and updated as risks evolve, and any significant changes to the document should be submitted to the relevant regulatory authority as a substantial modification.
The IB also contains the reference safety information (RSI) for the product under clinical development which is used to determine the expectedness of serious adverse reactions (SARs) within a clinical trial. The RSI is contained within a stand-alone section of the IB. The RSI, for example, can be included as a subsection under the ‘Summary of Data and Guidance for the Investigator’ section, and should be clearly named as ‘Reference safety information for assessment of expectedness of serious adverse reactions’ in line with the European Commission Questions and Answers document (EU Commission, 2023).
The RSI section should contain a tabular list of expected SARs, classified by the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. Any SAE which is considered related to the investigational product and is not listed in the RSI must be classified as a SUSAR and reported to the relevant EU and European Economic Area (EEA) authorities.
Overall, the IB plays an important role in the ongoing benefit-risk analysis of a medicinal product and is a crucial document for Sponsors, Investigators and Regulators.
The Development Safety Update Report (DSUR)
Sponsors are required to submit a comprehensive annual report updating regulators on the clinical development of an investigational drug and the pertinent safety-related information collected or published during the annual reporting period. The information is collated into the Development Safety Update Report (DSUR). The DSUR serves as an important document in assessing the evolving benefit-risk profile of an investigational drug and allows regulators to appraise if safety actions have been adequately undertaken to address concerns and newly identified risks. The annual reporting period of the DSUR is determined by the “Development International Birth Date” (DIBD) which is the date of the Sponsor’s first authorisation to conduct a clinical trial with the investigational product worldwide. The DSUR is product-, or in some cases, trial-specific and contains information collected for ongoing clinical trials up to the data lock point (DLP): the last date of the annual reporting period. The RSI that received regulatory approval at the start of the reporting period [either a section of the IB or Section 4.8 of the SmPC (Summary of Product Characteristics) where applicable] will be used for the purpose of writing the DSUR.
It is the Sponsor’s responsibility to prepare and submit the DSUR, but the preparation can be delegated to a third party such as a regulatory consultancy like Scendea, pharmacovigilance consultancy such as Signal Pharma Experts or contract research organisation (CRO). The content and format of the DSUR in the EU conforms to common standards set in the International Conference on Harmonisation (ICH) E2F Guideline (European Medicines Agency, 2011).
The format of the DSUR should contain a summary of:
Worldwide marketing approval status.
Actions taken during the reporting period for safety reasons.
Changes to reference safety information.
Inventory of clinical trials ongoing and completed during the reporting period.
Estimated cumulative exposure and data in line listings/summary tabulations of SAEs/SUSARs.
Significant findings from clinical trials, non-interventional studies and marketing experience during the reporting period.
Nonclinical data, literature and other DSURs.
Information indicating lack of efficacy.
Region-specific information.
Late-breaking information after the data lock point.
Overall safety assessment, evaluation of the risks and benefit-risk considerations.
Similar region-specific information is required by EU Member States, the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA) and Health Canada. In 2021, the UK MHRA and Health Canada published a guidance aiming to improve the safety of patients in clinical trials. Sponsors are required to describe how each safety signal identified during the reporting period was evaluated and the decision process behind closure of the signal or keeping it open for additional surveillance (MHRA and Health Canada, 2021). Sponsors should consider this guideline and include the relevant information when authoring their annual reports.
Similar requirements are also described in the Questions and Answers to the Clinical Trial Regulation (EU) NO 536/2014 as additional ‘Region-Specific Information’ required in the Annual Safety Report in the EU/EEA (see question 7.44) (EU Commission, 2023).
In the EU, DSURs should be submitted via the Clinical Trial Information System (CTIS) under the EU Clinical Trial Regulation (EU CTR).
Regulatory Requirements for Safety Reporting in Clinical Trials:
From The First Dose
So far we have explored some of the key regulatory documents in which patient safety is considered when designing and managing a clinical trial. From the first administration of an investigational drug to study subjects, ensuring adverse reactions are effectively monitored and reported to regulatory authorities and that urgent actions are implemented quickly where required are crucial components of clinical development.
On 31 January 2022, the EU CTR was launched, aiming to harmonise the process for assessment and management of clinical trials throughout the EU. The CTR repealed the previous Clinical Trial Directive (CTD) and since 31 January 2023 all new initial clinical trial authorisation (CTA) applications have been submitted through CTIS. From 31 January 2025, all ongoing trials with at least one active site, which were previously approved under the CTD, will need to comply with the CTR.
There are several safety reporting requirements that Sponsors need to comply with under the CTR and these are summarised in Table 1.
Table 1. Safety reporting requirements under the Clinical Trials Regulation (CTR)
Adapted from (European Medicines Agency, 2022b)
The CTR aims to simplify safety reporting in the EU by allowing a single safety report to be submitted for clinical studies involving more than one investigational drug. Sponsors should ensure they are familiar with the updates introduced in the new regulation and that new and ongoing trials comply with the transition.
Overall, the introduction of the Regulation marks an important milestone in the harmonisation of clinical trials throughout EU and EEA countries and ensures the simplified submission of safety reports by Sponsors throughout clinical development, to protect the safety of all participants in EU clinical trials.
The Risk Management Plan
Preparation for Marketing Authorisation and Post-Marketing Pharmacovigilance
The Risk Management Plan (RMP) outlines how a company will identify, assess, minimise, and communicate the risks associated with a medicinal product throughout its lifecycle. In the EU, companies must submit an RMP to the EMA at the time of application for a marketing authorisation (MA). For medicines that do not have an RMP (i.e. approval was granted before the requirement to submit an RMP was mandatory), an RMP may be required with any application involving a significant change to the MA.
In addition, for nationally authorised medicinal products, any national competent authority (NCA) in the EU can request an RMP whenever there is a concern about a risk affecting the benefit-risk balance of a medicine. The requirements are spelled out in the Good Pharmacovigilance Practices (GVP) Module V – Risk Management Systems (EU) and ICH E2E – Pharmacovigilance planning (global) (European Medicines Agency, 2006, 2017).
Early in the clinical development process, some companies may choose to create a developmental Risk Management Plan (dRMP). This document is a live document that is amended according to the evolution of the safety profile throughout clinical development. The dRMP becomes the basis for the RMP that will be submitted at the Marketing Authorisation application (MAA) stage. If a dRMP has not been developed, the RMP will be drafted at the time of the MAA.
Creating an RMP is a crucial part of the pharmaceutical development process. It is a multidisciplinary process that involves regulatory, clinical development and pharmacovigilance (PV) experts [under the guidance of the Qualified Person for Pharmacovigilance (QPPV)] as well as statisticians. Additionally, conversations with Regulators (pre-submission advice meetings, etc.) may occur to solicit feedback on the proposed risk mitigation measures.
RMP Content
As specified in EU-RMP template, there are three main components of the RMP:
The Safety Specification - identification or characterisation of the safety profile of the medicinal product, concluding with the list of safety concerns to be managed or further studied.
The Pharmacovigilance Plan - the planning of PV activities to characterise and quantify clinically relevant risks, and to identify new adverse reactions.
The Risk Minimisation Plan - the planning and implementation of risk minimisation measures, including the evaluation of the effectiveness of these activities.
What are The Main Documents Needed to Compile a Comprehensive RMP?
Note: the availability of these documents depends on provision/ development by other departments/subject matter experts. Some of these documents may be provided in draft early in the process, whereas other documents (e.g. SmPC) may not be available until much later in the RMP drafting process (close to MAA submission time).
Risk Management Plan (RMP) Template:
The EMA publishes a template and guidance on how to populate the template.
Relevant sections of the template should be populated based upon the legal-basis for the application – some modules are not required for a well-established use application, for example.Summary of Product Characteristics (SmPC) or other labelling information (e.g. labels from other territories if product approved in other jurisdictions):
The SmPC is an essential element of the RMP preparation. The labelling messages around risks serve as routine risk minimisation measures. The document provides comprehensive information about the medicinal product, including indications, dosage, contraindications, and safety information. It is important that the drafting of the SmPC is done in parallel with the description of the risk profile that is presented in the RMP.
Common Technical Document (CTD) Modules including Clinical Overview, Nonclinical Overview and Study Reports:
These are documents prepared to support the MAA and summarise key nonclinical and clinical data. The study reports provide an overview of pivotal trial data that forms part of the application. All of this information feeds into the development of the risk profile that is presented in the RMP.Investigator Brochure (IB):
The IB feeds into the development of the SmPC/ labelling and also acts as the basis of the safety profile/ risk profile that is described in the RMP.
Developmental Safety Update Reports (DSURs):
DSURs including information for clinical trials that are completed/ may still be ongoing.
Post-marketing sales data, post-marketing safety reports (e.g. PSURs), worldwide MA status:
If an RMP is being prepared for a product that is approved in other territories/ for other indications then sales data, post-marketing safety reports and an overview of where the product is approved is needed to contextualise the safety data being presented in the RMP.
Post-Authorisation Commitments
Post-authorisation commitments may be mandated at approval of an MA.
The necessity to take additional measures to manage risks associated with a medicinal product may emerge during the product development or during the MAA review. These additional measures should be included in the RMP at the time of submission or after request from NCAs during MAA assessment. The specific post-authorisation commitments associated with the RMP vary depending on the nature of the medicinal product and the summary of safety concerns. The additional activities should detail the information to be collected and how that information will enhance the understanding of the risk-benefit balance.
Post-approval commitments associated with RMPs often include the following:
Educational programmes and communications: These are targeted communications aimed at supplementing the product information. The materials should positively influence the use of the medicine by healthcare professionals and patients. Examples include patient reminder cards and Direct Healthcare Professional Communications (DHPC).
Post-approval organised data collection programmes: These are conducted to further assess safety aspects of the medicinal product after the product has been approved and is available on the market. Examples include Post-Authorisation Safety Studies (PASS), interventional or non-interventional studies, drug utilisation studies, analysis of real-world data and pregnancy prevention programmes.
Controlled access programs: These are designed to ensure that the risks associated with a medicinal product are managed by exposing the appropriate patient population to the product itself. An example is access granted via a patient registry.
All additional measures should be proportional to the risks and have demonstrable impact. They require approval by the Regulatory Authorities prior to dissemination or initiation.
A key consideration when determining the required additional risk management measures is the mechanism to measure their effectiveness. This will be assessed and presented at regular intervals during the post-approval product lifecycle via interim and final study reports, aggregate reports such as the Periodic Benefit-Risk Evaluation Reports (PBRERs), and during signal detection activities as part of the RMP review.
RMP Evolution
As mentioned previously, the RMP is a dynamic document that evolves over time. The RMP should be updated as the safety profile of the product is further characterised and actions are completed:
Addition of safety concerns where required – e.g. further to signal detection activities
Reclassification of safety concerns – e.g. reclassifying a potential risk as an identified risk
Removal of safety concerns as information is received
Addition of study results – ongoing clinical trials/ study data can be added to the RMP as/ when the information is available. This information may have an impact on the classification of safety concerns and amendments may be required based upon the results
Completion and removal of additional PV actions – this step can be completed as/ when PV actions are completed (e.g. completion of a PASS)
Update/ modification of RM activities
Significant change to an existing MA e.g., new indication/ route/ dosage form
The MA Holder (as owner) and the QPPV (as approver) are responsible for ensuring that processes are in place to identify new PV data which may impact the RMP, for ensuring the RMP is maintained and that any actions are implemented.
RMP Lifecycle
Conclusions
Throughout clinical development Sponsors are expected to author and maintain a number of key regulatory documents that provide an overview of the safety profile of the medicinal product such as the IB, trial protocol and DSURs. Additionally, trial Sponsors are required to comply with safety reporting requirements to ensure that adverse events are documented, assessed and acted upon, as necessary, in order to protect the safety of trial participants.
Patient safety also needs to be addressed when applying for marketing authorisation, and the RMP provides regulators with an outline of how a company will manage the risks associated with a medicinal product throughout its lifecycle. These documents must be kept up to date in order to allow Sponsors and regulators to take appropriate decisions regarding patient safety.
References
EU Commission (2023) CLINICAL TRIALS REGULATION (EU) NO 536/2014 Q and A document. (Version 6.6). https://health.ec.europa.eu/system/files/2023-09/regulation5362014_qa_en.pdf.
European Medicines Agency (2006) E2E Pharmacovigilance Planning (Pvp).
European Medicines Agency (2016) Guideline for good clinical practice E6(R2). https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-good-clinical-practice-e6r2-step-5_en.pdf.
European Medicines Agency (2017) Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems (Rev 2).
European Medicines Agency (2011) ICH guideline E2F on development safety update report. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-e2f-development-safety-update-report-step-5_en.pdf.
European Medicines Agency (2022a) International Conference on Harmonisation (ICH) M11 Clinical Electronic Structured Harmonised Protocol Template. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-m11-template-step-2b_en.pdf.
European Medicines Agency (2022b) Reporting safety information on clinical trials. 2022. European Medicines Agency. https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials/reporting-safety-information-clinical-trials [Accessed: 18 November 2023].
MHRA and Health Canada (2021) Guideline on how to increase transparency when presenting safety information in the Development Safety Update Report (DSUR): region-specific requirements for Canada and the United Kingdom. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/993808/DSUR-Guideline-08June2021.pdf.
World Medical Association (2013) World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA. 310 (20), 2191–2194. doi:10.1001/jama.2013.281053.
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