What to Consider while Writing Patient Safety Narratives
Patient safety narratives (PSNs) are an important component of the clinical study reports (CSRs). These narratives contain clear and concise descriptions of adverse events (AEs), serious adverse events (SAEs), or an event of specific interest encountered by participants in a clinical trial. As per the Food and Drug Administration’s (FDA) guidance for the format and content of the clinical data section of an application, ‘for all deaths and all potentially serious adverse experiences, there should be a brief narrative describing each event and assessing the likelihood that the drug was responsible.’1
A patient narrative is written for each patient who experiences at least one of the qualifying events as per the criteria defined or agreed upon with the regulatory authority. The PSNs should be written for all phases of a clinical trial (Phase I-IV) for all therapeutic areas and submitted to the regulatory authorities under the US FDA along with the CSR.
Understanding the Purpose of Patient Safety Narratives
The primary purpose of the PSN is to provide a summary of each AE, SAE, discontinuation from the study, and death and to determine whether an interventional drug is associated with an event of specific interest that occurs in patients. Besides, according to International Conference on Harmonization (ICH) E3 guideline, a PSN serves a vital role in CSR, and the main purpose is to describe the following:2
- The nature and intensity of the event
- The clinical course leading up to the event (providing a time reference for the administration of the test substance or investigational product)
- Relevant laboratory measurements
- Whether the drug was stopped and when
- Post mortem findings
- Investigator’s opinion on causality
- Sponsor’s opinion on causality
Why are Patient Safety Narratives important?
A PSN provides a detailed and therapeutically relevant sequential outline of an event that occurred during or immediately after a clinical study, which plays a crucial role during regulatory submission. There are several reasons why a PSN is important, a few of which are outlined below:3
- Thorough identification and examination of AEs and SAEs that require further observation
- Monitoring the frequency and severity of an unexpected AE during the study procedures
- Evaluating the significance and suitability of data supporting safety analysis
- Determination of the drug’s limitations on the basis of data
- To discover and anticipate the factors that influence the occurrence of adverse drug reactions, including factors related to patients (age, sex, ethnicity, metabolic status, plasma concentration, duration of exposure, etc.)
- Analyzing drug-drug interactions, if applicable.
Tips for Writing Patient Safety Narratives
Writing PSNs requires a careful and systematic approach to ensure accurate and comprehensive reporting of AEs, SAEs, deaths, and other events of special interest. Usually, there are two ways of generating PSNs: manually or automated.
PSNs are normally produced manually by medical writers (if there are <150 PSNs); however if the narratives in a clinical study are more than that, it might be exhausting and challenging. But in the current modern era of the healthcare industry, automation in narrative writing is the latest efficient and convenient trend being utilized by the pharmaceutical industries to generate large qualitative batches of PSNs within a short time. These tools, which help in the generation of automated PSNs, extract and compile relevant data for all applicable patients in a specified template. Such tools are extremely useful for clinical studies with high numbers of narratives (often >150). The following points are key features of such an automated narrative:3
- Consistency in the representation of data
- Qualitative output with minimal or no errors
- Reduced time for the generation of narratives
- Generation of tables and bar graphs
- Audit trail at each stage
- Generation of preformatted and customizable narratives, allowing flexibility in modifying them as needed
In the following subsections, we will briefly discuss various tips and tricks for writing PSNs in order to deliver high-quality output.
Adhering to Regulatory Requirements
- While writing PSN, a medical writer has to keep various factors in mind while compiling with the regulatory requirements. Noncompliance by the writer can have a significant impact on the CSR submission process since the concerned regulatory authority can reject it. Hence, adhering to and complying with the regulatory requirements is essential.
ICH E3 guideline2:
‘There should be brief narratives describing each death, each other serious adverse event, and those of the other significant adverse events that are judged to be of special interest because of clinical importance. These narratives can be placed either in the text of the report or in section 14.3.3, depending on their number.’
21 CFR 312.32(c)(1)(v)4:
‘The sponsor must submit each IND safety report in a narrative format or on FDA Form 3500A or in an electronic format that FDA can process, review, and archive… Reports of overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies must be submitted in a narrative format.’
US FDA for safety reporting requirements 5:
As per the US FDA’s guidance for industry for safety reporting requirements for INDs and BA/BE studies, the IND safety reports for individual cases, aggregate reports, and all other reports should be submitted in a narrative format (as explained in the above point of CFR).
Utilizing Standardized Medical Terminology
Using standardized medical terminologies in clinical research has improved patient data documentation and interpretation with regulatory bodies. It makes no difference where the study was done or what language the data was collected in; adopting standardized terminologies allows for uniform and accurate reporting and interpretation of the clinical data. In PSNs, following standardized terminologies can be used:
- MedDRA: The medical conditions and AEs/SAEs are interpreted as per the Medical Dictionary for Regulatory Activities (MedDRA). It is an internationally used set of terms created to assist regulators, pharmaceutical companies, clinical research organizations, and healthcare professionals with sharing clinical information.6
- WHODrug Dictionary: The prior or concomitant medications utilized by the patient are reported as per the WHODrug Dictionary in PSNs. It is a comprehensive dictionary that serves as a standardized reference for classifying and naming medicinal products used in clinical trials globally.7
- CTCAE: In case of addressing the severity of an AE, the Common Terminology Criteria for Adverse Events (CTCAE) grading should be utilized. According to this, ‘Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE; Grade 2 Moderate AE; Grade 3 Severe or medically significant but not immediately life-threatening AE; Grade 4 Life-threatening consequences; Grade 5 Death related to AE.’8
Inclusion of Essential Components
A complete PSN has several essential components that should be carefully included while writing. As per ICH E3 guideline, these factors include ‘patient identifier; age and sex of the patient, general clinical condition of patient (if appropriate); disease being treated with duration of illness; relevant concomitant/ previous illnesses with details of occurrence/duration; relevant concomitant/previous medication with details of dosage; test drug/investigational product administered, drug dose, if this varied among patients, and length of time administered.’2
The data which is included in the PSNs is extracted from the Council for International Organizations of Medical Sciences (CIOMS) forms, MedWatch Forms, Study Data Tabulation Model (SDTM) or Analysis Dataset Model (ADaM) datasets, Tables, Listings, and Figures (TLFs) of the study, Case report Forms (CRFs), and Adverse Event of Special Interest (AESI) forms.
Presenting Information Chronologically
The patient information in the narratives should be chronologically outlined as it occurred throughout the clinical study. It means that the narrative should be written in a streamlined and consistent structure, which should be determined before writing the PSN.
A predetermined template, including all of the components of a PSN in chronological order, should be created, and the writers should write the PSNs based on that finalized template. The PSNs should be written in a consistent way. The chronological representation of the information also helps in making the review process easier and more efficient for the reviewer.
In addition, maintaining clarity and objectivity in PSNs is essential for ensuring that the information presented is accurate, unbiased, and easy to understand. It is crucial to provide only the relevant information related to the patient without any speculations or personal opinions to avoid biases.
Providing Supporting Evidence
While writing the PSN of a clinical study report, it is essential to provide supporting evidence for the reported safety data. Supporting evidence strengthens the credibility of the safety findings and helps regulatory authorities assess the reliability and validity of the results. This supporting information (such as patient baseline characteristics) can be provided or added in tables and figures. However, it is also necessary to refer to the source of that evidence, including the data sources (TLFs, CIOMS and AESI forms, and clinical databases, if appropriate).
Review and Quality Control
The internal review and quality control of PSN is an important step to assure accuracy, consistency, and regulatory compliance before sharing the final PSNs with the study sponsors. The following points represent the steps and considerations for conducting a thorough review and quality control:
- Cross-check the information with the source data
- Adherence to the regulatory guidelines
- Consistent language and formatting
- Grammar and writing style
- Use of standardized terminologies
- Adverse event severity grading
- Supporting data presentation
Moreover, a quality control checklist should be prepared, with each point listed individually with a checkbox on the left or right side. It will be helpful while performing a final review of the narratives, ensuring that every point has been reviewed.
The PSNs are important documentation in regulatory submissions through CSRs. This blog emphasizes how to adopt best practices to ensure that PSNs are of high quality and submitted on time to regulatory authorities. Furthermore, it is critical to follow regulatory standards while writing or automating the narratives using specified templates. In addition, review and quality control of the PSNs are crucial to ensuring accuracy and compliance at each step before submission.
- US Food and Drug Administration. Format and content of the clinical and statistical sections of an application. fda.gov. Published August 24, 2018. Accessed July 29, 2023.
- International conference on harmonization. Structure and content of clinical study reports. ich.org. Published November 30, 1995. Accessed July 29, 2023.
- Ledade SD, Jain SN, Dari AA, Gupta VH. Narrative writing: Effective ways and best practices. Perspect Clin Res. 2017 Apr-Jun;8(2):58-62. doi: 10.4103/2229-3485.203044
- Code of federal regulations. 21 CFR Part 312—Investigational New Drug Application. ecfr.gov. Accessed August 02, 2023.
- US Food and Drug Administration. Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies. Published December, 2012. Accessed August 02, 2023.
- Medical Dictionary for Regulatory Activities (MedDRA). Welcome to the ICH MedDRA website. meddra.org. Accessed July 29, 2023.
- WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2023. whocc.no. Accessed July 29, 2023.
- National Institute of Health. Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Published November 27, 2017. Accessed July 31, 2023.