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Reporting Events

Patient safety narratives form an important part of clinical study reporting. They should be prepared for all phases of clinical studies, whether conducted in healthy volunteers, or in patients with a disease or condition.

This article describes current regulatory requirements with regards to safety narratives, a proposed process for their development, and examines ways to simplify the reporting process, thereby reducing time and cost.

Clinical Account

According to the ICH’s E3 Guideline on the structure and content of clinical study reports (CSRs), a CSR should contain brief narratives describing each death, each other serious adverse event (SAE), and all other signifi cant adverse events that are judged to be of special interest due to clinical importance (1).

The guidance indicates that events clearly unrelated to the test drug/investigational product may be omitted or described very briefly. In the interests of transparent reporting, it is suggested that patient safety narratives be prepared for all the criteria detailed above.

A patient safety narrative provides a full and clinically relevant, chronological account of the progression of an event experienced during or immediately following a clinical study. As per the ICH E3 Guideline, a patient safety narrative should describe:
  • The nature, intensity and outcome of the event
  • The clinical course leading to the event
  • An indication of timing relevant to study drug administration
  • Relevant laboratory measures
  • Action taken with the study drug and timing in relation to the event
  • Treatment or intervention
  • Post-mortem findings, if applicable
  • The investigator’s and sponsor’s opinion on causality, if appropriate 
Specifically, narratives should include:
  • Patient identifier
  • Age and sex of patient, and general clinical condition of patient, if appropriate
  • Disease being treated (if this is the same for all patients, such information is not required) with duration of current illness episode
  • Relevant concomitant and previous illnesses, with details of occurrence and duration
  • Relevant concomitant and previous medication, with details of dosage
  • Rest drug administered, including dose, if this varied among patients, and length of time administered
Format and Location

The guidance is less specific with regards to the format and location of patient safety narratives, stating that they can be placed either in the text of the CSR or in Section 14.3.3 (Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events), depending on their number.

Although no cut-off is specified, it is suggested that five or fewer narratives may logically and clearly be reported in text – although this is dependent on several factors including therapeutic area, complexity of reporting, relevant course of events, and flow of information in the CSR. If in doubt, it is recommended that narratives should be prepared as separate documents and compiled in Section 14.3.3 during CSR publishing.

Additional Considerations

It is important to identify the approximate number of patient safety narratives to be prepared early in the planning process. This determines the narrative format and impacts the timing of production; whether it is prior to or following database lock.

If patient safety narratives are written from draft, unclean data prior to database lock, updates are required based on the final, clean data. This approach can consume more time than preparing all narratives after database lock, but is more feasible for projects where a large number are required to be drafted in a short timeframe – for a regulatory submission, for instance.

Information Sources

A medical writer will use various sources of information when preparing patient safety narratives. These include Council for International Organisations of Medical Sciences (CIOMS) forms, case report forms (CRFs), MedWatch forms, data clarification forms and clinical database listings.

Since source data are captured during study conduct and narratives are often prepared prior to database reconciliation and lock, a medical writer is often able to identify data discrepancies between the clinical study database and other sources. As CIOMS forms are updated on an ongoing basis during a clinical study, the writer is well placed to provide feedback to a sponsor, assisting with the data cleaning stage.

Production Process

The narrative production process differs across companies and is dependent, to a small degree, on whether reporting is performed internally or by a CRO. When significant numbers of narratives are required, it is useful to develop a template to define overall structure and content, and obtain approval from all stakeholders, prior to initiation of work. In the template, consideration should be given to a number of factors, such as order of information, sentence structure, date format, relevance of specific medical history and concomitant medications, use of trade or generic names for medications, and whether normal ranges should be included for some or all of laboratory test results.

A comprehensive template that is flexible enough to suit sponsor requirements, while also maintaining internal consistency, is a very effective tool. However, care should be taken to ensure all writers involved in the preparation of the narratives understand the limitations of the template, and feel empowered to deviate from it as the data requires, to ensure transparent reporting.

When producing narratives, it is recommended that the following stages be performed:
  • The preparation of the first draft narrative from patient/subject data by the medical writer
  • A scientific and editorial peer review by the CRO project lead to check the document is accurate, complete, and consistent with requirements and across documents
  • A clinical review of the draft narrative – it is recommended that this be performed by the sponsor or designate, although the CRO can provide this service as necessary
  • A revision by the medical writer, based on the clinical review – if the writer does not agree with clinical review comments (for example, where requested amendments conflict with the evidence, or where changes would introduce inconsistencies between narratives, or review comments are unclear) these should be discussed with the sponsor or designated as appropriate, with the responses being retained on file
  • A quality control (QC) review based on the final patient/subject data – given the often large number of narratives required for individual studies and the small size of each document relative to the CSR, it is recommended that a single QC review be performed towards the end of the process, rather than a QC review of the first draft and final deliverable
  • A further revision by the medical writer, based on the QC review findings. Note that, where significant findings are identified during the QC review, these should be discussed with the sponsor and clinical reviewer as appropriate, and further updates should be checked for consistency and accuracy
  • Approval by the sponsor after a final review
Project Consistency

When preparing a large number of documents for a single purpose, it is essential that consistency is maintained. A large project will require the involvement of several medical writers, and a CRO project lead should be assigned to act as a single point of contact to work closely with the sponsor and other stakeholders. In addition to managing communication and delivery, a CRO project lead should act as a peer reviewer, ensuring consistency of reporting across all narratives, reviewing them as if he/she is part of the sponsor study team.

During a large project, it is not unusual for the scope of work and content of narratives to evolve over time, particularly when they are prepared on an ongoing basis. For example, it may become apparent from events reported during an ongoing study that specific end-points, like liver function test results, are more important than originally considered.

An effective single point of contact will be able to work with the sponsor to ensure the process specifications are adapted quickly, and will disseminate the relevant information to the writing team in a timely manner through meetings and the use of study-specific documents. Where it is necessary to update narratives already prepared and possibly reviewed, this person will again work with the sponsor to identify a solution that integrates updates into the overall narrative development process in the most effective and expeditious way.

Tracking Studies

The majority of Phase 2-4 studies have a large number of patients meeting pre-agreed patient safety narrative criteria. Excellent project management skills are essential for tracking such studies, where a large number of narratives are written by several writers – particularly later in a project where the delivery of new drafts overlaps with the return of clinical review comments and QC checking, and the finalisation of narratives at the end of the process. The importance of careful management should not be underestimated; ensuring accuracy and consistency across a large number of narratives is a challenging and time-consuming task.

Sponsor Review

Whatever the size of the project, it is beneficial to deliver narratives in batches with pre-agreed units/numbers for sponsor review. The batch size will be dependent on the total number of narratives to be prepared, data availability, completion timelines, number of writers working on the project and reviewer availability, and should take into account any ramp-up time required.

Experience shows that it is preferable to deliver a small number of narratives (five to ten, depending on complexity) prepared by one writer, usually the project lead, for sponsor review in the first instance. This allows for fine-tuning of the content, presentation and process, prior to implementing preparation on a larger scale. Restricting the number of people involved early in the process allows for faster resolution of any issues so that a streamlined route can be agreed quickly, minimising confusion when rolled out to the larger team. Duplication of efforts can be kept to a minimum, which is beneficial to all parties. The in-house team can subsequently be trained on the agreed sponsor requirements.

Future Directions

CIOMS Forms
It is becoming more common for sponsors to consider including direct links to CIOMS forms from CSR appendices, instead of including individual narratives – an approach which should be used with caution. CIOMS forms are completed by an investigator in the country in which the study is being conducted – sometimes with English not being his or her first language.

These forms are updated frequently as key information becomes available, which makes data repetitive and unmanageable. One patient may have several CIOMS forms for separate events, which cross-reference one another. A medical writer can spend several hours distilling the most relevant and up-to-date information from such forms in order to prepare a narrative that is succinct, accurate and readable for a single patient. Since the purpose of a patient safety narrative is to present a full and clinically relevant, chronological account of the progression of an event or events, a regulatory reviewer may not take kindly to having to derive a clear account from one or more lengthy CIOMS report(s).

Furthermore, the EMA’s Note for Guidance on the Inclusion of Appendices to Clinical Study Reports in Marketing Authorisation Applications specifies that in Appendix 16.3 of the CSR, CIOMS reports (or equivalent) and CRFs should be available on request (2). Since CIOMS forms should be made available as required and are not mandated, it may be considered less acceptable for them to be linked routinely to the CSR in place of narratives.

Automation of Patient Safety Narrative Preparation

Another development in clinical study reporting is the automation of patient safety narrative preparation using programming and statistical support to prepare output directly from statistical analysis system (SAS) datasets. Several case studies and papers are publicly available which document the benefits of such an approach – this includes increased standardisation, reduced preparation time and less cost.

With time invested at the start of an individual project or programme to define the fields to be presented, the benefits are real, particularly for patient safety narratives for significant non-SAEs that are judged to be of special interest. However, there are some limitations to this approach which should be considered at the outset:

SAEs
Since data relating to SAEs are obtained directly from other sources such as CIOMS forms, routine automation of reporting is generally not practical. However, such narratives can be partially automated with information like demographics, study treatments, event details (onset and resolution dates, severity, relationship to study drug, and so on), prior medications, ongoing medications at event onset, and medications started during an event. Such information is useful to the medical writer and can save a significant amount of time when drafting a narrative.

Timing
As detailed above, the timing of narrative preparation is a key decision at the start of the reporting process. When following an automated process, there is little benefit to starting prior to database lock, as any changes made during medical writer review will be lost when the narratives are re-run from clean data. If timings require increased efficiencies, this approach may be followed as long as the programmed outputs based on clean and draft data are compared – preferably via an automated process – with changes flagged to the medical writer for late inclusion in the narrative writing process, but ideally prior to sponsor review.

When working with sponsors, a low-cost solution is available by providing a defined output where SAS datasets are provided in a specific format. If SAS datasets are not available, but other formats such as spreadsheets are, the same information may be extracted through additional programming techniques. It is recommended that the medical writer review be included to ensure complete, coherent and consistent reporting.

Individual CSRs

It is important to avoid confusion between patient safety narratives and individual case safety reports (ICSRs). These are a core component of pharmacovigilance services and drug safety, and differ from patient safety narratives in a number of respects.

A patient safety narrative in, or appended to, a CSR describes all relevant events for a single patient, with relevant background information as detailed above. An ICSR concerns one patient, one or more identifiable reporters, one or more suspected adverse reactions that are clinically and temporally associated, and one or more suspected medicinal products (3).

In the context of a clinical trial, an individual case is the information provided by a primary source to describe a SAE related or unrelated to the administration of one or more investigational medicinal products to an individual patient, at a particular point of time (4). The event reported should be the diagnosis. If a diagnosis has not been made at that time, the case may contain several signs and symptoms instead and, therefore, more than one reported event.

ICSRs prepared post-marketing can differ from this in that several event terms may be reported in a single case; these events should be temporally or clinically associated, and they will be ordered according to clinical relevance for the product: a serious unexpected event would be designated the ‘primary event’ for reporting purposes, whereas non-serious or expected events would be ranked lower within the case.

Furthermore, in post-marketing ICSRs, all spontaneous reported events are considered related to the medicinal product – unless specified otherwise by the reporter – and, in a clinical setting, the investigator will make his or her interpretation as to the causality.

The regulations pertaining to ICSRs are both complex and precise, and dictate that reports be presented in a standardised format. This can prove to be challenging, particularly for smaller companies involved in drug development that often outsource this work to CROs who can provide an end-to-end pharmacovigilance service on their behalf.

References
1. ICH, Section 12.3.2, Topic E3 Structure and Content of Clinical Study Reports, July 1996
2. EMA, Note for Guidance on the Inclusion of Appendices to Clinical Study Reports in Marketing Authorisation Applications, December 2004
3. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use, Part II, 2011. Visit: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf
4. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use, Annex 1.2, 2011. Visit: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf


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Yvonne Moores is Head of Operations at Quanticate. She joined the company in 2008 after working as a Programming Group Manager at AstraZeneca for eight years. In collaboration with Quanticate’s medical writing and pharmacovigilance specialists, Yvonne and her team have authored several articles around industry topics related to medical writing and pharmacovigilance. Quanticate’s medical writers are experts in medical narrative preparation, having worked closely with several customers preparing narratives in recent years.
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