The study protocol is the core document of a study that should be drafted as one of the first steps in any research project once the research question has been clearly defined. The final version must precisely describe everything being done in the study so that the study can be reproduced. It should be amended and updated as needed and amendments should be justified.
For PASS described in the Guideline of good pharmacovigilance practices (GVP) Module VIII - Post-authorisation safety studies, the Commission Implementing Regulation (EU) No 520/2012 provides legal definitions of the start of data collection (the date from which information on the first study subject is first recorded in the study dataset, or, in the case of secondary use of data, the date from which data extraction starts) and of the end of data collection (the date from which the analytical dataset is completely available). These dates provide timelines for the commencement of the study and the submission of the final study report to the competent authorities. It also provides the format of protocols, abstracts and final study reports for imposed PASS. Based on these formats, the European Medicines Agency (EMA) published detailed templates for the protocol and final study report which it recommends to be used for all PASS, including meta-analyses and systematic reviews. The ISPE Guidelines for Good Pharmacoepidemiology Practices (GPP) provides guidance on what is expected from a pharmacoepidemiology study protocol and on the different aspects to be covered. It states that the protocol should include a description of the data quality and integrity, including abstraction of original documents, extent of source data verification, and validation of endpoints. The FDA’s Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Health Care Data Sets includes a description of the elements that should be addressed in the protocols of such studies, including the choice of data sources and study population, the study design and the analyses. The ENCePP Checklist for Study Protocols seeks to stimulate researchers to consider important epidemiological aspects when designing a pharmacoepidemiological study and writing a study protocol. The Agency for Healthcare Research and Quality (AHRQ) published Developing a Protocol for Observational Comparative Effectiveness Research: A User’s Guide including best practice principles and checklists on a wide range of topics that are also applicable to observational studies outside the scope of comparative effectiveness research. The Appendix 1 of the CIOMS International Ethical Guidelines for Health-related Research Involving Humans (Geneva: 2016) provides a list of 48 items to be included in a protocol or associated documents for health-related research involving humans.
It should be kept in mind that different regulators and stakeholders (e.g., data owners) might require different protocol structure from the one recommended by the above mentioned guidances and several versions of the protocol for the same study might be required.
The protocol should cover at least the following aspects:
Ethical considerations, as described in the section on governance of the current document.
The various data collection forms including the Case Report Form (CRF) or descriptions of the data elements may be appended to the protocol, providing an exact representation of how the data will be collected. The study protocols could include a section specifying ways in which the CRF will be piloted, tested and finalised. Amendments of final CRFs should be justified. For field studies, physician or patient forms would be included depending on the data collection methodology. Other forms may be included as needed, such as patient information or patient-oriented summaries.
|10. Specific topics|
|Annex 1.||Guidance on conducting systematic revies and meta-analyses of completed comparative pharmacoepidemiological studies of safety outcomes|