VIII.B.3. Study protocol

Location:
VIII.B.
In force from:
13.10.2017

Non-interventional PASS conducted pursuant to an obligation imposed by an EU competent authority or conducted voluntarily shall have a written study protocol. The study protocol should be developed by individuals with appropriate scientific background and experience. An overview of study designs and databases frequently used in post-authorisation safety studies is provided in VIII.App.1.

For non-interventional PASS imposed as an obligation, the draft study protocol shall be submitted by the marketing authorisation holder to the PRAC or to the national competent authority of the Member State that requested the study if the study is conducted in only one Member State [DIR Art 107n(1)] (see VIII. C.2.).

The marketing authorisation holder may be required by the national competent authority to submit the protocol to the competent authorities of the Member States in which the study is conducted [DIR Art 107m(5)]. Requirements and recommendations for submission of the study protocol to the Agency and national competent authorities are specified in GVP Module VIII Addendum I.

In order to ensure compliance of the marketing authorisation holder with its pharmacovigilance obligations, the qualified person responsible for pharmacovigilance (QPPV) or his/her delegate should be involved in the review and sign-off of study protocols required in the risk management plan agreed in the EU or conducted voluntarily in the EU (see GVP Module I).

Where applicable, the marketing authorisation holder’s pharmacovigilance contact person at national level should be informed of any study sponsored or conducted by the marketing authorisation holder in that Member State and have access to the protocol.

VIII.B.3.1. Format and content of the study protocol

For non-interventional PASS conducted pursuant to an obligation imposed by an EU competent authority, the study protocol shall follow the format described in this section [IR Annex III]. This format should also be followed for non-interventional PASS required in the risk management plan agreed in the EU or conducted voluntarily in the EU.

 

1 Title: informative title including a commonly used term indicating the study design and the medicinal product, substance or medicinal product class concerned, and a sub-title with a version identifier and the date of the last version. If the study protocol has been registered in the EU PAS Register, subsequent versions of the protocol should mention on the title page “EU PAS Register No:” with the registration number.
2 Marketing authorisation holder: name and address of the marketing authorisation holder.
3 Responsible parties: names, titles, qualifications, addresses, and affiliations of all main responsible parties, including the main author(s) of the protocol, the principal investigator, a coordinating investigator for each country in which the study is to be performed and other relevant study sites. A list of all collaborating institutions and investigators should be made available to the Agency and national competent authorities upon request.
4 Abstract: stand-alone summary of the study protocol including the following sub-sections:
  • Title with subtitles including version and date of the protocol and name and affiliation of main author
  • Rationale and background
  • Research question and objectives
  • Study design
  • Population
  • Variables
  • Data sources
  • Study size
  • Data analysis
  • Milestones.
5 Amendments and updates: any substantial amendment and update to the study protocol after the start of data collection, including a justification for each amendment or update, dates of each change and a reference to the section of the protocol where the change has been made.
6 Milestones: table with planned dates for the following milestones:
  • Start of data collection
  • End of data collection
  • Interim report(s) of study results, where applicable, in line with phases of data analyses (see VIII.B.4.3.1.)
  • Any other important timelines in the conduct of the study should be presented.
7 Rationale and background: short description of the safety hazard(s), the safety profile or the risk management measures that led to the initiation or imposition of the study, and short critical review of relevant published and unpublished data to explain gaps in knowledge that the study is intended to fill. The review may encompass relevant animal and human experiments, clinical studies, vital statistics and previous epidemiologic studies. The review should cite the findings of similar studies, and the expected contribution of the current study.
8 Research question and objectives: research question that explains how the study will address the issue which led to the study being initiated or imposed, and research objectives, including any pre-specified hypotheses and main summary measures.
9 Research methods: description of the research methods, including:
9.1. Study design: overall research design and rationale for this choice.
9.2. Setting: study population defined in terms of persons, place, time period, and selection criteria, including the rationale for any inclusion and exclusion criteria. Where any sampling from a source population is undertaken, description of the source population and details of sampling methods should be provided. Where the study design is a systematic review or a meta-analysis, the criteria for the selection and eligibility of studies should be explained.
9.3. Variables: outcomes, exposures and other variables including measured risk factors should be addressed separately, including operational definitions; potential confounding variables and effect modifiers should be specified.
9.4. Data sources: strategies and data sources for determining exposures, outcomes and all other variables relevant to the study objectives, such as potential confounding variables and effect modifiers. Where the study will use an existing data source, such as electronic health records, any information on the validity of the recording and coding of the data should be reported. In case of a systematic review or meta-analysis, the search strategy and processes and any methods for confirming data from investigators should be described. If data collection methods or instruments are tested in a pilot study, plans for the pilot study should be presented. If a pilot study has already been performed, a summary of the results should be reported. Involvement of any expert committees to validate diagnoses should be stated.
9.5. Study size: any projected study size, precision sought for study estimates and any calculation of the sample size that can minimally detect a pre-specified risk with a prespecified statistical precision.
9.6. Data management: data management and statistical programmes to be used in the study, including procedures for data collection, retrieval and preparation.
9.7. Data analysis: the major steps that lead from raw data to a final result, including methods used to correct inconsistencies or errors, impute values, modify raw data, categorise, analyse and present results, and procedures to control sources of bias and their influence on results; statistical procedures to be applied to the data to obtain point estimates and confidence intervals of measures of occurrence or association, and sensitivity analyses. The primary analyses should be clearly identified from sub-group analyses and secondary analyses.
9.8. Quality control: description of any mechanisms and procedures to ensure data quality and integrity, including accuracy and legibility of collected data and original documents, extent of source data verification and validation of endpoints, storage of records and archiving of statistical programmes. As appropriate, certification and/or qualifications of any supporting laboratory or research groups should be included.
9.9. Limitations of the research methods: any potential limitations of the study design, data sources, and analytic methods, including issues relating to confounding, bias, generalisability, and random error. The likely success of efforts taken to reduce errors should be discussed.
10 Protection of human subjects: safeguards in order to comply with national and European Union requirements for ensuring the well-being and rights of participants in non-interventional postauthorisation safety studies.
11 Management and reporting of adverse events/adverse reactions: procedures for the collection, management and reporting of individual cases of suspected adverse reactions and of other medically important events that might influence the evaluation of the risk-benefit balance of the product while the study is being conducted. For studies with primary data collection where information on certain adverse events will not be collected (see GVP Module VI), the marketing authorisation holder should provide in the protocol a justification for the overall approach to the collection of safety data. Any reference to adverse events that will not be collected should be made using the appropriate level of the MedDRA classification. If information on certain adverse events will not be collected, the channels and documents to be used to inform the healthcare professionals and consumers of the possibility to report suspected adverse reactions to the marketing authorisation holder or to the national spontaneous reporting system should be included in this section (see GVP Module VI). In certain circumstances where suspected adverse reactions with fatal outcome will not be subject to expedited reporting as individual case safety reports (see GVP Module VI), each of these adverse reactions should be listed in a table using the appropriate level of the MedDRA classification with a rationale for not reporting them. For studies based on secondary use of data, a statement should indicate if adverse events/adverse reactions are analysed; in this instance they should be specified using the appropriate level of the MedDRA classification. The reporting of suspected adverse reactions in the form of individual case safety reports is not required (see GVP Module VI). For combined study designs, the same requirements as for studies with primary data collection should be followed for adverse events obtained through primary data collection and the guidance for studies with design based on secondary use of data should be applied to adverse events based on secondary data collection (see GVP Module VI).
12 Plans for disseminating and communicating study results, including any plans for submission of progress reports and final reports.
12 References.
The format of the study protocol should follow the Guidance for the Format and Content of the Protocol of Non-Interventional Post-Authorisation Safety Studies (9). Feasibility or pilot studies that were carried out to support the development of the protocol, for example, the testing of a questionnaire or simple counts of medical events or prescriptions in a database to determine the statistical precision of the study, should be reported in the appropriate section of the study protocol with a summary of their methods and results. The full report should be made available to the Agency and national competent authorities upon request. Feasibility or pilot studies that are part of the research process should be described in the protocol, for example, a pilot evaluation of the study questionnaire(s) used for the first set of patients recruited into the study.

The format of the study protocol should follow the Guidance for the Format and Content of the Protocol of Non-Interventional Post-Authorisation Safety Studies9. Feasibility or pilot studies that were carried out to support the development of the protocol, for example, the testing of a questionnaire or simple counts of medical events or prescriptions in a database to determine the statistical precision of the study, should be reported in the appropriate section of the study protocol with a summary of their methods and results. The full report should be made available to the Agency and national competent authorities upon request. Feasibility or pilot studies that are part of the research process should be described in the protocol, for example, a pilot evaluation of the study questionnaire(s) used for the first set of patients recruited into the study.

An annex should list all separate documents and list or include any additional or complementary information on specific aspects not previously addressed (e.g. questionnaires, case report forms), with clear document references.

VIII.B.3.2. Substantial amendments to the study protocol

The study protocol should be amended and updated as needed throughout the course of the study. Any substantial amendments to the protocol after the study start should be documented in the protocol in a traceable and auditable way including the dates of the changes. If changes to the protocol lead to the study being considered an interventional clinical trial, the national competent authorities and the Agency should be informed immediately. The study shall subsequently be conducted in accordance with Directive 2001/20/EC and Volume 10 of The Rules Governing Medicinal Products in the European Union.

For non-interventional PASS conducted pursuant to an obligation imposed by an EU competent authority, see VIII.C.2. for the submission of substantial amendments to the study protocol.

Requirements and recommendations for the submission of substantial amendments to the study protocol are specified in GVP Module VIII Addendum I.