VIII.B.4. Reporting of pharmacovigilance data to competent authorities

VIII.B.4.1. Data relevant to the risk-benefit balance of the product

The marketing authorisation holder shall monitor the data generated while the study is being conducted and consider their implications for the risk-benefit balance of the medicinal product concerned [DIR Art. 107m(7)]. Any new information that may affect the risk-benefit balance of the medicinal product should be communicated immediately in writing as an emerging safety issue to competent authorities of the Member States in which the product is authorised and to the Agency via email (P-PV-emerging-safety-issue@ema.europa.eu). Information affecting the risk-benefit balance of the medicinal product may include an analysis of adverse reactions and aggregated data.

This communication is without prejudice of the information on the findings of studies which should be provided by means of periodic safety update reports (PSURs) (see GVP Module VII) and in the RMP updates (see GVP Module V), where applicable.

VIII.B.4.2. Reporting of adverse reactions/adverse events

Individual cases of suspected adverse reactions should be reported to competent authorities in accordance with the provisions of GVP Module VI.

Adverse events/adverse reactions collected in studies with primary data collection should be recorded and summarised in the interim safety analysis and in the final study report.

Adverse events/adverse reactions collected in studies with secondary data collection should be recorded and summarised in the interim safety analysis and in the final study report unless the protocol provides for different reporting with a due justification.

Procedures for the collection, management (including a review by the marketing authorisation holder if appropriate) and reporting of suspected adverse reactions/adverse events should be put in place and summarised in the study protocol. If appropriate, reference can be made to the pharmacovigilance system master file (see GVP Module II) but details specific to the study should be described in the study protocol.

VIII.B.4.3. Study reports

VIII.B.4.3.1. Progress report and interim report of study results

The progress report is meant to include relevant information to document the progress of the study, for example, the number of patients who have entered the study, the number of exposed patients or the number of patients presenting the outcome, problems encountered and deviations from the expected plan. The progress report may include an interim report of study results.

The interim report of study results is meant to include results of any planned interim analysis of study data before or after the end of data collection.

Upon request from a national competent authority, progress reports for PASS imposed as an obligation or conducted voluntarily shall be submitted to the competent authorities of the Member States in which the study is conducted [DIR Art 107m(5)]. They may also be requested by the Agency for PASS concerning centrally-authorised products. Requests for progress reports may be made before the study commences or any time during the study conduct. They may be guided by the communication of riskbenefit information arising from the study or the need for information about the study progress in the context of regulatory procedures or important safety communication about the product. Requirements and recommendations for submission of progress reports are specified in GVP Module VIII Addendum I.

The timing of the submission of progress reports should be agreed with the relevant competent authorities and specified in the study protocol when they have been agreed before the study commences.

VIII.B.4.3.2. Final study report

For non-interventional PASS conducted pursuant to an obligation imposed by an EU competent authority, the final study report shall follow the format described in this section [IR Annex III) and shall be submitted within 12 months of the end of data collection [DIR Art 107p(1)] (see VIII.C.2.). This format and timeline should also be followed for PASS required in the risk management plan agreed in the EU or conducted voluntarily in the EU.

Requirements and recommendations for submission of the final study report are specified in Module VIII Addendum I.

If a study is discontinued, a final report should be submitted and the reasons for terminating the study should be provided.

The final study report should include the following information:

1	Title: title including a commonly used term indicating the study design; sub-titles with date of final report and name and affiliation of main author. If the study has been registered in the EU PAS Register, the final study report should mention on the title page “EU PAS Register No:” with the registration number and the web link to the study record.
2	Abstract: stand-alone summary in the format presented below [IR Annex III].
3	Marketing authorisation holder: name and address of the marketing authorisation holder.
4	Investigators: names, titles, degrees, addresses and affiliations of the principal investigator and all co-investigators, and list of all collaborating primary institutions and other relevant study sites. Such information should be provided 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.
5	Milestones: dates for the following milestones:
	Start of data collection (planned and actual dates) End of data collection (planned and actual dates) or date of early termination, if applicable, with reasons for termination Study progress report(s) (see VIII.B.4.3.1.) Interim report(s) of study results, where applicable (see VIII.B.4.3.1.) Final report of study results (planned and actual date) Any other important milestone applicable to the study, including date of study registration in the EU PAS Register and date of protocol approval by an Institutional Review Board/Independent Ethics Committee if applicable.
6	Rationale and background: description of the safety concerns that led to the study being initiated or imposed, and critical review of relevant published and unpublished data evaluating pertinent information and gaps in knowledge that the study is intended to fill.
7	Research question and objectives: research question and research objectives, including any pre-specified hypotheses, as stated in the study protocol.
8	Amendments and updates to the protocol: list of any substantial amendments and updates to the initial study protocol after the start of data collection, including a justification for each amendment or update.
9	Research methods:
	9.1 Study design: key elements of the study design and the rationale for this choice.
	9.2. Setting: setting, locations, and relevant dates for the study, including periods of recruitment, follow-up, and data collection. In case of a systematic review or meta-analysis, study characteristics used as criteria for eligibility, with rationale.
	9.3. Subjects: any source population and eligibility criteria of study subjects. Sources and methods of selection of participants should be provided, including, where relevant methods for case ascertainment, as well as number of and reasons for dropouts.
	9.4. Variables: all outcomes, exposures, predictors, potential confounders, and effect modifiers, including operational definitions and diagnostic criteria, if applicable
	9.5. Data sources and measurement: for each variable of interest, sources of data and details of methods of assessment and measurement. If the study has used 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, description of all information sources, search strategy, methods for selecting studies, methods of data extraction and any processes for obtaining or confirming data from investigators.
	9.6. Bias: any efforts to assess and address potential sources of bias at the design stage.
	9.7. Study size: study size, rationale for any study size calculation and any method for attaining projected study size.
	9.8. Data transformation: transformations, calculations or operations on the data, including how quantitative data were handled in the analyses and which groupings were chosen and why.
	9.9. Statistical methods: description of the following items:
	Main summary measures All statistical methods applied to the study, including those used to control for confounding and, for meta-analyses, methods for combining results of studies Any methods used to examine subgroups and interactions How missing data were addressed Any sensitivity analyses Any amendment to the plan of data analysis included in the study protocol, with rationale for the change.
	9.10. Quality control: mechanisms to ensure data quality and integrity.
10	Results: presentation of tables, graphs, and illustrations to present the pertinent data and reflect the analyses performed. Both unadjusted and adjusted results should be presented. Precision of estimates should be quantified using confidence intervals. This section should include the following sub-sections:
	10.1. Participants: numbers of study subjects at each stage of study, e.g. numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing followup, and analysed, and reasons for non-participation at any stage. In the case of a systematic review or meta-analysis, number of studies screened, assessed for eligibility and included in the review with reasons for exclusion at each stage.
	10.2. Descriptive data: characteristics of study participants, information on exposures and potential confounders and number of participants with missing data for each variable of interest. In case of a systematic review or meta-analysis, characteristics of each study from which data were extracted (e.g. study size, follow-up).
	10.3. Outcome data: numbers of participants across categories of main outcomes
	10.4. Main results: unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (e.g. 95% confidence interval). If relevant, estimates of relative risk should be translated into absolute risk for a meaningful time period.
	10.5. Other analyses: other analyses done, e.g. analyses of subgroups and interactions, and sensitivity analyses.
	10.6. Adverse events and adverse reactions: summary of all adverse events/adverse reactions collected in the study, in line with requirements described in GVP Module VI.
	Discussion:
	11.1. Key results: key results with reference to the study objectives, prior research in support of and conflicting with the findings of the completed post-authorisation safety study, and, where relevant, impact of the results on the risk-benefit balance of the product.
	11.2. Limitations: limitations of the study taking into account circumstances that may have affected the quality or integrity of the data, limitations of the study approach and methods used to address them (e.g., response rates, missing or incomplete data, imputations applied), sources of potential bias and imprecision and validation of the events. Both direction and magnitude of potential biases should be discussed.
	11.3. Interpretation: interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies and other relevant evidence.
	11.4. Generalisability: the generalisability (external validity) of the study results.
11	Other information: any additional or complementary information on specific aspects not previously addressed.
12	Conclusions: main conclusions of the study deriving from the analysis of the data.
13	References.

The format of the final study report should follow the Guidance for the Format and Content of the Final Study Report of Non-Interventional Post-Authorisation Safety Studies (10).

The abstract of the final study report should include a summary of the study methods and findings presented in the following format:

1. Title, with subtitles including date of the abstract and name and affiliation of main author
2. Keywords (not more than five keywords indicating the main study characteristics)
3. Rationale and background
4. Research question and objectives
5. Study design
6. Setting
7. Subjects and study size (including dropouts)
8. Variables and data sources
9. Results
10. Discussion (including, where relevant, an evaluation of the impact of study results on the riskbenefit balance of the product)
11. Conclusion
12. Marketing authorisation holder
13. Names and affiliations of principal investigators.