Annex III: Protocols, abstracts and final study reports for post-authorisation safety studies

Location:
Annex
Source:
Eur-Lex

1.   Format of the study protocol

1.   Title: informative title including a commonly used term indicating the study design and the medicinal product, substance or drug class concerned, and a sub-title with a version identifier and the date of the last version.

2.   Marketing authorisation holder.

3.   Responsible parties including a list of all collaborating institutions and other relevant study sites.

4.   Abstract: stand-alone summary of the study protocol, including the following subsections:

(a)

title with subtitles including version and date of the protocol and name and affiliation of the main author;

(b)

rationale and background;

(c)

research question and objectives;

(d)

study design;

(e)

population;

(f)

variables;

(g)

data sources;

(h)

study size;

(i)

data analysis;

(j)

milestones.

5.   Amendments and updates: any substantial amendment and update to the study protocol after the start of data collection, including a justification for the amendment or update, the date of the 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:

(a)

start of data collection;

(b)

end of data collection;

(c)

study progress report(s) as referred to in Article 107m(5) of Directive 2001/83/EC;

(d)

interim report(s) of study results, if applicable;

(e)

final report of study results.

7.   Rationale and background: description of the safety hazard(s), the safety profile or the risk management measures that led to the study being imposed as an obligation for a marketing authorisation.

8.   Research question and objectives in accordance with the decision of the national competent authority that imposed the study as an obligation.

9.   Research methods: description of the research methods, including:

(a)

study design;

(b)

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, a description of the source population and details of sampling methods shall be provided. Where the study design is a systematic review or a meta-analysis, the criteria for the selection and eligibility of studies shall be explained;

(c)

variables;

(d)

data sources: strategies and data sources for determining exposures, outcomes and all other variables relevant to the study objectives. 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 shall be reported. In the case of a systematic review or meta-analysis, the search strategy and processes and any methods for confirming data from investigators shall be described;

(e)

study size: any projected study size, precision sought for study estimates and any calculation of the study size that can minimally detect a pre-specified risk with a pre-specified interpretative power;

(f)

data management;

(g)

data analysis;

(h)

quality control;

(i)

limitations of the research methods.

10.   Protection of human subjects: safeguards in order to comply with national and Union requirements for ensuring the well-being and rights of participants in non-interventional post-authorisation safety studies.

11.   Management and reporting of adverse events/adverse reactions and other medically important events while the study is being conducted.

12.   Plans for disseminating and communicating study results.

13.   References.

2.   Format of the abstract of the final study report

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 risk–benefit balance of the product).

11.   Marketing authorisation holder.

12.   Names and affiliations of principal investigators.

3.   Format of the final study report

1.   Title: title including a commonly used term indicating the study design; sub-titles with date of final report and name and affiliation of the main author.

2.   Abstract: stand-alone summary referred to in Section 2 of this Annex.

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.

5.   Milestones: dates for the following milestones:

(a)

start of data collection (planned and actual dates);

(b)

end of data collection (planned and actual dates);

(c)

study progress reports;

(d)

interim reports of study results, where applicable;

(e)

final report of study results (planned and actual date);

(f)

any other important milestone applicable to the study, including date of study registration in the electronic study register.

6.   Rationale and background: description of the safety concerns that led to the study being initiated, 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.

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 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 the 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 for study subjects. Sources and methods for selection of participants shall 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. Diagnostic criteria shall be provided, where 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 shall be reported. In the 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.

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:

(a)

main summary measures;

(b)

all statistical methods applied to the study;

(c)

any methods used to examine subgroups and interactions;

(d)

how missing data were addressed;

(e)

any sensitivity analyses;

(f)

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: comprising the following subsections:

10.1.

Participants: numbers of study subjects at each stage of study. 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. In the case of a systematic review or meta-analysis, characteristics of each study from which data were extracted.

10.3.

Outcome data: numbers of study subjects across categories of main outcomes.

10.4.

Main results: unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision. Where relevant, estimates of relative risk shall be translated into absolute risk for a meaningful time period.

10.5.

Other analyses.

10.6.

Adverse events and adverse reactions.

11.   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, the 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, sources of potential bias and imprecision, and validation of the events. Both the direction and magnitude of potential biases shall 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.

12.   References.

Assistance
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Section 3 point 5(f)