Preparation of Aggregate Reports - A-consult · 5 Archiving 9 6 Appendices 9 7 ... The purpose of this quality instruction is to ensure consistency in preparation of aggregate reports

Instruction

ID number: QI07 Version number: 4.0 Number of appendices: 5 Effective date: 15 April 2017 Page: 1 of 11

Preparation of Aggregate Reports 1 Purpose and Scope 1 2 Responsibilities 1 3 Definitions 2 4 Procedure 2

4.1 PSUR: Objective, content and frequency of submission 2 4.1.1 Objective of PSUR 2 4.1.2 Frequency of submission of PSURs 2

4.2 DSUR: Objective, periodicity and submission 3 4.2.1 Objective of DSUR 3 4.2.2 Periodicity, DSUR data lock point and submission 3

4.3 Preparation of PSURs and DSURs 3 5 Archiving 9 6 Appendices 9 7 References 9 8 Change Log 9

1 Purpose and Scope The purpose of this quality instruction is to ensure consistency in preparation of aggregate reports as Periodic Update Safety Reports (PSURs) and Development Safety Update Reports (DSUR) written by A-consult employees. This instruction introduces the formal requirements to be followed and the responsibilities to be taken when preparing aggregate reports at A-consult.

2 Responsibilities This instruction must be read and understood by:

• PSUR/DSUR Writers • PSUR/DSUR Reviewers • QPPV

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3 Definitions Please refer to QI02 for Definitions and Abbreviations used in this instruction. The term aggregate report covers both PSUR and DSUR.

4 Procedure

4.1 PSUR: Objective, content and frequency of submission

4.1.1 Objective of PSUR The main objective of a PSUR is to present a comprehensive, concise and critical analysis of the risk-benefit balance of the medicinal product taking into account new or emerging information in the context of cumulative information on risks and benefits. The overall building of the PSUR:

• Data presentation (exposure and use patterns including off-label use), summary tabulations, findings from studies and literature

• Risk evaluation (signal evaluation and evaluation of risk minimisation) • Benefit evaluation (focus on new significant knowledge for use in the authorised

indications) – direct link to the product approval (baseline description of efficacy) • Integrated benefit-risk analysis (from authorised indications, profile may be divided in

populations, recommendations, SPC changes, new risk minimisation actions) – direct link to RMP.

Detailed guidance is given in GVP module VII and E2C (R2).

4.1.2 Frequency of submission of PSURs MAHs are required to submit PSURs to national competent authorities or EMA according to the dates published at EMA’s website in the List of European Union reference dates and frequency of submission of PSURs commonly known as the “EURD list”. Deadline for PSUR submission in EU depends on the length of the period covered: PSURs covering ≤ 12 months: Submission within 70 days after DLP PSURs covering >12 months: Submission within 90 days after DLP

Ad hoc PSURs requested by CA: Normally specified in request (otherwise within 90 days after DLP). Submission of PSURs for medicinal products authorised before 02 Jul 2012 (CAPs) and 21 Jul 2012 (NAPs) for which the frequency and conditions is not laid down as a condition in the marketing authorisation or determined otherwise in the EURD list, should follow the standard submission schedule:

• At 6-month intervals once the product is authorised, even if it is not marketed; • Once the product is marketed, PSUR submission every 6 months should be continued

following initial placing on the market in the EU and until 2 years of marketing

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experience in the EU, then once a year for the following 2 years and thereafter at 3-yearly intervals.

4.2 DSUR: Objective, periodicity and submission

4.2.1 Objective of DSUR The main objective of a DSUR is to present a comprehensive, thoughtful annual review and evaluation of pertinent safety information collected during the reporting period related to a drug under investigation, whether or not it is marketed, by:

• examining whether the information obtained by the sponsor during the reporting period is in accord with previous knowledge of the investigational drug’s safety;

• describing new safety issues that could have an impact on the protection of clinical trial subjects;

• summarising the current understanding and management of identified and potential risks

• providing an update on the status of the clinical investigation/development programme and study results

Detailed guidance is given in ICH guideline E2F on development safety update report.

4.2.2 Periodicity, DSUR data lock point and submission The “Development International Birth Date” (DIBD) is used to determine the start of the annual period for the DSUR. This date is the sponsor’s first authorisation to conduct a clinical trial in any country worldwide. The start of the annual period for the DSUR is the month and date of the DIBD. The DSUR should be submitted to all concerned regulatory authorities no later than 60 calendar days after the DSUR data lock point. When clinical development of a drug continues following a marketing approval in any country worldwide, both a PSUR and a DSUR should be submitted as specified by national or regional laws or regulations. If desired by the sponsor, a DSUR can be prepared based on the PSUR International Birth Date (IBD) so that the DSUR and the PSUR can be synchronised. In synchronising the data lock points for the DSUR and PSUR, the period covered by the next DSUR should be no longer than one year.

4.3 Preparation of PSURs and DSURs The PSUR template is provided in QI07AP01 – use word version. The DSUR template is provided in QI07AP02 – use word version. The process for preparation of the aggregate report depends on whether the report concerns:

• An external Client from whom all documentation for preparation of aggregate report must be obtained or

• A Client who beforehand had outsourced pharmacovigilance activities to A-consult, thus A-consult is in possession of pharmacovigilance data in the database: PV247 or

• A Client who solely needs assistance to preparation of selected sections of the aggregate report.

Instruction

ID number: QI07 Version number: 4.0 Number of appendices: 5 Effective date: 15 April 2017 Page: 4 of 11 For PSUR: Use QI07AP03 PSUR Data Package: Documentation to be obtained from MAH to assure that the relevant information is requested. For DSUR: Use QI07AP04 DSUR Data Package: Documentation to be obtained from MAH to assure that the relevant information is requested.

Completion of critical steps of the report shall be tracked with date, name and signature in the Check list for report compilation (QI07AP05). All employees involved in the preparation of the aggregate report should have access to Check list for report compilation (QI07AP05). The flow for preparation of an aggregate report is depicted below. Step Role Actions Task

1. PSUR/DSUR Writer

Send request to Client for: 1. Relevant information needed to prepare the report. Adjust one of the below lists of full content of the report to the need of the Client by deleting irrelevant sections: • QI07AP03 PSUR Data Package:

Documentation to be obtained from MAH

• QI07AP04 DSUR Data Package: Documentation to be obtained from MAH

Sign this step in the Check list for report compilation (QI07AP05)

2. Clarification of responsibilities concerning external review, approval of the final report and report submission. (See questions in QI07AP05)

Deadline: Before DLP or as soon as possible after day 0

Request of Data Package Fill in QI07AP05

2. PSUR/DSUR Writer

Prepare a timetable for the report preparation and circulate it to the involved persons at A-Consult and to the Client. The timetable should include the following steps:

- Request of Data Package from Client - Preparation of Data Package at A-Consult:

Lists in PV247 and/or literature screening - Circulation of draft report for review - Draft report back with comments - Circulation of final report for review to A-

Consult or to the Client - Final report back with comments - Approval of final report by QPPV or

delegated person. - Submission of report

Timetable for report preparation

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ID number: QI07 Version number: 4.0 Number of appendices: 5 Effective date: 15 April 2017 Page: 5 of 11 Step Role Actions Task

Document this step in Check list for report compilation (QI07AP05) Deadline: Before DLP or as soon as possible after day 0

Fill in QI07AP05

3. PSUR/DSUR Writer

Assure that all relevant documentation has been received from the Client. Sign this step in the Check list for report compilation (QI07AP05) Assure that the Client has answered questions regarding clarification of responsibilities concerning external review, approval of the final report and report submission. Fill in tick boxes in Check list for report compilation (QI07AP05) The documentation from the customer must be saved on the K: drive.

Adequate documentation received from Client Fill in QI07AP05 Fill in QI07AP05 Archiving

4. PSUR/DSUR Writer

Note: This step only applies if A-Consult holds the global database. • Prepare a Clinical Sign Incidence report, line-

listings, summary tabulations and cumulative tabulations from PV database. (See QI31 and QI34AP02 for guidance on how to prepare the reports)

• Collect CIOMS reports on selected cases containing new or relevant safety information

• Perform in-depth analysis of the selected CIOMS reports for cases containing new or relevant safety information


Preparation of lists in PV247 and data analysis Fill in QI07AP05

5. PSUR/DSUR Writer

Note: This step only applies if A-Consult performs weekly literature searches or if the literature screening is to be performed by A-Consult.

The report section “Literature” should include a summary of new and significant safety information of relevance for the product in the period covered by the report.

Literature screening and selection for inclusion

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Literature screening and selection for inclusion in the report can be performed in two different ways:

1. Review “PSUR relevant” articles from weekly

literature searches. Articles for inclusion in the PSUR are selected. Any lacking full articles are ordered from the library. If the weekly literature searches do not cover the whole PSUR reporting period, a literature search is performed to cover the rest of the period.

2. Literature search for the whole period can be constructed and performed. The literature search should cover:

• pregnancy outcomes (including termination) with no adverse outcomes;

• use in paediatric populations; • compassionate supply and named patient use; • lack of efficacy; • asymptomatic overdose, abuse or misuse; • medication error where no adverse events

occurred; • important non-clinical safety results.

Study reports are included based on the following criteria: • Must be studying the active substance (or

combination of substances); publications on other combinations of the drug are discarded, as are publications where the active substance is used as the reference/comparator

Perform selection of literature to be included in the report.


6. PSUR/DSUR Writer

Prepare a draft report. Sign this step in the Check list for report compilation (QI07AP05)

Prepare draft report Fill in QI07AP05

7. PSUR/DSUR Reviewer

The following should be considered by the reviewer of the draft PSUR:

• That data are appropriately presented and that calculations are correct

• All commitments made to the health agencies in previous reports have been properly addressed

Scientific review of draft report

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• Alignment of the PSUR with the RMP, if applicable

• That there are no missed signals and that the data analysis and conclusions are appropriate.

Comments are provided as track-changes and/or comments in the document. Sign this step in the Check list for report compilation (QI07AP05)

Fill in QI07AP05

8. PSUR/DSUR Writer

Late-breaking information is any potentially important safety, efficacy and effectiveness findings that arise after the data lock point but during the period of preparation of the report. Check if any late-breaking information has been received after the DLP, and if yes include the late-breaking information in the final report.

Check if any Late-breaking information has been received Fill in QI07AP05.

9.

PSUR/DSUR Writer

The final version of the report is prepared by • Implementation of comments from the scientific

review • Addition of any late-breaking information and

performing any necessary adjustments to other sections of the report

Sign this step in the Check list for report compilation (QI07AP05) Proceed to Step 10 or 11 and 12 as appropriate (see QI07AP05).

Preparation of final report Fill in QI07AP05

10. PSUR/DSUR Reviewer (preferably QPPV)

Review the final report to assure that comments from the Scientific review have been properly addressed and that any Late-breaking information has been adequately presented and incorporated to report. Sign this step in the Check list for PSUR compilation (QI07AP05)

Review of final report at A-consult Fill in QI07AP05

11. PSUR/DSUR Writer

Note: This step is only applicable if specified in an agreement with the Client. Send the final report to the Client. The Client should return any amendments or comments as specified in the timetable. Sign this step in the Check list for report compilation (QI07AP05)

External review by Client Fill in QI07AP05

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12. PSUR/DSUR Writer

Note: This step is only applicable if amendments or comments have been received from the Client. Update the final report according to the review comments. Sign this step in the Check list for report compilation (QI07AP05)

Update of final report Fill in QI07AP05

13. QPPV (or person delegated by QPPV)

Approve the final version of the report. Note: The PSUR shall be signed by the QPPV or a delegated person. The delegation shall be documented. Sign this step in the Check list for report compilation (QI07AP05)

Approval of report either by A-Consult or by the Client Fill in QI07AP05

14. PSUR/DSUR writer Or Client

Note: This step is only applicable if specified in an agreement with the Client. Submit of the final report:

• For PSUR: Use PSUR repository • For DSUR: Submit to the national

authorities and Ethics Committees Sign this step in the Check list for report compilation (QI07AP05)

Submission from A-Consult Fill in QI07AP05

15.

PSUR/DSUR Writer Or Reviewer

Following the completion of each report, a quality check of the established procedure and deadlines shall be performed. In practice, the QC is done by reviewing QI07AP05 and asking the following questions: • Were deadlines complied with? • Were activities performed by appropriate

personnel (cf. QI07 roles and Job Descriptions)?

• Any comments which indicate an issue that potentially could have compromised the quality of the report or delayed timely completion of the report?

Sign and add comments to this step in Check list for report compilation (QI07AP05). Refer to deviation number, if any deviations were necessary.

Quality control of the report preparation process Fill in QI07AP05

Instruction

ID number: QI07 Version number: 4.0 Number of appendices: 5 Effective date: 15 April 2017 Page: 9 of 11 5 Archiving All documents and emails are archived as original pharmacovigilance documents (see QI05 Archiving at A-consult a/s).

6 Appendices QI07AP01 PSUR template QI07AP02 DSUR template QI07AP03 PSUR Data Package: Information to be obtained from MAH QI07AP04 DSUR Data Package: Information to be obtained from MAH QI07AP05 Check list for report compilation

7 References • Guideline on Good Pharmacovigilance practices (GVP). Module VII – Periodic Safety

Update Report • Periodic Benefit-Risk Evaluation Report (PBRER) E2C (R2). • E2C(R2) Implementation Working Group ICH E2C(R2) Guideline: Periodic Benefit-

Risk Evaluation Report. Questions & Answers • ICH guideline E2F on development safety update report • QI05 -Archiving at A-consult a/s • QI23 Deviations (pharmacovigilance)

8 Change Log Version Change description Effective date

4.0 QI07 has been renamed from “Preparation of Periodic Safety Update Report” to “Preparation of Aggregate Reports”, and thus to include preparation of PSUR as well as DSUR. The structure of this QI has been changed from the following 4: Procedure 4.1 Content of PSURs 4.2 Process 4.3 Literature search 4.4 List of European Union reference dates and frequency of submission of PSURs 4.5. Deadline for PSUR submission in EU

To the following: 4.1 PSUR: Objective, content and frequency of submission

4.1.1 Objective of PSUR 4.1.2 Frequency of submission of PSURs

4.2 DSUR: Objective, periodicity and submission 4.2.1 Objective of DSUR 4.2.2 Periodicity, DSUR data lock point and submission

4.3 Preparation of PSURs and DSURs Appendices have been renamed and updated from: QI07AP01 PSUR template QI07AP02 List of data and documentation to be obtained from

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ID number: QI07 Version number: 4.0 Number of appendices: 5 Effective date: 15 April 2017 Page: 10 of 11 Version Change description Effective date

MAH QI07AP03 Check list of PSUR Data Package QI07AP04 Check list for PSUR Compilation QI07AP05 PSUR - Selection of Literature The new appendix structure is as follows: QI07AP01 PSUR template QI07AP02 DSUR template QI07AP03 PSUR Data Package: Information to be obtained from MAH QI07AP04 DSUR Data Package: Information to be obtained from MAH QI07AP05 Check list for report compilation

3.0 New templates for QIs and appendices in effect from 15 Jan 2015. • Section 2. The list of roles of the persons involved in the

PSUR process and to whom this SOP is directed has been updated.

• Section 4.1. The objectives of the PSUR from the GVP module VII has been included.

• Section 4.2. The PSUR process has become further detailed. Roles and Responsibilities in the PSUR process have been updated, “Medical review” has been changed to “scientific review” and 2 QC steps have been added.

• Section 5. Text adjusted • New Section 6. Appendices • Section 7. References added.

Appendices now managed separately: • Former Appendix 1 of QI07 created as an independent

document named QI07AP01. • Former Appendix 2 of QI07 created as an independent

document named QI07AP02. New appendices • QI07AP03 Checklist of Product Data • QI07AP04 Check list for PSUR Compilation • QI07AP05 PSUR - Selection of Literature

15 February 2015

2 The new PV legislation (Regulation (EU) No 1235/2010 and Directive 2010/84/EC, of 15 Dec 2010, entailed new requirements and a complete rewrite of guidance (Vol9A exchanged by GVP modules), which includes a new PSUR template. “Safety reports” has been exchanged by “PSUR” throughout the instruction as the PSUR is now regarded as a stand-alone document based on cumulative data (“addendum report” and “summary bridging report” (vol9A3) are no longer accepted). Accordingly the title of instruction was changed from “Preparation of safety reports” to “Preparation of PSURs”.

15 March 2013

Instruction

ID number: QI07 Version number: 4.0 Number of appendices: 5 Effective date: 15 April 2017 Page: 11 of 11 Version Change description Effective date

1 New document 01 June 2008

Documents

Preparation of Aggregate Reports - A-consult · 5 Archiving 9 6 Appendices 9 7 ... The purpose of this quality instruction is to ensure consistency in preparation of aggregate reports