General principles of Periodic Safety Update Reports(PSUR)

2014-09-26Dr. Julia Appelskog EU QPPVHead of PharmacovigilanceBluefish Pharmaceuticals

2014-09-26

2 PUBLIC

Disclaimer

The views and opinions expressed in the following PowerPoint slides are

those of the individual presenter and should not be attributed to Bluefish

Pharmaceuticals.

These PowerPoint slides are the intellectual property of the individual

presenter and are protected under the copyright laws. Used by permission.

All rights reserved.

2014-09-26

3 PUBLIC

Abbreviation

CAP Centrally Authorised Product

CHMP Committee for Medicinal Product for Human Use

CMDh Coordination Group for Mutual Recognition and Decentralised Procedures

– Human

DLP Data Lock Point

DCP Decentralised procedure

EMA European Medicines Agency

MA Marketing Authorisation

MAH Marketing authorisation holder

MA Member State

MRP MRP: Mutual Recognition procedure

NAP Nationally Authorised Product (in the frame of this presentation includes

also DCP/MRP)

PRAC Pharmacovigilance Risk Assessment Committee

PSUR Periodic Safety Update Report

2014-09-26

4 PUBLIC

Agenda

1 History of the PSUR

2 PSUR preparation

3 PSUR submission: Outcome of the transitioning to the new system

4 PSUR Assessment

2014-09-26

5 PUBLIC

Purpose of the Periodic Report

PSURs as benefit risk decision-making tool

The main purpose of PSUR is to present a comprehensive, concise, and

critical analysis of new or emerging information on the risks of the medicinal

product

To consider whether any action concerning the MA for the medicinal

product is necessary

Relates safety data to patient exposure

Consider changes to product information to optimise product use

2014-09-26

6 PUBLIC

1996

Step 4 – ICH E2C Guideline -

Clinical Safety Data Management

- Periodic Safety Update

Reports for Marketed Drugs

2003

Step 4 - Addendum to ICH

E2C (R1) published

2012

ICH guideline

E2C (R2) on periodic

benefit-risk evaluation

report (PBRER)2012-2013

GVP Module VII –

PERIODIC SAFETY

UPDATE REPORT

1992

CIOMS II Guideline on PSURs

published

History of the PSUR

2014?

2014-09-26

7 PUBLIC7

Spirit of the legislation

New legal requirements for PSURs:

Risk-based and proportionate approach

Central repository

PSUR single assessment: strengthens the Community system instead of

fragmented approaches on a national level

Extended preparation and submission deadlines

2014-09-26

8 PUBLIC

Old legislation

PSUR

RMP PSUR RMP PSUR

New legislation

2014-09-26

9 PUBLIC

Relief for well-known products

Article 10(1)

Generic products

Article 10a

Well established use products

Article 14

Homeopathic medicines

Article 16

Traditional herbal medicines

The legislation waives the obligation to

submit PSURs routinely (unless there is a

condition in the MA or requested by a CA):

2014-09-26

10 PUBLIC

Implementation

July 2012

- New format and content of PSUR + PRAC involvement in CAPs

1 April 2013

- EURD list binding => PSUSA procedure involving PRAC implemented

for CAPs and NAPs containing the same active substance or

combination of active substances

-

31st of August 2014

- Establishing of PSUR single assessment for NAP

2014-09-26

11 PUBLIC

EURD list

EURD = EU reference date list for PSUR submissions

Harmonisation of DLP and frequency of PSUR submission for products

authorised in several Member States

Periodicity defined on a risk-based approach

Increase of predictability in terms of PSUR submission

2014-09-26

12 PUBLIC

EURD list

Monthly updated by EMA (Updates published at end of each month with

changes highlighted in colour)

- Outcomes of procedures (e.g. referrals, safety variations, extension of

indication, renewal, PSUR assessments that result in change in DLP,

PSUR frequency)

- Authorisation of a new substance

- Harmonisation of DLP with IBD

The revised EURD List is adopted by the CHMP/CMDh after consultation of

the PRAC

Any change to the dates of submission and frequency takes effect 6 months

after the publication date

2014-09-26

13 PUBLIC

PSUR Work Sharing

During the transition period until single assessment is established some

active substances for NAPs have been temporarily removed from the EURD

and have been included in the ‘List of Substances under PSUR Work

Sharing Scheme and Other Substances contained in Nationally Authorised

Products with DLP Synchronised’.

2014-09-26

14 PUBLIC

New PSUR services

Changes to EMA organisation announced 26

March 2014

Revised operations for PSURs

New roles:

- Procedure Manager (PM) - oversees all

aspects of the management of procedure

(main contact).

- Procedure assistant (PA)

- Specialised input from risk management

specialist, or regulatory affairs as needed.

Allocation of PM and PA well in advance of

submission

Pre-submission queries:

PSURquery@ema.europa.eu

2014-09-26

15 PUBLIC

PSUR preparation

2014-09-26

16 PUBLIC

New PSUR

Structure

- PSUR structure defined by law and includes a scientific evaluation of the

benefit-risk balance

- Regulation 520/2012, GVP Module VII, ICH E2C(R2) provide the

guideline on the format and structure

- Line listings no longer required

Benefit evaluation

- Important efficacy-effectiveness information

- Newly identified efficacy-effectiveness information

Integrated benefit-risk analysis

- Importance of benefits and risks

- Discussion of the benefit-risk balance

2014-09-26

17 PUBLIC

Format

Part I Title page including signature

Part II Executive Summary

Part III Table of contents

1. Introduction

2. Worldwide marketing authorisation status

3. Actions taken in the reporting interval for safety

reasons

4. Changes to reference safety information

5. Estimated exposure and use patterns

5.1. Cumulative subject exposure in clinical trials

5.2. Cumulative and interval patient exposure from

marketing experience

6. Data in summary tabulations

6.1. Reference information

6.2. Cumulative summary tabulations of serious adverse

events from clinical trials

6.3. Cumulative and interval summary tabulations from

post-marketing data sources

7. Summaries of significant findings from clinical trials

during the reporting interval

7.1. Completed clinical trials

7.2. Ongoing clinical trials

7.3. Long-term follow-up

7.4. Other therapeutic use of medicinal product

7.5. New safety data related to fixed combination

therapies

9. Information from other clinical trials and sources

10. Non-clinical data

11. Literature

12. Other periodic reports

13. Lack of efficacy in controlled clinical trials

14. Late-breaking information

15. Overview on signals: New, ongoing or closed

16. Signal and risk evaluation

16.1. Summaries of safety concerns

16.2. Signal evaluation

16.3. Evaluation of risks and new information

16.4. Characterisation of risks

16.5. Effectiveness of risk minimisation (if applicable)

17. Benefit evaluation

17.1. Important baseline efficacy and effectiveness

information

17.2. Newly identified information on efficacy and

effectiveness

17.3. Characterisation of benefits

18. Integrated benefit-risk analysis for authorised

indications

18.1. Benefit-risk context — Medical need and

important alternatives

18.2. Benefit-risk analysis evaluation

19. Conclusions and actions

20. Appendices to the periodic safety update report2014-09-26

18 PUBLIC

General principles

All relevant safety information- non-clinical studies;

- clinical trials, including research in unapproved indications or populations;

- spontaneous reports (for example, on the MAH’s safety database);

- MAH-sponsored websites

- product usage data and drug utilization information;

- published scientific literature or reports from abstracts including information presented at

scientific meetings; unpublished manuscripts;

- observational studies such as registries; active surveillance systems; systematic reviews

and meta-analyses;

- information arising from licensing partners, other sponsors or academic

institutions/research networks; patient support programmes;

- investigations of product quality;

- information from regulatory authorities.

Worldwide market authorization status- Should be by date so that the reader can follow the issues

(frequently ordered alphabetically by country)

Update on Regulatory or MAH actions taken for safety reasons

2014-09-26

19 PUBLIC

General principles

One report for one active substance

- Separate section for data relating to particular indication, dosage form, route of

administration, dosing regimen, patient population (eg paediatric use)

Separate PSUR in exceptional cases

Fixed combination:

- Separate PSUR with cross reference to PSUR for each substance

Joint PSURs possible (>1 MAH)

Each MAH responsible for PSUR

- Companies must share information

- Specify in the Agreement who is responsible

In-Licensed products

- Either submit licensor's PSUR report OR

- Submit own (refer to licensors report or include licensor's data)

2014-09-26

20 PUBLIC

Industry experience

Multiple request from CA to present data in “old style” PSUR format

Requests to include full narratives and CIOMS I forms

Requests presentation of cases by listedness

Requests for more details on individual cases rather than summary

Inclusion of line listings of all fatal cases

Requests for different presentations of data:

- HCP and consumer reports by SOC;

- Data presented by source, seriousness, listedness, medically confirmed etc.

Clinical Trial Information

- Requests to use the PSUR as a tool to update recruitment status of studies.

- Requests to provide a complete overview of all CTs

Signals

- Requests for cumulative signal data in the Table in Section 15

20

2014-09-26

21 PUBLIC

Procedural Issues

Challenges with timelines

-6 month PSURs overlap with Preliminary AR from previous PSUR,

expectation of MAH to complete AR process and next PSUR at the same time

-Final PRAC assessment report is not always received in time to incorporate

the comments into the next PSUR

-Short timeframe (changes to SmPC required within short time frames).

MAH Engagement

-Perceived lack of EMA contact for questions within tight timeframes

-Lack of direct contact with PRAC Rapporteur for any clarifications required

-Limited Opportunity for MAH interaction - day 90, PAR only. Opportunity to

appeal a decision?

21

2014-09-26

22 PUBLIC

PSUR SUBMISSION

2014-09-26

23 PUBLIC

PSUR submission

According to the EU reference dates list

- The list overrules any PSUR requirements laid down in the MA

According to a condition of the MA or

According to Art 107c (2) of Directive 2001/83/EC and Art 28 (2) of

Regulation (EC) N. 726/2004:- Every 6 months during the first 2 years

- One a year for the following 2 years

- Three-yearly intervals thereafter

PSURs also need to be submitted upon request from a CA

“If substance not in the list : follow the submission frequency as per condition

in the MA if any, otherwise, follow the standard submission schedule”

2014-09-26

24 PUBLIC

Pre-submission phase

Extended pre-submission phase to prepare submission with MAHs.

Notification to be sent to MAHs identified as part of the PSUSA in advance

of the submission date (advice note will be sent ca. 2 month prior to

submission date)

Advice note will include information such as:

- Procedure number

- Submission deadline

- Lead PRAC Rapporteur

- Submission requirements

- Line listing of authorised products

2014-09-26

25 PUBLIC

Pre-submission phase

Consolidation of submissions in the MS and/or Agency

- Experience shows that there is a need to consolidate submissions at

MS-level prior to start of PSUSA

After successful audit of PSUR repository, MAHs may still submit only to

MS for 12 more months

Introduction of a 10 working days delay between submission and start for

PSUSAs containing NAPs (for MS reconciliation)

Consolidated package will be made available to lead Rapporteur at start of

procedure

New terminology: “PSUSA cut-off date”.

2014-09-26

26 PUBLIC

To whom shall you submit PSUR?

CAPs

• PSURs to be submitted to:

• The EMA

• The Rapporteur appointed for the procedure

• All other Committee Members of the PRAC.

NAPs* involved in a PSUSA

• PSURs to be submitted to:

• All Member States in which the medicinal product has been authorised

• The EMA

• The PRAC Rapporteur appointed for the procedure.

Note: The term Nationally Authorised Product is intended to encompass medicines

authorised through MRP and DCP and purely nationally authorised products where

authorised in more than one Member State.

2014-09-26

27 PUBLIC

Requirements of the (Co-) Rapporteurs and other Committee members

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guidelin

e/2009/10/WC500003980.pdf

2014-09-26

28 PUBLIC

Current situation

Different formats of PSUR submissions in the MS for NAPs:

- eCTD

- NeeS

- Paper

Different extent of use of CESP

PSUR within eCTD product lifecycle in most MS preferred

PSUR submissions mostly stored within product related repository

2014-09-26

29 PUBLIC

Current situation

Submission requirements % NCA

Submissions through CESP can be used (optional) 58%

A signed copy of the cover letter should be provided in paper

together with the CD/DVD (wet signature)55%

A copy of the cover letter should be provided in paper with the

CD/DVD (no wet signature needed)26%

The eCTD or NeeS must include a scanned copy of the signed

Cover Letter39%

Email/EudraLink is accepted instead of the CD/DVD

(Max 80 MB)23%

National portal can be used (optional) - see NCA website. 3 % (UK)

National portal must be used - see NCA website. 3% (ES)

Electronic signatures are accepted 19%

2014-09-26

30 PUBLIC

PSUR submissions

E-Mail

Eudralink

Post

CESP

EudraVigilance

PRAC Recommendations

PSUR PSUSA

PSUR Repository

Current From Q1 2015

2014-09-26

31 PUBLIC

PSUR repository

Legal requirement for EMA to set up a PSUR repository (Article 25a of

Regulation (EC) 726/2004 as amended:

- The Agency shall, in collaboration with the national competent authorities and the

Commission, set up and maintain a repository for periodic safety update reports (hereinafter

the “repository”) and the corresponding assessment reports so that they are fully and

permanently accessible to the Commission, the national competent authorities, the PRAC,

the Committee for Medicinal Products for Human Use and the coordination group referred to

in Article 27 of Directive 2001/83/EC.

A common storage place for:

- PSUR

- PSUR assessment reports

- PRAC recommendations

Advantages:

- Centralised PSUR reporting

- Enhance access to data and information

- Fast benefit risk assessments of medicines.

PRAC Recommendations

PSUR PSUSA

MAH 1 MAH 2 MAH 3 MAH 4

CA 1 CA 2 CA 3 CA 4

2014-09-26

32 PUBLIC

PSUR Repository

Legal References

Regulation (EC) 726/2004 as

amended

- Article 25a

- Article 28 paragraph 3

Directive 2001/83/EC as

amended

- Article 107b paragraph 2

- Article 107b paragraph 1

Requirements

Accessibility of documents

Allow search and queries

Possibility to export the information

Performances requirements (speed,

scalability)

Allows unique identification

Submission of documents

Allow validation and quality monitoring

Download functionality

Storage capacity requirements:

- To store and archive a significant amount of

documents and the different versions

- The number of individuals PSURs received

per year is estimated to be 10,000

2014-09-26

33 PUBLIC

Documents to be stored in the repository

MAH cover letter

PSUR

Timetable for PSURs related procedure

PSURs Assessment Reports

Final assessment conclusions

Comments on PSURs Assessment Report

ICSRs Line Listing from the EudraVigilance Database

Summary Tabulations from the EudraVigilance Database

PRAC Recommendations following adoption of the Assessment Report

Coordination Group Position and detailed explanation on scientific grounds for the

differences to PRAC recommendations

1. CHMP opinion

2. Detailed explanation on scientific grounds for the differences to PRAC recommendations

Commission Decision

Update to the Product Information related to the procedure

List of Union Reference Dates and Frequencies of PSURs submission

2014-09-26

34 PUBLIC

Access to the PSUR Repository

European Commission

National Competent Authorities

PRAC Members

CHMP Members

Coordination Group Members

EMA Secretariat

MAHs

- Restricted access to MAH will simplify the process. This capability will be considered

based on a cost-implication analysis. If access cannot be granted, the EMA will provide the

MAH with the relevant documents via alternative methods (e.g. email or web posting).

The General Public.

- Final assessment conclusions, recommendations, opinions and decisions will be made

publicly available by means of the European medicines web-portal. Technical links may

have to be established between the PSUR repository and the web-portal.

2014-09-26

35 PUBLIC

Legal requirement

Q1-Q2 2014

Definition of user requirements

Q4 Pilot phase with

MAHs

Available in

Q1 2015

PSUR Repository

PSUR Repository planned to be available in Q1 2015 and compulsory in 2016

2014-09-26

36 PUBLIC

PSUR ASSESSMENT

2014-09-26

37 PUBLIC

PSUR single assessment (PSUSA)

Started in July 2012

CAPs

Started in April 2013 (EURD list

entered into force)

CAPs +

NAPs

DLP after 31st

August 2014

NAPs

2014-09-26

38 PUBLIC

Assessment report

A unique version of the AR is sent to all MAHs that submitted as part of a

PSUSA.

The EMA is redacting the documents by deleting confidential commercial

information and patient personal data (PPD) in accordance with the criteria

described in the HMA/EMA document on handling requests for access to

PSURs applied (EMEA/743133/2009).

A disclaimer is included in the EURD list:

- “Single Assessment Reports of PSURs are shared among all Marketing

Authorisation Holders involved in the concerned procedure.”

2014-09-26

39 PUBLIC

Recommendations on the handling of access to PSURs

EMEA/743133/2009. Access to PSURs has to be

only reactive and on request

The minimum personal data to be deleted to ensure

anonymisation of the information would require the

deletion of information on:

- Date of birth, (Reporting) country, Patient

identification code

“Commercially confidential information” is generally

considered to fall broadly into two categories:

- Confidential intellectual property, “know-how”,

and trade secrets (including e.g. formulas,

programs, process or information contained or

embodied in a product, unpublished aspects of

trade marks, patents, etc).

- Commercial confidences (e.g. structures and

development plans of a company).

2014-09-26

40 PUBLIC

Timetable

Day Action

Day 0 Start of the procedure according to the published timetable

Day 60 PRAC Rapporteur’s / Member State preliminary assessment report

Day 90* MAH and PRAC members’ / Member States comments

Day 105 PRAC Rapporteur’s / Member State updated assessment report (if

necessary)

Day 120 PRAC recommendation adoption with the final PRAC assessment

report

Day 134 CHMP opinion / CMDh position (in case PRAC recommends a

variation, suspension or revocation of the MA)

2014-09-26

41 PUBLIC

Day 90

The MAH is expected to provide, as applicable, by Day 90:

- responses to the “request for supplementary information” as outlined in the

relevant section of the PRAC Rapporteur / Member State PSUR preliminary

assessment report,

- comment on the proposed wording (in case the recommendation is a

variation),

- propose a wording in case the recommendation is a variation but no exact

wording is proposed by the PRAC Rapporteur / Member State,

- provide a justification in case the MAH does not agree with the PRAC

Rapporteur / Member State recommendation to vary, suspend or revoke the

MA; and/or

- include additional comments or clarification deemed necessary by the MAH.

2014-09-26

42 PUBLIC

Deviation from Principles of EU Legislation and ICH E2C

Inconsistent requests and interpretation by Assessors

- Lack of clarity regarding how assessors review signals and conclude on the data

- Expectation that old style PSUR will be followed re reviews

- Wide range of difference in experience and quality of Assessment Reports

Lack of understanding of the Global Nature of the PSUR/ PBRER

- Global implications of changing the EURD date/impact on submission outside

the EU

- Specific indication requests for Europe – this results in multiple and duplicated

work when annual PSUR/PBRER is not accepted in place of a six monthly report

( deviation from international harmonisation principles)

- Question in an AR: “What does PBRER stand for?”

42

2014-09-26

43 PUBLIC

PSUR assessment

SCOPE

Strengthening Collaborations for

Operating Pharmacovigilance in

Europe http://www.scopejointaction.eu/

Delivering tools for regulators

- “best practice”,

recommendations, guidance

based on successful

implementations

- Training (such as for PSUR

assessment)

WP 8 – Lifecycle PV

1. Identification of available data

sources outside spontaneous

reporting – lead: AIFA

2. Risk Management Plan assessments

– lead: NOMA

3. Post Authorisation Safety (and

Efficacy) Studies protcols and study

reports – lead: MPA

4. Benefit/risk assessment in the context

of PSUR and referral procedures -

lead: AIFA

5. Competency – lead: AIFA

2014-09-26

44 PUBLIC

SCOPE WP 8

2014-09-26

45 PUBLIC

Regulatory actions following assessment report

Maintenance of the MA

Suspension of the MA

Revocation of the MA

Variation of the MA

- new contraindication

- restriction of the indication

- reduction of the recommended dose

- SmPC/PL update (mainly changes to section 4.4 and 4.8 of the SmPC)

2014-09-26

46 PUBLIC

Maintenance of the MA

No change to Product Information/ Conditions of MA

Request for cumulative review

RMP update

Amendment of the EURD list:

- frequency of PSUR

- separate/single PSUR per indication, pharmaceutical form, fixed-dose

combination

Example from Jul 2014 PRAC meeting: Abatacept – ORENCIA

2014-09-26

47 PUBLIC

8th Stakeholder meeting

2014-09-26

48 PUBLIC

PSUR fee

REGULATION (EU) No 658/2014 OF THE EUROPEAN PARLIAMENT AND OF THE

COUNCIL of 15 May 2014 on fees payable to the European Medicines Agency for the

conduct of pharmacovigilance activities in respect of medicinal products for human use

From 26th of August 2014 the Agency charges procedure-based fees for the single assessment

of PSURs

- The fee for the assessment of PSUR is EUR 19 500 per procedure

For the PSUR assessment under a PSUSA procedure involving more than one MAH, the total

amount of the fee will be divided among all the MAHs concerned proportionately to the number

of chargeable units.

The MAH concerned will be established on the basis of the obligation to submit the PSUR(s)

and not on the basis of the actual PSUR submission(s) received by the EMA.

The total of chargeable units in the procedure will be identified from the Art. 57 database.

An advice note will be sent 3 months prior to the start date to the relevant QPPVs

The invoice will be sent to each MAH with the relevant chargeable units calculation. The fee will

be due to the EMA within 30 calendar days.

Reduced fee for an SME (i.e. micro-, small- or medium-sized enterprise) companies

2014-09-26

49 PUBLIC

Common inspection findings

Non-submission

- Complete non-submission of PSURs

- Submission the correct time frames

Poor quality reports

- Incorrect format of the document

- New safety signals not or poorly assessed

- Medication error not highlighted

- Absence of use of standardized medical terminology (e.g. MedDRA)

- Published literature is not properly reviewed

- No conclusion drawn

Omission of required information

- Update of Regulatory or MAH Actions taken for Safety Reasons

- Changes to Reference Safety Information

- Patient Exposure (poorly calculated, explanation of calculation is missing)

Previous requests from Competent Authorities not addressed (e.g. close

monitoring of specific safety issues)2014-09-26

50 PUBLIC

Conclusions

Where we are?

Still in learning phase

Gained experience with CAP and mixed

single assessments for CAPs and NAPs

- Harmonization and efficiency

- Rapid update of product information

- Areas for clarification

Room for improvement

Transparency

What is next?

PSUR single assessment for NAP (PSUSAs)

PSUR repository

Planned update of the PSUR template

2014-09-26

2014-09-26