New EU-PV Regulations

Dr. Vijay bhushanam

New legislation - Goals

Reduce the burden of ADRs and optimise the use of medicines Clarify roles and responsibilities Science based, Risk based/proportionate approach Increase proactiveness, Reduce redundancy Integrate benefit and risk Ensure robust and rapid EU decision-making Strengthen the EU Network Engage patients and healthcare professionals Increase transparency, awareness and accountabilityProvide better information on medicines

New legislation - Aims

Improve the EU-PV system Simplify regulatory decision making Provide a legal basis for proactive Pharmacovigilance Involve patients more closely in the reporting of ADRs

Overall Objective: “To protect public health”

New legislation - Timeline

2003: EC decision to undertake an assessment of PV system2005: Independent study completed2006- 2008: Research, consultation, policy development2010: New legislation adopted by the European Parliament

and European Council (Dec 2010)2012: First wave of requirements entered into force (2nd July)2012: GVP Guidelines (16 modules) finalized after public

consultation (February and December 2012)

Major/Key changes1. The new Good Vigilance Practice Guidelines (GVP)2. The Pharmacovigilance Risk Assessment Committee (PRAC)3. The Pharmacovigilance System Master File (PSMF)4. Using a Periodic Benefit Risk Evaluation Report (PBRER)5. More stringent ICSR submission rules6. Publishing summaries of Risk Management Plans (RMP)7. Requirement to perform Post-Approval Safety Studies (PASS)8. Assignment of an Additional Monitoring Status 9. Commitment to openness and transparency10. Eudravigilance policy to disclose postmarketing safety

information to the Public

Major/Key changes – GVP

Good Pharmacovigilance Guidelines(GVP):

Replaces Eudralex Volume 9A.Applies to all medicinal products, irrespective of the MA

granting procedure.Divided into 16 modules.Uses MedDRA terminology.

Major/Key changes – GVPGVP - Table of Contents Status

Introduction Completed

Final GVP chapters

• Modules Most of them Adopted

•Product or populationb specific considerations Open for public consultation

Final GVP Annex I - Definitions Adopted

Final GVP annex II - Templates Adopted

Final GVP annex III - Other pharmacovigilance guidance Most of them Adopted

Final GVP annex IV - ICH guidelines for pharmacovigilance Adopted

Final GVP annex V - Abbreviations Published

Draft GVP chapters and annexes for public consultation Open for public consultation

Templates for submission of comments Published

Privacy statement for public consultation Published

Major/Key changes – GVPMod. no.

Title Status Effective from

I Pharmacovigilance systems and their quality systems Adopted 2nd July 2012

II Pharmacovigilance system master file Adopted 12th April 2013

III Pharmacovigilance inspections Adopted 12th Dec 2012

IV Pharmacovigilance audits Adopted 12th Dec 2012

V Risk management systems Adopted 2nd July 2012

VI Management and reporting of adverse reactions Adopted 2nd July 2012

VII Periodic safety update report Adopted 2nd July 2012

VIII Post-authorisation safety studies Adopted 25th April 2013

VIII add-I

Member States' requirements for transmission of information on non-interventional PASS

Adopted 25th April 2013

Major/Key changes – GVPMod. no.

Title Status Effective from

IX Signal management Adopted 2nd July 2012

X Additional monitoring Adopted 25th April 2013

XI Public participation in pharmacovigilance Under Dev. Q3, 2013

XII Continuous PV, ongoing benefit-risk evaluation, regulatory action, planning of public communication

Under Dev. Q3, 2013

XIII Incident management (to be included in module XII) Under Dev. Q3, 2013

XIV International cooperation Under Dev. Q3, 2013

XV Safety communication Adopted 23rd Jan 2013

XVI Risk-minimisation measures: selection of tools and effectiveness indicators

Under Dev. Q2, 2013

Major/Key changes - PRAC

Pharmacovigilance Risk Assessment Advisory Committee (PRAC): A new EMA committeeMeets monthly from September 2012Replaces the Pharmacovigilance Working Party

Advises toCHMP and CMDh

Members include (appointed by MS and EC)

Experts from the EU Member States Representatives from Patient organisations Representatives from Healthcare professionals

Major/Key changes - PRAC Due regard to

Risk Management Systems Therapeutic effect of the products Periodic Safety Update Reports Signal detection Additional Monitoring Status Urgent procedures Design and evaluation of PASS Pharmacovigilance inspections

Major/Key changes - PRAC

Major/Key changes - PSMF

Pharmacovigilance System Master File (PSMF) replaces DDPS.MA applicants and MAHs are required to maintain PSMF.To be provided within 7 days upon request by the EMA.

The Pharmacovigilance System Summary comprises of:a signed statementthe location of PSMFthe name and contact details of the QPPVthe Member States in which the QPPV resides and operatesproof that the applicant has a QPPV

Major/Key changes - PBRER

Periodic Benefit Risk Evaluation Report (PBRER)Replaces Periodic Safety Update Report (PSUR)Scope changed from interval safety analysis to benefit-risk

evaluationIncludes a Benefit versus Risk statement New evaluation sections, including a section to give an

overview on signals (tabulated as new, ongoing or closed)Interval listings no longer required Deletion of the chapter “Analysis of individual case histories”

Major/Key changes - PBRER Not required for generic products, well-established use products,

homoeopathic products and traditional herbal productsSix-monthly reports, summary bridging reports, or addendum

reports will not be accepted. Time interval between data-lock point and submission –

expanded.New assessment procedure involving PRAC.Assessment will lead to automatic regulatory action (i.e,

variation, suspension or revocation).Assessment reports of PSURs will be published on a European

medicines web portal.

Major/Key changes - ICSR

Individual Case Safety Report (ICSR) Submission RulesRequirement to submit non-serious ICSRs is extended to cases

reported from Post-authorization solicited settings such as: Post-Authorisation Safety Studies (PASS) Post-Authorisation Efficacy Studies (PAES) Non-Interventional Studies (NIS) Patient Support Program (PSP) Market Research Studies (MRS)

Non-serious ICSRs shall be submitted within 90 days to EudraVigilance

Major/Key changes - RMP

Risk Management Plan (RMP) is divided into several parts.The RMP will include

a summary of the efficacy of the product.an evaluation of the effectiveness of risk minimisation

measures.PRAC will have regulatory oversight of RMPs.PRAC will appoint a rapporteur for an individual RMP, who

will work with the (co-) rapporteur appointed by CHMP.Summaries of RMPs shall be made publicly available via web

portals.

Major/Key changes - RMP

Educational materials for health professionals and patients are required in RMP for a new product.

UK version must be submitted to the MHRA prior to issue. MA application (after 21 July 2012) are required to submit a

RMP. Includes generic MA applications also. Should be submitted in template for the EU-RMP.

For MAs granted before 21 July 2012 without an existing RMP - no obligation to submit a RMP (unless concerns arise).

Major/Key changes – PASS/PAESPerforming a PASS/PAES may be required at first

authorisation as well as post-authorisation.The Competent Authority may impose an obligation on

the MAH to conduct such a study.If the same safety concern applies to more than one

product a joined PASS may be advised.New information detected during such studies shall be

communicated to the competent authority.Proposed format and content of study protocols/reports.

(outlined in GVP module VIII)

Major/Key changes – Additional monitoring list

The Additional Monitoring Status Can be assigned at any time of the product life cycle

Subjected to more intense scrutiny (same as UK’s ‘Black Triangle’ list).

Published on MHRA site www.mhra.gov.uk/blacktriangle.Also available on the EMA website.

EU-wide list (published by EMA) will replace the Black Triangle list previously published by the MHRA.

MAHs can remove Black Triangle status without contacting the MHRA. (for products that are not listed on additional monitoring list)

Major/Key changes – Openness and transparency

Provides the public with information aboutThe safety of marketed medicines.How to report suspected ADRs.

If MAHs want to make a public announcement, they shall inform the NCA, the EMA and the EC.

Two important changesEU public hearings.Creation of medicines web portals.

Major/Key changes – Openness and transparencyThe UK web portal is required to host

SPCs and PILsUKPARs (now a legal requirement)Summaries of RMPs for medicines authorisedProducts subject to additional monitoringThe MA conditions with deadlines for fulfilment

Setup of interconnected web-portals: European medicines web-portal (www.ema.europa.eu)

maintained by the EMA Will be linked to national web-portalsAlternative reporting media remains available

Major/Key changes – EudraVigilance Access Policy

ICSRs are expected to be submitted by MAHs directly to EudraVigilance rather than via National Health Authorities

Formerly, only Member State HA, the EMA and the European Commission had access to EudraVigilance.

The EudraVigilance access policy is changed to allow HCPs, patients and consumers, as well as MAH and research organisations accessing the information

Major/Key changes – ADR reporting/Signal management

New Definition of Adverse Reaction*: A response to a medicinal product which is noxious and

unintended.Also covers

Medicinal errors Uses outside the terms of the MA

off-label use misuse abuse

*Article 1, 11-D

Major/Key changes – ADR reporting/Signal managementCentralised reporting

By industry to the Eudravigilance database at EMA. Will come into effect 6 months after the Eudravigilance functionality is

approved. Likely to be sometime in 2015.Until then transitional measures will apply.

Inclusion of reports from patients as valid, reportable ADRs. Only medication errors that result in a serious ADR should be submitted.Non-serious cases should not be reported to EudraVigilance during the

transitional period.Sending non-UK serious consumer reports by the company is not

mandatory.

Major/Key changes – ADR reporting/Signal management

OLD NEW

Major/Key changes – ADR reporting/Signal management

MAHs should report cases from the literature. Avoid duplication by monitoring the MHRA website.

MAHs should review sites under their control for valid cases.No need to review internet sites not under the MAH’s

control (blogs, chatrooms and social media pages).MAHs will also be required to monitor the Eudravigilance

database according to their level of access. Signals should follow a process of validation, prioritisation

and assessment.

Major/Key changes – Audit/Inspection

PSMF should be made available to the NCA upon request.Changes to PSMF will not be automatically notifiable to the

Competent Authorities. Transitional period for introduction of PSMF ends in July 2015.Quality Systems:

MAHs, NCAs and the EMA will be required to have a quality system in place.

Particularly for resource management, staff training, procedural documentation, quality control, monitoring, and improvement.

Major/Key changes – Audit/Inspection

Inspections:Harmonisation of inspection activities in the EU.Legal basis for the conduct of pre-authorisation inspections. Adequate pharmacovigilance system as a condition of MA. MA applicants should be aware that the PSMF may be

requested.For centrally authorised products, the Supervisory Authority

will be determined by the PSMF location. MHRA will continue to operate a risk-based inspection

programme.

ConclusionNew legislation:

Provides strong legal basis for use of MedDRA through all steps of the pharmacovigilance process

Major change project that will take a few years to fully implement

Provides an opportunity to greatly improve the European system for the benefit of public health

THANK YOU