Pharmacovigilance Inspection - AIFA

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Pharmacovigilance Inspection

Angela Del Vecchio

7 settembre 2013

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Public Declaration of transparency/interests*The view and opinions expressed in the following PowerPoint slides

are those of the individual presenter and should not be attributed to AIFA

Activity for a company related to a singleproduct/group of products NO Currently Last 2 years

More than 2 years but less than 5 years

ago

More than 5 years ago(optional)

Employee x

Consultant x

Principal Investigator x

Member of a steering committee , an advisory board or similar body x

Investigator (not principal) for a medicinal product development x

Financial interests in a pharmaceutical company x

I own a drug patent x

I work in an organisation that receives grant or other funding from a pharmaceutical company (I do not receive personal gain) x

NB: The compensation received is based on the collective bargaining agreement

*Angela Del Vecchio, in accordance with the Conflict of Interest Regulations approved by AIFA Board of Directors (26.01.2012) and published on the Official Journal of 20.03.2012 according to 0044 EMA/513078/2010 on the handling of the conflicts of interest for scientific committee members and experts

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Overview

• What is Pharmacovigilance with references• Why Pharmacovigilance inspections with references• Preparation for the inspection• At the inspection site• Reporting and post inspection• Common findings

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What is Pharmacovigilance?The process of monitoring, evaluating andimproving the safety of medicines in use

Why?

• Limited exposure to product during clinical trials in controlled populations

• Important to monitor medicines post authorisation as new safety issues can became apparent, e.g. Lipobay

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References (1)Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use as amended- (Dir.2010/84/EU) TITLE IX: PHARMACOVIGILANCE (Art.101-108b)

Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community Procedures for the authorisation and supervision of Medicinal Products for human and veterinary use and establishing an European Medicines Agency, as amended (Reg.1235/2010)

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References (2)Commission Implementing Regulation N.520/2012 of 19 June 2012 on the performance of the pharmacovigilance activities provided for in Reg.N.726/2004 and Dir. 2010/83

Volume 9A “Guidelines on Pharmacovigilance for Medicinal Products for Human Use” of the Rules Governing Medicinal Products in the European Union

GVP

Good Vigilance Practice (GVP)

• Good pharmacovigilance practices (GVP) are a set of measures drawn up to facilitate the performance of pharmacovigilance in the European Union (EU)

• Key deliverable of the 2010 pharmacovigilance legislation

• Drawn up based on Article 108a of Dir 2001/83, as amended

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Who?

HCPsPatients

Companies

MAH

NCAs

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Every day a MAH can receive different types of reports

Spontaneous Report

Clinical Trial Reports

Solicited reports

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Definitions• Adverse event

Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment (Eudralex vol.9A-directive 2010/20/EC).

• Adverse Drug Reaction A response to a medicinal product which is noxious and unintended (Eudralex vol.9A-directive 2001/83 as amended). It means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility

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Information sources

HCPs

Regulatory reports

Consumer/patient reports

Interventional and non interventional clinical studies

Literature reports

Registries

Other Company’s personnel

Other Companies

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What does the Company have to do? REVIEW

Seriousnessan ADR that results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect (Eudralex vol.9A-Directive 2001/83/EC as amended)

Expectednessan unexpected ADR is when the nature, severity or outcome of the reaction is not consistent with the SPC (Eudralex vol.9A-Directive 2001/83 as amended) or Investigator’s brochure

CausalityIf an AE is reported to the Company spontaneously, it should be treated as causally related unless the reporter explicitly states otherwise, that means there is a possible causal relationship between

the drug and the event

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Next step

• Case narratives

• Coding (medDRA)

• Follow up

• Reporting

An identifiable patient

A suspect drug

A suspect reaction

An identifiable HCP reporter

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MAHs tasks• To establish and maintain a PHV system:

-To have permanently and continuously at its disposal an appropriately qualified person responsible for pharmacovigilance, who resides in EU-To operate a risk management system for each medicinal product-To collect and evaluate suspected adverse drug reaction (ADR) reports-To maintain records of all suspected ADRs whether reported spontaneously by patients or HCPs or occurring in the context of a post-authorisation study-To maintain a PSMF-To submit electronically to Eudravigilance both serious and non serious suspected ADRs-To maintain and record all AE detected during a CT-To report to NCAs and ECs SUSARs (7 or 15 days)

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Other Pharmacovigilance Activities of MAH

Signal Detection PSURs

Annual Safety

Reports

Comply with actions requested by NCA and EMA

Training

C

C

o

l

l

Contract/

agreement

Risk management plans

Quality Assurance Audit

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Why Pharmacovigilance Inspections?

• To safeguard public health by assessing whether a MAH is complying with applicable pharmacovigilance legislation and guidelines

• To protect the patients by detecting and taking appropriate action in response to non-compliance with pharmacovigilance obligations

References

D.Lvo 219/2006Transposition law of Directive 2001/83 on the Community code relating to medicinal products for human use

Art.134Aifa shall ensure, by repeated inspections, that the dispositions of title IX are followed, inspecting the premises, records and documents of marketing authorisation holders

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ReferencesDirective 2001/83/EC, as amended

TITLE XI: SUPERVISION AND SANCTIONS

Article 111 (1)

The Competent authority of the Member State concerned shall, in cooperation with the Agency, ensure, that the legal requirements governing medicinal products are complied with, by means of inspections, if necessary unannounced, …………….

Such inspections shall be carried out by officials representing the competent authority that shall be empowered to: (d) inspect the premises, records, documents and PSMF of the MAH or any firms employed by the MAH to perform the activities described in Title IX.

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Regulation (EC) No 726/2004, as amended

TITLE II: AUTHORISATION AND SUPERVISION OF MEDICINAL PRODUCTS FOR HUMAN USE

Chapter 2: Supervision and penalties

Article 19 (1)

The supervisory authorities for pharmacovigilance shall be responsible for verifying on behalf of the Union that the marketing authorisation holder for the medicinal product satisfies the pharmacovigilance requirements laid down in Titles IX and XI of Directive 2001/83/EC. They may, if this is considered necessary, conduct pre- authorisation inspections to verify the accuracy and successful implementation of the pharmacovigilance system as it has been described by the applicant in support of his application.

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TITLE IV: THE EUROPEAN MEDICINES AGENCY - RESPONSIBILITIES AND ADMINISTRATIVE STRUCTUREChapter 1: Tasks of the Agency

Article 57 (1)

…..the Agency, ……. shall undertake the following tasks:

coordinating the monitoring of medicinal products for human use which have been authorised within the Union and providing advice on the measures necessary to ensure the safe and effective use of these medicinal products for human use, in particular by coordinating the evaluation and implementation of pharmacovigilance obligations and systems and the monitoring of such implementation

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Volume 9A “Guidelines on Pharmacovigilance for Medicinal Products for Human Use”

PART I: GUIDELINES FOR MARKETING AUTHORISATION HOLDERSChapter 2: Requirements for Pharmacovigilance Systems, Monitoring of

Compliance and Pharmacovigilance Inspections

2.1.4 Pharmacovigilance InspectionsThe legal basis for the conduct of Pharmacovigilance inspections is set out in Article 111 of Directive 2001/83/EC and in Article 19 (1) of Regulation (EC) 726/2004.2.3 Monitoring of Compliance by the Competent AuthoritiesCompetent authorities will ensure that a system of pharmacovigilance is in place within Marketing Authorisation Holders through scrutiny of the detailed description of pharmacovigilance, procedures, safety reports and through pharmacovigilance inspections.

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GVP

Module Number

Module title Publication date

I Pharmacovigilance Systems and their Quality Systems

2 July 2012

III Pharmacovigilance Inspections12 December

2012IV Pharmacovigilance Audit

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Inspection procedures for PHV inspections conducted in the context of the Centralised

ProcedurePROCEDURE FOR THE PREPARATION OF A RISK-BASED PROGRAMME FOR ROUTINE PHARMACOVIGILANCE INSPECTIONS OF MAHs CONNECTED WITH HUMAN CENTRALLY AUTHORISED PRODUCTS (CAPs)

PROCEDURE FOR COORDINATING PHARMACOVIGILANCE INSPECTIONS REQUESTED BY THE CHMP

PROCEDURE FOR CONDUCTING PHARMACOVIGILANCE INSPECTIONS REQUESTED BY THE CHMP

PROCEDURE FOR REPORTING OF PHARMACOVIGILANCE INSPECTIONSREQUESTED BY THE CHMP

National SOPs (1/2)

• POS 282 “STESURA ED AGGIORNAMENTO DELLA LISTA DEGLI ISPETTORI DI FARMACOVIGILANZA”

• POS 283 “FORMAZIONE, AGGIORNAMENTO E COMPETENZA DEGLI ISPETTORI DI FARMACOVIGILANZA”

• POS 284 “PROGRAMMAZIONE DELLE ISPEZIONI DI FARMACOVIGILANZA”

• POS 285 “RICHIESTA DI ISPEZIONI DI FARMACOVIGILANZA DA PARTE DI ALTRI UFFICI/UNITA’ DELL’AIFA”

• POS 286 “PREPARAZIONE DELLE ISPEZIONI DI FARMACOVIGILANZA”

• POS 287 “CONDUZIONE DELLE ISPEZIONI DI FARMACOVIGILANZA”

National SOPs (2/2)

• POS 288 “STESURA DEL VERBALE DELLE ISPEZIONI DI FARMACOVIGILANZA”

• POS 289 “GESTIONE DELLE DEVIAZIONI E DEL FOLLOW UP”• POS 290 “ARCHIVIAZIONE DELLA DOCUMENTAZIONE DELLE

ISPEZIONI DI FARMACOVIGILANZA ”• POS 291 “GESTIONE DELLE ISPEZIONI DI FARMACOVIGILANZA

RICHIESTE DALL’EMA”

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Routine PhV inspections of MAHs with CAPs

According to the Volume 9A, the CHMP, in conjunction with the Competent Authority of the Member State (MS) in whose territory the MAH’s QPPV is located and applicable Pharmacovigilance and Inspectors’ Working Parties, will determine a programme for inspection in relation to centrally authorised products (CAPs). These inspections will be prioritised based on the potential risk to public health, the nature of the products, extent of use, number of products that the MAH has on the EEA market and other risk factors.

EMEA/INS/PhV/105504/2008PROCEDURE FOR THE PREPARATION OF A RISK-BASED PROGRAMME FOR ROUTINE PHARMACOVIGILANCE INSPECTIONS OF MAHs CONNECTED WITH HUMAN CENTRALLY AUTHORISED PRODUCTS (CAPs)

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Who is the responsible authority?

Routine inspections of MAHs with CAPsIt is anticipated that national inspection programmes will fulfill the need for the routine inspections of this programme and, therefore, it is expected that this programme focused on CAP products will be achieved mainly through the national programmes. Therefore, when a Competent Authority has carried out, or intends to carry out an inspection covering the scope of that requested within the required timeframe, this inspection will suffice and its results will be made available to the CHMP or to the applicable reviewing agency.

EMEA/INS/PhV/105504/2008PROCEDURE FOR THE PREPARATION OF A RISK-BASED PROGRAMME FOR ROUTINE PHARMACOVIGILANCE INSPECTIONS OF MAHs CONNECTED WITH HUMAN CENTRALLY AUTHORISED PRODUCTS (CAPs)

GVP National ProgrammeRoutine programme

Selection of MAHs, based on a systematic and risk-bases approach (GVP III, B.2)

MAHs included in EMA programme

Triggered inspections

Inspection requests from PV office or other AIFA offices

Inspection requests from CHMP/EMA

Panoramica del processo di ispezione di Farmacovigilanza

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INSPECTION Phases

1.Preparation2.Conduction3.Reporting

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1. Preparation

• RSF (Summary of Pharmacovigilance System)It is submitted in paper and electronic format and contains:

-address and contact details-list of the products marketed in the EU-list of clinical trials-PHV system description-computerised system description-description of contractual agreements with third parties-description of quality management system-description of archives

In addition to the RSF, specific SOPs and PSURs may be requested in advance of the inspection

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1. Preparation

• External resources-Internet

#Company’ website#EMA’s website#FDA ‘s website

-Other PHV Inspectorates• Internal resources

-Feed back from assessors-Information from other AIFA inspectorates-Actual documents sent and received by AIFA-Check of the Italian Pharmacovigilance Network

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1. Preparation• Formulate an Inspection Agenda• Send it to the Company (approx.2 weeks before)

– Availability of key personnel

• Travel arrangements

• Fees

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2. Conduction

The aim is to review global and local PHv activities

• Opening meeting• Interview sessions• Document review• Demonstration of the safety database• Closing meeting

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2. Conduction (1)

Opening meeting

• introductions• confirm purpose of inspection• explain the regulatory framework for the conduct of the

inspection• review inspection plan & methodology• confirm that the resources, documents and facilities are

available• confirm the time and date for the closing meeting• questions• obtain overview of the organisation

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2. Conduction (2)

The Qualified Person for Pharmacovigilance (QPPV)

• Roles and responsibility• Oversight of the compliance of the system with regulatory

requirements• Availability (outside normal working hours, deputy)• Training (appropriately qualified)• Authority to make changes• Knowledge of the Company’s PHV processes• Notification to NCAs (name and contact details)• Contract (if applicable)• Availability of a Physician • SOPs

2. Conduction (3)

Management of pharmacovigilance ADR reports

– Receipt and case tracking– Duplicate checks

Collection

– Coding

– Medical review– Causality assessment

Evaluation

– Expectedeness/Listedness

– Data entry

Processing– Follow up

– Reporting to Authorities

Reporting

– QC– SOPs

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2. Conduction (4)

Database• Validation

– User requirements– Validation master plan– Validation reports– Change control

• Data protection• Back up• Data migration• SOPs

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2. Conduction (5)

PSUR• Production according to guidelines:

• Data from relevant sources• Line listing/ summary tabulations• Coding according to MedDra

• Quality Control• Schedule for submission • Conclusion on overall risk-benefit balance • QPPV oversight

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2. Conduction (6)

Signal detection

• Consistency and adequately of data included in the review• Frequency of review• Confirmation of signal:

• Evaluation• Update of SPC

• Documentation of decisions

• SOPs

• Training

2. Conduction (6)

PSUR: where and what we can look for

• PSUR schedule including submission dates & EU HBDs• Details of products under PSUR work-sharing process• PSUR covering letters, assessment reports• PSUR SOPs/Work Instructions/templates• Current/previous versions of RMPs• Line listings of adverse reactions • PSURs & assessment reports for review

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2. Conduction (7)

Training• PHV personnel• Clinical department personnel• Manufacturing personnel

……but also• Sales representatives • Receptionists

• SOPs

• Training records and plans

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2. Conduction (8)

Procedural documents• Policies, SOPs, work instructions• Approval, distribution, revision, destruction, archive• Paper and/or electronic documents • SOPs Training

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2. Conduction (9)

Quality assurance• Audit scope, methodology, plan• Audit report, distribution, follow up• External auditor: selection, contractual agreement, training and

SOPs• Affiliates, co-partners, CRO

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2. Conduction (10)

Literature Searches

• Frequency of searches• Search criteria• Database• Processing of ADRs identified

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2. Conduction (11)

Clinical Trials• Interactions between Clinical Team and PHV personnel

• Investigator’s Brochure • Protocol• New studies

• Processing of AE/SAE

• Reporting of SUSARs to NCA, ECs, Investigators

• Annual Safety Reports/Development Safety Update Report (DSUR)

• Riconciliation between clinical trial database/safety database

• SOPs

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2. Conduction (12)

Interaction between PHV department and other departments

• Interface between PHV and Medical Information• Interface between PHV and Product quality• Interface between PHV and Regulatory Affairs• Interface between PHV and Marketing

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2. Conduction (13)

Contracts and agreements (outsourcing, co-licensing/ marketing, distributors/manufacturers)

• Availability• Signatures and dates• Roles and responsibilities• Maintenance, review and update• SOPs

2. Conduction (13)

Contracts and agreements

• Is there a list of agreements available and update?-who is responsible for its preparation and update?-it is made available to uther functions/departments inside the company?

• Is PV personnel informed and involved in agreements preparation?• Are roles and responsibilities for PV between parties clearly defined

in the agreements?• Is the management of safety agreements described in a SOP/WI?• Is the topic of use of SOPs covered in the agreements?

2. Conduction (14)

Updating Reference Safety Information (CCDS, SPC, IB)Common inspection findings

Following identification of a new safety signal & MAH decision to update the CCDS, delays in submitting variation(s) to update the SPC(s). Delays of over a year have been observed.

Delays in implementing SPC and PIL changes following approval of safety variations.

Poor processes for ensuring that the minimum core safety information contained in the CCDS is consistently represented, as appropriate, in local product information.

Unwarranted inconsistencies in safety information between reference documents e.g. CCDS, SPC(s) and IB.

Use of inappropriate reference safety document for the determination of expectedness.

Wrong version of the SPC made available to health care professionals e.g. on the eMC web site.

2. Conduction (15)Transition from Detailed Description of the Pharmacovigilance System (DDPS) to the Pharmacovigilance System Master File (PSMF)

The new legislation requires the introduction of a Pharmacovigilance System Summary in the marketing authorisation (MA), and removes the requirement for new applications to contain a Detailed Description of the Pharmacovigilance System, DDPS. From July 2012, new applications should be prepared and should not contain a DDPS. DDPS variations for existing applications are still required until a Pharmacovigilance System Summary has been introduced, and therefore will continue to be required for some MAs until July 2015.

2. Conduction (15)

Transition from Detailed Description of the Pharmacovigilance System (DDPS) to the Pharmacovigilance System Master File (PSMF)

DDPS: A document describing the different procedures and actors dealing with a MAH’s pharmacovigilance activities for specific licensed products.

PSMF: Essential documents describing the phv system to reflect global safety information

description of the- processes - data handling - records

2. Conduction (15)

Content of PSMF

• QPPV/back-up• Organisational structure• Sources of safety data• Computer system/databases• Processes• Phv system performance• Quality system• Annexes

2. Conduction (15)

PSMF – annexes

• List of medicinal products covered by the phv system• List of products monitored in different phv systems• List of products/MAHs sharing a phv system• List of contractual agreements/delegations• List of tasks delegated to different QPPVs• List of completed audits last 10 years and scheduled• List of performance indicators• List of other phv systems hold by the same MAH• Logbook on the performance of phv activities

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2. Conduction (16)

Closing meeting

At the end of the inspection, the inspector(s) should hold a closing meeting with the inspectee(s).

The main purpose of this meeting is to present inspection findings to the inspectee(s) and to ensure that the results of the inspection are clearly understood and that there are no misunderstanding by either the inspector(s) or the inspectee(s).

-Feedback-Issues-Observations-Recommendations for corrective actions

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3. Reporting

• Must be clear and understandable

• Must reflect the conduction of the inspection

• Must evaluate the compliance with (EU and) national regulations and guidelines

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CLASSIFICATION OF INSPECTION FINDINGS

Critical: a deficiency in pharmacovigilance systems, practices or processes that adversely affects the rights, safety or well-being of patients or that poses a potential risk to public health or that represents a serious violation of applicable legislation and guidelines. Major: a deficiency in pharmacovigilance systems, practices or processes that could potentially adversely affect the rights, safety or well-being of patients or that could potentially pose a risk to public health or that represents a violation of applicable legislation and guidelines. Minor: a deficiency in pharmacovigilance systems, practices or processes that would not be expected to adversely affect the rights, safety or well-being of patients

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POST-Inspection

• Report written in 60 days• Company’s response (CAPA) within 30 days• Evaluation of CAPA• If it is the case, second follow up• Close out inspection

Common findings (1)• The Qualified Person for Pharmacovigilance (QPPV)

– No QPPV or interim measures (change of QPPV, back-up procedures for absence etc.)

– Failure to notify Competent Authorities of QPPV details– Inadequate oversight of the pharmacovigilance system (ICSRs,

PSURs, PASS, Safety profile of products, audits, SOPs, database)– Lack of training and/or experience– Roles and responsibilities not formally defined (especially

important if parts of role are delegated)– Inadequate access to medically qualified personnel

Common findings (2)• PSUR

Common inspection findings before GVP 7

– Production – No procedure, not in desired format, not a consistent standard

– Standard searches not validated (no impact assessment of database changes on queries generated)

– Lack of Quality control– Incomplete – missing cases, no summary tabulation, does not

address Competent Authority requests– Submissions – No mechanism to track (QPPV oversight), late

submissions, no submission– No simultaneous submission (or deadline to submit included in

cover letter) of a Type II variation where proposed changes to SPC have been included in PSUR

– We have very limited experience of reviewing new format PSURs

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Common findings (3)

• Quality assurance:– Lack of PHV audits (no plans)– Lack of audits of affiliates, contractors– External auditor with inadequate experience- no

training• Procedural documentation:

−Procedures do non reflect the practice

−Lack of key procedures

−Poor procedures

−No revision

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Common findings (4)

• Case processing:– ADRs do not collected in a single point in UE– No reconciliation– No follow up– No medical review– No QC– Late reporting

Common findings (5)• Contracts and agreements (outsourcing, co-licensing/ marketing,

distributors/manufacturers)

– Lack of contracts with third parties, or contracts still in draft– Insufficiently detailed

• Responsibilities of each party• Exchange of ADRs (and other special situation cases) and

product complaints• Exchange of changes to Reference Safety Information• Timelines• Reconciliation

– Review period (changing regulations will likely change the agreement)

http://www.agenziafarmaco.gov.it/it/content/ispezioni-di-farmacovigilanza

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CONTATTI

Tel: 0039 06 5978 4357email: [email protected]: www.agenziafarmaco.it