VOLUME 9A guidelines for Pharmacovigilance in EU& key differences in US & Japan

Dr. Siddarth S. ChachadMedical & Safety Expert (Regulatory Affairs), Cipla Ltd., India

Treatment may be worse than the disease

During the 1990’s, the deaths of two healthy volunteers

in the US made their way to the highest political levels

and forced a review of protection of human subjects.

Ellen Roche24 year old

Healthy Volunteer

Asthma study

Jesse Gelsinger18 year old

Healthy VolunteerGenetic Study

In March of 1994, the U.S. Office of

Research Integrity announced that

Dr. Roger Poisson from Montreal

admitted having falsified data (99

cases) in a breast cancer clinical trial

sponsored by the U.S. National

Cancer Institute (NCI).

This well-intended falsification

compromised the contribution of

hundreds of women enrolled in the

protocol as all data from the 389

patients enrolled by Dr Poisson were

removed from the analysis.

Dr. Roger Poisson

We need sound science, ethics and safety in clinical trials to sustain the trust of government, public and, especially, the research subjects.

Limitations of addressing Patient Safety in clinical trials The opinion of clinicians only what they feel is right is

not sustainable.

Healthcare is a system, and so standardization of patient safety research methods is essential.

Off-label use also needs to be addressed.

Clinical trial is a model situation that has little value in terms of real life health outcomes.

Thus, in order to have complete assessment of the drug in real life setting, safety reporting in post-authorisation era or pharmacovigilance is equally important.

Legal Basis of Volume 9A Article 106 of Directive 2001/83/EC and Article 26

of Regulation (EC) No 726/2004 specifically requires the European Commission in consultation with the European Medicines Agency (EMEA – “the Agency”), Member States and interested parties to draw up guidance on the collection, verification and presentation of adverse reaction reports in order to facilitate the exchange of information about human pharmacovigilance within the Community.

The pharmacovigilance obligations apply to all medicinal products authorised in the EU.

Structure of Volume 9A Part I deals with Guidelines for Marketing

Authorisation Holders (MAHs);

Part II deals with Guidelines for Competent Authorities and the Agency;

Part III provides the Guidelines for the electronic exchange of pharmacovigilance in the EU; and

Part IV provides Guidelines on pharmacovigilance communication.

Part I - Roles & Responsibilities of the MAH

Ensure that an appropriate system of pharmacovigilance is in place in order to assume responsibility and liability for his products on the market and to ensure that appropriate action may be taken when necessary.

Report all information relevant to the risk-benefit balance of a medicinal product to the Competent Authorities and the Agency fully and promptly in accordance with the legislation.

Should have permanently and continuously available a Qualified Person Responsible for Pharmacovigilance, residing in the EU.

EU Qualified Person for Pharmacovigilance

QPPV responsible for Establishing & maintaining the MAH’s PV system Having an overview of the safety profiles and any

emerging safety concerns Acting as a single contact point for the Competent

Authorities on a 24-hour basis.

QPPV may delegate specific tasks to appropriately trained/qualified persons Provided QPPV maintains oversight of the system

and safety files of all products Delegations must be fully documented.

QPPV responsible for: Collection and collation of all suspected ADRs; to

be accessible at least at one point within the EU Preparation of expedited and periodic safety

reports, and reports on post-authorisation safety studies

Ongoing pharmacovigilance evaluation Responding to requests for information from

regulatory authorities Provision of additional information upon request

from Competent Authorities relevant to evaluation of benefits & risks

Notifying changes to benefit-risk profile QC/QA of the pharmacovigilance system

EU Qualified Person for Pharmacovigilance

Responsibilities of MAH The Marketing Authorisation Holder should ensure that the

QPPV has sufficient authority To implement changes to the MAH’s PV system in order

to promote, maintain and improve compliance; and To provide input into Risk Management Plans and into

the preparation of regulatory action in response to emerging safety concerns.

The Marketing Authorisation Holder should assess risks with potential impact on the pharmacovigilance system.

A Marketing Authorisation Holder may transfer any or all of the pharmacovigilance tasks and functions, including the role of the QPPV, to another person(s) or organisation. In such cases, clear documented contractual agreement for meeting PV obligations should be in place between the parties involved.

I have the drug license

Detailed Description of the PV System The Applicant for a marketing authorisation is

required to provide a detailed description of the system of pharmacovigilance. QPPV details Organisation details Standard Operating Procedures Databases Contractual agreements Brief description of training system Quality Management System

Pharmacovigilance Inspections Competent Authorities conduct PV inspections to ensure

that MAHs comply with the PV regulatory obligations. Inspections could be routine or targeted. System inspections / Product-Specific Inspections Common Inspection findings

Insufficient QPPV oversight of PV system Insufficient control of agreements Insufficient control of IT systems Inadequate training of PV personnel Inadequate archiving facilities Inadequate procedures, management & QC Insufficient reporting / literature review & limited signal

detection

Risk Management System Need for risk management

What is Risk Management?

EU legislation

Description of risk management system should be submitted in the form of an EU-RMP during both the pre-authorisation and post-authorisation phases of the product’s life-cycle . Safety Specification Pharmacovigilance Plan Risk Minimisation

Safety Reporting in Post-authorisation period Individual Case Safety Report (ICSR)

Identifiable Healthcare Professional Reporter Identifiable Patient At least one suspected active substance/medicinal

product At least one adverse reaction

The Marketing Authorisation Holder should transmit all ICSRs requiring expedited reporting promptly and no later than 15 calendar days from receipt.

Reports published in Worldwide Literature, Information from the Internet, reports from Organised Data Collection systems, reports from Patients and other non-medical sources

Safety Reporting in Post-authorisation period

Periodic Safety Update Report (PSUR) - an update of the worldwide safety experience of a medicinal product to Competent Authorities at defined time points post-authorisation

Summary Information & critical evaluation of all the relevant new safety data from the appropriate sources

Once a medicinal product is authorised in the EU, even if it is not marketed, the Marketing Authorisation Holder is required to submit PSURs at 6-monthly intervals.

Once marketed, 6-monthly PSUR submissions should be continued following initial placing on the market in the EU and until two full years of marketing experience in the EU has been gained. Then, PSURs should be submitted once a year for the following two years and thereafter at 3-yearly intervals.

Post-Authorisation Safety Studies Need for post-authorisation studies (PASS)

May be required by Competent Authorities either as a commitment or in the post-authorisation phase to further assess a signal.

Situations where studies may be appropriate may include: Uncertainty to chemical structure, clinical relevance,

safety profile Quantify off-label use of the product Evaluate the effectiveness of a risk minimisation measure

MAH is responsible for the conduct and overall pharmacovigilance obligations concerning PASS.

Risk-Benefit Assessment Both the Marketing Authorisation Holder and the Competent

Authorities must keep abreast of all relevant information in order to fulfil the following responsibilities: Ensuring that all sources of information are screened

regularly to identify any potential signals; Ensuring that appropriate action is taken in response to

new evidence which impacts on the known risk-benefit balance; Variation of marketing authorisation Provision of important safety information to Healthcare

Professionals and Patients. If the safety concerns require urgent action, the MAH should

initiate an urgent safety restriction followed by variation filing. Product withdrawal from the market should be discussed with

all the concerned competent authorities before communication to the public.

Part II – Undertaking of PV activity by Competent Authorities and the Agency Each Member State should monitor Marketing Authorisation

Holder compliance with PV obligations and should undertake PV inspections.

Each Member State should have in place systems for receipt and evaluation of all pharmacovigilance data and to ensure that appropriate regulatory action may be taken.

For centrally authorised products, the European Commission is the Competent Authority. The responsibility for the conduct of pharmacovigilance of any MRP or DCP product rests with the Competent Authorities of all individual Member States who have granted the authorisation.

Competent authorities should ensure that appropriate and timely information is provided to WHO and other international bodies.

Rapid Alert and Non-Urgent Information System in Pharmacovigilance During the marketing period of a medicinal product,

urgent measures to safeguard public health may be necessary.

Information regarding safety concerns, particularly those which may result in major changes to the marketing authorisation status or revocation or withdrawal of a product, is exchanged between the Member States, the Agency and the European Commission with the appropriate degree of urgency.

Rapid Alert (RA) / Non-Urgent Information (NUI)

Part III – Electronic exchange of PV information in the EU Provides reference to the electronic transmission

of ICSRs

Applies to national Competent Authorities, the European Medicines Agency and Marketing Authorisation Holders in the EU.

EU legislation (EC) No. 726/2004, Article 24(2) and Directive 2001/83/EC, recital 56 and Article 104(1)

EudraVigilance – European pharmacovigilance database and data-processing network

Part IV – Direct Healthcare Professional Communications Information aimed at ensuring safe & effective use of

medicinal products which is delivered directly to Healthcare Professionals by a MAH or Competent Authority.

Dissemination is usually required in following situations: Suspension / Withdrawal of marketing authorisation Important Changes to the Summary of Product

Characteristics Change in the risk-benefit balance of the drug Availability of new recommendations for treating adverse

reactions

The Competent Authorities are those who have issued a marketing authorisation for the medicinal product concerned.

PV Regulatory Environment in the US and Japan

Pharmacovigilance Situation in the US Organisational Aspects: FDA Title 21, Code of Federal Regulations 5-Day (unreasonable risk from devices), 7-Day (serious

unexpected related), 15-Day (serious unexpected), 30-Day (serious injury from devices) and Periodic Reports (non-serious)

Pharmacovigilance Situation in Japan Organisational Aspects: MHLW, PMDA Revised Pharmaceutical Affairs Law (PAL) Good Vigilance Practices (GPV) Good Postmarketing Study Practices (GPSP) Early Postmarketing Pharmacovigilance (EPPV) 15-Day (unknown serious cases), 30-Day (known

serious cases), Periodic Reports (non-serious cases)

Final thoughts

Ensure a well-defined pharmacovigilance system in place

Ensure clear contractual agreements with the external PV service providers

Ensure adequate global literature review for new safety information

Ensure proper coordination between safety and other departments

Conduct thorough potential case assessment and ensure expedited reporting of serious unexpected ICSRs

Ensure timely preparation and submission of PSURs and RMPs

Ensure appropriate action in case of a new safety signal

Study Protocol : PRC/CRD/33/08 Capecitabine 500 mg tablets