Good Pharmacovigilance Practices

Over recent years, there has been an increasing public awareness of safety issues relating to medicinal products.

ADRs are one of the most common causes of either death, hospitalization or other serious disability.

Adverse event of medicine is among the first ten causes of death in patients.

Results from pre-marketing clinical trials are only sufficient to justify the efficacy of a drug so as to sustain the application of its license approval.

Also, at the time of approval, clinical trial data are available on limited numbers of patients treated for relatively short periods

Both regulatory agencies and pharmaceutical companies ensures that emerging safety information is reported and an appropriate action taken to safeguard public health.

The recognition of the importance of Pharmacovigilance is increasing.

Need for Pharmacovigilance:

Once a product is marketed, large numbers of patients may be exposed, including:

Patients with co-morbid illnesses
Patients using concomitant medications
Patients with chronic exposure
Hence, necessity for collecting, recording, coding of ADEs / ADRs, analyses, assessment and communication of these reports which would help in promoting the safe use of drugs
Both regulatory agencies and pharmaceutical companies ensures that emerging safety information is reported and an appropriate action is taken to safeguard public health

After marketing, new safety information may become available:

Through use of the product domestically or in other countries
Through use of other drugs in the same class
From preclinical studies
From pharmacologic studies
From controlled clinical trials

What is Pharmacovigilance (PV)?

The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem

Pharmacovigilance helps in

Indicating changes in the product labeling
Warning
Indicating changes in product characteristics
PV may lead to Withdrawal or termination of product

Steps involved:

AE Study Reports

All AEs, both serious and unexpected are subject to expedited reporting

Aggregate Reporting

To review the cumulative safety information from a wide range of sources, on a periodic basis and submit the findings to regulators worldwide.

Signal Detection

Process of determining incidence of particular AEs associated with particular drugs and comparing the same to that for other similar drugs.

Risk Management

To monitor any reported AE of the Product (Investigational or Marketed) on a patient or patient population and to seek methods or rationales to minimize or remove such AE from such patient or a specific patient population.

ALSO READ: SOP for QPPV Role and Responsibilities

Good Pharmacovigilance Practice:

The Guidance for Good Pharmacovigilance Practice in order to

To request healthcare providers, pharmacies and pharmaceutical companies to collect, evaluate and study drug safety information in a proactive manner
To take their responsibilities for adverse drug reaction reporting.
To identify the safety issues after a product is launched with exposure of huge number of patients.
Assessment of the risks and benefits of marketed medicines
Reduce the risks and take prompt measures to protect public health.
Providing information to consumers, practitioners and regulators on the effective use of drugs
The framework for good Pharmacovigilance process (GPVP) is proposed as a subset of good post marketing surveillance process (GPMSP).
It is a functional structure for both a public health and corporate risk management strategy.
GPVP has good practices that implement each step within a defined process.
These practices are designed to efficiently and effectively detect and alert the drug safety professional to new and potentially important information on drug-associated adverse reactions.
These practices are enabled by applied technology designed specifically for the review and assessment of spontaneous reports
These practices and the overall GPVP are supported by state-of-the-art web-based systems with powerful analytical engines, workflow and audit trails to allow validated systems support for valid drug safety signaling efforts.

Specific practices include rules-based triage, active query prompts for severe organ insults, contextual single case evaluation, statistical proportionality and correlational checks, case-series analyses, and templates for signal work-up and interpretation.

Good Pharmacovigilance practice are applicable to:

Qualified Person Responsible for Pharmacovigilance
Adverse Drug Reaction Reporting and Requirements
Risk Management
Training and education
PV inspection

QUALIFIED PERSON RESPONSIBLE FOR PHARMACOVIGILANCE (QPPV)

Volume 9A reinforces the requirement to appoint a Qualified person responsible for Pharmacovigilance (QPPV)
The QPPV should be able to demonstrate through qualifications, work experience and formal training.
QPPV should have a relevant biological sciences/pharmacy/medical degree and should have worked for some years in field of Pharmacovigilance.
QPPV should have knowledge of applicable EU PV legislation and guidance, ICH and CIOMS and of key Pharmacovigilance activities performed as part of MAH’s PV system.

QPPV Responsibilities

Establishing and managing system to ensure proper collection, evaluation and collation of all suspected adverse reactions.
Preparation for competent authorities of suspected serious adverse reaction reports and PSUR
Ensuring any request for additional information necessary for evaluation of benefits and risks afforded by a medicinal product is answered fully and promptly.

ADVERSE DRUG REACTION REPORTING & REQUIREMENTS

Spontaneous reporting
PSUR
Expedited reporting

SPONTANEOUS REPORTING

Healthcare providers, pharmacies and pharmaceutical companies are advised to inform the health authority or its delegate agencies of any suspected adverse drug reactions involved with marketed drugs.
Reporting method: Post, fax or via the internet

GPVP for Spontaneous Reports

Good Pharmacovigilance Practices (GPVP) focus on Enhancement of the Spontaneous reports by

Effectiveness: rigorous alerting, signal detection and handling.
Efficiency: focus on ‘important’ reactions.
Consistency: one global corporate opinion on
The nature and level of causality of the reaction.
Validity: evaluation and assessment tools yield correct results.

Purpose is -

To clearly and accurately identify rare, serious, unusual or unexpected adverse drug reactions as soon as possible after market launch.

Assessment of Spontaneous Reports

GPVP for spontaneous reports is proposed in a step-wise approach:

Data triage
Information acquisition
Single case assessment
Technical checks
Case-series (content and context assessment)
Interpretation
Communication.

Good pharmacovigilance processes (GPVP) focus on the enhancement of the reports that are most likely to be important. In parallel to any regulatory reporting (submission) triage these reports need to have both their potential maximised and the value measured. That measurement must be both as an individual and in a case-series. All activity must be well documented.

The goal of GPVP is to clearly and accurately identify rare, serious, unusual or unexpected adverse drug reactions as soon as possible after market launch.

Step-wise approach

The first step in GPVP is a rules-based data triage. An active effort must be applied to sort those reports that are more likely to be important from those that are less likely to be important.

Enhanced information acquisition is the rationale for step 2 of GPVP. There needs to be an active query performed for ‘important’ reports at the point of initial contact. That is, maximal data collection with the goal of increasing the likelihood of making a causality determination.

This third step in GPVP has two parts: initial single case assessment and signal-based evaluation. The initial assessment is an ‘on the way in’ to the database review, and is a step conducted before regulatory submission.

A vital component of GPVP are the technical checks. They are necessary for the efficient and effective utilisation of GPVP since we often need to assure ourselves that there are no sharp needles hidden in the ever-growing haystacks of reports.

Here in step five of GPVP, the electronic inbox of the specified clinical reviewer is loaded with alerts defined from important new cases and the thresholds set in the various technical checks

ALSO READ: SOP for Preparation and submission of Periodic Adverse Drug Event Reports (PADERs)

PERIODIC SAFETY UPDATE REPORT

What is Aggregate Reporting?

Aggregate reporting is the process that reviews the cumulative safety information from a wide range of sources, on periodic basis and submit the findings to regulators worldwide.
Report includes the benefit – risk analysis of SAE and ADR’s, pregnancy reports , overdose and lack of efficacy reports.
Aggregate report examines and summarize all existing safety experience with a medicinal product.
The aggregate safety reports are submitted to regulators for as long as the medicine is marketed anywhere in the world and enables understanding of risk benefit profile of product over a period of time.

Periodic reporting in US, Europe and Japan

EXPEDITED REPORTING

An "unexpected" adverse reaction is one, the nature or severity of which is not consistent with information in the relevant source documents
Purpose: To make regulators, investigators, and other appropriate people aware of new, important information on serious reactions.

Criteria's for EP are -

Single Cases of Serious, Unexpected ADR.
Expected but increase in rate of occurrence
Significant hazard in patient population.
A major safety finding from a newly completed animal study (such as carcinogenicity).

What should not be reported?

Serious but expected
Clinical cases: Unrelated to drug even if unexpected
Non-serious Adverse reaction

Time frame for reporting

Fatal or life-threatening: Within 7 calendar days
Other serious unexpected ADR: Within 15 calendar days.

RISK MANAGEMENT

A risk management system is a set of pharmacovigilance activities and interventions designed to identify, characterize, prevent or minimize risks relating to medicinal products, including the assessment of the effectiveness those interventions.
In Europe: EU RMP: measures proposed to minimize risk
In US: US RiskMAP: Closely reflects the purpose of risk- minimisation.
RMP is required with marketing authorisation applications for :

All new active substances
Significant changes to marketing authorization (eg: new indication, new formulation)
When an unexpected new hazard is identified

EU RMP:

Part I:

Safety specification
Pharmacovigilance plan (ICH E2E)

Part II:

Risk minimization plan
An evaluation of the need for risk minimisation activities

Risk Management Plan Development

Part I

Safety Specification
Important identified risks
Potential risks
Missing information
Populations at risk
Drug interactions

Pharmacovigilance Plan

Summary of safety issues
Action plan for safety issues
Important identified risks
Important potential risks
Important missing information including potentially at risk populations

Part II

Evaluation of the need for Risk Minimization Activities

Additional Safety concerns like potential for medication errors
Need for more actions beyond PV action Plan

Risk Minimization Plan

Lists of risk minimizing activities
Assessment of their effectiveness
Revision of SmPC
Education: Disease and product related
Audit

PV inspection:

Pharmacovigilance (PhV) inspections are performed to ensure that the Marketing Authorisation Holders (MAHs) for Centrally Authorised Products (CAPs) comply with PhV regulatory obligations and to facilitate compliance.

Types of PV inspections:

Routine national inspections
For cause national inspections
CHMP- Requested inspections

Phases of Inspection Process

Planning
Conduct of inspection
Reporting and follow up

Difference between US/MHRA PV inspections:

	FDA	MHRA
Advance Notice	None to a couple of days (US) A few weeks (outside US)	4 months
Preparation Phase	Communication of Studies/Products to be reviewed No clear agenda/plan communicated in advance (compliance program guidance manuals publicly available)	Use of pre-inspection questionnaire (SPS) Detailed agenda/plan for the inspection a few days in advance. The company has to identify the most relevant people to discuss each topic listed.
Conduct Phase	All operational processes covered Inspection style historically data-centered but tends to focus more on processes More data/document review than interviews but changing Duration: 1-3 days 1-2 Inspectors Presentation of early results at closing meeting	All operational processes covered + supporting processes Very process-oriented Very much interview driven Duration: 5 days 3-4 Inspectors Presentation of early results at closing meeting
Reporting	Very slow if at all Warning letters and FDA 483 immediately. List of deviations without significance rating or proposed corrective actions	Very slow List of deviations with significance rating but no proposed corrective actions