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Impact of new EU regulations

New pharmacovigilance legislation (Regulation (EU) No 1235/2010 and Directive 2010/84/EU) was adopted by the European Parliament and European Council in December 2010.This was accompanied by the implementing regulation # 520/2012, a legally binding act, published by the European Commission in 19 June 2012 that provides details on the operational aspects for the new legislation.

To help implementation, a new set of guidelines (Good PV Practice) for the conduct of pharmacovigilance in the EU is under development. These guidelines are organised into 16 modules, of which about 10 have been published

Together this has brought in a dramatic change in the handling of pharmacovigilance data and in the way Pharmacovigilance will be looked at in future. Although volumes can be written about each change implemented, here is a brief summary

Aims of the new legislation

Major aims of these new regulations are (2)

• To make roles and responsibilities clear, between the authorities, sponsors, licensees etc

• To minimise duplication of effort, as in dual reporting of the same AE by sponsor and licensee

• To free up resources by rationalising and simplifying adverse drug reaction (ADR) reporting and periodic safety update report (PSUR) reporting

• To establish a clear legal framework for post authorisation monitoring indicating when such a demand could be made and how it is expected to be fulfilled by the sponsor

Impact of the changes

Pharmacovigilance has changed from a passive discipline to a proactive one. Earlier sponsors used to report AEs in time and feel contented. The authorities, WHO Upsala center or other bodies, analysed available data and raised concerns to which sponsors responded by providing past data, creating additional data and agreeing to make changes in the package insert, product withdrawal being the last resort. Only on rare occasions did we find sponsors proactively discussing the product with authorities.

All this is about to change. PV plan including risk management plan will now be a part of every new drug applications. The sponsor will evaluate all data available till submission, evaluate the possible risks, point out gaps in data and provide a plan to manage the same. Risk management system will be part of every new application.

Post-authorisation safety and efficacy studies could be a condition for authorization if the available data so indicates. Earlier sponsors were not very enthusiastic about fulfilling these obligations, hence focused studies needed to evaluate certain risks did not happen in time.

Such studies, when asked for, will be mandatory. The marketing authorization will be conditional, based on completing these studies expeditiously. There is a provision of withdrawal of authorization for non compliance


In keeping with the thought to reduce duplication, as far as EU is concerned, there will be a single assessment for the same active substance or a combination of active substances. So, various formulations and combinations of a molecule will be evaluated in one PSUR (Periodic Safety Update Report). For old established products and those with low risk, even the once in a few years reporting is not necessary. However if a safety concern arises, reporting will be required. Reporting will now be electronic, directly to the European Medical Agency (EMA) since a EU repository(Eudravigilance database) has been established(3)

The PSUR will now be called PBRER( Periodic Benefit Risk evaluation Report). The EMA is clearly asking the Marketing Authorization Holder(MAH) to shoulder the responsibility of evaluating the benefit risk of the product. This will be based on all available data, new and old, at every scheduled submission. EU directive of December 2010 states “As a result of the submission of all suspected adverse reaction data directly to the Eudravigilance database, it is appropriate to amend the scope of periodic safety update reports so that they present an analysis of the risk-benefit balance of a medicinal product rather than a detailed listing of individual case reports already submitted to the Eudravigilance database”(4)

The PBRER retains most of the basic elements of the PSUR .Compared to the PSUR, the PBRER has more information on:

  • Clinical trials and observational studies
  • Signals that are new, ongoing, or closed
  • Risk evaluation and effectiveness of risk minimization
  • Benefit evaluation
  • Benefit-risk analysis for approved indications

The PBRER is a more comprehensive document The construction is modular so that sections can be used as is for other regulatory submissions e.g. risk management plan.

PV System Master File (PVSMF)

PVSMF is a detailed description of the pharmacovigilance system used by the MAH with respect to one or more authorised medicinal products. It need not be submitted along with marketing application but should be ready for review by authorities anytime . Over time, it will help do away with DDPS( Detailed Description Of Pharmacovigilance System). The file could exist electronically on various servers in the company but the company should be able to provide a soft or a hard copy of the PMF within 7 days if requested.

Elements of PVSMF

This file will be a one stop shop for all information related to pharmacovigilance in the company. Where is the QPPV(Qualified Person for Pharmacovigilance) located, the site(s) where the pharmacovigilance functions are undertaken covering individual case safety report collection, evaluation, safety database case entry, PSUR production, signal detection and analysis, risk management plan management and regulatory status of various products. It will also cover computer systems, outsourcing agreements, quality systems and change logs (5)

Role of QPPV

The role of QPPV has now become much more important. Earlier he/she was only the responsible person for pharmacovigilance, but now he/she will be the custodian of the total pharmacovigilance process. He will oversee and manage the system, ensure compliance with requirements, operate a risk management system for each medicinal product , monitor the outcome of risk minimisation measures and monitor pharmacovigilance data to determine whether there are changes to the benefit-risk balance of medicinal products. If there is a change in the balance, ensure that appropriate action is taken.

Individual Safety Case Reports (ISCRs)

These are the basic elements in PV. Changes due to new regulations have been summarized in GVP module VI. Here are a few points in short.

The definition of adverse reaction has been modified to include response to normal dose as well as misuse and abuse, medication error, overdose and occupational exposure.

The MAH has to report all serious and non serious adverse reactions within the stipulated timelines. It is important to note here that relatedness is no longer relevant

The case is to be submitted electronically on Eudra Vigilance database, where it will be visible to various stakeholders. This will make the process transparent by making data available to all concerned parties, and also eliminate duplication.

An internationally standardised reporting format across regulators, with agreed terminologies, formats and standards is being generated to make data sharing and analysis easy.

Administrative guidance

Each member state will have its own pharmacovigilance system to be able to review the risk status of authorized products in the state. At the EMA level a Pharmacovigilance Risk Assessment Committee (PRAC) has been formed. Each state will nominate members to this committee. At the state level if any safety issue of concern is noticed the state will submit it to the EMA so as to have a union wide assessment of the issue through the PRAC. This committee will guide on all issues regarding pharmacovigilance.

In case of signals where urgent action is deemed necessary the PRAC may hold public hearings involving the MAH, and subject experts.

Even when the Committee for Medicinal Products for Human Use (CHMP) or the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) have to decide on any issue, they will take the views of the PRAC into consideration.(4)


  1. GVP Modules, a summary. Clinical Research Advisor (2012) September
  2. EMA PV legislation 2010
  3. ICH E2C R2
  4. Directive 2010/84/Eu Of The European Parliament And Of The Council of 15 December 2010
  5. http://www.ottosen.com/pharmacovigilancesystemsmasterfiles download may 13
Dr. Vishwas Sovani, June 2013

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New EU legislation, impact, PSUR, PBRER, Pharmacovigilance system master file, PVSMF, Role of QPPV, Individual case safety reports, ISCR