The Concepts behind use of Pharmacovigilance

Every medicative merchandise has its ain risk-benefit ratio. The merchandises, whose benefits to the patients overweigh its hazard, are approved by the Competent Authorities ( CA ) . The sanctioned merchandises do non intend that they have no side effects. Actually every medicative merchandise has some side-effects and it ‘s really of import to place the side-effects throughout its lifecycle. The procedure of changeless monitoring of the medicative merchandise throughout the merchandise lifecycle is called Pharmacovigilance. The purpose of pharmacovigilance is to protect people by placing, observing, characterizing, monitoring and communication hazard for rational and safe usage of medicines.1 These benefit-risk findings helps to take determination sing safety of the medicative merchandise by regulators, company, doctors and patients.2


In 1961, after catastrophe of thalidomide, it has been brought frontward that post-authorisation informations was non sufficient to observe early warning marks of the drug safety.3 If Pharmacovigilance system were in topographic point during that clip ; such a catastrophe would be minimised. To avoid any such catastrophe in future Marketing Authorisation Holder ( MAH ) & A ; Competent Authority ( CA ) work together to guarantee that pharmacovigilance system is maintained and patient ‘s safety is non compromised.


In general, pharmacovigilance have no boundaries and it should be performed to all medicative merchandises throughout its lifecycle. Rapid and effectual appraisal of drug safety is achieved by early information of any unintended consequence. Innovative and generic companies have to follow the same demands with respects to updating the safety specification.4

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Presently, the pharmacovigilance system is set as per counsel,

  • Regulation EC/726/2004
  • Directing 2004/27/EC.
  • Volume 9A and
  • ICH guidelines


Marketing Authorisation Holder ( MAH ) :

In current state of affairs, it ‘s really hard to place a new merchandise and new merchandise application is expensive and time-consuming procedure. To do a blockbuster merchandise ; MAH focus exhaustively on Pharmacovigilance system to avoid any letdown at the ulterior phase of the merchandise lifecycle as it ‘s really indispensable for endurance of the company. The importance of Pharmacovigilance is that if successful merchandise fails to observe early signals, company besides fails to protect its trade name individuality.

The first measure initiated by MAH is to guarantee that proper pharmacovigilance system is set up to observe signal of any inauspicious consequence and hazard direction programs should be in topographic point to understate its impact.3

To execute above activities, MAH appoints a QPPV who is responsible for,5

  • Roll uping and collating all suspected inauspicious effects globally and set up benefit-risk balance to subject to CA.
  • Fixing and subjecting Periodic Safety Update Review ( PSUR ) , Individual Case Safety Review ( ICSR ) , pre & A ; post-authorisation surveies to the CA through electronic coverage.
  • Reviewing safety issues and merchandise defects.
  • Conducting internal audit of pharmacovigilance system and guarantee direction of database.

Along with Pharmacovigilance squad, company besides build Risk Management Team or Crisis Management Team who plays a critical function in understating the impact of any inauspicious reactions on the merchandise and the company.

Competent Authorities ( CA )

Along with MAH, CA besides develop their Pharmacovigilance squad who performs surveies like MAH to measure the safety public presentation of the medicative merchandise. It is besides the duty of MAH to supply seasonably and right information of any signal detected to the CA. CA besides evaluate Pharmacovigilance system of the MAH by everyday reviews conducted by national governments to look into the system and installations are in conformity as mentioned in Detailed Description of Pharmacovigilance System ( DDPS ) 6. Apart from everyday reviews, certain factors that triggers the reviews are,5

  • Delaies in carry out safety coverage
  • Incomplete or hapless quality coverage
  • Incompatibility between studies
  • Changes in benefit-risk balance and failure to pass on to CA.

Therefore sing the importance of Pharmacovigilance, both MAH and CA take joint duty to safeguard public wellness.


Once the MAH Pharmacovigilance system is set, the cardinal factors are,

Signal sensing

Signal sensing is initiated by MAH every bit good as CA. At any phase during the merchandise lifecycle, if unintended consequence is detected, it prompts to measure the ground for its occurrence. Generally MAH should be foremost to observe any signal, but if is detected by CA, it means that MAH pharmacovigilance system is non efficient and reviews are required to verify the pharmacovigilance set up.

The inauspicious consequence signal can be detected by:

  • Changeless monitoring in-house surveies conducted by MAH.
  • Spontaneous ADR coverage: where a healthcare professional studies any inauspicious consequence to the MAH or CA from patients experiences every bit good as from his ain studies.5

MAH evaluates if a insouciant or suspected relationship is determined between inauspicious reaction and medicative merchandise. Once it is confirmed that relationship exists, MAH should inform CA within 15 yearss of the occurring of the inauspicious reaction.5

For instances where patient contacts the MAH straight sing any inauspicious reaction, MAH should advice the patient to reach the healthcare professional. Once the inauspicious reactions are confirmed by health care professional, it should be documented by MAH as self-generated inauspicious reactions.

  • Prescription Event Monitoring ( PEM ) : It is a intercrossed method of informations aggregation from surveillance every bit good as self-generated inauspicious effects. Here all the prescriptions when dispensed are collected and analysed to give an thought of which patients are exposed to which medical specialties, clip of exposure and any signal detected during their therapy.3
  • Worldwide studies published for ICSR published on Medline or Embase etc helps MAH to be cognizant of the incidents and can acquire prepared for such inauspicious reaction incidents.5 Such literature or cyberspace mentions should be reviewed atleast one time or twice fortnight.

If the merchandise is authorised by CP, it should be reported to Eudravigilance, but if the merchandise is authorised through MRP or DCP, CA of the RMS should be reported. Here RMS takes the prima function and contacts several CMS regarding of describing any such inauspicious reaction.25

All the regional wise signals detected are collected by local affiliates and so they are reported to the chief office The MAH collects this information globally through local affiliates and describing to the cardinal office every bit good as roll uping information through web sites.

Benefit-risk Appraisal

Once the signal is detected, benefits of medicative merchandise are assessed on the information of remedy or better rate of the symptoms, the response rate and quality of life. The hazard involved is assessed as self-generated inauspicious reactions, frequence and presence of hazard factors, epidemiological information every bit good as overdose, abuse or medicine errors.5 MAH should seek to better the benefit-risk balance to optimize safe usage of the medical specialties.

To efficaciously supervise the safety public presentation of the medical specialty by the CA, it is decided to describe sporadically which is known as Periodic Safety Update Review ( PSUR ) .

Pharmacovigilance during pre-authorisation

From drug find till the application is submitted, MAH performs several non-clinical and clinical surveies to set up benefit-risk balance. Once the merchandise is in application but non granted, if any unintended consequence is seen, MAH evaluate the impact of unintended consequence and inform to the CA. But there are several restrictions to pre-authorisation phases like, 5

  • limited people population,
  • limited clip of exposure of medical specialty,
  • limited age & A ; sex, geographical, ethnicity people & A ;
  • limited range of interactions with other medical specialties.

Pharmacovigilance during post-authorisation

But when the merchandise is authorised, it is widely prescribed in different category of patients. This gives more chance to place any unintended hazard or potency hazard which was non identified during pre-authorisation surveies. Hence post-authorisation surveies are really indispensable to observe any such alterations in benefit-risk balance and its coverage is through PSUR.

To do the post-authorisation robust, MAH maintains the list of information sing safety, indicants, dosing and pharmacological medicine which is called Company Core Data Sheet ( CCDS ) . CCDS proves as a mention to measure the alteration in benefit-risk balance. If any new inauspicious reaction is reported, CCDS information is updated to reflect changes.27


Periodic Safety Update Reports ( PSUR )

PSUR is intended to reexamine world-wide safety profile of the merchandise and guarantee that SmPC, labelling and cusp are up-to-date. It is performed to measure the informations of latest safety studies and to reason that safety benefit-risk balance is non changed. If there is any alteration in safety informations, appropriate actions should be taken for amendments of current information through increased market surveillance.7 Single PSUR is required to be submitted per MA which include all indicants, dose signifiers and path of disposal.

The chief contents of PSUR are,5

  • Executive sum-up
  • Introduction
  • Worldwide market mandate position
  • Update to regulative authorization
  • Changes to cite safety information
  • Patient exposure
  • Individual instance histories
  • Overall safety rating
  • Decision
  • Appendix: company nucleus informations

PSUR coverage to CA is derived from the day of the month of birth of the medicative merchandise. The day of the month when the medicative merchandise was approved is call International Birth Date ( IBD ) .5

Sing IBD, PSUR is submitted,

  • Every six months from mandate until it is placed in the market
  • Every six months for first two old ages
  • Annually for following two old ages and thenceforth every 3 old ages
  • Merchandise submitted for reclamation

In certain instances, where PSUR is non submitted on clip, extra 30 yearss are allowed to subject PSUR. For generic and good established merchandise, PSUR entry day of the months can be amended depending on the benefit-risk profile of the merchandise. But in all instances, anterior permission should be taken from CA.5

During renewal entry, the PSUR study should cover 4 old ages and 4 months. Renewal can be submitted before 6 months.5 As PSUR entry is calculated as per IBD, reclamation should non be affect by PSUR coverage and similar coverage rhythm should be followed.


As all existent or possible side-effects are non identified during surveies, so along with pharmacovigilance activities which detect any unintended effects, there should besides be Risk Management Plan ( RMP ) to understate the impact of any such unintended effects.

RMP identifies the hazard, clarifies the safety profile and make up one’s mind alternate ways to understate hazard to the patients.15 As every merchandise has different pharmacological actions and differ in safety profiles, separate RMP should be designed for each merchandise. RMP should besides place multiple hazards. RMP comprised of 4 steps:5

  • Hazard sensing
  • Hazard appraisal
  • Hazard minimization
  • Hazard communicating

EU Risk Management Plan

All merchandises authorised within the EU should hold approved EU-RMP maintained throughout the merchandise lifecycle. EU RMP contains,

Safety Specification – These are certain informations which are non clearly addressed during non-clinical and clinical tests like toxicity, drug interactions, pharmacological medicine & A ; pharmacological category, population non studied, epidemiology and inauspicious events.

Hence it is the sum-up of of import identified hazards, possible hazard and some losing information.13 It should besides foreground the population at hazard and high spots the demand for farther survey. The safety specification is itself a stand-along papers along with pharmacovigilance program and the specific elements are incorporated in CTD.5

A Pharmacovigilance Plan – It is based as per safety specifications. For certain merchandises where less hazard is expected, routine Pharmacovigilance program is designed. For certain merchandise which involves more complexness and were less safety specifications are available, extra stairss are taken to guarantee that any signal detected is evaluated in early phases. Action programs are prepared depending on the safety issue. The chief points for action program are safety issue, objective of proposed action, action proposed, rational for proposed action, monitoring and eventually measuring & A ; reporting.5

Risk minimization activities – It can be achieved through cognition of Safety Specifications by curtailing adding suited warning on the labelling and bundle cusp. Medicine mistakes should besides be considered with regard to trade name names, presentations & A ; instructions for use.5 Appropriate warning should besides be mentioned if it can be dangerous due to improper usage of path of disposal or due to blending of different strength. Hazard can be minimised through extra surveies, legal position of medical specialties, control at pharmaceutics degree and prescription size and cogency.

Hazard communicating – Hazard communicating is a much apprehended measure for hazard minimization. Hazard should be communicated to healthcare professionals through literatures, educational preparations and enlightening cyberspace beginnings so that they can take disciplinary stairss while ordering to the patient and can understate the risk.5

EU-RMP is required to be submitted for,5

  • Application for new active substance, pediatric merchandise, biological merchandise or generic merchandise where more information is required for mention medicative merchandise.
  • Application for important alteration in MA like new dose signifiers, path of disposal or alteration in fabrication procedure
  • On petition of CA or if any safety issue arises of the merchandise.

EU-RMP program is submitted in Module 1.8.2 for rating by pharmacovigilance and hazard direction experts.5


Every MAH has to adhere to pharmacovigilance system. Non-compliance in the UK will hold all right upto ?5000 or if it is strong belief it is limitless mulct and imprisonment for upto 2 old ages to QPPV or company direction.

As per EU Torahs, if non-compliance is knowing or negligent, the mulct is upto 5 % of the one-year gross revenues or 2.5 % per twenty-four hours norm or if it is failure to co-operate or supplying deceptive information, the mulct is upto 0.5 % of entire one-year or per twenty-four hours mean gross revenues. Apart from mulct, it gives a signal that company is non looking about patient ‘s safety, seting their net incomes foremost and an embarrassment in the industry.


From November 2005, electronic coverage became compulsory. The coverage of European pharmacovigilance activities is supported by package called Eudravigilance. Eudravigilance maintains the database of inauspicious reactions reported for any medicative merchandise which are capable to clinical trials.8 Eudravigilance provides entree of inauspicious reactions to CA, health care professionals, patients every bit good as pharmaceutical industry. It besides maintains the information of ICSR and other suspected inauspicious reactions. While reexamining the pharmacovigilance system, it helps to place inauspicious events to the rapporteur by making regular overview of inauspicious events throughout the lifecycle of medicative merchandise. Besides Eudravigilance interfaces with EU-RMP in supplying systemic description of hazard in footings as defined by MEDdra.8 It is found that 40 % of safety issues can be detected earlier if Eudravigilance is used in add-on to other PV sources.9 The typical flow of information from PV and EU hazard direction scheme deduction are,


  • Pharmacovigilance system is dependent on coverage and analysis of unintended effects. But all the side effects can non be classified as unintended effects. Hence its MAH determination to sort which they consider as serious unintended effects.
  • As doctor did non acquire any feedback of their coverage of unintended consequence which ends up in reluctance to describe to the MAH.10
  • In the EU as the merchandises are granted through different processs, the demands for labelling are different which makes it hard to understand benefit-risk balance which pose a hazard to public health.10
  • MAH along with makers should responsible for overall detection and measuring the inauspicious effects of the medicative merchandise.
  • Duplicate of work is involved for coverage by both generic and pioneer companies for same medicative merchandise and deficiency of communicating between them.10
  • Important safety information should be treated as precedence alternatively of documenting, formalizing, measuring and describing all experiences with the same grade of urgency.
  • PSUR coverage is complex as it involves different presentations, different blessing times and state specific labelling.10

As per invention in health care engineering, Pharmacovigilance system should be developed to place the possible association of side consequence with a comparing of patient who was given medicine v/s patient who has non taken the medicine.10


The current statute law will amended by Regulation EU/1235/2010 and Directive 2010/84/EC from July 2012.39 The new statute law aims to understate duplicate of describing system & A ; simplifies describing of inauspicious drug reactions and PSUR. It besides aims to inform patients about benefit-risk facets and promote patient to describe any effects through online signifiers, have explanatory dictions on patient cusp and SmPC for particular safety monitoring medical specialties. The chief deductions are,40

  • MAH have to subject ADR studies merely to Eudravigilance and non required to subject to single national CAs.
  • PSUR will hold individual appraisal for same active substance hence all fluctuations ; care should be done through brotherhood process to keep harmonization.
  • PSUR coverage is non required for low hazard or established molecules unless there is some safety concern. So generic companies will be benefitted by non subjecting PSUR unless requested.
  • Presently DDPS will be replaced by Pharmacovigilance System Master File ( PSMF ) which should be for good available for entry or review on petition of national CA.
  • All pharmacovigilance referrals will be discussed by Pharmacovigilance Risk Assessment Committee ( PRAC ) and to avoid duplicate CMDh should hold on the individual sentiments for all member provinces.
  • Environmental hazard factors should be considered as safety of the people in the peculiar country of the EU.


In last few old ages, there were certain medicative merchandises which were demoing positive benefit-risk balance during blessing, but on changeless monitoring for 5 to 10 old ages, their safety profile has changed and they started to demo negative benefit-risk balance. The few merchandises are,

  • Avandia
  • Avandamet
  • Acomplia
  • Vioxx etc.

Avandia and Avandamet have shown good direction of diabetes, but along with that they besides pose a hazard of cardiovascular events which were unintended inauspicious effects. MAH have provided extended research paperss to back up their merchandise, but eventually it was found that benefits were less compared to hazards imposed. Hence sing the public safety, these merchandises are withdrawn at their adulthood phases. As a portion of pharmacovigilance surveies, it was found that due to long exposure clip of the medical specialty, it has shown inauspicious effects which were non possible during pre-authorisation surveies. Besides it proved the strength of pharmacovigilance surveies, which has avoided any such catastrophe among the patients.


Pharmacovigilance plays really of import portion in health care system. As the new molecules are complex with limited studies, pharmacovigilance is the tool to supervise the safety benefits. Though it creates more and more hurdlings to the MAH with regard to supply more informations and justification, it really provides more safety towards the public wellness. Without accurate pharmacovigilance system, it may stop up with batch of dangerous incidence globally.

New statute law from July 2012 will convey a major alteration in current pharmacovigilance system, but it is more acceptable in footings of avoiding duplicate of work, systematic coverage and monitoring and consonant attack.


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