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Brief history ofPharmacovigilance in India

Even though pharmacovigilance is stillin its infancy, the concept is not new to India.It was not until 1986 that a formal adversedrug reaction (ADR) monitoring systemconsisting of 12 regional centers, eachcovering a population of 50 million, wasproposed for India. In 1989, under the aegisof the Drug Controller of India, six regionalcentres were set up in Mumbai, New Delhi,Calcutta, Lucknow, Pondicherry andChandigarh. In 1997, India joined the WHOProgramme for International Drug Monitoringmanaged by the Uppsala Monitoring Centre,Sweden. The centre in New Delhi (atDepartment of Pharmacology, AIIMS) wasidentified as the national centre, while thecentre in Mumbai (at KEM Hospital) wasidentified as the WHO special centre. Of thesix centres, only the centres in Mumbai andNew Delhi were active, yet spontaneousreporting of ADRs was poor. The monitoringcentres were considered ad hoc andappropriate levels of funding were not madeavailable, which put severe constraints onthem. Recognising the need for improvedADR monitoring in India, the Governmentof India sent a proposal to the World Bankfor funding. The World Bank approved theproposal with an annual grant of $US 0.1mill ion for 5 years and the NationalPharmacovigilance programme waslaunched in November 2004.

Ensuring Patient Safety - Launching the NewPharmacovigilance Programme of IndiaDr. Y. K. Gupta*, Professor, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi

Co-ordinator, Pharmacovigilance Programme of India

Pharmacovigilance is defined by the World Health Organization (WHO) as "the science and activities relating to the detection,assessment, understanding and prevention of adverse effects or any other drug related problem". An adverse drug reaction (ADR)has been defined as any noxious, unintended and undesired effect of a drug which occurs at a dose used in humans for prophylaxis,diagnosis, therapy or modification of physiological functions (WHO).

Adverse drug events lead to significant mortality and morbidity world over. In developing countries, comprehensive information onthe safety of drugs used in the patient population is meagre and very few studies have been carried out to detect the incidence ofADRs in the young and the elderly population.

Although, the thalidomide tragedy stressed the need for an effective pharmacovigilance system, it was the withdrawal of rofecoxibthat renewed interest in drug safety mechanisms. Safety issues with other drugs like erythropoetin, rosiglitazone, rimonabant havealso highlighted the need for an effective and comprehensive pharmacovigilance system.

The National PharmacovigilanceProgram (NPVP) was overseen by theNational Pharmacovigilance AdvisoryCommittee based in the Central DrugsStandard Control Organization (CDSCO),New Delhi. Two zonal centers-the South-West zonal centre (located in theDepartment of Clinical Pharmacology, SethGS Medical College and KEM Hospital,Mumbai) and the North-East zonal centre(located in the Department of Pharmacology,AIIMS, New Delhi), collated information fromall over the country and sent it to theCommittee as well as to the UppsalaMonitoring centre in Sweden. Three regionalcenters reported to the Mumbai center andtwo to the New Delhi. Each regional centerin turn would have several peripheral centersreporting to it. The program had three broadobjectives: the short-term objective was tofoster a reporting culture, the intermediateobjective was to involve a large number ofhealthcare professionals in the systems ininformation dissemination and the long-termobjective was for the program to be abenchmark for global drug monitoring.However, the World Bank funding for thenational programme ended in mid 2009 andthe programme was temporarily suspended.

Recognizing the need to restart thenational pharmacovigilance programme, ina brainstorming workshop jointly organizedby Department of Pharmacology, AIIMS andCDSCO in late 2009, the framework of thenew programme was formulated. The

programme now rechristened as thePharmacovigilance programme for India(PvPI) is operational from mid July 2010.

Role of Pharmacovigilanceprogramme in drug safetymonitoring

Safety problems with pharmaceuticalproducts can be identified in Phase I, PhaseII, and Phase III clinical studies conductedprior to regulatory approval of the drug.However, the numbers of patients enrolledin these studies are usually inadequate toallow for reliable detection of less frequentadverse events. The routine three phaseclinical trials do not always guarantee safetyof a new drug as the human trials usuallycover only a few thousands of volunteers, butseveral lakhs of people take the drug after itis allowed to be marketed. It is essential tofollow a drug from pre-marketing clinicalstudies into the real life conditions. As a newdrug is released, safety issues can arise dueto several reasons like trial participants notbeing a true representative of end users,genetic variations in the patient population,co-morbidities and concomitant medicationsand little prior information on the use of drugin special populations like elderly, childrenand pregnant women. One option forimproving the government's ability to detectadverse events before a regulatory approvalis to increase the numbers of patientsenrolled in pre-registration clinical trials,

*E-mail : yk.ykgupta@gmail.com

Article

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particularly in the larger Phase III trials. Afternew drug products have received approvalfor marketing, the Drug regulatory authoritiesrely largely on a voluntary spontaneousreporting system to generate signals of asafety problem.

The need for pharmacovigilance is wellunderstood by the government and thescientific community in the country, in thecontext of increasing number of recalls ofdrugs worldwide from the market due to theirserious side effects. Recent withdrawal ofcertain blockbuster drugs in the US andEurope is a testimony to the successfulfunctioning of ADR reporting system indeveloped countries.

All medicines (pharmaceuticals andvaccines) have side effects. Some of theseside effects are known, while many are stillunknown even though that medicine hasbeen in clinical use for several years. It isimportant to monitor both the known andhitherto unknown side effects of medicinesin order to determine any new informationavailable in relation to their safety profile. Ina vast country like India, with a population ofover 1.2 billion which has vast ethnicvariability, different disease prevalencepatterns, practice of different systems ofmedicines, different socioeconomic statusit is important to have a standardized androbust Pharmacovigilance and drug safetymonitoring programme for the nation.Collecting this information in a systematicmanner and analyzing the data to reach ameaningful conclusion on the continued useof these medicines is the rationale to institutethis program for India.

Since, there are considerable socialand economic consequences of ADRsthere is a need to engage health-careprofessionals, in a wel l structuredprogramme to bui ld synergies formonitoring ADRs. The purpose of thePharma-covigilance Program of India is tocollect, collate and analyze data to arriveat an inference to recommend regulatoryinterventions, besides communicatingrisks to healthcare professionals and thepublic.

SWOT analysis ofPharmacovigilance in India

The Pharmaceutical industry in India isvalued at Rs. 90,000 Crore and is growingat the rate of 12 - 14 % per annum. Exportsare growing at 25 % Compound AnnualGrowth Rate (CAGR) every year. The totalexports of Pharma products are to the extentof Rs. 40,000 Crore. India is now beingrecognized as the 'Global pharmacy ofGeneric Drugs' & has distinction of providinggeneric quality drugs at affordable cost. India

is also emerging rapidly as a hub of GlobalClinical trials & a destination for DrugDiscovery & Development.

Further, more & more new drugs arebeing introduced into the country whichinclude New Chemical Entities (NCE), hightech pharma products, vaccines as well asnew dosage forms, new routes of drugadministrations and new therapeutic claimsof existing drugs.

Such rapid induction of NCEs and Hightech Pharma products in the market throwup the challenges of monitoring AdverseDrug Reactions (ADRs) over largepopulation base.

(a) Strengths

The biggest strength of India is its largepopulation and a large pharmaceutical andbiotech industry base. According to thereport of the National Commission onpopulation in the year 2000, India wasprojected to have 1 billion people, i.e. 16percent of the world's population

If current trends continue, India mayovertake China in 2045, to become the mostpopulous country in the world. While globalpopulation has increased threefold duringthis century, from 2 billion to 6 billion, thepopulation of India has increased nearly fivetimes from 238 million (23 crores) to 1 billionin the same period.

According to the OPPI and Ernst andYoung report published in 2009, It hasmanufacturing prowess in both APIs, Indiais the 3rd largest player in the world with500 different APIs and in formulations whereit manufactures 60,000 packs across 60therapy areas. India currently accounts for8% of the global pharmaceutical productionmaking it the world's 4th largestpharmaceutical producer.

Also, the focus is on to further enhanceIndia's capability to contribute moremedicines to the world by increasing thefocus on research and development. TheIndian government has recognized the needto build an environment conducive forresearch and innovation and has planned/implemented a number of initiatives toprovide the much needed impetus toresearch and innovation in pharma & biotech.The Government of India is embarking on amajor multi-billion dollar initiative with 50%public funding through a public privatepartnership model to harness India'sinnovation capability. The vision is to catapultIndia into one of the top five pharmaInnovation hubs by 2020 with one out ofevery five to ten drugs discovered worldwideby 2020 coming from India. With a largepopulation being exposed to a large portfolio

of drugs there is a huge mine of data thatcan be explored to learn more about thesafety profile of our drugs.

(b) Weaknesses

As per the estimates during 2009-10,the allocation of budget for health by theCentre stood at Rs 21680 crore, whichaccounted for 2.1 per cent of the totalexpenditure and 0.35 per cent of the GDPof India. The overall spend for the vitalhealthcare sector always remained far lessthan half a percent of the India's GDPhovering around a maximum of 2% of thetotal budget.

In comparison The United States spent16% of its national income (GDP) on healthin 2007. France, Switzerland and Germany,the countries which, apart from the UnitedStates, spend the greatest proportion ofnational income on health, spent over 5percentage points of GDP less: respectively11.0%, 10.8% and 10.4% of their GDP.

Thus low availability of spend on healthhas an impact on the manpower andresources that are available forimplementing programs and issues ofnational importance such aspharmacovigilance. A case in point is theerstwhile National Pharmacovigilanceprogram launched in 2004. One of thereasons for the failure of the program wasthe continuous availability of funds to sustainthe program.

(c) Opportunities

The opportunities are immense. Indiaconstitutes 16% of the world's populationand is one of the largest source of humanbiodiversity, consisting of 4635 culturally andanthropologically well-defined populationswith little or no gene flow between them.

Hence, study on Indian populations,who are known for their cultural and geneticdiversity, not only provides insight into theircomplex origin, history and relatedness, butalso helps in understanding molecularpathology of genetic diseases. As eachIndian population is unique in their geneticcomposition, etiologies of genetic diseasesare often different from other globalpopulations. Indian populations are uniquein their genetic origin as well as in themutations underlying in the susceptibility todisease. Therefore, what is true for otherglobal populations, in terms of their geneticbasis for disease susceptibility, may not betrue for Indian populations.

Collection of vital data on the behaviorof drugs in the Indian population will revealadditional information on the safety profileof these drugs. Once the ADR data iscollected, signaling can help determine if a

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particular ADR was caused by a particulardrug and if it had any correlation with thegenetic diversity of the Indian population.

Moreover, with more 300 medicalcolleges, 230 dental colleges, 830 pharmacycolleges and 657 recognized nursingcolleges, there is a great opportunity for Indiato tap the potential human resourcesrequired for an effective pharmacovigilancesystem.

(d) Threats

Ensure availability of and management offunds:

Advance contingency fund and salaryof the technical associates appointed at theADR monitoring centre should reach to thecentre coordinator a month in advance i.e.in the month of December for first half andMay for second half of the year. Centrecoordinator should send the utilizationcertificate along with original bills dulyverified to the CDSCO zonal office within 15days of the following month.

Conduct frequent training and awareness ofPharmacovigilance:

AMC coordinator must organize at leasttwo meetings with HCP in their areas.Expenses should be met from thecontingency fund. Coordinator should be theresource person for such meetings.

Detect and respond to under reporting ofADRs:

Periodic sensitization of HCP throughvarious modes viz poster, pamphlets, SMS,etc. by the center coordinator will improveAE reporting. The technical associateappointed at the centre should visit daily towards, OPDs and private clinics etc.Undertake appropriate measures to createawareness among the public through massmedia to increase the reporting.

Ensure quality of filled ADR forms:

Quality Review Panel (QRP) will ensurequality of reports during their visit to the AMCand also at the PvPI National CoordinatingCentre (NCC).

Proper supervision of functioning of thecenters:

A Quality Review Panel (QRP) shallvisit a sample set of AMCs at least once ayear to monitor functioning of these centres.If functioning of the Centre is foundunsatisfactory or not working as per SOPs,an appropriate warning shall be issued. Thereport should decide the status of the centre.If performing well, the AMC shall be givendue recognition for its achievements.

Feed back to the Health Care Professionals

AMC coordinator will circulate thereports generated by the PvPI National

Coordinating Centre and give feedback ofthe programme progress to the Health CareProfessionals.

Attitude towards ADRreporting and practices ofhealth care professionalstowards ADR reporting

Adverse events are preventable if theclinician maintains a high degree ofsuspicion and pays close attention to detailsregarding adverse events following drugadministration. Another way of prevention isby efficient reporting and monitoring of ADRswhich can help in generation of safetysignals. However, under-reporting of ADRsby health care physicians is a majorproblem, even in countries like, UK, US andJapan, where pharmacovigilance systemshave been well established.

Numerous studies have attempted tounderstand the attitude of physicianstowards reporting ADRs. European studieshave revealed that physicians inclined toreport only adverse reactions that areserious, unusual or rare and are do not reportnon-serious or common adverse reactions.Unlike that in the west, few such studieshave been carried out in India. Surprisingly,these studies have revealed that manyphysicians are unaware of the pharma-covigilance programme and the ADRreporting systems existing in the country.Other reasons for low ADR reporting ratesare lack of feedback regarding the reportsand lack of time due to high clinical load.Nevertheless, many of these factors arepotentially modifiable.

The studies have also attempted toidentify, possible measures that mayenhance involvement of physicians in theADR reporting system. These measuresinclude, creating awareness aboutpharmacovigilance, implementing ADRreporting as integral part of UG, internshipand PG training, providing active manpowerto collect ADR reports from busy clinicians,provision of feedback to reporting health careprofessionals, automatic membership to"ADR reporters club", provision ofinformation about drug safety andmedication errors, involvement of nursesand paramedical staff in reporting ADRs andgiving small economic incentives to regularreporters. In addition, impressing upon theclinicians the importance of reportingrelatively common ADRs, in order to identifydrug epidemics, may also help in increasingthe volume of ADR reports.

However, although many of thesemeasures have been suggested to increase

the reporting rates, only few, such asawareness and training programmes,provision of feedback to reporters, involvingnurses and giving small economic incentivesfor reporting have actually been tested andproven to increase the reporting rates.

Stakeholders inPharmacovigilancePatients

The patients are the most importantstakeholders in drug safety monitoringsystem as they are the ones who experiencethe adverse drug reactions. Promptidentification and feedback to the prescribingphysician regarding ADR following usage ofa drug is imperative to capture the harmfuleffects of the drug early in the product cycle.Moreover, it is also important for patients tomaintain a high index of suspicion forcounterfeit drugs especially when a drug thatis usually effective fails to provide the samelevel of effectiveness. Generally, in the moredeveloped countries, patients can directlyreport ADRs to the pharmacovigilancecentres. However, in India due low literacyand lack of understanding of medical signsand systems, patients notifiy the physicianwho after proper history taking report theADR to the pharmacovigilance centres.

Pharmaceutical IndustryThe amended schedule Y (2005) of the

Drugs and Cosmetics Act mandated thesubmission of periodic safety update reports(PSURs) for a period of four yearspostmarketing. Moreover, it was recognizedthat there was a need to carry out safetysurveillance studies to answer specific drugrelated issues. In addition, as many drugsare also licensed in other countries, safetydata from those regions was required to becollected, analyzed and reported in PSURs.This change has led to massive expansionof pharmacovigilance activities in theindustry. However, the nature of suchactivities remains focused to only thosedrugs manufactured by it. Unfortunately,even after amendments in the regulations,the quantity and quality of ADR data providedby the industry is often below specifiedstandards. Further, as industry drivenpharmacovigilance is mandated only for newdrugs, ADRs related to generics may bemissed. This may be due to lack of staffexperienced in pharmacovigilance.Nevertheless, as awareness about drugsafety monitoring is increasing, the industryhas the responsibil ity of training itsprofessional sales representatives andpharmacovigilance executives to interactwith treating physicians and collect ADRreports.

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RegulatorsThe drug regulator is one of the most

important stakeholders in the Pharma-covigilance system. The onus of constantlyreviewing updated drug safety informationand ensuring that public at large is protectedfrom the possible adverse effects of drugsconstantly lies with the drug licensingauthority. Moreover, regulators are oftenfaced with the prospect of either banning,suspending the marketing, or changing thesafety specifications in the label of drugs withpotential safety issues reported from otherregions of the world. Thereforepharmacovigilance data becomes a majordecision making tool in the hands of theregulator. In addition, constant generationand review of safety data of drugs alsobolsters public confidence in the licensingauthority.

Academicians - Post graduate andundergraduate training and curriculum

One of the key skills that undergraduatemedical students should develop during theirundergraduate training is to be prepared forsafe medical practice. This concept isusually diluted or ignored in most medicalcurricula and course designers usually focuson content such as causes of diseases,pathogenesis, clinical picture, investigations,differential diagnosis and case management.The focus should also be on risk assessmentof medications, evaluation of adverseeffects, contraindications and druginteractions while designing the course forpharmacology and medicine curricula. Theundergraduate students should especially betaught about common medication errors thatoccur with high risk drugs such as warfarin,hypoglycaemic agents, opioids andcorticosteroids and measures to preventthem. The students can also play active rolein collecting ADR reports during their clinicalwards posting.

Interns and PG students can play amajor role in interacting with patients andtheir peers in the clinical departments. Theirtraining should be oriented towards,identifying ADRs, assessing theirpreventability and reporting them. Besidesthey can, by interacting with their peers andother para medical staff, increase theawareness about pharmacovigilancesystems and enhance ADR reporting rates.Moreover, interns and PG students are aninvaluable source for collecting, analyzingfor causality and reporting ADRs andauthoring case reports and case series andcohort event monitoring studies. However,their training should be largely self directedand dynamic, albeit with proper mentoring,thus enabling them to provide appropriateand up-to-date feedback regarding ADRsand other drug related problems to others.

Role of other partnersRole of other stakeholders like media

representatives, lawyers, health insuranceproviders and non-governmentalorganizations in development of robustpharmacovigilance system and sound drugpolicies cannot be undermined. Media bypromoting good ADR reporting practices andtheir relevance to the patients and consumergroups can play an important role inencouraging them to report the adverseevents to their clinicians. These groups byvoicing public opinion and expectations canfacil itate the evolution of a pharma-covigilance programme that enjoys favorablepublic opinion and trust. Co-operation andcommunication with these partners needsto be as clear and open as possible.Misrepresentation of facts in the form of'attention grabbing' drug safety concerns canwreak havoc on the public confidence in theexisting drug safety policies as well as thepharmaceutical industry.

Synergy between academia, regulator and industry for effectivepharmacovigilance

Pharmacovigilance cannot be anexercise in isolation. In order to bemeaningful, it has to involve all the majorstakeholders. A collaborative model involvingthe three major stakeholders; the academia,the industry and the regulators has beenenvisaged to enhance the effectiveness ofthe pharmacovigilance system in India.

Under the erstwhile pharmacovigilanceprogramme, drug safety monitoring activitieswas more or less restricted to a few centresand were carried out by highly motivatedpeople (mostly pharmacologists) despitefinancial / resource constraints. Moreover,these activities were secondary to theirprimary job of teaching. Owing to manpowerand resource constraints (lack of dedicatedcomputers, access to literature sources,poor archiving facilities etc.) the quantity andthe quality of ADR data collected wasinsufficient to propel any real regulatorydecision regarding drug safety. Further, asthe onus was on "all drugs and all ADRs",and there was a definite loss in focus.However, the new pharmacovigilanceprogramme envisages involving most of theapproximately 300 registered medicalcolleges across the country to ensure thatmeaningful and country specific dataregarding ADRs can be collected from allparts of the country. Not only spontaneousreport collection, the new programme willalso encourage and facilitate monitoringcentres to undertake and reportpostmarketing safety studies, drug usereviews and registry/database based studiesindependently or in collaboration withindustry partners.

After submission of PSURs were mademandatory in India as per the amendedschedule Y of the Drugs and Cosmetics Act,pharmacovigilance as a core activity withinthe pharmaceutical industry increasedtremendously. However, within a company,the nature of such activities remains focusedto only those drugs manufactured by it.Therefore to broaden the scope of drugsafety monitoring, it is proposed that industrysynergizes and supports the initiative ofacademia in undertaking pharmacovigilanceprojects, especially cohort event monitoring,safety trials and other pharma-coepidemiological studies. Further, industryinputs and support for organizing trainingworkshops, symposia etc, in collaborationwith the academia and regulators will alsohelp in increasing the awareness andoutreach of the programme amongst theprescribers and will make it more effective.

Data generated from the collected ADRreports enable the regulators to makeimportant regulatory decisions such asbanning, restricting the use or makingchanges in the label of a drug. However, inIndia due to the absence of any substantialADR data, regulators are often forced to relyon western ADR data to make suchdecisions. Under the new pharmacovigilanceprogramme, a proactive role for regulatorshas been envisaged, wherein they do notmerely end-users of ADR data but alsofacilitate and oversee academia-industrycollaborative pharmacovigilance projects.The new programme also seeks to activelyinvolve the regulators in drug safety trainingprogrammes, providing operational supportto the ADR monitoring centres, carrying outperiodic quality assurance activities andassuring continued funding for sustaining theprogramme.

PharmacovigilanceProgramme for India (PvPI)

The Central Drugs Standard ControlOrganization (CDSCO) under the aegis ofMinistry of Health & Family Welfare,Government of India in collaboration withDepartment of Pharmacology, All IndiaInstitute of Medical Sciences (AIIMS), NewDelhi has initiatited a nation-widepharmacovigilance programme forprotecting the health of the patients byassuring drug safety which will include datafor drugs, biologicals, vaccines, diagnosticsand medical devices from public and privatesector. The comprehensive nationalprogramme is coordinated by theDepartment of Pharmacology at AIIMS as aNational Coordinating Centre. The centreoperates under the supervision of a SteeringCommittee.

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The Goal of the program is to ensurethat the benefits of medicine used outweighthe risks and thus safeguard the health ofthe Indian population. The objectives are:

To monitor Adverse Drug Reactions(ADRs) in Indian population

To create awareness amongst healthcare professionals about theimportance of ADR reporting in India

To monitor benefit-risk profile ofmedicines

Communicate findings with all keystakeholders

Generate independent, evidence basedrecommendations on the safety ofmedicines

Support the CDSCO for formulatingsafety related regulatory decisions formedicines

Create a national centre of excellenceat par with global drug safety monitoringstandards

Key features of this programme1. There is an organized project

management approach to theprogramme.

2. All the key stakeholders have beeninvolved in this namely (and not limitedto) Government, Academia, HealthCare professional bodies, Industry,National Immunization programmes,WHO-Uppsala monitoring centre,Industry professional bodies, Medicalcolleges, autonomous institutes,corporate hospitals, CDSCO Zonalcentres.

3. Data on Indian population will enableinformed decision making by the Indianregulatory authority by performingsignal detection once the data reachesa threshold size

4. The CDSCO Zonal centres will provideadministrative oversight to the ADRmonitoring centres at the medicalcolleges.

5. Training and Quality assurance are keyessential elements intertwined withevery aspect of the programme.

Framework of the new programmeThe programme is envisaged to be

rolled out in three phases. Phase I wouldinclude 40 adverse drug reaction monitoringcentres (AMC) and will be rolled out in 2010.The programme would be expanded inPhase II to include up to 140 MCI recognizedmedical colleges by 2011. Phase III wouldultimately cover the healthcare system by2013. Phase I will be further divided intophase Ia and Ib. Phase Ia will involveupgrading 10 centres in terms ofinfrastructure (computer and ancillaries).

Phase Ib will include the rest of the 40centres by end of 2010. The centres forPhase Ia have been shortlisted based onletter of intent received from interestedfaculty, duly forwarded by the head of theinstitution. The AMCs will get operational andlogistic support from their respective zonalCDSCO centres, situated at Ghaziabad,Kolkata, Mumbai and Chennai. The zonalCDSCO centres will be under administrativecontrol of the CDSCO headquarter at NewDelhi.

The coordinating centre ofPharmacovigilance Programme for India willbe housed at Department of Pharmacology,All India Institute of Medical Sciences, NewDelhi and will provide technical support tothe CDSCO headquarter. All the centresunder the programme will function inaccordance with the protocol and SOPsdeveloped by expert committees.

transmitted through vigiflow interface into theUMC ADR database where signal processingcan be carried out.

Collaboration with WorldHealth Organization andthe Uppsala MonitoringCentre (UMC)/WHO

WHO and UMC work with and/orprovide technical support to more than 94countries worldwide. The long term objectiveof the PvPI is to establish a 'Centre ofExcellence' for Pharmacovigilance in India.To achieve this objective, the PvPI NationalCoordinating Centre will collaborate with theWHO Collaborating Centre - UppsalaMonitoring Centre (UMC) based in Sweden.

Training of the staff at the PvPI nationalcoordinating centre at AIIMS, the ADRMonitoring centres in medical collegesacross the country

ADR data flowAdverse drug reaction reports will be

collected at the ADR monitoring centres(AMCs). The pharmacovigilance staff at theAMCs will check for validity of the report andif possible conduct provisional causalityassessment. The ADR forms will then bedispatched to the co-ordinating centre as perthe SOPs. The AMC staff will also maintaina log of all the centre activities. SelectedAMCs will also carry out focused ADRmonitoring of drugs in the focused ADRmonitoring watch list. The co-ordinatingcentre will conduct causality assessmentand upload the reports into the nationalpharmacovigilance database. The co-ordinating centre will prepare a consolidatedreport of ADRs collected at defined timeintervals. All the ADRs from all other sources(industry, Health care professionals, nationalimmunization programmes etc.) will also bedatabased at the co-ordinating centre.

The centre will also implement andintegrate pharmacovigilance activities intopublic health programmes involving massusage of drugs, such as for anti-malarial,anti-tubercular and anti-retroviral drugs.Lastly, the integrated ADR data will be

Usage of UMC's Vigiflow software (formedicines) and Paniflow (for vaccines)

Access to Vigibase, which containsworldwide medicines safety data

Access to early information aboutpotential safety hazards of medicines(worldwide data)

Technical collaboration for Pharma-covigilance Programme of India

Technical collaboration for a regularpublication that will be issued by thePvPI National Coordinating Centre fordistribution to the ADR Monitoringcentres and other health careprofessionals.

Linking Pharmacovigilancewith Public HealthProgrammes

Drug safety concerns one and all andhence a robust pharmacovigilance systemis the clear need of the present and futuretimes. A good plan is half the job done.However successful start is just the

Fig. 1. Proposed growth phases ofPharmacovigilance Programme for India

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beginning and it is important to stay focused.A continued interest of all the stake holdersin pharmacovigilance activit ies wil ldetermine the success of the programme.One of the many ways to ensure ongoinginterest in pharmacovigilance is to include itin the public health programme. This willserve the dual purpose of continued interestin drug safety at the grass root level of healthcare system as well as catering to the safetyissues important for public in general.

One such issue important for India isthe recent switch over to artemisinincombination therapies for treatment ofmalaria in view of increasing chloroquineresistance. In this respect, the NationalInstitute of Malaria Research, incollaboration with the National CoordinatingCentre at Department of Pharmacology,AIIMS initiated a World Bank funded studyfor pharmacovigilance of anti-malarialmedicines. This is the first attempt to involvepharmacovigilance in a public healthprogramme in India. The study aims toassess the safety of artemisinin combinationtherapies in real life settings in India. Theultimate goal is to influence the behavior ofthe healthcare physicians in the remoteareas of the country with respect to adverseevent reporting.

Following successful implementation ofpharmacovigilance in malaria, the next stepshould be involvement of other public healthprogrammes like HIV, Leprosy, Tuberculosisetc. Such efforts will help in making thepharmacovigilance programme a self-sustaining system if the logistics can betaken care of. It will also help in buildingpatient trust in the healthcare system whichis the eventual expectation from thePharmacovigilance programme in India.

Linkingpharmacogenomics withpharmacovigilance

Many different types of drugs areavailable to treat a wide variety of disorders.Why some patients respond to a particulardrug and others do not respond, or whysome patients tolerate a drug well and othersare intolerant of the same drug, are importantclinical issues in medicine. Geneticdifferences among patients may contributeto differences in medication response, aswell as the development of adverse effects.'Pharmacogenomics' and 'pharma-cogenetics' refer to the use of moleculargenetic approaches to understanddifferences in drug response and tolerability.Many types of putative ADRs are likely to becomplex and to have multifactorial etiologies.Examples include the metabolic syndrome,tardive dyskinesia, suicidality, hepaticdysfunction and cardiac abnormalities

following drug administration. Theseconditions are clinically significant and oftenlinked to drug therapies, but they cannot beeasily or solely attributed to a drug exposure.Pharmacogenetics can help identifyindividuals who are susceptible to adversedrug reactions (ADRs) has the potential toreduce the personal and population costs ofdrug-related morbidity.

The most common enzyme deficiencyworldwide is glucose-6-phosphatedehydrogenase (G6PD) deficiency, withmany allelic variants. It is associated withacute haemolysis on exposure to oxidisingdrugs such as primaquine, chlorproguanil-dapsone, sulfonamides, and sulfones,nitrofurantoin, nalidixic acid, quinine,flutamide Phenotypic tests for G6PDdeficiency are recommended before usingdrugs such as primaquine, but it is not knownhow often this is carried out. Abacavir an HIV-1 reverse transcriptase inhibitor, causes ahypersensitivity reaction (skin rash, fever,gastrointestinal and respiratory effects) inabout 5% of patients and is associated withan HLA allele, HLA-B*5701. Pre-prescriptiongenotyping prevents abacavir hyper-sensitivity and is cost-effective. In Europe,screening for HLA-B*5701 is now mandatorybefore prescribing abacavir. Similarly, severeimmune-mediated adverse effects includingStevens-Johnson syndrome and toxicepidermal necrolysis has been reported withcarbamazepine. In Han Chinese patients thisis associated with HLA-B*1502, and the drugis avoided in those with this phenotype. In arecent study, the investigators evaluated theimplications of single nucleotidepolymorphism of CYP2C9 and CYP2C19genes on phenytoin pharmacokinetics inhealthy South Indian voulnteers andconcluded that *2 - *3 alleles of CYP2C9led to decreased hydroxylation of the drug,thereby increasing the risk of ADRs

Although promising, the eventualimpact of pharmacogenomic profiling foridentification of ADR susceptibility amongindividuals would depend upon incidence ofdrug related toxicity, prevalence of variantalleles, severity of consequences and alsothe availability of rapid, reliable and costeffective assays. Several researchers haveproposed the integration of genomicinformation with the pharmacovigilancedatabases, which can not only enhancesignal detection but also aid in determiningwhether genotyping should be performedprior to initiation of drug therapy. However,several key operational, regulatory, ethicaland legal issues need to be addressedbefore the potential role of pharma-cogenomics in ADR detection andprevention can be realized. These includethe complexity of database which integratesinformation on drug transporters,

metabolism and therapeutic targets, publicprivate sector cooperation, funding ofresearch, ensuring privacy andconfidentiality of data to preventstigmatization as well as educating themedical and lay communities.

India's 2020 Vision forPharmacovigilance1. Being the second most populous

country in the world, it should constitutethe largest contributor to the adverseevent database as a result of a largenumber of ADRs being reported to thenational drugs regulatory authority.

2. The actual number of ADRs shouldactually show a declining trend as thecountry should aim to achieve the realaim of pharmacovigilance i.e. to providesafer medicines for the population ofIndia. The aim therefore should be tocollect data and learn from that dataso much that we are able to take adecision on continuing or discontinuingthe use of a drug based on its ongoingrisk benefit assessment. The focusshould move from pharmacodiligenceto pharmacovigilance. The targetshould be to prevent ADRs and theassociated loss of costs in managingthose ADRs.

3. Each stakeholder to not only beconscientious of their rights but alsotheir responsibil it ies towards thepatients and the society at large

4. The Program for Pharmacovigilance inIndia should be viewed as a centre ofexcellence and the model pursued anddemonstrated in the past 10 yearsshould become a role model for the restof the world to follow.

5. India should aim to be self dependentand have its own National Drug Safetydatabase with electronic reportingcapabilities to all the other major Globalregulatory agencies

6. Globally regulatory agencies in theworld should view India as the GlobalPharmacy of the world and as aresource of knowledge and a treasuryof information related to the safety ofmolecules.

7. Not only will the safety database coverpharmaceutical products, but alsobiological, devices, vaccines and stemcell therapies.

Acknowledgementsl gratefully acknowledge the

contributions of Dr. Vivek Ahuja, Mr. PaulLalvani, Dr. Biswa Mohan Padhy, Dr. PoojaGupta and Dr. Ashish Kakkar in preparationof the article.