Yogesh K. ChaudhariM Pharm (Pharmacology)

Mumbai University,Mumbai

1.INTRODUCTION2.AIMS3.RESPONSIBILITIES4.NEED OF PHARMACOVIGILANCE5.GOVERNING BODIES6.METHODS OF PHARMACOVIGILANCE7. PHARMACOVIGILANCE INSPECTION8.ADVERSE DRUG REACTION9.APPLICATION OF PHARMACOVIGILANCE10.TERMINOLOGY11.POST MARKETING SURVEILLANCE12. PHARMACOVIGILANCE PROGRAMME IN INDIA13.WHO PROGRAMME FOR INTERNATIONAL DRUG MONITORING14.PHARMACOVIGILANCE OF MEDICAL DEVICES15.PHARMACOVIGILANCE OF HERBAL MEDICINES

Pharmacovigilance(PV) also called as drug safetyPharmakon-------in greek----drugVigilare -----------in latin------to keep watch

def: Pharmacovigilance is the science &activities relating to the detection , assessment, understanding and prevention of adverse effects (WHO collaborating centre for international drug monitoring)

AIMS To improve patient care and safety To improve public health and safety To contribute to the assessment of

benefit, harm ,effectiveness and risk of medicines

To promote education and clinical training

To promote rational and safe use of medicines

RESPONSIBILITIES

Timely collection of data ,recording and notificationAppropriate assessments (data completeness , seriousness)Expedited and periodic reporting Creates appropriate structures for communication

1.HUMANITARIAN CONCERN -Animal toxicology is often not a good predictor for human effects .

-Evidence of safety from clinical trials is insufficient due to some limitations LIMITATIONS (phase 1-3): limited size , narrow population (age &sex specific), narrow indications (only specific disease), short duration

2. SAFE USE OF MEDICINES it has been suggested that ADRs may cause 5700 deaths per year in UK3.ADRs ARE EXPENSIVE 4.PROMOTING RATIONAL USE OF MEDICINES 5.ENSURING PUBLIC CONFIDENCE6.ETHICAL CONCERN not reporting is serious reaction is unethical

The pharmaceutical industry Regulatory authorities WHO collaborating centre for

international drug monitoring CIOMS(Council for International

Organization of Medical Sciences )

METHODS 0F PHARMACOVIGILANCE

1.Individual case safety reports2.Clinical review of case reports 3.Cohort event monitoring 4.Longitudinal electronic patient records 5.Spontaneous reporting 6.Periodic Safety Update Reports (PSUR)7.Expedited report8.Record linkage

1.INDIVIDUAL CASE SAFETY REPORTS: -Like yellow card system of the Pharmacovigilance section of the U.K. -Their strength in signaling causal associations depend on the skill and experience of the reporter and the documentation and characteristics of the event.

2.CLINICAL REVIEW OF CASE REPORTS: -The quality of reports is variable , large national and international organizations collect hundreds of thousands of reports each year , every one of which can’t possibly be reviewed by the available experts. -Even if each report could be reviewed , important reporting patterns would be missed. -Computational have therefore been developed to help highlight the most urgent problems .

3.COHORT EVENT MONITORING: -Cohort Event Monitoring (CEM) systems for intensified follow up of selected medicinal products. -The main limitations are its restriction to small subset of medicinal products , the relatively small fraction of the population covered .

4.LONGITUDINAL ELECTRONIC PATIENT RECORDS: -It is extremely valuable but underused. -They cover large populations, provide detailed

information on both exposed and unexposed patients. -Information is extracted directly from the computer systems in which physicians store patient’s data. -Privacy protection for patients and physicians is

of the utmost importance.

5.SPONTANEOUS REPORTING: -The reporting might be directly to the company , or it could be to the regulatory authority. -Main limitation is under reporting.

-However , their main purpose is not the quantification of the frequency, but identification of signals.

-When becoming aware of a serious adverse drug reaction , health care providers, pharmacies, pharmaceutical companies shall report to the health authority.

-Time frame of reporting , report within a specific time frame(ex:7days) upon knowing of any serious ADR.

-REPORTING METHODS AND TEMPLATE : shall submit reports by post, fax or internet .

-A verbal report is acceptable in urgent situations, but written submission should be completed before the deadline.

-Additional information on a serious ADR report, not available at the time of the initial report , should be provided in follow up reports.

6.PERIODIC SAFETY UPDATE REPORTS(PSUR): -Pre marketing clinical trials may not be sufficient to reflect the product safety profile. -Therefore medically advanced countries impose the “post marketing drug safety monitoring period ” on new drugs.

-license holders shall proactively collect post marketing safety data, prepare PSUR and submit them to the health authority.

-According to the “regulation of medical products under safety monitoring” ,if pharmaceutical companies fail to submit PSUR as required , then the health authority may reassess the safety of the concerned product. -The last PSUR should be submitted before the expiration of the drug safety monitoring period.

-The “summary bridging report” provides summarized information of the PSURs.

7.EXPEDITED REPORT: -If there has been spontaneous reporting of a suspected ADR to a pharmaceutical company , there are legal obligations on the company to report serious reactions within a specified time frame to the regulatory authority. -based on the results of drug safety assessment , license holders shall report to the health authorities in an expedited manner

8.RECORD LINKAGE: - Bring together a variety of patient records . -A specific example is prescription event monitoring scheme. -It is less expensive but time consuming method.

PHARMACOVIGILANCE INSPECTION two types - 1.routine inspection 2.targeted inspection

1.Routine inspections - To make sure that pharmaceutical companies have the ability in performing Pharmacovigilance activities

2.targeted inspections a) inspections irrelevant to drug safety -companies that have not yet been inspected -companies that launch their first product -companies which are newly merged

b) inspections relevant to drug safety -companies that delay or fail to take their obligations on safety monitoring -companies that delay to submit or submit incomplete periodic safety update reports -companies that failed to report drug safety related issues (like drug withdrawal with out reporting )

ADVERSE DRUG REACTIONS

Adverse event reporting –comprises 4 elements

1.an identifiable patient 2.an identifiable reporter 3.a suspect drug 4.a suspected adverse event

TYPES OF ADRnon immunological a) TYPE A (or) predictable b) TYPE B (or) unpredictable

immunological a) TYPE -I (Ig E mediated) b) TYPE -II (cytotoxic) c) TYPE -III (immune complex) d) TYPE -IV (cell mediated)miscellaneous a) jarisch - herxheimer reaction b) infectious mononucleosis

NON IMMUNOLOGICAL TYPE A (or) predictable 1.side effects 2.secondary effects 3.toxic effects 4.mutagenicity&carcinogenicity 5.drug interactions 6.teratogenicity 7.nonimmunological activation of effector pathways 8.exacerbation of disease 9.Metabolic alterations 10.drug induced chromosomal damage 11.effect on spermatogenesis

TYPE B (or) unpredictable 1. intolerance 2. idiosyncrasy

Type A1.Side effects : - undesirable and unavoidable effects of drugs due to their pharmacological property at recommended doses. Ex-dry mouth from atropine therapy2.Secondary effect: -Indirect effects of drug due to its principal action. Ex-occurrence of TB in corticosteroid therapy.

3.toxic effect: -It is a pharmacological action due to over dosage or prolonged usage. Ex-coma with barbiturates

4.mutagenicity & carcinogenicity: -metabolites from drugs can cause structural changes in chromosomes to produce mutations. Ex-anti cancer drugs

5.drug interactions: -Can occur before its absorption into systemic circulation . Ex- phenobarbitone inhibits griseofulvin absorption from intestine

6.teratogenicity: -Fetal abnormalities produced due to drug intake by the pregnant woman Ex-androgens cause virilization of fetus

7.non immunological activation of effector pathways: -Some drugs cause release of mediators from mast cells resulting in urticaria. Ex-radio contrast media

8.exacerbation of disease : -Barbiturates precipitate symptoms of porphyria

9.metabolic alterations : Ex- isotretinoin interferes with VLDL metabolism and causes xanthoma

10.drug induced chromosomal damage: -Also called clastogens Ex-antibiotics, anticonvulsants

11.effect on spermatogenesis: -Cytotoxic drugs causes oligospermia.

Type B1.intolerance: -Appearance of toxic effects in a recipient to therapeutic doses of drug Ex- trifluperazine single dose causing muscle dystonia in children2.idiosyncrasy: -Uncertain reaction to a drug in a genetically defect patient Ex-chloramphenicol causes bone marrow depression

IMMUNOLOGICAL1.Type 1 (immediate or anaphylactic):

Ex:-penicillin, lignocaine

Mediators

urticaria

Earlier exposure

AB formed

AG:AB reaction

mast cells

Re exposure to the same Drug (AG)

2.Type 2 (cytotoxic): Drug + particular tissue AB (AG) AG:AB reaction complement cytolysis

Ex: blood transfusion reactions, cephalosporins

3.Type 3 (retarded or arthus ): Drug (AG) AB

AG : AB complex

Complement

Inflammatory reaction

Ex:- acute interstitial nephritis with NSAIDs

4.Type 4 (delayed hypersensitivity reactions ):

Ex:-contact dermatitis

Prior sensitization T lymphocytes c receptors (AB)

Re exposure of the drug (AG)

Release of lymphokines

AG:AB reaction

Attracts granulocytes

Inflammatory response

MISCELLANEOUS1.jarisch-herxheimer reaction: -This is seen when an infective disease is treated with antimicrobials , due to release of active substances from dead micro organisms and injured tissue resulting in focal exacerbation of the lesions.2.infectious mononucleosis: -Ampicillin induced morbilliform rash in patients suffering from infectious mononucleosis.

Steps of ADR monitoring: 1.identifying adverse drug reactions

2.assessing causality

3.documentation of ADR

4.reporting serious ADRs to PV centres/ADR regulatory authorities

NARANJO algorithm

For assessing the causality--definite = 9-probable = 5-8-possible = 1-4-doubtful = 0

Hartwig and Seigels scaleFor assessing the severity- 1.mild ADRs-are self limiting and do not contribute to prolongation of length of hospital stay. 2.moderate ADRs- require therapeutic intervention or hospital admission or prolonged hospital stay by at least one day . 3.severe ADRs- life threatening, requiring intensive medical care or produce disability or lead to death.

APPLICATION OF PHARMACOVIGILANCE

1. in national drug policy2.in the regulation of medicines3.in clinical practice4.in disease control public health programmes (problems are apparent in situations for the treatment of tropical diseases)

TERMINOLOGY

1.SIGNAL-reported information on a possible causal relationship which is being unknown or incompletely documented previously.

-usually more than 1 report is required to generate a signal

-before signals are published they are first clinically assessed by PV experts at UMC(Uppsala monitoring centre ,Sweden)

-there are 3types of signals 1.confirmed signals-causal relationship

between the drug and adverse event 2.refuted(false) signals-no causal

relationship 3.unconfirmed signals-require further

investigation

2.TRIAGE-process of placing a adverse event report into one of these 3 categories . a) non serious case b)serious case c)no case3.ADVERSE DRUG REACTION –any noxious change which is suspected to be due to a drug, occurs at doses normally used in man , requires treatment or decrease in dose or indicates caution in the future use of the same drug.

4.ADVERSE DRUG EVENT-any untoward medical occurrence that may present during treatment with a medicine , but which does not necessarily have a causal relationship with the treatment.5.WHOART-WHO Adverse Reaction Terminology is dictionary for coding adverse reactions . This system is maintained by the UMC.6.COSTART-COding Symbols for a Thesaurus of Adverse Reaction Terms developed by USFDA . But recently COSTART was replaced by MedDRA.

7.MedDRA-Medical Dictionary for Regulatory Activities - International medical terminology dictionary -Originally available in English &Japanese - MedDRA is organized as System Organ Class(SOC).which is divided into a)high level group terms(HLGT) b)high level terms(HLT) c)preferred terms(PT) d)lower level terms(LLT)

-MedDRA is managed by MSSO(Maintenance and Support Services Organization)

-MSSO releases new version in twice a year(march& September)

-March release is the main ,contains changes at the HLT level &above -September release contains changes at the PT level -Latest version(16.1) was updated on sept 2013

8.DATA MINING-extract information from a data and transform it into an understandable structure for further use -it is practical machine learning tools &techniques with java -the term data mining appeared around 1990. -currently data mining and knowledge discovery are used interchangeably

Six tasks-a)anomaly detection –identification of unusual data &data errors that require further investigations. b)association rule learning-searching relationship between variablesc)clustering-discovering groups that are in some way similard)classification-to apply to new datae)regression-models the data with least error f)summarization-compact representation of data

-Medical data mining-HITECH act(Health Information Technology for Economic and Clinical Health act) -by this data mining opportunities are maximized a)Free open source data mining soft ware & applications- carrot 2 GATE Orange rapid minerb)Commercial data mining software & application -clara bridge -oracle data mining -statistica data miner

9.VIGI FLOW-it is a web based ICSR(Individual Case Safety Report) system designed for national centres ,which does not have ICH-E2B compatible data base. -ICH-International Conference on Harmonization -Vigiflow is based on ICH-E2B -ICH-E1-E2F -----clinical safety -E3 ----------clinical study reports -E4 ----------dose response studies -E5 ----------ethnic factors -E6 -----------good clinical practice -E7-E11 -----clinical trials -E12 ---------clinical evaluation by therapeutic

category -E14 ---------clinical evaluation - E15-16 ----pharmacogenomics

a)input-ICSR data can be manually entered into vigiflow with support from the

latest version of terminologies such WHO-ART or MedDRA b)handling of ICSRs-it is easy to communicate within the vigiflow by adding a

digital note to the ICSR. - once a report is complete the first version of the ICSR is considered to be finalized.

c)analysis-search& statistics module is part of vigiflow .the results can be exported in

different output formats.d)communication-data can be sent to external contacts such as companies or other regulatory agencies. -Technical information-requirements are web browser , internet connection. - information stored in vigiflow is only accessible by users within the same country. -There are downloadable pdf information sheets available here

10.VIGIBASE-a unique collection of international drug safety data. Vigibase is the name of the WHO ICSR data base . Its consists of reports of adverse reactions common uses- -signal detection -updating product safety update reports -compare the reports - WHO member countries have access to the collected data and analyze - Vigibase comprises 8million reports in which 2 lack new reports are added quarterly

11.VIGI SEARCH- a search service for accessing ICSRs stored in the vigibase , offered by UMC to national centres.

12.VIGIMED-share point based conferencing facility ,exclusive to member countries of the WHO. For fast communication .

13.VIGIMINE-a statistical tool within vigisearch. It allows filtering of the results by age , sex , country.

14.VIGILYZE- during may & June 2013 vigisearch & vigimine were replaced by

this. Its a search and analysis tool that provide access to vigibase.

15.DECHALLENGE AND RECHALLENGE-a drug being stopped &restarted in a patient to confirm causal relationship.

16.PHARMACOEPIDEMIOLOGY- study of the incidence of adverse drug reactions in patient populations.

17.PHARMACOGENETICS-genetic variation that gives rise to differing responses to drugs including ADR.

18.PHARMACOGENOMICS-application of genomic technologies to new drug discovery.

19.PHARMACOENVIRONMENTOLOGY-form of pharmacovigilance which deals specifically with those pharmacological agents that have impact on the environment via elimination through living organisms subsequent to pharmacotherapy.

Post marketing surveillance(PMS)

-Is the practice of monitoring the safety of a pharmaceutical drug or medical device often it has been released on the market and is an important part of the science of Pharmacovigilance.

-Since drugs are approved on the basis of clinical trials, which involve relatively small numbers of people & do not have other medical conditions.

Approaches are –spontaneous reporting database - prescription event monitoring -electronic health records -patient registries

Uses-no fixed duration or patient population starts immediately after marketing report all ADRs helps to detect rare ADRsPMS-consists of 3 systems 1.ADR collecting and reporting system 2.reexamination system 3.reevaluation system

Sources-focus groups - customer surveys - customer complaints& warranty claims - literature reviews - mediaBenefits-improvement of medical device quality -verification of risk analysis -detection of chronic complaints -performance in different user population - customer satisfaction

Needs of PMS--to develop information about drug effects

- to find rare adverse events -assess to more patient

dataMethods of surveillance- -controlled clinical trials -spontaneous recording -cohort studies -case control studies-All adverse events occurring in a PMS should be submitted to UMC in the form of fact sheet.

Fact sheet should be-email to vigibase@whoumc.org - confirmation will be sent of received cases within 3 days -case report format-ICH E2B -both serious and non serious cases should be submitted -reporter qualification should be specified in the ICSR -ICSR on veterinary medicines , cosmetics should not be submitted to UMC -either of the two ADR terminologies WHOART (or)MedDRA can be used .

Pharmacovigilance programme of India (PVPI)

Introduction –-officially started on 23 November 2004 at new Delhi -pharmaceutical industry in India is valued at 90,000crore and is growing at the rate of 12-14% per annum -total export of pharma products is to the extent of 40,000crore. - India is now being recognized as the “global pharmacy of generic drugs”

-India is also emerging rapidly as a hub of global clinical trials & destination for drug discovery and development

-In a vast country like India with a population of over1.2 billion with vast ethnic variability ,different disease prevalence patterns , practice of different systems of medicines, different SES , it is important to have robust Pharmacovigilance and drug safety monitoring programmes.

PVPI is under control of-1.CDSCO(Central Drugs Standard Control Organization) 2.directorate general of health services 3.indian pharmacopeia commission (Ghaziabad)

-The programme is conducting by NCC(National Coordinating Centre) .

Goals & objectives- goal- to ensure that the benefits of use of medicine outweighs the risks objectives-1. to monitor ADRs 2. to create awareness among health care professionals about

ADRs 3.to monitor benefit –risk profile of medicines 4. generate independent ,evidence based recommendations 5.support the CDSCO 6.communicate findings with all stake holders 7.create a national centre

PVPI will be administered and monitored by the following committees1.steering committee2.strategic advisory committee

Technical support by –1.signal review panel 2.core training panel3.quality review panel

STEERING COMMITTEE Chairman-drugs controller general (India), New DelhiMembers-1.scientific director , Indian pharmacopoeia commission , Ghaziabad 2.head of dept of pharmacology ,AIIMS 3.Nominee of director general ,ICMR 4.Assisstant director general as representative of directorate general health services 5.under secretary as representative of the ministry of health & family welfare 6.nominee of vice chancellor of medical/pharmacy university 7.nominee of the medical council of India 8.nominee of the pharmacy council of India

-PVPI is a 3 layered structure consisting of 1.peripheral 2.regional 3.zonal centres

programme road map

Collaboration with WHO- UMCLong term objective of the PVPI is to establish a centre of excellence- for that training of the staff at the PVPI NCCUsage of UMC s vigiflow (for medicines), paniflow (for vaccines)Access to vigibaseAccess to early information about safety hazards

OPERATIONAL ASPECTS Roles and responsibilities of different personnel in PVPI Centre management Processing and reporting of suspected ADRs Quality assurance in the programmeRegulatory decision making Communication among various stake holders

Risk managementEnsure availability and management of funds Conduct frequent training and awareness Detect and respond to under reporting ADRsQuality review of filled ADR forms Proper supervision of the centres Feed back to the health care professionals

Programme communications

A,B,C,D,E- programme communications

1,2,3,4- ADR reporting

Monitoring and evaluation1.Process indicators – -number of ADR monitoring centres

participating -number of personnel trained in a year -funds budgeted and spent 2. Out come indicators – -number of ADR reports received in year -number of ADR reports processed in year -number of ADR reports submitted to vigiflow 3. Impact indicators – -number of signals generated and confirmed -number of safety related alerts issued by

CDSCO

WHO Pharmacovigilance programmeIntroduction : -Started in 1978 - Known as WHO programme for international drug monitoring, which is located in Uppsala, Sweden. -As of October 2013, 117 countries have joined

Functions – 1. identification and analysis of new ADR signals from national centres & sent to the WHO ICSR database 2. provision of the WHO database as a reference source. 3. information exchange between WHO UMC , national centres through vigimed

4. Publications, news letters, guidelines and books in the pharmacovigilance

5. supplying tools like WHO drug dictionary and WHO adverse reaction terminology

6. training to national centres

7. Maintaining of computer software(vigiflow)

8. annual meetings

9. research on Pharmacovigilance

REPORTING TRENDS:1. preferred report format is the ICH E2B

2.but some members still use the old WHO format(INTDIS)

3.ICSRs should be sent once every month but at least every quarterly

DISTRIBUTION OF ICSR WORLD WIDE

PHARMACOVIGILANCE OF MEDICAL DEVICES - medical device reporting(MDR) which is the reporting of adverse events with medical devices

PHARMACOVIGILANCE OF HERBAL MEDICINES - the safety of herbal medicines has become a major concern to both national health authorities and public -however mass media reports of adverse events with herbal medicines can be incomplete and therefore misleading regarding the use of herbal medicines

Thank

you