Pharmacovigilance in India: Dreams Vs Reality

National Seminar on Pharmacovigilance, CADD and Drug Development

Pushpagiri College of Pharmacy, Tiruvalla 16th Sept 2011

Unnikrishnan M K College of Pharmaceutical Sciences, Manipal 576 104

The Healers Doubtful Credentials!

Do you know the meaning of allopathy ? Doctors have been the butt of many jokes! Vaidayraja namasthubhyam Yamaraja sahodara Yamo harathi pranaani Vaidyo praana dhanaanicha To undergo treatment you have to be healthy, because you have to withstand both sickness and the medicine! - Moliere

Iatrogenic Deaths in USA

12,000 -----unnecessary surgery 7,000 -----medication errors in hospitals 20,000 -----other errors in hospitals 80,000 -----infections in hospitals 106,000 ----non-error, negative effects of drugs Total = 250,000 deaths/year are iatrogenic
Third leading cause of death in U S A
after heart disease and cancer

Only 60,000 Americans died in Vietnam war!

(Report in JAMA by B Starfield of Johns Hopkins School of Hygiene & Public Health)

Evolution of Pharmacovigilance
Thalidomide tragedy in 1961 first systematic international efforts to address drug safety
Led to WHO Pilot Research Project for International Drug Monitoring in 1968

WHO Collaborating Centre for International Drug Monitoring Uppsala Monitoring Centre (UMC)
Creation of International Society of Pharmacoepidemiology (ISPE) in 1984 & European Society of Pharmacovigilance (ESOP later ISoP the International Society) in 1992
PV formally introduced into research & academic world, PV integrated with clinical practice

Evolution of Pharmacovigilance
Pharmacovigilance Defn: science & activities relating to detection, assessment, understanding, prevention of adverse effects of drugs/herbals/traditional and complementary
medicines/blood products/biologicals/medical devices/vaccines

Development of pharmacovigilance over last 30years under the aegis of WHO

The Global burden of Unsafe Care

Patient safety global public health problem WHO estimates
millions of disabling injuries/death every year ~1 in 10 harmed while receiving health care in wellfunded & technologically advanced hospital settings

Very little evidence for burden of unsafe care in developing countries where :
16 billion injections administered each year for curative care 40% of this administered by reusing unsterilized syringes & needles

Global Burden of Unsafe Care (contd)

Economic burden is compelling
Added medical cost in some countries between US$ 6 - 29 billion a year

World Alliance for Patient Safety

Mobilize global efforts in health care safety in WHO Member States
Develop a global research agenda & locally adapted research tools Training & research funding Creating a global research network Translating research into safer care

International Pharmacovigilance(PV) Landscape

ADRs cause of hospitalizations, morbidity & even death Pharmacovigilance aims at preventing: ADRs & its impact on patients both in premarketing & post marketing phases of drug development

International Pharmacovigilance(PV) Landscape

Pharmacovigilance
began with WHOs Program for International Drug Monitoring (1968) extends beyond detecting new signals of safety concerns a tool for development & marketing of safer medicines

Drug Expertise: a sine qua non for safety

Number of drugs has increased dramatically
36th Edn of Martindale has > 430 pages of general index!

Two stories of contrast India Vs Australia

Zolpidem story

Alendronate story

Australian ADR Database

Up to 4 January 2008, 1032 reports of suspected ADRs to zolpidem entered TGA's ADR database
394 of 1032 reports mentioned parasomnia events

103 reports (10% ) included sleep driving

Therapeutic Goods Administration, Australia Warning Feb 2008

TGA Issues Black Box Warning! "Zolpidem may be associated with potentially dangerous complex sleep-related behaviours which may include sleep walking, sleep driving and other bizarre behaviours. Zolpidem is not to be taken with alcohol. Caution is needed with other CNS depressant drugs. Limit use to four weeks maximum under close medical supervision.

Bisphosphonates induced osteonecrosis of jaw

Severe pain, numbness, soft tissue infection, loosening of teeth Excruciating pain, disfigurement leading to suicides The strategy is to warn doctors, healthcare team, dentists etc.

Picture in UK, a developed country

National Health Services spends ~ 2bn a year treating patients with adverse reaction to prescribed drugs Enough to pay for 10,000 new midwives or cost of combating MRSA infections ADRs result in 6.5% of hospital admission = I million / year in UK alone average stay of 8 days in hospital @ 228 a day

Drug Companies Suppress Information on ADR

Merck knew that Vioxx, caused heart attacks, GSK knew that Antidepressant Seroxat, ( Paroxetin) increased suicidal thinking in young
There are instances when Glaxo paid up to 3 billions to escape litigation without admitting guilt Weve agreed to this settlement to avoid the delay, expense and uncertainty of litigation,
Mary Anne Rhyne, a company spokeswoman.

Why dont we have data like Australia?

1070 million Indians Vs 20 million in Australians Much more opportunity to gather data Much more racially diverse, Many more diseases in abundant numbers!
A visiting team of Australian health care providers witnessed Typhoid for the first time in India!

Many more systems of medicine Much more freedom to bend & twist rules
Much greater nefarious opportunity to improvise

 We dont have a good system of keeping records Still thrive on an oral tradition Very little discussion between the Prescriber, the Dispenser and Patient (Overworked Doctor, busy Pharmacists, high cash transactions) We lack faith in ourselves We want our observations to be supported by published literature from the West India has not contributed a single innovation in therapy

Some Attitude problems; some Resources problems!

Major flaw: poor networking!

We are working in isolation We have to learn from our own mistakes Developed countries learn from others mistakes!

How things go wrong a Case Study in Kerala

Nair 47 yrs h/o diabetes goes to hospital with vomiting and respiratory difficulty Decides for himself that his case must be seen by a gastroenterologist 9 days in the hospital, returns with the foll diagnosis (Hospital bill > Rs 25000/-)
Upper esophageal polyps, LRT, Pleural effusion, Functional bowel disorder

Mr Nairs prescription on discharge

1 2 3 4 5 6 7 8 9 10 11 T deriphyllin retard 500 T glimipiride 2 T Cefuroxime 500 Seroflo 100 (rotahaler) Tegasarod 6mg* Sod picosulphate 10 0-0-2 Deflazocort 6 mg Faropenem 200 Flupentixol 0.5 + melitracen 10 Clonazepam 1 Rappit + (??) 1-0-1 1-0-1 1-0-1 1-0-1 1-0-1 1-0-1 1-1-1 1-1-0 0-0-1 1-0-0

Nair Discharged!!
At home, Nair is feeling worse His wife and mother in law very anxious But they think the treatment is over with discharge! Blames fate! Waits for things to worsen!!

Nair hopelessly ill; off to the next hospital

Breathless, pedal edema, very sick Goes to another (bigger, more famous) hospital The revised diagnosis
CCF Dialated cardiomyopathy Severe LV dysfunction Type 2 DM Coronary angiogram shows Triple vessel disease

Tegaserod withdrawn from USA

On March 30, 2007, FDA requested Novartis to withdraw Zelnorm from shelves. FDA found a relationship between tegaserod and increased risks of heart attack or stroke Was still available as generic in India
Prescribed for constipation, irritable bowel syndrome Recently banned in India along with Gatifloxacin

Nairs prescription on discharge

T clopidogrel 75 1-0-1 T Amiodarone 100 T Ramipril 5 Glimipiride 2 Spironolactone 25 Carvedilol 12.5 Digoxin 0.5 Isosorbide dinitrate 10 1-1-1 Lasix 40 Pantoprazole 40 1-0-0 1-0-0 1-0-1/2 1-0-1 1-0-1 1-0-1 1-0-1-0 1-0-1

Nair back on his feet!

Now much better, takes medicines regularly Short morning walks to the gate and back Breathless after about 10 min walk Advised CABG Now waiting to get fit for CABG

 Male >55 yr Dx: HTN (uncontrolled) Rx: Clonidine, Beta blocker & CCB. After 3 days patient c/o eye pain, dryness & discomfort ,
Suggests referral to ophthalmology

Pharmacist suspects that it is due to Clonidine Physician decreased the dose of Clonidine & added Prazosin Eye discomfort resolved

 A patient with Zinc phosphide poisoning Physician query: on Clinical presentation & Treatment Pharmacists response: an article stating the use of steroids and immunosuppressants Physician:Starts Steroids & Immunosuppressants

 Female 48 yrs pesticide: contact poisoning C/o : pigmentation , vesicles, rash & itching, burning on right hand malar area, right side of neck & palmar region of left hand. H/o application of pesticide powder to buffaloes and while washing she came in contact with pesticide on Hands, malar area and right side of neck Medication History: Chlophenirmine and dexamethasone. (after 8 hr of exposure) Symptoms didn't subside admission to KMC Dermatologist's opinion: possible photo toxic reaction by unidentified pesticide

 Pharmacist analysed the pesticide contents & read up on its photo toxic effects
Pesticide found to be " METHYL PARATHION an Organo phosphorous compound. Methyl parathion on exposure to atmosphere reacts with oxygen to form methyl paraoxan, which binds to non vital organs pigmentation, irritation and burning Pharmacist recommends acetyl cholinesterase level in blood
AchE level below normal 4963 ( normal 5300-12500)

No systemic complaints: prescribed betamethasone cream

Female 54yrs k/c/o type 2 diabetes mellitus c/o pain abdomen, fever & vomiting for 10 days. On admission CXR showed Rt lower zone(LZ) haziness. Repeat CXR worsening of left LZ haziness for which tazobactum was started. She improved significantly 16th day Pt febrile , developed pain abdomen, itching & rash WBC drastically decreased (neutropenia).
Query to Pharmacist : Pipzo produces neutropenia rarely

Drug stopped
WBC Improved to 7300 after 4 days

 A 55 yr old female k/c/o cellulitis (MRSA) Type 2 DM, Hypertension Rx Inj. H.Actrapid 25-25-15 s/c, Inj .Tazomac (piperacillin-tazobactam) 4.5 gm, Inj. Linid (Linezolid) 600mg IV BD, T. wysolone 20mg , T.Calcimax forte , T.Pantocid 40mg, T.Glytop 5mg, Inj. Tramazac (Tramadol) Pharmacist: warns interaction b/n linezolid & tramadol serotonin syndrome (hyperthermia, hyperreflexia, myoclonus,). Can be fatal! Suggests replacing Linezolid with Inj. Cloxacillin Physician: approves

Indians Ignore ADRs !

Why?
Reluctance to admit error! (The Indian Ego!)
Ego is part of our Caste-ridden Patriarchy! Apology is considered as a sign of weakness Bigger the man, greater the reluctance !

Afraid of legal wrangles!

ADR is NOT medical negligence! Sabrina Brierton Johnson, unsuccessfully sued Johnson & Johnson, after SJS blinded her ADR is a part of accepted risk
You cannot sue Maruti when there is a car accident!

Pharmacovigilance Programme of India (PvPI)

Constituted Under the.. Central Drugs Standard Control Organization, Directorate General of Health Services, Min of Health & Family Welfare Govt of India in collaboration with Indian Pharmacopoeia Commission, Ghaziabad, U.P.

Goal of PvPI
To ensure that the benefits of use of medicine outweighs the risks and thus safeguard the health of the Indian population.

Objectives
To monitor ADRs in Indian population To create awareness among health care pros about the imp of ADR reporting in India To monitor benefit-risk profile of medicines Generate independent, evidence based recommendations on the safety of medicines Support the CDSCO for formulating safety related regulatory decisions for medicines Communicate findings with all key stakeholders Create a national centre of excellence at par with global drug safety monitoring standards

Programme governance and reporting structures

The PvPI administered and monitored by the I. Steering Committee II. Strategic Advisory Committee Technical support will be provided by I. Signal Review Panel II. Core Training Panel III. Quality Review Panel

ADR MONITORING CENTRES

MCI Approved Medical Colleges & Hospitals Private Hospitals ( Manipal is among the proposed centres) Public Health Programmes Autonomous Institutes (ICMR etc.)

5 YEAR ROADMAP (Year 20102015 )

Purpose of collaboration with WHO-Uppsala Monitoring Centre (UMC)

Training of staff at PvPI national coordinating centre Usage of UMCs Vigiflow software (for medicines) & Paniflow (for vaccines) at no cost to PvPI Access to Vigibase, containing worldwide medicines safety data

Selection of ADR Monitoring centers

Medical Colleges as centres
In 2012-13 and 2013-14 (100 centres each will be enrolled) Technical, administrative & financial support by CDSCO

Medical institutes/central institutes/autonomous institutes will be included (no CDSCO support) Public & corporate hospitals inclusion on voluntary basis (no CDSCO support)

Operational Aspects
Roles and responsibilities of different personnel in PvPI Training of program personnel Centre management (including infrastructure, manpower, status reports) Processing & reporting of suspected ADRs Compliance & quality assurance Regulatory decision making Communication among stakeholders

Functions of stakeholders in Programme

PvPI ADR Monitoring Centre in Medical College Collection of ADR reports Perform follow up with the complainant Data entry into Vigiflow Reporting to PvPI National Coordinating Centre Training/ sensitization/ feedback to physicians through newsletters circulated by PvPI NCC

PvPI ADR Monitoring Centre other than medical colleges [Corporate hospitals, autonomous institutes, Pharmaceutical industry, public health programmes]

Collection of ADR reports Perform follow up with the complainant Report the data to CDSCO HQ

PvPI National Coordinating Preparation of SOPs, guidance documents & Centre training manuals (PvPI NCC , IPC Ghaziabad) Data collation, Cross-check completeness, Causality Assessment Conduct Training workshops of enrolled centers Publication of Medicines Safety Newsletter Reporting to CDSCO HQ Analysis of the PMS, PSUR, AEFI data received from CDSCO HQ ZONAL/Subzonal CDSCO Offices Provide procurement, financial and administrative support to ADR monitoring centers Report to CDSCO HQ Take appropriate regulatory decision & actions on the basis of recommendations of PvPI NCC Propagation of medicine safety related decisions to stakeholders Collaboration with WHO-Uppsala Monitoring Center - Sweden Provide for budgetary provisions & administrative support to run National PvPI

CDSCO, HQ, New Delhi

Safety Database
Vigiflow software provided by WHO-Uppsala Monitoring Centre utilized as safety database All data originating from India will be maintained in a secure and confidential manner

Risk Management
Ensure availability & management of funds Conduct frequent training & awareness of Pharmacovigilance Detect & respond to under reporting of ADRs Ensure quality of filled ADR forms Proper supervision of functioning of centers Feed back to Health Care Professionals

Monitoring & Evaluation

i. Process Indicators
No. of ADR monitoring centers, AMC personnel trained Funds budgeted & spent

ii.

Outcome Indicators
Software platform established No. of ADR reports received/processed/submitted to Vigiflow

iii.

Impact Indicators
No. of signals generated & confirmed No. of safety related alerts issued by CDSCO

FDAAA (FDA Amendments Act)

Passed in 2007; Effective since 2008

FDAA Title XI :
demands REMS (Risk Evaluation & Mitigation Strategy) for identified drugs imposes stricter post marketing safety surveillance from marketing authorization holders (MAH)

New FDA Initiatives to enhance Drug safety during development

Industry guidance document for premarketing safety assessment for drug induced liver injury Safe Use Initiative, 2009 - to reduce the likelihood of preventable harm from medication use & devising mechanism to overcome harm
IND regulation revision, Sep 2010 - governs safety reporting requirements for INDs & BA/BE studies

 New FDA requirements designed to :

New FDA Initiatives to enhance Drug safety during development (contd)

Improve usefulness & quality of safety reporting & ability

to review critical information Strengthen ability to review critical safety information Improve safety monitoring of human drug & biologicals Harmonize safety reporting with recommendations by ICH, CIOMS, EU

Some EU Legislation in Pharmacovigilance development

Risk Management Plan - introduced in 2005 to ensure that benefits of a particular medicine exceed risks
EU Directive 2010/84 -(published in Dec 2010; to be in effect from July 2012) - enforces EU coordination of PV activities via coordination group/PV Risk Assessment Committee

Direct reporting of SAR (suspected adverse reactions)by HCPs & patients

Improved SmPC (Summary of Product Charateristics) of a drug

Newer EU initiatives in drug safety

ENCePP: European Network of Centres for Pharmacoepidemiology & Pharmacovigilance
To enhance post authorization monitoring of medicinal products by multicentre safety / lack of efficacy studies

EU Innovative Medicines Initiative : IMI

Stakeholder collaboration to accelerate development of effective medicines with fewer adverse effects
by improved predictivity of safety & efficacy; knowledge management; education & training

Are we truly committed to Pharmacovigilance?

1986 Proposal for a formal ADR monitoring in 12 regional centres, each covering 50 million, 1989, Drug controller ,India set up , 6 regional centres
Mumbai, New Delhi, Kolkata, Lucknow, Pondicherry & Chandigarh.

1997, India joined WHO International Drug Monitoring Program by Uppsala Monitoring Centre, Sweden.
Dept of Pharmacology, AIIMS was identified as the national centre, Of the six centres, only Mumbai & Delhi were active, Yet spontaneous reporting of ADRs was poor.

 CDSCO launched NPVP in November 2004.

Became functional from January 2005

National Pharmacovigilance Programme (NPVP) : Abortive attempt?

World Bank annual grant of US$ 0.1 million for 5 yrs

2 zonal centres with 3 regional centres under them Manipal reported ADRs to regional centre at JIPMER

World bank funds ended in 2009

Manipals ADR reports started piling up Nobody forwarded our reports to Uppsala
Uppsala suspended its India connection.

PvPI is the third attempt at Pharmacovigilance!!

Global PV Challenges
Globalization increased exposure of massive populations to large volumes of medicines Web-based sales and information uncontrolled sale of medicines across national borders Broader safety concerns- array of medicinal products grows Public health versus pharmaceutical industry economic growth

Global PV Challenges (contd)

Monitoring of established products
Monitor safety of generics throughout the world

Developing and emerging countries

Outside OECD countries, pharma industry not been committed to pharmacovigilance

Attitudes and perceptions to benefit and harm

Morbidity/mortality from drug-induced diseases recently being recognized as important in public health.

Outcomes and Impact

Conclusion
FROM thalidomide tragedy (1950) TO recent rofecoxib & rosiglitazone controversy science of PV has come a long way PV very reactive nature
Evolved from a mere regulatory requirement for marketing proactive generation of safety signals for marketed drugs

PV most important bridge between patient, HCPs & pharma companies for safer health care India is waking up!! Professional

Thank you!

Jai PvPI Jai Hind!