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PV-PG Dr. Anjan Adhikari
PV-PG Dr. Anjan Adhikari
Dr. Anjan Adhikari Assistant Professor Department of Pharmacology R G Kar Medical College Kolkata
Drugs can do good Drugs can do harm Whenever a drug is taken a risk is taken
Thalidomide 1st introduced in 1957 as sedative for morning sickness and nausea
Thalidomide
Thalidomide German Pharmaceutical Company Marketed at least 40 Brand name- Talimol,
Nibrol, Sedimide, Softenon, Neurosedyn, Quietoplex, Contergan
From 1956 to 1962, approx. 10,000 children in Africa and Europe were born with severe malformation
Thalidomide
Early in 1962 Speirs tried to identify whether the mothers of babies born with limb deformities in Stirlingsire, Scotland, had taken thalidomide Smithells, searching for the same cause in Liverpool
Thalidomide
It was established that thalidomide main cause of thousands of babies with birth defects-Seal babies, Phocomelia
Thalidomide
1965 removed from market
Thalidomide
In 1964 Israeli physician Jacob Sheskin was trying to help a critically ill French patient with erythema nodosum leprosum (ENL), a severe painful condition, complication of leprosy. He searched in his small nursing home for anything to help his patient to relieve his pain and for a good sleep. He found a bottle of thalidomide tablets in one corner of his table. Dr.Jacob remembered that thalidomide had been effective in inducing sleep and it was also known to him that the drug was banned. Desperately, Sheskin administered two tablets of thalidomide, and the patient slept for hours and was able to get out of bed without aid upon awakening.
Thalidomide
This starts the new era of evolution of thalidomide. This result was followed by more favorable experiences and a number of clinical trials started to investigate the antiinflammatory and immunomodulatory effects of thalidomide.
Adverse reaction
Aplastic anaemia Myeloptic neuropathy Cholestatic hepatitis Haemolytic anaemia Thromboembolism Sclerosing peritonitis Rhabdomyolis
What is ADR ?
What is adverse drug reaction? It is defined as any noxious change which is suspected to be due to a drug, occurs at doses normally used in men, requires treatment or decrease in dose or indicates caution in the future use of the drug. This definition excludes trivial or expected side effects and poisoning or overdose.
Adverse Drug Reaction (ADR) recently emerged as leading killers, management of drug induced illness requires more than 100billion US dollars annually
Experience in India 3.7% of patients in hospital 0.7 % of admissions 1.8% fatal Cost Rs 187-2820, mean Rs 690 per ADR
How do we get information on drug safety? animal experiments (Toxicity studies, organ damage, metabolism, kinetics, carcinogenicity, mutagenicity, teratogenicity) clinical trials epidemiological methods meta-analysis
Drugs are marketed after phase III clinical trial has the following limitations: Conducted in a small number of patients Duration of trial is usually short Conducted in well controlled patients avoiding the vulnerable groups (children, pregnant women, elderly patients, patients with hepatic or renal insufficiency)
Naturally the phase III clinical trial fails to detect: Rare but serious adverse drug reactions Chronic toxicity of the drug ADR in vulnerable groups Information about drug interactions
In fact, there is nothing that could tell you whole story of a drug
It is the benefit-risk profile which is more important It is never possible to know the whole story of a drug through clinical trials A clinical trial can inform the minimum information determined by the legislation and by contemporary judgments about the acceptable balance between benefit and harm
To overcome the shortcomings of premarketing trial, WHO has formulated a global Pharmacovigilance Program as an important post marketing tools in ensuring the safety of pharmaceutical and related health products.
Pharmacovigilance
It is an umbrella term used to describe the process of monitoring and evaluating ADRs is a key component of effective drug regulation systems, clinical practice and public health programmes
What is Pharmaco-vigilance ?
Pharmaco = Drug Vigilance = To keep alert, To keep watch
Pharmacovigilance is defined as the science and activities concerned with the detection, assessment, understanding and prevention of adverse effects of drugs (adverse drug reactions or ADR) or any other drug related problem. problem.
(WHO, 2002, ISBN 9241590157)
To identify new information about hazards associated with medicines Preventing harms to the patients Pharmacovigilance is related with adverse effects or any other possible drug-related problems Treatment evaluation science
Why Pharmacovigilance?
First, do no harm Economical concerns Drug monitoring & surveillance Pharmacovigilance: check the drugs on the market to fulfill their intended role in society
The ultimate goal of this activity is to improve the safe and rational use of medicines, medicines, therapy by improving patient care and public health
It is basically deals withCollecting Monitoring Researching Assessing and evaluating ------information from health care providers and patients on the adverse effects of medication
Pharmacovigilance in practice
Cerivastatin
1st approved in 1997 lipid-regulating agent By 2000 549 cases of rhabdomyolysis reported esp. in combination with gemfibrozil a signal was issued regarding the association between Cerivastatin, myopathy and rhabdomyolysis Warning statement in the PI contraindication for this combination (USA Nov 1999, Canada Mar2000, Aust. Feb 2001, Europe June 2001) 8 Aug 2001 manufacturer voluntarily withdrew from market
Cisapride 1st approved in 1993 gastroesophageal reflux disease (GERD) 1999 - 341 reports of heart rhythm abnormalities including 80 reports of deaths Labeling has been revised several times July 14, 2000 manufacturer voluntarily withdrew from market
Presently, its concerns have been widened to include herbals traditional and complementary medicines blood products biological medical devices vaccines.
Other issues relevant to PV Substandard medicines Medication errors Lack of efficacy Use of medicines for indications that are not approved and for which there is inadequate scientific basis
Other issues relevant to PV Acute and chronic poisoning Assessment of drug- related mortality Abuse and misuse of medicines Adverse interactions of medicines with chemicals, other medicines and food
Widening horizons
Within the last decade, there has been a growing awareness that the scope of pharmacovigilance should be extended beyond the strict confines of detecting new signals of safety concerns. These changes have given rise to new kinds of safety concerns such as: illegal sale of medicines and drugs of abuse over the Internet increasing self-medication practices irrational and potentially unsafe drug donation practices widespread manufacture and sale of counterfeit and substandard medicines increasing use of traditional medicines outside the confines of the traditional culture of use increasing use of traditional medicines and herbal medicines with other medicine with potential for adverse interactions
Aims of Pharmacovigilance
Improve patient care and safety in use of drugs Improve public health and safety in use of drugs Contribute to the assessment of benefit, harm, effectiveness, and risk of drugs Encouraging safe, rational and more effective (including cost-effective) use of drugs Promote understanding, education and clinical training in pharmacovigilance Effectively communicate to the public
-- World Health Organization
Vigilance
Open question: looking for the unexpected Hypothesis generation (problem raising) Exploratory, controversial (SR, PEM, CCS) No comparison Continuous, all drugs, total population
How pharmacovigilance?
Spontaneous Reporting Intensive monitoring (hospital) Prescription Event Monitoring Case Control Surveillance Comprehensive population databases, datamining Patient series Observational studies
Spontaneous reporting is the core data generating system of international pharmacovigilance Proactive pharmacovigilance throughout the product life cycle is the only way for drug safety
Partners
The management of the risk associated with the use of medicines demands close and effective collaboration between the key players in the field of pharmacovigilance
Partners
Government Industry Hospitals and academia Medical and pharmaceutical associations Poisons information centers Health professionals Patients Consumers Media WHO
Pharmacovigilance responsibilities
Timely collection of data: recording and notification Appropriate assessments (data completeness, seriousness, relatedness, expectedness) Periodic reporting
Now.What to do?
Participate in the Pharmacovigilance Programme Set your mind Start sending report Send not only quantity reports But.
QUALITY REPORTS
Because different
diseases and prescribing practices genetics, diet, traditions drug manufacturing process drug distribution and use use of traditional and complementary drugs
How?
Monitor clinical status of patients Identify the correct ADRs not side effects
Get more information Investigate at hospital level Help others to fill-up the ADR forms Keep patients record if more information needed
Report about any drug which are suspected of significantly affecting a patients management, including reactions suspected of causing : * Death * Life threatening with real risk of dying * Hospitalization * Disability * Congenital anomaly * Required intervention to prevent permanent impairment or damage
How to report?
The report should be sent by filling up a proforma known as Adverse Drug Event Reporting Form for the purpose of National Pharmacovigilance Programme.
Where to report?
To the same Pharmacovigilance Centre from it is collected OR To any one of the Pharmacovigilance Centre nearest to the reporter OR To the NPC at CDSCO, Directorate General of Health Services ( DGHS), Ministry of Health and Family Welfare, Nirman Bhawan, New Delhi-11011
Where to report?
Hospital
Regional Centre
Patient
Health Professional
National Centre
Manufacturer
Causality assessment
It is the method by which the extent of relationship between a drug and a suspected reaction is established
Currently wide variety of causality assessment scales exist, to attribute clinical events to drugs in individual patients or in case reports, each with their own advantages and limitations
Karch & Lasagna scale Naranjo's scale WHO probability scale Spanish quantitative imputation scale Kramer's scale Jones scale European ABO system Bayesian system.
The Naranjo's scale and the WHO scale are the most commonly used scales.
Naranjo's Scale
Question Yes No
+1
Did the adverse event appear after the suspect drug was administered?
+2
-1
Did the AR improve when the drug was discontinued or a specific antagonist was administered?
+1
Naranjo's Scale
Question Yes No
+2
-1
Are there alternate causes [other than the drug] that could solely have caused the reaction?
-1
+2
-1
+1
Naranjo's Scale
Was the drug detected in the blood [or other fluids] in a concentration known to be toxic? +1 0
Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?
+1
Did the patient have a similar reaction to the same or +1 similar drugs in any previous exposure?
+1
Naranjo's Scale-Scoring
A METHOD FOR ESTIMATING THE PROBABILITY OF ADVERSE DRUG REACTIONS
> 9 = definite ADR 5-8 = probable ADR 1-4 = possible ADR 0 = doubtful ADR
Severity Assessment
Hartwig Scale
Preventability assessment
Signal
Reported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information The publication of a signal usually implies the need for some kind of review or action
Signal
This describes the first alert of a problem with a drug By its nature a signal cannot be regarded as definitive but indicates the need for further enquiry or action.
ADR Database
Examples of computerized databases Data base G Practice Res Data Base Medicaid PHARMO data base Location UK USA Netherlands
Examples of computerized databases Data base Odense Ontario Drug Benefit Location Denmark Canada
Vigibase
Vigibase is the name of the WHO ADR database. VigiBase is a unique collection of international drug safety data UMC receives summary clinical reports about individual suspected adverse reactions to pharmaceutical products from National Centres in countries participating in the WHO Programme for International Drug Monitoring Only limited details about each suspected adverse reaction are received at the centre. The member countries have access to the collected data and analyze it in order to investigate potential ADR signals and statistics
Vigibase
The data collected from countries participating in WHO Programme for International Drug Monitoring VigiBase comprises more than 4.7 million case reports, to which around 50,000 new reports are added quarterly. All of these cases are available to anyone with a health professional degree-level education (physician, dentist, nurse, pharmacist). The Vigibase data resource is the largest and most comprehensive in the world and is developed and maintained by the UMC on behalf of the World Health Organization.
Vigibase include reports from manufacturers All reports in Vigibase are sent from the responsible authority in each country However, these may originally be sent in by manufacturers.
Vigiflow
It is web based and designed to allow for simultaneous multiple use All customer-specific data is stored in the database connected to the specific customer and not accessible to others It is web designed and hosted by the UMC, Sweden Maintained centrally by UMC
Vigiflow Advantages of Vigiflow server setup -Data security -Work balancing -Performance
Vigiflow is a cost effective system built with a modern design which ensures quality, performance and reliability with a future increasing usages
Vigiflow
The Uppsala Monitoring Centre Stora Torget 3, 75320 Uppsala, Sweden www.who-umc.org
IMPORTANCE OF ADR REPORTING IN INDIA There is a rapid increase in the number of new drugs entering the market from last few decades India being the second most populated country has over one billion potential drug consumers, and no amount of pre-clinical and clinical data is sufficient to conclude the complete safety of a drug
IMPORTANCE OF ADR REPORTING IN INDIA In India, general practitioners, with an large outpatient base tend to be among the first ones to use the drugs entering the market, hence they are in the best position to assess the adverse drug reactions associated with drugs ADR in India is increasing
Objectives
To identify previously unrecognized adverse effects or changes in the patterns their adverse effects. To assess the risk benefit of medicines To provide information to users to optimize safe and effective use of medicine
THE NATIONAL PHARMACOVIGILANCE CENTRE AT CDSCO The National Pharmacovigilance Centre is based at CDSCO Monitor in order to identify previously unexpected adverse drug reactions or indicate that certain reactions occur more commonly than previously believed Collation, review and evaluation of all spontaneous ADR reports received by the unit on a nation-wide basis Maintain contacts with international regulatory bodies Assess the regulatory information relating to safety in order to determine action on product label amendments, product withdrawals and suspension Provide information to end-users through adverse drug reaction news, bulletins, drug alerts and seminars.
India
AIIMS-National Pharmacovigilance coordinating centre Actively participated by Central Drug Standard Control Organization CDSCO Drug Controller General of India Director General of Health Service Supported by WHO Financed by World bank
Very few reports have been sent to UMC's Vigibase, which is relatively a less figure considering the number of healthcare professionals in our country.
Pharmacovigilance
Summary Now global activity All kinds of drug related problems Acknowledged as major concern Laws and regulations Public health programmes Data mining, internet reporting and new data sources Traditional medicines Influencing safe prescribing and use Tool for Rational Drug Use
Thank you