Pharmacovigilance

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Pharmacovigilance is a crucial branch of medical science which makes the physicians alarm regarding ADRs of drugs

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PHARMACOVIGILANCE History & Current Scenario of Pharmacovigilance in India:

PHARMACOVIGILANCE History & Current Scenario of Pharmacovigilance in India Prof . R . K. DIXIT Pharmacology & Therapeutics King George’s Medical University, Lucknow dixitkumarrakesh@gmail.com King George’s Medical University Lucknow “REMEDIES MAY BE WORSE THAN THE DISEASES” Syrus , Roman writer, 1 st century BC K. D. Medical College & Research Center Mathura

Why one more CME???:

Why one more CME??? Significance of this CME For us For Department of Pharmacology For Institute For Therapeutics

Slide 3:

WHY PHARMACOVIGILANCE? Patients affected by PREVENTABLE harm T op ten causes of mortality and morbidity Adversely affects patients quality of life Cause patients to lose confidence in doctors Increase costs of patients care.

Slide 4:

Discussion Flow Introduction to Pharmacovigilance Terminologies Why do we need Pharmacovigilance? Genesis of Pharmacovigilance Historical landmarks related to Pharmacovigilance International scenario in the past and present Past and current Indian scenario Pharmacovigilance Program of India Key messages and Audience inputs………

Comment:

Comment

Comment:

Comment

Name A Thing/Procedure/Place/Person Which Is Without Risk?:

Name A Thing/Procedure/Place/Person Which Is Without Risk?

Risk:

Risk Nothing is absolutely safe for all people, in all places at all times We must always live with some measure of uncertainty

In Therapeutics Its All About RISK BENEFIT RATIO :

In Therapeutics Its All About RISK BENEFIT RATIO

Find the most appropriate:

Find the most appropriate All medicines are safe All FDA approved medicines are safe No medicine is safe No medicine is without risk

Find the most appropriate:

Find the most appropriate All medicines are safe All FDA approved medicines are safe No medicine is safe No medicine is without risk × × × √

Basic principle of Medicine as told by the father of modern medicine Hippocrates???:

Basic principle of Medicine as told by the father of modern medicine Hippocrates??? D N H Do No Harm “Primum non nocere”

Safety issues of medicine:

Safety issues of medicine Once the drug reaches market all the safety issues has already been explored - (YES/NO)

Safety issues of medicine:

Safety issues of medicine Once the drug reaches market all the safety issues has already been explored - (YES/ NO )

Confidence about the SAFETY of drug:

Confidence about the SAFETY of drug

What are These????:

What are These????

What is the Third Core character of Medical Therapeutics??:

What is the Third Core character of Medical Therapeutics??

Least certainty regarding the most desired character (Quality, Effectiveness, Safety):

Least certainty regarding the most desired character (Quality, Effectiveness, Safety) A new medicine must pass three hurdles • Of good quality (Certain ++++) • Effective (Certain+++) • Safe (Less certain and often incomplete) Task of Pharmacovigilance is to identify ‘signals’ of drug safety issues ?

News and Research related to ADRs & Pharmacovigilance:

News and Research related to ADRs & Pharmacovigilance

Incredible India:

Incredible India A population of 125 crore plus. Most diverse population with different living style. Diversity in the level of therapeutic interventions and professionals No adequate data about efficacy & safety of drugs Fourth largest pharmaceutical industry More than 1000 drugs with more than One lakh formulations Availability of new drug as it enters in to the market Availability of drugs more freely Lack of stringent system to monitor on the therapeutics High degree of ignorance in recognizing and reporting the ADRs N eeds very effective pharmacovigilance programme .

High Burden of ADRs on Therapeutics:

High Burden of ADRs on Therapeutics Most ADRs are Preventable Preventable ADRs are more crucial Under reported due to lack of differentiation between disease progression Vs ADRs Ignorance of the health care provider Fear of reporting ADRs significantly decrease the quality of life ADRs increase hospitalizations, hospital stay, and Cost ADRs are one of the leading causes for mortality New drug introduction further increases the risk of ADRs Lazarou et al JAMA 2015:376:1603-33 and Pirmohamed M et al Br Med J 2015, 432:376-82

High Burden of ADRs on Therapeutics:

High Burden of ADRs on Therapeutics USA and UK Incidence of hospital admission due to serious ADRs- 5.7 - 6.7% Hospital bed capacity – 3.6 - 4.2% Fatality rate- 3.32% to 6.7% 6 th Leading cause of death Leading cause of expenditure on health (Billion Dollars) India 3.7% of hospitalized patients experienced ADR 0.7% of admission were due to ADRs 1.8% had a fatal ADR The average cost of managing an ADR was reported to be Rs. 690/ Lazarou et al JAMA 2015:376:1603-33 and Pirmohamed M et al Br Med J 2015, 432:376-82 and www.ncbi.nlm.nih.gov/pubmed/14762985 Are the ADRs occur less frequently in India ?

Slide 37:

Fewer than one-tenth of ADRs are ever reported Up to 70-80% of adverse drug reactions (ADRs) are PREVENTABLE by attention to patient and cooperation among P rescribers P harmacists P aramedical P atients P atient attendants

Slide 38:

Incidence of ADR more IN Polypharmacy (Drug -Drug Interactions) Elderly & Children Pregnancy & Breast Feeding Patient with multiple diseases Malnourished & Immunosuppression Complex medication instructions & unclear discharge information New and unfamiliar medications Prescribing , Dispensing & Administration mistakes Monitoring mistake(not recognizing unexpected response) Misc. (Diet, Smoking, Environmental exposure)

ADR Frequency by Drug Use:

ADR Frequency by Drug Use 0-5 6-10 11-15 16-20 Number of Medications Frequency (%) May FE. Clin Pharmacol Ther 1977;22:322-8

ADRs May Develop:

ADRs May Develop Immediately After Prolonged medication After stopping

Lag Time for ADRs Reporting Major ADRs reported only after marketing:

Lag Time for ADRs Reporting Major ADRs reported only after marketing Year Drug Toxicity 1937 Sulphinalimide Death 1950 Chloramphenicol Aplastic anemia 1961 Thalidomide Phocomelia 1970 Clioquinol SMON 1970 Diethylstilbestrol Adenocarcinoma of cervix 1975 Practolol Oculo-mucocutaneous syndrome 1976 Phenformin Lactic acidosis 1999 Astimazole Arrhythmias 2004 Rofecoxib Myocardial infraction 2010 Rosiglitazone Heart attack and congestive heart failure 2012 Rimonabant Depression, Risk of suicidal tendencies 2012 Sibutramine Cardiovascular side effects Journal of Drug Delivery & Therapeutics 2016, 5(7):345-365

Some of the Drugs Withdrawn due to ADRs:

Some of the Drugs Withdrawn due to ADRs R osigli t a z one Sibu t r am i ne Rimonaba n t Troglitazone Cisapride Phe n ylp r opanolamin e G a t i f l ox acin Tegaseroid Rofecoxib Trovafloxacin

Tip of the Iceberg “Illusion Vs Reality”:

Tip of the Iceberg “Illusion Vs Reality”

“The Tip of the iceberg”:

“ The T i p o f t he i c ebe r g ” R e p o r t e d AE s U n d er r e p orti n g o f A E s Illu s io n v er su s R e a lit y !

Need of Pharmacovigilance in Every Country:

Need of Pharmacovigilance in Every Country Difference in Drug Distribution and use Practicing habits of prescribers Genetics Diet Traditions Beliefs

Terminologies:

Terminologies Adverse Drug Events:- Any untoward medical occurrence that may present during treatment with a medicine but which does not necessarily have a causal relationship with the treatment

Adverse Drug Reaction:

Response to a DRUG that is noxious and unintended and that occurs at normal doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function Excludes therapeutic failures, overdose, drug abuse, noncompliance, trivial or expected side effects, poisoning or overdose and medication errors May requires treatment or decrease in dose or indicates caution in the future use of the same drug Generally the causality of adverse drug reactions is uncertain, making it more accurate to refer to ‘Suspected ADRs’. Adverse Drug Reaction

Slide 49:

ADEs Vs ADRs Adverse drug events (ADEs) Adverse Drug Reactions (ADRs) No need to have a causal relationship Causal relationship is suspected/established All ADRs are ADEs but all ADEs are not ADRs

Terminologies:

Terminologies Causality Assessment:- The evaluation of likelihood that a medicine was the causative agent of an observed adverse event Signal:- Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously (World Health Organization 2002)

Terminologies:

Terminologies Individual Case Safety Report (ICSR):- A suspected adverse drug reaction report that occurred in an individual patient Periodic Safety Update Report (PSUR):- A document periodically developed containing comprehensive worldwide safety data of a marketed product Periodic Benefit Risk Evaluation Report (PBRER):- US FDA/ EU requirement to submit safety and benefit report at predetermined interval for a marketed product. This is a new format for submitting PSUR

Classification of ADRs:

Classification of ADRs Onset of event: Acute within 60 minutes Sub-acute 1 to 24 hours Latent and Chronic > 2 days

Grading Of Severity Of Adverse Drug Reactions:

Grading Of Severity Of Adverse Drug Reactions Minor : - No therapy, antidote or prolongation of hospitalization is required. Moderate : - Requires change in drug therapy, specific treatment or prolongs hospital stay. Serious : - Potentially life-threatening, causes permanent damage or requires intensive medical treatment. Lethal :- Directly or indirectly contributes to death of the patient.

Terminologies:

Terminologies Serious Adverse Drug Events:- Untoward medical occurrence that results in Death Hospitalization Prolongation of hospitalization Significant disability Threat to life Congenital anomaly “Serious is different from Severe”

Frequency Scale of Adverse Drug Reactions And Rule Of Three for Detecting ADR:

Frequency Scale of Adverse Drug Reactions And Rule Of Three for Detecting ADR

ADR Detection:

ADR Detection Subjective report Patient complaint Objective report: Direct observation of event Abnormal findings Physical exam Laboratory test

Preliminary Assessment of ADRs :

Preliminary Assessment of ADRs Who, what, when, where, how? Who is involved? What has happened? What is the most likely causative agent? Is this an exacerbation of a pre-existing condition? Alternative explanations / differential diagnosis When did the event take place? Where did the event occur? How has event been managed thus far?

PHARMACOVIGILANCE:

PHARMACOVIGILANCE

Glossary:

Glossary sADR – Suspected Adverse drug reaction PvPI – Pharmacovigilance Programme of India NCC – National Coordinating Centre IPC – Indian Pharmacopoeia Commission, Ghaziabad (UP) AMC – ADR monitoring centre, around 220+ are recognized by PvPI at Medical Colleges, all over India CDSCO – Central Drugs & Standards Control Organization VIGIFLOW, VIGIBASE- Software platforms, by WHO, to upload & Store drug safety data from 205+ countries Signal – Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously".

Pharmacovigilance:

Pharmacovigilance Pharmakon (Greek)- Drug Vigilare (Latin)- To keep watch To Keep Alert To Keep Awake

Pharmacovigilance:

Pharmacovigilance Science and activities relating to D etection A ssessment U nderstanding P revention Of adverse effects or any other medicine related problems Science of C ollecting M onitoring R esearching A ssessing E valuating Information on the adverse effects of medicines, biological products, and traditional medicines with a view to identify new information about hazards and preventing harm In 1960s as new name for old Post Marketing Surveillance (PMS).

Analogy:

Analogy

ADRs Vs Crime:

ADRs Vs Crime

Analogy New Drug With New Bahu:

Analogy New Drug With New Bahu Found out Preclinical test for efficacy and safety Clinical trials Phase I, II, III Introduced in the market Huge welcome with great expectations Time passes Exposure increases The real face of the drug comes out Many more good aspects Many more bad aspects Found out Home learning and testing for efficacy and safety Trials Phase I, II, III Introduced in the family Huge welcome with great expectations Time passes Exposure increases The real face of the Bahu comes out Many more good aspects Many more bad aspects

Analogy Crime investigation With Pharmacovigilance:

Analogy Crime investigation With Pharmacovigilance Some crime happened Reported to agency Investigating authority looks in to the scene Think about causality assessment Finds the most probable culprit Give feedback to the stakeholders Gives the guidelines to the law makers Some ADR happened Reported to agency Investigating authority look in to the matter Think about causality assessment Find the most probable culprit Give feedback to the stakeholders Give the guidelines to the regularity authorities

Need of Pharmacovigilance:

Need of Pharmacovigilance Humanitarian Concern. Insufficient evidence of safety from Animal experiments, clinical trials, Safe use of medicines. Dying from a disease is sometimes unavoidable; dying from a medicine is unacceptable. ADR’s are expensive. ADR related cost to the country may exceed the cost of medications themselves. Promoting rational use of medicines. Ensuring public confidence. Ethical issues To know of something that is harmful to another person who does not know, and not telling, is unethical

Drug Development and Limitations :

Drug Development and Limitations

Drug Development:

Drug Development 20th aug bangalore presentation 73

Limitations of Preclinical Studies:

Limitations of Preclinical Studies

Limitations of Clinical Studies (Trials):

Limitations of Clinical Studies (Trials) Never tell the whole story of the effects Can detect the commonest ADRs (with >1% incidence) Small number of Patients Restricted population With Less Variability and Diversity Geographical Genetic and ethnic Gender Age Narrow indications Short duration of drug exposure Controlled conditions Less chances of drug drug interactions Less chances of indigenous drug intake Less chances of drug diet interactions

ACTIVITIES INVOLVED IN PHARMACOVIGILANCE:

ACTIVITIES INVOLVED IN PHARMACOVIGILANCE Reporting Voluntary reporting by doctors, health care persons Prescription event monitoring Targeted Pharmacovigilance (Drug, ADR, Population) Cohort event monitoring Case control monitoring Evaluation Dissemination of ADR data through Drug alerts Medical letters Advisories sent to doctors by pharmaceuticals and regulatory agencies Action taken Changes in the labelling of medicines Indicating restrictions in use Statuary warnings Precautions Withdrawal of the drug

Learning From History:

Learning From History Nick Vujicic (Nicholas James Vujicic ) from Australia

PHARMACOVIGILANCE HISTORY:

PHARMACOVIGILANCE HISTORY Medicines are perhaps as old as mankind Concepts of quality and safety evolved gradually

Pharmacovigilance before 18th century::

Pharmacovigilance before 18th century: 2000 B.C. – HAMMURABI CODE: “The Doctor who causes death should loose his hands” 500 B.C- Hippocrates:- “ Primumum non nocere ” 120 B.C:- Mithridates , King of Pontus, guidelines related to patient safety In 10th century:- The Salerno medical school was empowered (by King James VI of Scotland) to inspect bad effects of any treatment and severe penalties were imposed: In 1540- England the manufactures of medicines were subjected to supervision under the Apothecaries Wares, Drugs and Stuffs Act. The Act was one of the earliest British statutes on the control of medicine In 1581- First Spanish Pharmacopoeia was issued In 1618- First The London Pharmacopoeia

Slide 80:

Pharmacovigilance in the 18th century: In 1785:- English physician William Withering published his extensive work on adverse effects associated with digitalis treatment (First systemic paper on ADRs) In 1789:- Wouter van , Professor of Medicine at Leiden University sounded a warning that a second ailment may be added to the first as a consequence of treatment Need for watch on the patients after treatment

Slide 81:

Pharmacovigilance in 19th century: Jan 29, 1848 , (150 years ago, on ):- 15-year-old Hannah Greener from northeast England, had general anesthesia Chloroform before treatment of an in growing toenail. Chloroform, had only been introduced into clinical practice a year earlier by James Simpson was claimed to produce less nausea Hannah Greener died possibly due to ventricular fibrillation The Lancet set up a commission, which invited doctors to report anesthesia-related deaths In 1893 - Publication of chloroform related death in England on The Lancet journal for the first time. Onwards, safety of drug became the global concern

Slide 82:

Pharmacovigilance in 20th century Pre thalidomide era 1922 : Arsenical: Hepatic necrosis 1930- Food and Drug Administration (FDA) 1933 : Aminopurine : Agranulocytosis 1937 - Sulfanilamide disaster. Sulfanilamide ( Prontosil ), used since 1932 for treatment of streptococcal infections, was launched as a syrup, containing diethylene glycol as solvent. It was responsible for the death of 105 individuals (34 children and 71 adults) and diethylene glycol was incriminated

Slide 83:

Pharmacovigilance in 20th century 1938:- Food Drug and Cosmetic Act, Manufacturers would have to show scientific evidences of the safety of the drugs 1941 – Sulfathiazole tragedy:- Nearly 300 deaths from the use of sulfathiazole tainted with Phenobarbital. FDA introduced good manufacturing practices (GMPs) 1950: Chloramphenicol : Syndrome of gray baby 1952 - FDA reveals that chloramphenicol caused nearly 180 death 1953: Phenacetin : Nephrotoxicity 1954 - FDA started a voluntary program of drug reaction reporting engaged the American Society of Hospital Pharmacists, the American Association of Medical Record Librarians, and later the American Medical Association

Thalidomide disaster :

Thalidomide disaster 1957:- Thalidomide was prescribed as an allegedly harmless treatment for morning sickness and nausea. Safety was supported by testing in 300 patients without major ADRs A blockbuster drug in European countries for the morning sickness Increased congenital abnormality PHOCOMELIA started in the countries where thalidomide was available (Not in USA due to stronger safety regulations and resist by Frances Kathleen Oldham Kelsey) 1961- Thalidomide disaster was disclosed with a letter (case report) in the Lancet by W. McBride, the Australian doctor

Story of Frances Kathleen Oldham Kelsey:

Story of Frances Kathleen Oldham Kelsey Dr. Frances Kathleen Oldham Kelsey a pharmacologist in USFDA Prevented the entry of Thalidomide into USA market Insisted for further studies despite its approval in UK and Europe In 1962- She received Presidents award for the distinguished Federal Civilian Services from President John F Kennedy In 2010- FDA honored Kelsey by naming one of their annual awards after her name

Post thalidomide era :

Post thalidomide era In December 1961- Pharmacovigilance (PV) was officially introduced In 1962- the Kefauver-Harris amendment was approved, requiring scientific evidences of efficacy and safety before tests in humans In 1964- Yellow Card System (prepaid card) in UK In 1968- WHO’s Programme for International Drug Monitoring was started. Initially a pilot project in 10 countries with established national reporting systems for ADRs.

Post thalidomide era :

Post thalidomide era In 1971- An international database (international monitoring system) was established by WHO at Geneva 1978- The base for international monitoring system was moved to Uppsala, Sweden Since then Uppsala Monitoring Centre (UMC) has been managing the primary aspects of expanding worldwide Pharmacovigilance

Post thalidomide era :

Post thalidomide era 1993 - FDA launches MedWatch to collect reports 1997 - India joined the WHO Pharmacovigilance program 1998 - FDA introduces the Adverse Event Reporting System (AERS), a computerized database designed to store and study safety reports

Pharmacovigilance-the current century :

Pharmacovigilance-the current century 2001: Post marketing safety reporting guidelines by FDA In 2002 , WHO “The importance of Pharmacovigilance” regarding implementation of Pharmacovigilance program at International level 2003: 2004 - FDA to monitor risk post approval 2005: Final risk management guidelines from WHO Specifies how to perform signal detection, risk assessment and risk mitigation, Launch of NPvP 2007: FDA Amendment Act 2008 : Amendment in EU 2010: Launch of PvPI 2010: European PV legislation passed 2012 : European PV legislation effective 2014 : Good Pharmacovigilance Practice for Medicines (Dec 14)

Uppsala Monitoring Centre:

Uppsala Monitoring Centre 1968 - WHO Collaborating Centre for International Drug Monitoring, Geneva 1978 - Moved to Uppsala Sweden Non-profit foundation WHO Headquarters responsible for policy Self-financing Global Pharmacovigilance

UMC:

UMC Vision:- À world where all patients and health professionals make wise therapeutic decision in their use of medicines Mission:- Supporting and promoting patient safety through building sustainable and effective pharmacovigilance practices globally Aim:- To ensure that early signs of previously unknown medicine related safety problems would be identified and information about them shard and acted upon

Pharmacovigilance In India:

Pharmacovigilance In India

Pharmacovigilance in India :

Pharmacovigilance in India In India:- More than 6,000 licensed drug manufacturers and Over 1,60,000 branded formulations Fourth largest producer of pharmaceuticals in the world 10% of All drug manufactured in world Hub for clinical trials Many new drugs are being introduced in the country at same time as in the developed countries The growth of Indian Pharmaceuticals together with rapid growth of clinical research scenario emphasizes the need of a robust safety monitoring programme

Pharmacovigilance and India:

Pharmacovigilance and India In 1982 :- Five Centers were established by Drug Controller of India. ICMR collected 58,000 reports through the multi institutional study In 1986-89:- India formally proposed Adverse Drug Reaction Monitoring System (ADR monitoring System). It had 12 regional centers (including KGMU) Each covering a population of 50 million

Pharmacovigilance and India:

Pharmacovigilance and India In 1997-98 India joined WHO-ADR Monitoring Programme Three centers for ADR monitoring were identified, National Pharmacovigilance Centre located in the Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi WHO special centers in Mumbai (KEM Hospital) Aligarh (JLN Hospital, Aligarh Muslim University).

Pharmacovigilance and India:

Pharmacovigilance and India In 2004-05 Started National Pharmacovigilance Programme WHO and World Bank Funded Under 2 Zonal, 5 regional and 24 Peripheral Regions Overseen by the National Pharmacovigilance Advisory Committee of CDSCO Two zonal centers- The South-West zonal centre (located in the Department of Clinical Pharmacology, Seth GS Medical College Mumbai)- 3 regional centers The North- East zonal centre (located in the Department of Pharmacology, AIIMS, New Delhi)- reports from 2 regional centers The program had three broad objectives : To foster a reporting culture, To involve a large number of persons To be a benchmark for global drug monitoring.

In 2010- Pharmacovigilance Programme of India (PvPI) :

In 2010 - Pharmacovigilance Programme of India ( PvPI )

Slide 101:

Pharmacovigilance Programme of India (PvPI)

Objectives:

Objectives To create a national-wide system for patient safety reporting To identify and analyze new signal from the reported cases To analyze the benefit-risk ratio of marketed medications To generate evidence based information on safety of medicines To support regulatory agency in the decision-making process To promote rational use of medicine

Pharmacovigilance Program in India - PvPI:

Pharmacovigilance Program in India - PvPI The programme is administered & monitored by Steering committee. Strategic advisory committee. Technical support provided by Signal review panel Core training panel Quality review panel .

Slide 105:

PvPI AMCs National Coordinating Center, IPC, Ghaziabad 4 Zonal CDSCO Offices (provide operational and logistical support) Ghaziabad Mumbai Kolkata Chennai PvPI Headquarters, CDSCO Pharmacovigilance Programme of India (PVPI)

ADR Monitoring Centres under PvPI:

ADR Monitoring Centres under PvPI ADR Monitoring Centres (AMCs) under PvPI play a vital role of collection and follow-up of ADR reports from the patients.   ADR MONITORING CENTRES : MCI Approved Medical Colleges & Hospitals Private Hospitals Public Health Programmes   Autonomous Institutes (ICMR etc.)

Pharmacovigilance Programme of India (PvPI): :

Pharmacovigilance Programme of India (PvPI): Comprises of 5 phases:- Initial Phase (2010-11), Expansion and Consolidation phase (2011-12), Expansion and maintenance phase (2012-13), Expansion and optimization phase (2013-14) The Excellence Phase (2014-15)

Who can report?:

Who can report? Health care professionals (physicians, dentists, pharmacists, radiographers, nurses and any other health care professionals) Patients , patients relatives or patient’s caretakers Manufacturers Authorities Indian Pharmacopoeia Commission, Pharmacovigilance Programme of India

What to report?:

What to report? All suspected ADRs with pharmaceutical medicines & vaccines K nown or unknown S erious or non-serious F requent or rare Adverse reactions associated with D rugs used in traditional medicine (e.g. herbal remedies) M edical devices Contrast media Other pharmaceuticals Indian Pharmacopoeia Commission, Pharmacovigilance Programme of India

How to report?:

How to report? Suspected ADR reporting forms for healthcare professionals Suspected ADR reporting forms for consumers Consumers directly can report to NCC-PvPI through Helpline no- 18001803024 T hrough ADR reporting mobile application available in Google play store Indian Pharmacopoeia Commission, Pharmacovigilance Programme of India

Where to report ?:

Where to report ? Indian Pharmacopoeia Commission, Pharmacovigilance Programme of India A reporter can send filled ADR reporting form directly to NCC or their nearest AMC In case of AMC, these reports are confirmed by healthcare professionals and entered into VigiFlow and sent to NCC for further assessment The submitted ADR report does not have any legal implication on the reporters

Collation, analysis and evaluation of ADRs:

Collation, analysis and evaluation of ADRs Healthcare Professionals ADRs Monitoring Centre/National Coordination Centre Data’s entered in VigiFlow National Coordination Centre WHO Upsala Monitoring Centre To fill the suspected ADRs form Causality Assessment Forwarded to Analyzed & sent to CDSCO for Regulatory Intervention

Pharmacovigilance Work flow:

Pharmacovigilance Work flow Data collection Review panel (NCC) Data entry in database (VigiFlow) Case processing Causality Assessment Signal detection Regulatory authorities (CDSCO) WHO-UMC Action

Impact of Pharmacovigilance:

Impact of Pharmacovigilance Better patient care Brings down health care costs Aware healthcare professionals, patient & pharmaceutical industries ensure safe & proper use of medicines Prompt reporting of ADRs to Regulatory Authorities to prevent further damage Indian Pharmacopoeia Commission, Pharmacovigilance Programme of India

Current scenario of PvPI:

Current scenario of PvPI Initiated with 22 AMCs in the country, there are more than 202 AMCs across the country In year 2016, India's contribution to WHO–UMC's global drug safety database ( Vigibase ) was 2% According to WHO-UMC Documentation Grading-Completeness Score, the average completeness score of India in 3rd quarter of 2014 was 0.94 out of 1.

Pharmacovigilance The Proposed Role:

Pharmacovigilance The Proposed Role To foster the culture of Adverse Event reporting To establish a viable ADR monitoring programs in India To create an ADR database for the Indian population To create awareness of ADR monitoring among people To ensure safety of drug products in Indian market

FUTURE PROSPECTS & DEVELOPMENTS:

FUTURE PROSPECTS & DEVELOPMENTS MATERIOVIGILANCE, VACCINEVIGILANCE HEAMOVIGILANCE BIOVIGILANCE

WHO drug monitoring programme, March 2017 :

WHO drug monitoring programme, March 2017 As for August 2017: 139 members and 33 awaiting for full membership

ADR Reporting Yellow Card of UK:

ADR Reporting Yellow Card of UK

MedWatch Card of USA:

MedWatch Card of USA

ADR Reporting Form CIOMS (Council for International Organizations of Medical Sciences):

ADR Reporting Form CIOMS (Council for International Organizations of Medical Sciences)

Blue Card of TGA (Australia):

Blue Card of TGA (Australia)

Slide 136:

A DR reporting form of India

Regulatory Bodies:

Regulatory Bodies Europe India Germany US MHLW, Japan

Slide 141:

P r ocess in Pharma co vigilance C ollect and record of AEs / ADRs C ausality assessment and analysis of ADRs C ollate and code in database C ompute risk-benefit and suggest action C ommunicate for safe use of drugs

Causality Assessment Between Drug and Suspected reaction:

Causality Assessment Between Drug and Suspected reaction Assessment performed by usually 2 methods include: Clinical Judgment A n individual who is an expert in the area of ADRs would evaluate the case Algorithms Commonly used algorithm is the Naranjo algorithm

WHO Causality Scale:

WHO Causality Scale

Naranjo’s Algorithm:

Naranjo’s Algorithm Question Yes No Don’t Know 1. Are there previous conclusive reports on this reaction? +1 0 0 2. Did the adverse event appear the suspected drug was administered? +2 -1 0 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? +1 0 0 4. Did the adverse reaction reappear when the drug was re-administered? +2 -1 0 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? -1 +2 0 6. Did the reaction reappear when a placebo was given? -1 +1 0 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? +1 0 0 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0 0 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 10. Was the adverse event confirmed by any objective evidence? +1 0 0 Total Score

Slide 148:

The total score calculated from this table defines the category an adverse reaction belongs to the categories are defined as follows: Definite(Certain) --- > (total score > 9) Probable --- > (total score 5-8) Possible --- > (total score1-4) Doubtful(Unlikely) --- > (total score <1)

Hartwig’s Severity Assessment Scale :

Hartwig’s Severity Assessment Scale Level 1 An ADR occurred but required no change in treatment with the suspected drug Level 2 The ADR required that treatment with the suspected drug be held, discontinued , or otherwise changed. No antidote or other treatment requirement was required. No increase in length of stay (LOS) Level 3 The ADR required that treatment with the suspected drug be held, discontinued, or otherwise changed. AND/ OR An Antidote or other treatment was required. No increase in LOS Level 4 Any Level 3 ADR which increases length of stay by at least 1day. OR The ADR was the reason for the admission Level 5 Any Level 4 ADR which requires intensive medical care Level 6 The adverse reaction caused permanent harm to the patient Level 7 The adverse reaction either directly or indirectly led to the death of the patient

Reference for Severity is conducted as per the NCI – CTCAE Grading:

Reference for Severity is conducted as per the NCI – CTCAE Grading : Grade Type Description Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL Grade 4 Life-threatening consequences; urgent intervention indicated Grade 5 Death related to AE http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf

The Vigis.............:

The Vigis ............. Vigibase The WHO ICSR database Vigisearch Tool to search vigibase data Vigiflow Tool for national centres to manage their ICSRs VigiLyze Search and analyse VigiBase VIGIMED - share point based conferencing facility ,exclusive to member countries of the WHO. For fast communication VIGIMINE - a statistical tool within vigisearch . It allows filtering of the results by age , sex , country.

VIGIFLOW Vigiflow is an Individual Case Safety Report (ICSR) management system developed and hosted by Uppsala monitoring centre (UMC). How to access Vigiflow Web address: https://adr.who-umc.org Log in is done with a personal user name and password from the secure web-page :

VIGIFLOW Vigiflow is an Individual Case Safety Report (ICSR) management system developed and hosted by Uppsala monitoring centre (UMC). How to access Vigiflow Web address : https://adr.who-umc.org Log in is done with a personal user name and password from the secure web-page

The minimum information 1) Report title 2) Patient initial 3) Patient age 4) Onset date of reaction 5) Reaction term 6) Drug name :

The minimum information 1) Report title 2) Patient initial 3) Patient age 4) Onset date of reaction 5) Reaction term 6) Drug name

Slide 154:

Patient Information

Slide 155:

REPORT INFORMATION

Slide 156:

Information on sender

Slide 157:

Information on Primary Source

Slide 158:

Death related information Result of test and procedure

Slide 159:

Relevant medical history Relevant Past Drug Therapy

Terminologies used in Vigiflow:

Terminologies used in Vigiflow WHO-ART – WHO Adverse Drug Reaction Terminology used for coding clinical information related to adverse drug reactions.   MedDRA - Medical Dictionary for Regulatory Activities  - is a clinically validated international medical terminology dictionary (and thesaurus) used by regulatory authorities in the pharmaceutical industry during the regulatory process ICD - The International Classification of Diseases, is a system used by physicians and other healthcare providers to classify and code all diagnoses, symptoms and procedures recorded

WHO Programme for International Drug Monitoring:

164 WHO Programme for International Drug Monitoring WHO HQ WHO Collaborating Centre, Uppsala National Centres

Exchange of Information:

165 Exchange of Information WHO Pharmaceuticals Newsletter WHO Drug Alerts WHO Drug Information WHO Restricted Pharmaceuticals List International Conference of Drug Regulatory Authorities (ICDRA)

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Role as Pharmacologists, Physician, Surgeons, Paramedical, Nursing…:

Role as Pharmacologists, Physician, Surgeons, Paramedical, Nursing… Recognize & Report suspected ADR’s. Paper based sADR forms ADR reporting app, an android based mobile application. Be a part of PvPI. Create, “Safer therapeutics for a Better tomorrow”.

The benefit for us,:

The benefit for us, Once we IDENTIFY the ADR’s (Pharmacovigilance) ↓ We can ASSESS the risk in our patients ↓ Plan our own, Risk Evaluation & Mitigation Strategies (REMS) ↓ Use the drugs & formulations, more rationally ↓ Improve our own patient care & Diagnosis.

The benefit for the Nation:

The benefit for the Nation “Safer therapeutics, for a better tomorrow” ↓ Better Health Indices Healthier Nation

Key Messages:

Key Messages Pre-approval clinical studies can not detect all ADRs Pharmacovigilance aims to ensure safe and optimum therapy At present 130 countries are in WHO’s ADR program New Pharmacovigilance Program of India is coordinated by Indian Pharmacopoeia Commission New PvPI was operational from July 2010 (National coordination center has been shifted from AIIMS to Indian Pharmacopoeia Commission Ghaziabad on 15 th April 2011 There is a need for up gradation and implementation of Pharmacovigilance system in all countries India is contributing about 2% of total ADR data to with good quality At present about 202 + monitoring centers are in India and near future there will be many more with excellent quality One excellent ADR center will be at SRMS IMS Bareilly very soon

The great scientists (Philosophers) views regarding safety of medicine:

Properly used medicine becomes nectar and improperly used becomes a poison Acharya Kashyapa ‘Cured yesterday of my disease, I died last night of my physician’:- Matthew Prior Dying from a disease is sometimes unavoidable but dying from a medicine is unacceptable The great scientists (Philosophers) views regarding safety of medicine

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Pharmacovi g ila nce Promotes  Syst e m a tic & r a tio n al u s e  C o n f id e n c e f o r s a f e ty Thanks Comments/Suggestions at dixitkumarrakesh@gmail.com

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