Pharmacovigilance Historical Perspectives

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Pharmacovigilance has its history since the inception of medication in any form

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PHARMACOVIGILANCE “HISTORICAL PERSPECTIVE AND CURRENT SCENARIO”:

PHARMACOVIGILANCE “HISTORICAL PERSPECTIVE AND CURRENT SCENARIO” Prof. R. K. Dixit Pharmacology and Therapeutics King George’s Medical University Lucknow dixitkumarrakesh@gmail.com King George’s Medical University Lucknow Mayo Institute of Medical Sciences Barabanki

“The farther back you look the farther forward you can see” Winston Churchill:

“The farther back you look the farther forward you can see” Winston Churchill

Slide 3:

Discussion Flow Introduction to Pharmacovigilance Terminologies Genesis of Pharmacovigilance Why do we need Pharmacovigilance? Historical landmarks related to Pharmacovigilance International scenario in the past and present Past and current Indian scenario Key messages 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 entirely or absolutely safe for all people, in all places at all times We must always live with some measure of uncertainty.

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 × × × √

What is the basic principle of Medicine as told by the father of modern medicine Hippocrates???:

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

Paradox related to the safety issues of medicine:

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

Paradox related to the safety issues of medicine:

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

Comment On This:

Comment On This

Confidence about the safety of drug:

Confidence about the safety of drug

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

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 problems ?

Drug Development and Limitations :

Drug Development and Limitations

Drug Development:

Drug Development 20th aug bangalore presentation 22

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 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

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

Need of Pharmacovigilance in Every Country:

Need of Pharmacovigilance in Every Country Difference in Drug production Distribution and use Genetics Diet Traditions Beliefs

High Burden of ADRs on Therapeutics:

High Burden of ADRs on Therapeutics All drugs are associated with inevitable risks of ADRs Most ADRs are Preventable Preventable ADRs are more crucial Usually under reported due to lack of differentiation between disease progression Vs ADRs manifestations Ignorance of the health care provider Fear of reporting ADRs significantly decrease the quality of life ADRs increase hospitalizations, prolong 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- 0.32% to 6.7% Leading cause of death- 4 th to 6 th Leading cause of expenditure on health programs (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 ?

Major Adverse drug reactions reported only after marketing:

Major Adverse drug reactions reported only after marketing Year Drug Toxicity Remark 1937 Sulphinalimide Death Diluents responsible 1950 Chloramphenicol Aplastic anemia 1961 Thalidomide Phocomelia Medical Disaster 1970 Clioquinol SMON After 30 years of use 1970 Diethylstilbestrol Adenocarcinoma of cervix 1975 Practolol Oculo-mucocutaneous syndrome 5 years 1976 Phenformin Lactic acidosis Withdrawn 1999 Astimazole Arrhythmias 2004 Rofecoxib Myocardial infraction Withdrawn 2010 Rosiglitazone Heart attack and congestive heart failure Withdrawn 2012 Rimonabant Depression, Risk of suicidal tendencies Withdrawn 2012 Sibutramine Cardiovascular side effects Withdrawn Journal of Drug Delivery & Therapeutics 2016, 5(7):345-365

Lag Time for Adverse Drug Reactions:

Lag Time for Adverse Drug Reactions Oral Contraceptives – Pulmonary embolism – 3 yrs Halothane – Jaundice – 7 yrs Clindamycin – Colitis – 5 yrs

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

News related to ADRs and Pharmacovigilance:

News related to ADRs and Pharmacovigilance

“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 !

Indeed there is a need for Pharmacovigilance:

Indeed there is a need for Pharmacovigilance

Terminologies:

Terminologies Adverse Drug Event:- Any untoward medical related occurrence that may present, but not necessarily have a causal relationship with the treatment Adverse Drug Reactions:- A response to a medicine that is noxious and unintended and occurs at doses normally used in man for prophylaxis, diagnosis and therapy of disease. The WHO definition excludes well known side effects of drug from the ADRs All ADRs are ADEs but all ADEs are not ADRs

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

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”

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)

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 from healthcare providers and patients on the adverse effects of medicines, biological products, herbals and traditional medicines with a view to identify new information about hazards and preventing harm to patients In France in 1960s as new name for old terminology Post Marketing Surveillance (PMS). WHO introduced and has been adopted by International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for human use (ICH)

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 The use of drugs and Pharmacovigilance go hand in hand Science of Pharmacovigilance can be traced long before

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 45:

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 46:

Pharmacovigilance in 19th century: 1820 :- U.S. Pharmacopeia with first list of standard drugs 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 47:

Pharmacovigilance in 20th century Pre thalidomide era 1905 - American Medical Association (AMA) for drug approval 1906 - The original Food and Drug Act was established to impose quality criteria for drug manufacturing 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. Although tested regarding aspect, taste and odor, its safety was not evaluated before launching. It was responsible for the death of 105 individuals (34 children and 71 adults) and diethylene glycol was incriminated

Slide 48:

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 1951- Durham-Humphrey Amendment regarding safety of drugs 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 1963- Committee on the safety of Drugs (CSD) was formed in UK In 1964- Yellow Card System (prepaid card) by the CSD of 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. In 1968- The UK Medicines act was enforced In 1970- CSD was replaced by Committee on Safety of Medicine 1970- CSM was again replaced by Commission on Human Medicines

Post thalidomide era :

Post thalidomide era In 1971- An international database (international monitoring system) was established by WHO at Geneva 1972 - Over-the-Counter Drug Review for safety, effectiveness and appropriate labelling of drugs sold without prescription In 1974- The term PV proposed by French group of pharmacologists 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 network of more than 130 countries

Post thalidomide era :

Post thalidomide era In 1983- The UK Committee on Safety of Medicines set up the Grahame-Smith Working Party, which made 29 recommendations, most of them to address the problem of under-reporting of suspected ADRs. 1990- Establishment of International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH), a collaborative initiative between the EU, Japan and the United States with observers from WHO, EFTA and Canada. ICH harmonization

Post thalidomide era :

Post thalidomide era 1993 - FDA launches MedWatch to collect reports on problems with drugs and other medical products 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 1999: Revised MedWatch , MedDRA

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 after agreement between Sweden and WHO Non-profit foundation with international administrative board WHO Headquarters responsible for policy Self-financing Global Pharmacovigilance

Pharmacovigilance In India:

Pharmacovigilance In India

Pharmacovigilance in India :

Pharmacovigilance in India In India:- More than 6,000 licensed drug manufacturers and Over 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. Indian Council of Medical Research 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 Nothing much happened

Pharmacovigilance and India:

Pharmacovigilance and India In 1997-98 India joined World Health Organization- WHO-ADR Monitoring Programme Three centers for ADR monitoring were identified, mainly based in teaching hospitals: 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). Unsuccessful

Pharmacovigilance and India:

Pharmacovigilance and India In 2004-05 (1 st Jan 2005) 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 )

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)

PvPI - Programme governance and reporting structures :

PvPI - Programme governance and reporting structures

Pharmacovigilance The Proposed Role:

Pharmacovigilance The Proposed Role When adverse effects and toxicity appear, particularly when previously unknown it is essential that they are analyzed and communicated effectively 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

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% Among Asian countries, India is the only country having about 1 lakhs ICSRs in Vigibase 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.

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 84:

A DR reporting form of India

International Organizations:

International Organizations WHO:- Health agency of United Nation started on 7 th April 1948 WHO pilot research on drug monitoring on 1968 UMC- Uppsala Monitoring Center coordinate since 1978 Netherlands Pharmacovigilance Center Lareb also for WHO ICH- Common platform for regulatory authorities and pharmaceutical industries of European Union, USA, Japan to design common guidelines for development and registration of medicine (Since 1990)

International Organizations:

International Organizations CIOMS – Council for International Organizations of Medical Sciences was formed under WHO and UNESCO (United Nations Educational Scientific and Cultural Organization) COHM- Commission on Human Medicines in UK CSM- in UK introduced YELLOW CARD system by Prof. William Inman US FDA- introduced MedWatch and FDA Adverse Event Reporting System (FAERS) Australia- Office of Medicine Safety Monitoring (OMSM)and Adverse Drug Reaction Advisory Committee (ADRAC) uses BLUE CARD

Regulatory Bodies:

Regulatory Bodies Europe India Germany US MHLW, Japan

Slide 88:

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

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 The international agencies coordinating Pharmacovigilance are WHO, ICH (International Conference on Harmonization), CIOMS (Council for International Organizations of Medical Sciences) 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 UMC with good quality At present about 202 monitoring centers are in India and near future there will be many more with excellent quality

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

People who are vigilant do not die; people who are negligent are as if dead’. Buddha A drug which cures an ailment but does not produce any bad effect, is a whole and complete drug. Acharya Charaka 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 The great scientists (Philosophers) views regarding safety of medicine

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

To undergo treatment you have to be very healthy, because apart from your sickness you have to withstand the medicine. Molière My Doctor is a good doctor, He made me no iller than I was. Willem Hussem Fortunately a surgeon who uses the wrong side of the scalpel cuts his own fingers; if the same applied to medicines Physicians would have investigated very carefully a long time ago Rudolph Bucheim Dying from a disease is sometimes unavoidable but dying from a medicine is unacceptable The great scientists (Philosophers) views regarding safety of medicine

Slide 92:

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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