Why do we need Pharmacovigilance? Samira Saleh Prof. of Pharmacology Faculty of Pharmacy Cairo University

Before drugs become available to the patients, they are subjected to rigorous clinical studies. However, some adverse drug reactions (ADRs) are often detected ONLY after marketing.

The study of ADRs is the concern of the field known as pharmacovigilance

Adverse drug reactions ADR is defined as any harm associated with the use of given drugs at a normal dosage during normal use. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of ADR differs from the meaning of "side effect ", as this last expression might also imply that the effects can be beneficial.

Types of ADRs Type A: Augmented pharmacologic effects (dose dependent and predictable) Type B: Bizarre effects (dose independent & unpredictable) Type C: Chronic effects Type D: Delayed effects Type E: End-of-treatment effects Type F: Failure of therapy Type G: Genetic reactions

Serious and severe Serious (FDA): when the patient outcome: Death Life-threatening Hospitalization Disability - or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life Congenital abnormalities Requires intervention to prevent permanent damage Severity: intensity of the adverse effect

Possible causes of ADRS Intrinsic Idiosyncrasy Mutagenicity Carcinogenicity Teratogenicity Extrinsic Adulterations, contamination Underlying medical conditions Interactions Wrong use

Economic impact of ADRs In the USA, the cost of drug-related morbidity and mortality exceeded 177.4 billion dollars in 2000 (Ernst FR & Grizzle AJ, 2001: J American Pharm Assoc) The cost to the country of ADRs may exceed the cost of the medications themselves 30-60 % of ADRs may be preventable

Definition of Pharmacovigilance PV is the science and activities dealing with the detection, assessment, understanding and prevention of adverse effects of drugs. It has been widened to include biological products, herbals, traditional and complementary medicines.

Pharmaco - Vigilance Pharmaco (Greek): drug Vigilance (Latin): to keep awake or alert to keep watch the process of paying close and continuous attention

Why do we need pharmacovigilance? Reason 1: Insufficient evidence of safety Animal experiments Clinical trials prior to marketing Reason 2: Dying from a disease may be inevitable, dying from a medicine is unacceptable (WHO,2005) Reason 3: ADR are expensive

Limitations of clinical trials Number of patients is limited: ~ 5000 Narrow population: Specific age and sex Narrow indications: only those having the specific disease studied Short duration: often no longer than a few weeks

A lesson from history 1959 – 1961 thalidomide 4,000 - 10, 000 cases of phocomelia (congenital limb defects) This lead to withdrawal of the drug from the market

Pharmacovigilance is gaining importance as the number of stories of drug recalls increases

Examples of product recalls due to toxicity Thalidomide (1965) Phocomelia Practolol (1975) Sclerosing peritonitis Phenformin (1982) Lactic acidosis Rofecoxib (2004) cardiovascular effects Veralipride (2007) Anxiety, depression, movement disorders Rosiglitazone (2010 ( Increased risk of MI and death from CV causes

Pharmacovigilance Aims of Pharmacovigilance Pharmacovigilance cycle Regulatory actions to minimize risk WHO members of the drug monitoring programme The Egyptian Pharmacovigilance Center Middle East Members Top 10 contributors to the WHO database Yellow Card Scheme What should be reported? Who can report? Report to whom? Causality assessment

Aims of pharmacovigilance Identify previously unrecognized adverse effects or changes in the patterns of adverse effects Assess the risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe use Provide information to healthcare professionals and patients to optimize safe and effective use of medicines

Thus, the ultimate purpose of ADR reporting and monitoring is to reduce risks associated with drug prescribing and administration Improve patient care and patient safety Communication with international institutions working in pharmacovigilance

Pharmacovigilance cycle Collecting the data Analysis of the data ► Collection & management of data on the safety of medicines ►Analysis of the data to detect ‘signals’ ►Evaluation of the data ►Decision making with regard to safety issues ►Acting to protect public health (including regulatory action) ►Communicating with stakeholders ►Auditing, both of the outcomes of action taken and of the key Collection & management of data on the safety of medicines ►Analysis of the data to detect ‘signals’ ►Evaluation of the data ►Decision making with regard to safety issues Acting to protect public health Decision making with regard to safety issues

Changes that occur from the PV findings include Restriction in use Changes in the specified dose of the medicine Introduction of specific warnings in the product information Changing the legal status of a medicine, e.g., from over-the-counter to prescription only In rare cases, removal of the medicine from the market, if the risks of a medicine are found to outweigh the benefits

International collaboration in the field of pharmacovigilance WHO runs the Uppsala Monitoring Centre (Started in 1968, Located in Uppsala Sweden) European Union runs the European Medicines Evaluation Agency (EMEA) United States, the FDA is responsible for monitoring post-marketing studies. Egyptian PV center

Growth of membership of International Drug Monitoring Programme since 1968

As for August 2011: 106 members and 33 awaiting for full membership

WHO drug monitoring programme, 2001 As for August 2011: 106 members and 33 awaiting for full membership

Establishment of the Egyptian Pharmacovigilance Center (EPVC) December 2009 مركز اليقظة الدوائية المصري ديسمبر 2009 http://epvc.gov.eg

Middle East Members Morocco 1992 Tunisia 1993 Oman 1995 Iran 1998 Egypt 2001 Jordan 2002 Sudan 2008 Saudi Arabia 2009 Iraq 2010

Why is it important for countries to support their own PV programs? Citizens may have unique traditions and diets influencing reactions to medications ADRs may be associated with traditional or herbal remedies unique to each country In some cases, ADRs to certain drugs may only occur in particular ethnic groups Alternate brands of therapy may be imported or manufactured & differ in ingredients or production processes

Yellow Card Scheme The Yellow Card Scheme is the UK system for collecting information on suspected ADRs. The Scheme was founded in 1964 after the thalidomide disaster.

Essential information to include on a yellow card Patient details Suspected drug Suspected reaction Reporter details

Why is the yellow card scheme important? The scheme acts as an early warning system for the identification of previously unrecognised reactions It enables to identify risk factors, outcomes of the ADR and other factors that may affect clinical management

What should be reported? All suspected reactions including minor ones All serious, unexpected, unusual ADRs Change in frequency of a given reaction All suspected drug-drug, drug-food, drug food supplements interactions ADRs associated with drug withdrawal ADRs due to medication errors ADRs due to lack of efficacy or suspected pharmaceutical defect

Who can report? Patients, patients relatives or patients carers Health care professionals (physicians, dentists, pharmacists, radiographers, nurses) Manufacturers Authorities

Report to whom? ► Regulatory Authority ► Industry, manufacturers ► Health professionals ► Patient organizations ► General public ► Social security

Cumulative reports as of April 2004

Causality assessment How likely is this medication the cause of this problem in this particular patient?

Naranjo’s algorithm

Questionnaire Are there previous conclusive reports on this reaction? Did the adverse event appear after the suspected drug was given? Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given? Did the adverse reaction appear when the drug was readministered? Are there alternative causes that could have caused the reaction?

Questionnaire (cont) 6. Did the reaction reappear when a placebo was given? 7. Was the drug detected in any body fluid in toxic concentrations? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence?

Scoring Definite ADR > 9 Probable ADR 5-8 Possible ADR 1-4 Doubtful ADR 0

Take home message Pharmacovigilance is a dynamic clinical and scientific discipline ADR reporting is the cornerstone pharmacovigilance activity The majority of global information related to ADRs arises from Western countries Each country should support its own PV program

A successfully implemented pharmacovigilance centre can minimize, prevent and improve the use of drugs by discovering ADRs at the level of general public use.

Thank you