Why do we need Pharmacovigilance? Samira Saleh Prof. of Pharmacology Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University Egypt 5th Global Pharmacovigilance Summit, 8-29 April 2016, Dubai, UAE

? Outline Theme Ensure safer drugs to the healthcare community Adverse Drug Reactions Why is detection & assessment of ADRs inadequate in clinical trials? Pharmacovigilance Why do we need pharmacovigilance

The study of ADRs is the concern of the field of 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

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

Serious and severe Serious (FDA): when it meets one of the following criteria: Results in death Life-threatening Requires inpatient hospitalization or prolongation of hospitalization Results in disability - or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life Results in congenital abnormalities Requires intervention to prevent permanent damage Severity: intensity of the adverse effect

Economic impact of ADRs The cost to the country of ADRs may exceed the cost of the medications themselves 30-60 % of ADRs may be preventable

Before drugs become available to the patients, they are subjected to rigorous clinical studies. Post-marketing Surveillance in real life patients Pre-clinical Research However, some adverse drug reactions (ADRs) are often detected ONLY after marketing.

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

Why is detection & assessment of ADRs inadequate in clinical trials? Discovering ADR depends on: Frequency of occurrence Number of patients exposed to the drug Clinical trials are usually short-term studies conducted in a few hundred patients before marketing a drug. Therefore, further investigation on ADRs must be pursued in the post-marketing phase.

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

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.

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

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

A lesson from history 1959 – 1961 thalidomide 4,000 - 10, 000 cases of phocomelia (congenital limb defects) In 1961, it was determined that Thalidomide caused horrifying birth defects. It is estimated that between 10,000 to 20,000 people were affected in what is considered to be among the worst medical disasters in history.   This lead to withdrawal of the drug from the market

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

the Food and Drug Administration (FDA) recorded 337 pharmaceutical recalls in 2014, a 7% increase over 2013 and up 16% from 2012.

Examples of licensed drugs withdrawn after marketing for drug safety reasons Thalidomide (1965) Phocomelia Practolol (1975) Sclerosing peritonitis Phenformin (1982) Lactic acidosis Rofecoxib (2004) Cardiovascular effects Veralipride (2007) Anxiety, depression, movement disorders Troglitazone (Rezulin) (2000) Hepatitis Rosiglitazone (2010 ( Increased risk of MI and death from CV causes

Pharmacovigilance cycle Collection & Management of data Analysis & Evaluation of data Acting to protect public health ► 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

Actions taken 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 Product recall: 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, moved to Uppsala Sweden in 1978) 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

WHO drug monitoring programme, March 2006 As for August 2011: 106 members and 33 awaiting for full membership

Cumulative number of reports

Establishment of the Egyptian Pharmacovigilance Center (EPVC) December 2009 مركز اليقظة الدوائية المصري ديسمبر 2009 http://epvc.gov.eg Personnel training is ongoing in order achieve the highest level of competency

Middle East Members Morocco 1992 Tunisia 1993 Oman 1995 Iran 1998 Egypt 2001 Jordan 2002 Sudan 2008 Saudi Arabia 2009 Iraq 2010 United Arab Emirates The Jordanian Food and Drug Agency (JFDA) was established in 2001, gained WHO membership in 2002, and had their PV guidelines approved in 2006. The Tunisian National Centre for PV was created in 1984 and became a WHO CC for international drug monitoring in 1993. The EPVC guidelines for healthcare professionals and marketing access holders were released in 2009. Oman became a member of the UMC in 1995 The National Pharmacovigilance and Drug Safety Centre (NPC), created in association with the Saudi Food and Drug Agency (SFDA), was declared open in 2009 and became a member of the UMC in the same year.

Drugs - Real World Outcomes (2015) The First Eastern Mediterranean Region (EMR)/Arab Countries Meeting of pharmacovigilance was held in Rabat Morocco, from 22 to 26 September 2014. Drugs - Real World Outcomes (2015)

Harmonized Arab PV definitions and terms

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

How to report? 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 included on the yellow card Patient details Suspected drug Suspected reaction Reporter details

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

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

Who can report? ► Patients, patients relatives or patients carers ► Health care professionals (physicians, dentists, pharmacists, 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?

The Naranjo algorithm This is a questionnaire for determining the likelihood of whether an ADR is actually due to the drug  rather than the result of other factors. Probability is assigned by a score (definite, probable, possible or doubtful). Naranjo CA, Busto U, Sellers EM, et al. (1981). A method for estimating the probability of adverse drug reactions Clin. Pharmacol. Ther. 30 (2): 239–45.

Naranjo scoring system

Factors to be considered (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?

Categories of causality (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 Countries have to support their own national pharmacovigilance. Each country should support its own PV program

Ensure Safer Drugs to the Healthcare Community A successfully implemented pharmacovigilance centre can minimize, prevent and improve the use of drugs by discovering ADRs at the level of general public use. Ensure Safer Drugs to the Healthcare Community

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