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PHARMACOVIGILANCE : Principles of Drug Safety (Unit 2)

Arwa Dalal Gauri Bulbule Manasvi Parekh Rasika Natu

1. Pharamcovigilance Methods

2. Drug Safety Guidelines

3. Global Strategy

4. Prescription Event Monitoring Report

5. Record Linkage System

6. CIOMS Forms
7. ADR Reporting

Spontaneous reports

1.Passive Surveillance

Case series of spontaneous reports

Spontaneous Reports
A spontaneous report is an unsolicited communication by healthcare professionals or consumers to a national pharmacovigilance centre, pharmaceutical company, regulatory authority or other organization. Describes one or more suspected adverse drug reactions in a patient who was given one or more medicinal products. Does not derive from a study or any organized data collection scheme. Play a major role in the identification of signals of drug related problems once a drug is marketed. Also provide important information on at-risk groups, risk factors, and clinical features of known serious adverse drug reactions.

Case Series Of Spontaneous Reports

Provide evidence of an association between a drug and an adverse event. They are generally more useful for generating hypotheses than for verifying an association between drug exposure and outcome. A case series, involves reports on two or more people with common exposure to a drug, or a common outcome.

2. Stimulated Reporting
Stimulated reporting are those that may have been motivated , prompted or induced and can occur in certain situations such as notifications by a Health Care Professional Communication (HCPC), public advisory, literature report or questioning of health care professionals. These are unsolicited in nature and a form of Spontaneous Reporting. It mainly includes on-line reporting of adverse events and systematic stimulation of reporting of adverse events based on a pre-designed case definition.

3. Active Surveillance
Active surveillance, seeks to ascertain completely the number of adverse events via a continuous pre-organized process. It includes : Sentinel sites Drug event monitoring Registries

Sentinel Sites
Active surveillance can also be achieved by reviewing medical records or interviewing patients and/or physicians in a sample of sentinel sites. To ensure complete and accurate data on reported adverse events from these sites. The selected sites can provide information, such as data from specific patient sub-groups. Further, information on the use of a drug, such as abuse, can be targeted at selected sentinel sites. Some of the major weaknesses of sentinel sites are problems with selection bias, small numbers of patients, and increased costs.

Drug Event Monitoring

In drug event monitoring, patients might be identified from electronic prescription data or automated health insurance claims. A follow-up questionnaire can then be sent to each prescribing physician or patient at pre-specified intervals to obtain outcome information. Information on patient demographics, indication for treatment, duration of therapy (including start dates), dosage, clinical events and reasons for discontinuation can be included in the questionnaire. Limitations: Poor physician and patient response rates. Unfocused nature of data collection,which can obscure important signals.

A patient registry is a list of patients presenting with the same characteristic(s). This characteristic can be pregnancy (pregnancy registry), a disease (disease registry) or a specific exposure (drug registry). In each type of registry, which only differs by the type of patient data of interest, can be collected by a battery of information using standardised questionnaires in a prospective fashion.

Comparative Observational Studies

Traditional epidemiologic methods-key component for adverse event. Major types are Cross sectional study Case control study cohort study

Cross Sectional Study

Data of patient collected in interval of time Study is conducted for survey of disease These studies are best used to examine the prevalence of a disease at a one time point , when data for serial time points can be captured.

Case control study

Cases of disease are identified A case-control study is an analytical study which compares individuals who have a specific disease ("cases") with a group of individuals without the disease ("controls"). Control group selection Controls need not be in good health; inclusion of sick people is sometimes appropriate, as the control group should represent those at risk of becoming a case. Controls should come from the same population as the cases, and their selection should be independent of the exposures of interest

Usefulness and drawbacks

Case-control studies are a relatively inexpensive and frequently used type of epidemiological study that can be carried out by small teams or individual researchers They have pointed the way to a number of important discoveries and advances Most important drawback in case-control studies relates to the difficulty of obtaining reliable information about an individuals exposure status over time. Case-control studies are therefore placed low in the hierarchy of evidence.

Cohort study/follow up study

The subjects are selected on the basis of whether they are exposed to risk factor/treatment and then followed which one gets disease Risk factor disease Starts with people free of disease Example does exposure to X (say, smoking) associate with outcome Y (say, lung cancer)? Such a study would recruit a group of smokers and a group of non-smokers (the unexposed group) and follow them for a set period of time and note differences in the incidence of lung cancer between the groups at the end of this time.

Descriptive study
Descriptive studies are observational studies which describe the patterns of disease occurrence in relation to variables such as person, place and time Uses 1. Health care planning Descriptive studies provide knowledge about which populations or subgroups are most or least affected by disease. This enables public health administrators to target particular segments of the population for education or prevention programmes and can help allocate resources more efficiently.

2. Hypothesis generation Descriptive studies identify descriptive characteristics which frequently constitutes an important first step in the search for determinants or risk factors that can be altered or eliminated to reduce or prevent disease.

Drug Utilization Study

Study describes how a drug is marketed , prescribed and used in population. Data can be developed for determining rates of ADR. Study provides data on specific population i.e children ,elderly , age , gender .DUS helps to determine which product is been used in these population.

Global Strategy for Pharmacovigilance

New harmonization initiatives in pharmacovigilance New strategies in benefit risk optimization, risk communication, labeling & packaging Addressing drug counterfeiting issues & evaluating possible measures to combat & protect consumers EU and US reforms in pharmacovigilance legislation The economics of pharmacovigilance and pharmacoepidemiology Preparing for product specific inspections & compliance monitoring by authorities

Drug Safety Guidelines-ICH

Carcinogenicity Studies S1A - S1C Genotoxicity Studies S2 Toxic kinetics and Pharmacokinetics S3A - S3B Toxicity Testing S4 Reproductive Toxicology S5 Biotechnological Products S6 Pharmacology Studies S7A - S7B Immunotoxicology Studies S8 Nonclinical Evaluation for Anticancer Pharmaceuticals S9 Photo safety Evaluation S10

Prescription Event Monitoring Report

Prescription-Event Monitoring is both a hypothesis generating form of pharmacovigilance and a method which provides opportunities for quantitative analyses and comparative studies of drug safety signals. In addition, it has an excellent follow up procedure to obtain additional information about selected events of clinical importance. This enables clinical evaluation of the causal association of the event with the drug being monitored.

The methodology is flexible and has been adapted to address specific safety issues, for example for the PEM studies of the COX-2 inhibitors, information was collected on patients past medical history, also their past and current use of particular medications.
The drug regulator, MHRA, may license a new medicine on condition that the manufacturer agrees to commission a safety study by the DSRU

Six or twelve months after the first prescription for an individual drug in an individual patient, the DSRU sends a green form questionnaire to the general practitioner who wrote the original prescription. Thus, the prescriptions provide the exposure data showing which patients have been exposed to the drug being monitored, and the green forms provide the outcome data showing any events noted during the period of monitoring. The great strengths of this method are that it provides a numerator (the number of reports) and a denominator (the number of patients exposed), both being collected over a precisely known period of observation. The main weakness of PEM is that only 50%70% of the green forms are returned. In addition, because PEM limits follow-up to 6 or 12 months, it cannot identify events of long latency.

Record linkage system

Record linkage (RL) refers to the task of finding records in a data set that refer to the same entity across different data sources . (e.g., data files, books, websites, databases)
Also known as duplicate detection, record matching and data matching .

Record linkage in research

Creates data for examining the health of the public. It can be used to improve data holdings, data collection, quality assessment, and the dissemination of information. eliminates duplicate records. Identifies under-reporting and missing cases (e.g., census population counts)

Generates disease registries and health surveillance systems . Record Linkage helps in follow-up studies of cohorts or other groups to determine factors such as vital status, residential status, or health outcomes.
Record linkage is also used to create health indicators.

CIOMS is a body set up under WHO and UNESCO. It has developed a series of guidelines on pharmacovigilance, drawn up by a committee of volunteers from Industry, regulatory authorities, WHO and others.

The main guidelines concern the international reporting form (CIOMS I); periodic safety update reports (CIOMS II); core data sheets (CIOMS III); benefit-risk assessments (CIOMS IV); practical issues in pharmacovigilance (CIOMS V); clinical trial safety data (CIOMS VI); and development safety update reports (CIOMS VII)

ADR Reporting
Health professionals play an important role in monitoring the safety of medicines by reporting any suspected adverse drug reactions (ADRs)

As health professionals, you are likely to observe adverse reactions to medicines. When you submit a suspected ADR report, you contribute to the ongoing collection of information that occurs once health products are on the market.

What should you report?

Suspected ADRs to new medicines Suspected drug interactions Unexpected ADRs (i.e. reactions that are not described in the Product Information) Serious ADRs, such as those suspected of causing: 1. Absence from productive activity 2. Admission to hospital 3. Prolongation of hospitalization 4. Increased investigation or treatment costs 5. Danger to life 6. Birth defects 7. Death

What should you include?

Each ADR report must include: Patient identifier (e.g. initials) Contact details for the reporter A description of the reaction Medicines suspected of causing the reaction