Training Module Powerpoint Presentations

Joint Collaboration with World Health Organisation, India Country Office

TITLE
ADR Reporting - Medical Content
ADR Reporting and Patient Safety
ADR Reporting Design and Method
An Effective Pharmacovigilance System
Causality Assessment
Good Documentation Practices for AMCs
ICH Guidlines on PV
Pv Indicators
Pv Methods
Scope of PV
Terminologies of ADR & Drug Infomation
Vigiflow

Guidance Documents - Introduction Guidance Document PDF Manual

Adverse reactions of drugs continue to remain as an important public health issue. Safety monitoring of medicines is the responsibility of all stakeholders of the healthcare system since it continues to be an important cause of morbidity and mortality. In some countries adverse drug reactions are among the ten leading causes of mortality. The safety of patients and the safe use of medicines are crucial for health policy development and delivery of the best healthcare. To prevent or reduce harm to patients thereby improving public health, the safety of medicines in clinical use must be monitored and evaluated through specialised systems. This requires a need to establish a well-organised pharmacovigilance system. Thus, a pharmacovigilance system is defined as a system used by an organisation to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance. A pharmacovigilance system is characterised by its structures, processes and outcomes. To run an effective pharmacovigilance system a protocol is required for reporting adverse reactions associated with drug use. Therefore NCC aims to ensure the systematic and effective functioning of PvPI by publishing its guidance document for reporting ADRs.

This Guidance Document lays down requirements and guidance for reporting adverse drug reactions and significant safety issues related to drugs regulated by the Central Drugs Standard Control Organization. This document does not establish legally enforceable responsibilities. This has been prepared by the NCC and approved by Working Group. The purpose of this document is to present the importance of pharmacovigilance in India, to record the growth and potential as a significant discipline within medical science, and to describe its impact on patient welfare and public health. This document also highlights the importance of collaboration and communication at local, regional and international levels to ensure that pharmacovigilance delivers its full benefits. It also provides guidance to stakeholders on good pharmacovigilance practices, assessment of data regarding drugs including vaccines and blood products.

Scope of Guidance Document

This document helps to expand the role and responsibilities of stakeholders under PvPI to identify, analyse and minimise the risk associated with drugs. Further it promotes better and broader use of existing pharmacovigilance data for patient safety by spontaneous reporting system. The document is intended for the following stakeholders under PvPI:

• Professional staff at NCC
• Representatives of Adverse Drug Reaction Monitoring Centre
• National Health Programs integrated with PvPI
• Staff and consultants in CDSCO
• Policy makers at all levels of healthcare, particularly those concerned with drug policy
• Healthcare practitioners (clinicians, dentists, pharmacists, nurses and other healthcare professionals)
• Health epidemiologists
• Health economists

• SOP Documents
• Quality Manual

Pharmacovigilance methods

Several methods can be used to collect safety information in pharmacovigilance. In PvPI system, spontaneous reporting forms the basis of the ADR reporting system despite its well-known limitation of under-reporting. It is relatively inexpensive and provides a life-time monitoring of all medicines in all patients in any healthcare system. Brief highlights of various pharmacovigilance methods are given below

Passive surveillance

Passive surveillance means that no active measures are taken to look for adverse effects other than the encouragement of health professionals and others to report safety concerns. Reporting is entirely dependent on the initiative and motivation of the potential reporters.

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 (e.g., WHO, Regional Centres) that describes one or more suspected adverse drug reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organized data collection system where adverse event reporting is actively sought.

Spontaneous reports play a major role in the identification of signals of drug related problems once a drug is marketed. They can also provide important information on at-risk groups, risk factors, and clinical features of known serious adverse drug reactions.

All these cases - ‘Individual Case Safety Reports’ (ICSRs) - are entered on the safety database i.e. Vigibase, which are examined individually and in the aggregate for a product in order to identify clusters of reports that could represent a signal of a previously unknown adverse reaction or drug interaction or some change in the character of a known adverse reaction. It may also be possible to recognise a new risk factor for a reaction to a product, such as a sub-group of patients at particular risk.

Under-reporting, reports of known reactions, and false causality attribution are the common criticisms of spontaneous reporting systems

Reporting form: The NCC has designed a Suspected Adverse Drug Reaction Reporting Form (see Appendix) to record adverse reactions related to drugs. Separate forms are available to record adverse reactions associated with transfusion of blood and blood products and Adverse Event Following Immunization. A report that contains information describing a suspected adverse drug reaction related to the administration of one or more medicinal products to an individual patient is termed as individual case safety report.

What to Report?

In order to foster the habit of reporting PvPI encourages reporting of all types of suspected ADRs- irrespective of whether they are known or unknown, serious and non-serious, frequent or rare.Althoughpharmacovigilance is primarily concerned with pharmaceutical medicines, adverse reactionsassociated with drugs used in traditional medicine (e.g. herbal remedies) should also beconsidered. Special fields of interest are drug use in pregnancy, lactation, paediatric and geriatric. In addition, the reporting of lack of efficacy and suspected pharmaceutical defects isrecommended, especially when there is the possibility of manufacturing problems,counterfeit pharmaceuticals or of the development of resistance e.g. antibiotics.

Who can Report?

Under PvPI healthcare professionals (clinician, dentist pharmacist nurses and others) can report suspected adverse drug reaction. Pharmaceutical companies can also send ICSRs specific for their product to NCC.

Whom to Report?

Use the ‘Suspected Adverse Drug Reaction Reporting Form’ which is available on the official website of IPC (www.ipc.gov.in) as well as CDSCO (www.cdsco.nic.in) to report any ADR. A reporter who is not a part of AMC can submit the ICSR to the nearest AMC or directly to the NCC. A reporter can also mail the ICSR at pvpi@ipcindia.net or pvpi.ipcindia@gmail.com(See Appendix for the list and contact details for AMCs under PvPI)

Case series of Spontaneous reports

Series of case reports can provide evidence of an association between a drug and an adverse event, but they are generally more useful for generating hypotheses than for verifying an association between drug exposure and outcome. There are certain distinct adverse events known to be associated frequently with drug therapy, such as anaphylaxis, aplastic anaemia, toxic epidermal necrolysis and Stevens Johnson syndrome. Therefore, when events such as these are spontaneously reported, it is important that pharmacovigilance centres place emphasis on these reports for detailed and rapid follow-up. Case reports and series have a high sensitivity for detecting novelty and therefore remain one of the cornerstones of medical progress; they provide many new ideas in medicine.

Targeted Spontaneous reporting

This is a variant of spontaneous reporting. It focuses on capturing adverse drug reactions in a well defined group of patients on treatment. It also enables focus on a specific drug of interest a specific population of interest or a specific adverse drug reaction. Health professionals in charge of the patients are sensitized to report specific safety concerns. The method is intended to ensure that patients are monitored and that adverse drug reactions are reported as a normal component of routine patient monitoring and standard of care. This focused approach has the same objectives and flow of information as for spontaneous reporting. The reporting requires no active measures to look for the particular syndromes.

Stimulated Reporting

Several methods have been used to encourage and facilitate reporting by health professionals in specific situations (e.g., in-hospital settings), for new products or for limited time periods. Such methods include on-line reporting of adverse events and systematic stimulation of reporting of adverse events based on a pre-designed case definition. Stimulated reporting can occur in certain situations, such as direct healthcare professional communication (DHPC), a publication in the press or questioning of healthcare professionals by company representatives, and adverse reaction reports arising from these situations are considered spontaneous reports, provided the report meets the definition above.

Although these methods have been shown to improve reporting, they are not devoid of the limitations of spontaneous reporting, especially selective reporting and incomplete information.

Active surveillance

Active surveillance, in contrast to spontaneous reporting, seeks to ascertain completely the number of adverse events via a continuous pre-organised process. An example of active surveillance is the follow-up of patients treated with a particular drug as in Cohort Event Monitoring. Patients who fill a prescription for this drug may be asked to complete a brief survey form and give permission for later contact.

Active surveillance requires substantially more time and resources and is therefore less commonly used in emergencies. But it is often more complete than passive surveillance. In general, it is more feasible to get comprehensive data on individual adverse event reports through an active surveillance system than through a spontaneous reporting system.

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 that would not be available in a spontaneous reporting system. Further, information on the use of a drug, such as abuse, can be targeted at selected sentinel sites. Sentinel surveillance requires more time and resources, but can often produce more detailed data on cases of illness. It may be the best type of surveillance if more intensive investigation of each case is necessary to collect the necessary data.Some of the major weaknesses of sentinel sites are problems with selection bias, small numbers of patients, and increased costs.

Drug event monitoring

Drug event monitoring is a method of active pharmacovigilance surveillance. 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, dosage, clinical events and reasons for discontinuation can be included in the questionnaire. Limitations of drug event monitoring can include poor physician and patient response rates and the unfocused nature of data collection, which can obscure important signals. In addition, maintenance of patient confidentiality might be a concern. On the other hand, more detailed information on adverse events from a large number of physicians and/or patients might be collected.

Cohort event monitoring: A modification of drug event monitoring is cohort event monitoring (CEM), an active pharmacovigilance method promoted by the World Health Organization and other agencies. CEM is a method where information is collected, with focus on events, on all patients in a group being treated with a medicine or group of medicines. A pre-treatment questionnaire is filled at time of recruitment and post-treatment questionnaires are filled at times of follow up which may either be once e.g. for anti-malarials or life-long e.g. for antiretrovirals.

Registries

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). Both type of registries, which only differs by the type of patient data of interest, can be collected a battery of information using standardised questionnaires in a prospective fashion.

Comparative observational studies

Traditional epidemiologic methods are a key component in the evaluation of adverse events. A number of observational study designs are useful in validating signals from spontaneous reports or case series. Major types of these designs are cross-sectional studies, case-control studies, and cohort studies (both retrospective and prospective).

Cross-sectional study

Data collected on a population of patients at a single point in time (or interval of time) regardless of exposure or disease status constitute a cross-sectional study. These types of studies are primarily used to gather data for surveys or for ecological analyses. The major drawback of cross-sectional studies is that the temporal relationship between exposure and outcome cannot be directly addressed. These studies are best used to examine the prevalence of a disease at one time point or to examine trends over time, when data for serial time points can be captured. These studies can also be used to examine the crude association between exposure and outcome in ecologic analyses. Cross-sectional studies are best utilized when exposures do not change over time.

Case-control study

In a case-control study, cases of disease (or events) are identified. Controls, or patients without the disease or event of interest, are then selected from the source population that gave rise to the cases. The controls should be selected in such a way that the prevalence of exposure among the controls represents the prevalence of exposure in the source population. The exposure status of the two groups is then compared using the odds ratio, which is an estimate of the relative risk of disease in the two groups.

Cohort study

In a cohort study, a population-at-risk for the disease (or event) is followed over time for the occurrence of the disease (or event). Information on exposure status is known throughout the follow-up period for each patient. A patient might be exposed to a drug at one time during follow-up, but non-exposed at another time point. Since the population exposure during follow-up is known, incidence rates can be calculated. In many cohort studies involving drug exposure, comparison cohorts of interest are selected on the basis of drug use and followed over time. Cohort studies are useful when there is a need to know the incidence rates of adverse events in addition to the relative risks of adverse events. Multiple adverse events can also be investigated using the same data source in a cohort study. However, it can be difficult to recruit sufficient numbers of patients who are exposed to a drug of interest or to study very rare outcomes.

Targeted clinical investigations

When significant risks are identified from pre-approval clinical trials, further clinical studies might be called for to evaluate the mechanism of action for the adverse reaction. In some instances, pharmacodynamic and pharmacokinetic studies might be conducted to determine whether a particular dosing instruction can put patients at an increased risk of adverse events. Genetic testing can also provide clues about which group of patients might be at an increased risk of adverse reactions. Furthermore, based on the pharmacological properties and the expected use of the drug in general practice, conducting specific studies to investigate potential drug-drug interactions and food-drug interactions might be called for. These studies can include population pharmacokinetic studies and drug concentration monitoring in patients and normal volunteers.

Descriptive studies

Descriptive studies are an important component of pharmacovigilance, although not for the detection or verification of adverse events associated with drug exposures. These studies are primarily used to obtain the background rate of outcome events and/or establish the prevalence of the use of drugs in specified populations.

Natural history of disease

The science of epidemiology originally focused on the natural history of disease, including the characteristics of diseased patients and the distribution of disease in selected populations, as well as estimating the incidence and prevalence of potential outcomes of interest. These outcomes of interest now include a description of disease treatment patterns and adverse events. Studies that examine specific aspects of adverse events, such as the background incidence rate of or risk factors for the adverse event of interest can be used to assist in putting spontaneous reports into perspective. For example, an epidemiologic study can be conducted using a disease registry to understand the frequency at which the event of interest might occur in specific subgroups, such as patients with concomitant illnesses.

Drug utilization study

Drug utilization studies (DUS) describe how a drug is marketed, prescribed, and used in a population, and how these factors influence outcomes, including clinical, social, and economic outcomes. These studies provide data on specific populations, such as the elderly, children, or patients with hepatic or renal dysfunction, often stratified by age, gender, concomitant medication, and other characteristics.

Web-Based PV Tools

IPC-NCC has free access to the databases provided by WHO-UMC which helps in achieving the objectives of PvPI in a more efficient way.

VigiFlow

VigiFlow is a web-based ICSR management system that is specially designed for use by national centres in the WHO Programme for International Drug Monitoring. VigiFlow is based on and compliant with the ICH E2B standard and is a trademark of the UMC and maintained by the UMC in Uppsala, Sweden. It offers a simple, fast and secure web-based solution that improves all aspects of ADR reporting. ICSR data can be manually entered into VigiFlow with support from the latest versions of terminologies such as the WHO-DD and WHO-ART or MedDRA. Once a report is complete and committed the first version of the ICSR is considered to be finalized. It is easy to retrieve reports to amend the contents or add follow-up information. ICSRs will automatically be flagged for being copied to VigiBase, the WHO Global ICSR database when they are committed.

VigiMed

VigiMed is a web-based forum for those working at national centres in the WHO Programme to have easy access to safety concerns in other countries, to check regulatory status, and to expedite the sharing of drug information. VigiMed is part of the UMC collaboration portal, a web-based platform managed by the UMC.

VigiSearch

VigiSearch is a powerful search tool that provides access to all case reports in VigiBase. VigiSearch allows for report searching across multiple drugs and ADRs simultaneously, as well as incorporating a range of filters. Drugs can be searched on a generic substance level or a specific trade name. VigiSearch also supports browsing the ATC structure. The results can be accessed on an overview level and viewed from a number of aspects (country, year, reaction term) or at the level of individual case report. For members of the WHO Programme, VigiSearch enables an international comparison of national spontaneous reporting data, as well as giving access to ADR information on drugs that are not yet on the national market.

VigiLyze

VigiLyze is a powerful search and analysis tool that provides access to more than 8 million ICSRs in VigiBase, submitted from over 100 countries. VigiLyze includes data on conventional medicines, traditional medicines as well as biological medicines including vaccines. VigiLyze can be used to have a global, regional or national view of an ADR identify or monitor international patient safety data. It can be useful to find supporting evidence while assessing Indian case reports or to see how Indian data support global pharmacovigilance. VigiLyze enables international comparison with national spontaneous reporting data, as well as giving access to ADR information on drugs that are not yet on our national market. Results from VigiLyze are instantly available as graphics as well as in tabular format.

Important Definitions and Terminologies in Pharmacovigilance Complete Glossary of terms in PV

Definitions are important so that we can converse and write about pharmacovigilance with greater clarity. The following definitions are used in the PvPI for drug monitoring, most of which have been incorporated into guidelines issued by the ICH, EMEA and other competent national authorities.

Pharmacovigilance

The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems.

Side effect

Any unintended effect of a pharmaceutical product occurring at doses normally used in man which is related to the pharmacological properties of the drug.

Adverse reaction

A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.

A more recent definition is:

Adverse effect

An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.

‘Adverse reaction’ and ‘adverse effect’ are interchangeable but adverse effect is more patient-centred, and adverse reaction is more drug-centred.

Unexpected adverse reaction

An adverse reaction, the nature or severity of which is not consistent with domestic labelling or market authorization, or expected from characteristics of the drug.

Serious adverse event or reaction

A serious adverse event or reaction is any untoward medical occurrence that at any dose:

• results in death or
• requires inpatient hospitalisation or prolongation of existing hospitalisation or
• results in persistent or significant disability/incapacity or
• is life-threatening or
• is a congenital anomaly/birth defect

Signal

Signal is reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information.

General Approach

The identification of signals in the national pharmacovigilance centre’s database requires careful review of individual reports and events. Careful, informed, routine, systematic and standardized clinical review of the Centre’s reports with the recording and appropriate collation of good data provides the quickest and most satisfying way of identifying previously unsuspected adverse reactions. Following through the whole process from relationship assessment, to signal identification, to signal strengthening, to communicating the findings is essential.

The identification of signals in the national pharmacovigilance centre’s database requires careful review of individual reports and events. Careful, informed, routine, systematic and standardized clinical review of the Centre’s reports with the recording and appropriate collation of good data provides the quickest and most satisfying way of identifying previously unsuspected adverse reactions. Following through the whole process from relationship assessment, to signal identification, to signal strengthening, to communicating the findings is essential.

Database functionality should enable users to search and retrieve data to facilitate cumulative data review, signal detection and trend analysis. Standardised MedDRA Queries (SMQs) may be used for signal detection and the use of SMQs is recommended in order to retrieve and review cases of interest where signals are identified from adverse reaction databases. When a signal is identified, the possibility of a causal relationship should be considered and in these circumstances, all relevant adverse reaction data should be further analysed. All ICSRs fulfilling the minimum information requirements should be included in the overall analysis. Certain analyses (for example those concerning the role of risk factors) may be confined to cases where sufficient information is available, but it should be made clear that this is a subset of the data.

Competent Authorities and Marketing Authorisation Holders should inform each other of identified signals, which may impact on the known risk-benefit balance of nationally authorised medicinal products and in the case of products authorised through the centralised, mutual recognition or decentralised procedures in accordance with relevant guidance.

It is important to follow closely what is going on in other centres and also to rely on the PvPI Newsletters, WHO Pharmaceuticals Newsletter and the UMC’s Signal document to keep abreast of signals that may be of importance to them. International collaboration is always key to both signal identification and signal strengthening and should be encouraged.

Definition of a Signal

One way in which the adverse effects of drugs are studied is through pharmacovigilance signal detection. WHO defines a pharmacovigilance signal as "reported information on a possible causal association between an adverse event and a drug, the relationship being unclear or incompletely documented previously”.

Alternatively, there are several events (or sometimes a single event) with a strong relationship (“certain” or “probable” and sometimes “possible”) and there does not seem to be good evidence anywhere of it being recognized as a reaction. There may be one or two case-reports in the literature, but this is insufficient as validation and the signal needs to be strengthened.

Signal detection plays an important role in understanding adverse reaction to certain drugs. There have been cases where pharmacovigilance signal detection has resulted in withdrawal of drugs from the market.

Reference Sources on Adverse Reactions

In PvPI, following two sources are referred for information on adverse reactions of a drug.

1. Current Index of Medical Specialities (CIMS) India - Monthly Index of Medical Specialities (MIMS) is a reliable source of information in relation to established adverse reactions. MIMS Drug Information System is the most advanced, complete, and up-to-date information source on available products, delivering critical information needed at every point of care. MIMS Drug Information System is delivered across multiple platforms and channels, available in print, online and LAN, standalone or integrated.
2. electronic Medicines Compendium (eMC) is also useful and reliable source of information. It contains up to date, easily accessible information about medicines licensed for use in the UK. The eMC has more than 9,000 documents, all of which have been checked and approved by either the UK or European government agencies which license medicines. These agencies are the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA).

Good Data are Essential

If a signal of a new adverse reaction is to be considered, the data in the report(s) need to be of good quality. There should be sufficient data to fully assess the relationship of the drug to the event.

According to WHO, the strongest signals will have several reports with a “certain” or “probable” relationship. A signal may possibly be identified from one very good “certain” report. If there are no “certain” reports, at least three “probable” reports would be necessary for a signal. The first reports with a “certain” or “probable” relationship are called “index cases”. Cases with a “possible” relationship can only provide supporting evidence. A group of unexpected deaths coded as “possible” forms an exception to this general rule and will need to be taken seriously.

A group of “unlikely” reports may occasionally produce a signal of an unexpected reaction that was not recognized at the time of clinical assessment. However, they should not be included in the assessment of a signal for which there are reports with certain, probable or possible relationships because they are different and could mask the characteristics of the signal being investigated.

Cases coded as “unclassified” or “unassessable” should not be considered in the investigation of a signal.

Selection criteria for events to investigate

• There are sufficient data to fully assess the relationship of the drug to the event
• The event is medically confirmed
• There have been several reports of the event that show a credible and strong relationship with the drug (certain or probable).

If validated, the event is of sufficient importance or interest to:

• require regulatory action;
• require advice to prescribers;
• be of scientific importance.

Methods of Signal Identification

Signal detection process in a spontaneous ADR database is based on different statistical methodology - either the Bayesian or Frequentist statistical approach. Whichever method is employed, basically it involves computation of measures of disproportionality i.e. determination to what extent the number of observed cases differs from the number of expected cases. All disproportionality algorithms despite having operational technique variability actually calculate surrogate observed to expected ratios in which the reporting experience of each reported drug-adverse event combination is compared to the background reporting experience across all drugs and events in the database using an independence model.

The WHO UMC uses the BCPNN - (Bayesian Confidence Propagation Neural Network) while US FDA uses the MGPS- (Multi item Gamma Poisson Shrinker) methodologies. Other disproportionality analyses methods are ROR (Reporting Odds Ratio), PRR (Proportional Reporting Ratio) are employed by some national reporting centres (MHRA, UK) and drug safety research units.

According to WHO, signal detection include the following methods for signal detection:

• Clinical assessment of individual events
• Clinical review of collated events
• Record linkage
• Automated signal detection

The PVPI is currently analysing its own national database and a signal review panel will shortly formulate its strategy for signal detection and its assessment.

Clinical assessment of individual events

The quickest method for identifying signals is the careful, routine, standardized clinical assessment of individual reports with alertness to the possibility of a signal. This approach should be taken during routine review of incoming reports. During routine assessment of reports, if an assessor identifies an event and thinks that it could be a new type of adverse reaction, a search should be undertaken for records of other similar events to confirm the opinion. First, the national or global ICSR database should be checked for other similar reports or clinically related terms. Then the adverse reaction should be checked in appropriate reference sources. If there is no reference to the occurrence of the event as an adverse reaction, then the PV Centre should proceed with its investigation

Strengthening the signal

General approach

The magnitude and clinical significance of a signal may also be examined by descriptive analyses in other available data sources or by analysis of the characteristics of exposed patients and their medicinal product utilisation patterns (such analyses are also sometimes referred to as signal refinement, signal strengthening or signal substantiation). Validating a signal is generally a process of gradual strengthening arising from new findings in pharmacovigilance or research. The process entails examining other available data and also examining one’s own data in greater depth according to the following principles:

• Reviewing other experience
• Searching for non-random patterns
• Reviewing the pharmacology
• Consulting one’s expert safety review panel and other experts
• Undertaking epidemiological studies
• Communication and feedback

Reviewing other experience

When a signal has been detected, an evaluation of the data supporting the signal should be performed to verify that the available documentation is strong enough to suggest a new potentially causal association, or a new aspect of a known association, and therefore to justify further assessment of the signal.

Not simply a single event term but also related clinical events for the suspect drug are searched in the vigibase to find other similar reports in the database, if any. Literature is searched for similar reports, using search tools such as PubMed. Pharmaceutical company is referred for any similar reports received and details are enquired.

Search for non-random patterns

Non random pattern are searched from the examination of data and in the absence of biases, non-random patterns suggest that the events may be related to the medicine. According to WHO, following criteria is examined in particular:

• Onset times: Does the range of onset times cluster around a particular period (e.g. 5 days or 3 weeks), or are the onset times scattered randomly over time? Compare the onset times of the events with those for the rest of the cohort using life-table or survival analysis.

Mean dose

Is the mean dose significantly higher in those who experienced the event being studied than in those in whom the event did not occur?

Sex differences

When compared, are the rates of the event in men and women significantly different? A drug effect could be one reason for this.

Reviewing the pharmacology

Pharmacological mechanism by which the medicine could cause the event is studied and possibility of other drugs in the same class that can cause a similar problem and has a mechanism been described for the related drug(s) is also considered. Note that with a new medicine there may not be a known mechanism for a new adverse reaction. Sometimes the study of a previously unidentified adverse reaction brings to light new knowledge about the pharmacology of the medicine.

Consulting one’s expert safety review panel and other experts

Consulting experts regarding drug safety should be done routinely in any pharmacovigilance centre when drug safety signals are identified or suspected. In addition to members of Safety Review Panel or Steering Committee, the World Health Organization’s Advisory Committee on the Safety of Medicinal Products (ACSoMP) can be consulted through the WHO.

Communication with other parties to gain more information

Effective, well-presented communication of a signal to various stakeholders will inform and give feedback on its validity and its importance.The following stakeholders can provide invaluable advice:

• Expert Safety Review Panel and/or regulatory authority
• Health practitioners
• Uppsala Monitoring Centre
• The pharmaceutical company
• PvPI Newslwtter
• Letter or report to a medical journal

General Considerations

Relationship between medicine intake and the occurrence of adverse events is an important activity in pharmacovigilance. Causality assessment is the method by which the extent of relationship between a drug and a suspected reaction is established. It is the evaluation of the likelihood that a medicine is the causative agent of an observed adverse reaction. It is usually made according to the established algorithms.

An inherent problem in pharmacovigilance is that most case reports concern suspected adverse drug reactions. These reactions are rarely specific for the drug; diagnostic tests are usually absent and a rechallenge is rarely ethically justified. In practice few adverse reactions are ‘certain’ or ‘unlikely’; most are somewhere in between these extremes, i.e. ‘Possible’ or ‘Probable’. In an attempt to solve this problem many systems have been developed for a structured and harmonised assessment of causality. None of these systems, however, have been shown to produce a precise and reliable quantitative estimation of relationship likelihood. Nevertheless, causality assessment has become a common routine procedure in pharmacovigilance. The advances and limitations of causality assessment are reviewed

Advances and limitations of Standardised Case Causality Assessment

What Causality Assessment can do:

• Decrease disagreement between assessors
• Classify relationship likelihood
• Mark individual case reports
• Improvement of scientific evaluation; educational

What Causality Assessment cannot do:

• Give accurate quantitative measurement of relationship likelihood
• Distinguish valid from invalid cases
• Prove the connection between drug and event
• Quantify the contribution of a drug to the development of an adverse event
• Change uncertainty into certainty

The determination of causality in an individual case is quite different from the consideration of probabilities in an epidemiological study. In a single case the logic is clinical diagnosis, considering all the factors in that case.

Individual case assessment

Different pharmacovigilance centres have different procedures for carrying out case causality assessment, driven sometimes by differing philosophies on the need for and importance of case causality assessment. The causality assessment system proposed by the World Health Organization Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (WHO-UMC), is generally accepted and most widely used method for causality assessment in clinical practice as it offer a simple methodology. In PvPI also, WHO-UMC causality assessment system is followed for determining the relationship between the medicine intake and the adverse effect.

Background

Establishing causality or a relationship between a drug and an adverse event involves two basic questions. These questions need to be addressed separately:

• Is there a convincing relationship between the drug and the event?
• Did the drug actually cause the event?

Objective and subjective assessments

The Objective Phase

This takes into account actual observations and establishes the relationship. There should be sufficient data to fully assess the relationship of the drug to the event. The first reports with a “certain” or “probable” relationship are called “index cases”. Cases with a “possible” relationship can only provide supporting evidence.

A causality assessment should be seen as provisional and subject to change in the light of further information on the case, or new knowledge coming from other sources.

The Subjective Phase

This is the process of making an attempt to establish a firm opinion about causality in those events for which a close relationship has been established. It takes into account the plausibility of the drug being the cause of the event, after having considered the (known) pharmacology, other experience with the medicine or related medicines, and inferences made from epidemiological observations and statistical evaluations.

General understanding of causality/relationship assessment

Causality assessment is a process which begins by examining the relationship between the drug and the event. The relationship in a single case-report can be established by checking the way in which the diagnosis has been reached with positive reasons supporting the diagnosis with the drug as a cause, and the exclusion of other possible causes. The ultimate goal of assessment of each event, or a cluster of events being treated as a signal, is an answer to the question: Did the drug cause the event(s)? Yes or no?

Causality for individual reports, even those with a close relationship, can seldom be established beyond doubt and our assessments are based on individual case probability, the increasing support of a case series and then controlled observational or even interventional studies.

A causality assessment should be seen as provisional and subject to change in the light of further information on the case, or new knowledge coming from other sources.

Factors to consider when assessing the relationship between drug and event

• Did the event begin before the patient commenced the medicine? This may seem an obvious consideration, but reports are received in which this has not been taken into account, and a careful check has then revealed that the event preceded the use of the suspect medicine and therefore there was no relationship.
• Is there any other possible cause for the event?
• Could the event be due to the illness being treated?
• Could it be due to some other co-existent disease?
• Could it be due to some other medicine being used concurrently?
• Is the duration to onset of the event plausible?
• Is the event likely to have occurred in the time frame in question?
• Did it occur too quickly to be related to the particular medicine, taking into account its pharmacological action?
• Did the patient take the medicine for a long time without any problems? (Delayed reactions after long-term exposure do occur, but most reactions will occur soon after the patient starts to take the medicine.)

The nature of the event should be considered when assessing the significance of the period of exposure, for example:

• Some events take a long time to develop (e.g. cancer);
• Some develop quickly (e.g. nausea and headache);
• Allergic reactions to first-time exposure to a drug generally take around 10 days to appear. On repeat exposure they may occur immediately.
• Did the event occur after the commencement of some other medicine?

If the event began shortly after commencing another medicine, then two possibilities should be considered: The new medicine may have caused the event or there may have been an interaction between the two drugs and the interaction caused the event.

• Did the event occur after the onset of some new illness? If so, the event may be due to the new illness.
• What is the response to withdrawal of the medicine (dechallenge)?
• Did the patient recover?
• Did the patient improve?
• Was there no change?
• Did the patient get worse?
• Is the response to dechallenge unknown? If this is the case, then it should always be recorded as unknown.

If more than one medicine has been withdrawn, and if rechallenge is considered appropriate, it should be performed with only one medicine at a time.

• What is the response to rechallenge?

Conditions for a positive rechallenge are:

• the patient recovered on initial withdrawal;
• the patient developed the same problem again when re-exposed to the same medicine alone, although it may be of different severity;
• the patient recovered when the medicine was withdrawn once again;

It should be noted that it is not always safe to subject the patient to a rechallenge; If the response to rechallenge is unknown, this should be recorded.

Causality assessment in PvPI

In PvPI, AMC is responsible for performing causality assessment of reports which is reviewed at NCC. The PvPI follows WHO-UMC causality assessment scale for establishing the relation between the suspected drug and suspected adverse drug event. The WHO-UMC scale is used as a practical tool for the assessment of case reports. It is basically a combined assessment taking into account the clinical-pharmacological aspects of the case history and the quality of the documentation of the observation.

The WHO-UMC causality assessment system

The WHO-UMC system has been developed in consultation with the National Centres participating in the Programme for International Drug Monitoring and is meant as a practical tool for the assessment of case reports. It is basically a combined assessment taking into account the clinical-pharmacological aspects of the case history and the quality of the documentation of the observation.

Categories of relationship

The PvPI uses six standard categories of relationship or causality between a drug and an adverse reaction or event as given by WHO-UMC International Drug Monitoring Programme, which are as follows:

WHO-UMC Causality assessment scale

Casuality term	Assessment criteria
Certain	Event or laboratory test abnormality, with plausible time relationship to drug intake Cannot be explained by disease or other drugs Response to withdrawal plausible (pharmacologically, pathologically) Event definitive pharmacologically or phenomenologically (i.e. an objective and specific medical disorder or a recognised pharmacological phenomenon) Rechallenge satisfactory, if necessary
Probable/ Likely	Event or laboratory test abnormality, with reasonable time relationship to drug intake Unlikely to be attributed to disease or other drugs Response to withdrawal clinically reasonable Rechallenge not required
Possible	Event or laboratory test abnormality, with reasonable time relationship to drug intake Could also be explained by disease or other drugs Information on drug withdrawal may be lacking or unclear
Unlikely	Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) Disease or other drugs provide plausible explanations
Conditional/ Unclassified	Event or laboratory test abnormality More data for proper assessment needed, or Additional data under examination
Unassessable/ Unclassifiable	Report suggesting an adverse reaction Cannot be judged because information is insufficient or contradictory Data cannot be supplemented or verified

Some special cases of causality assessment

There are a group of events that do not fit the relationship assessment process and the coding can vary. Few examples are as follows:

Death

Deaths cannot be coded as probable because there is no opportunity to see the effect of withdrawal of the drug. If there is a plausible time relationship, a death should be coded as possible.

Myocardial infarction

Many patients recover from this event as part of the natural history of the disease and, with very few exceptions, recovery is not a response to withdrawal of a drug. Hence the result of “dechallenge” is meaningless. This type of reaction may be coded as “possible”.

Stroke

Some patients recover fully, some partially, some remain severely disabled and some die. All these outcomes are part of the natural history of the disease and, with very few exceptions, are unrelated to drug withdrawal. Again, the result of “dechallenge” is usually meaningless. This type of reaction may be coded as “possible”.

Acute Anaphylaxis Immediately Following an Injection

Here there is an obvious direct relationship, but the usual parameters for establishing relationship, e.g. dechallenge do not apply. In this example, the best category for the relationship is “certain”

To ensure the PvPI operates effectively and achieves its objectives, the center will establish key indicators to measure the efficiency of (i) process (ii) outcome and (iii) impact of the PvPI. The following indicators will be measured:

A. Personnel’s details:

1. Personnel prior education and GVP experience.
2. Whether GVP training provided by the Zone/NCC
3. Do personnel know the job descriptions/responsibilities?

B. Administrative Responsibility:

1. Whether infrastructure is sufficient for PV?
2. Whether sufficient working place?
3. Whether logistic support provided by NCC such as Computer system, internet connection are work properly?
4. Storage of hard copies as well as soft copies of documents.
5. Whether co-operation by other dept. to PV section?

C. Documents Review:

1. Verify version number and effective date of SOPs provided to NCC with AMC’s SOPs.
2. Verify Training Records/Certificates.
3. Randomly verify the data of source documents with entreated ICSRs.

D. Quality Assurance:

1. Does the source document mentions Essential Required Item such as patient information/ division/ reaction with date/ suspected drug with date/ outcome and sender information?
2. Determine whether data entry by TA in VigiFlow is same with source documents.
3. Whether all ADRs were reported in Suspected ADR Reporting Form.
4. Verify the timeline for reporting the SAE to NCC and CDSCO.

E. Data collection and its security:

1. Use of electronic data capture or data transcription from Suspected ADR Reporting into an electronic record (VigiFlow).
2. Record retention.
3. Data security in case of disasters, e.g., power failure.
4. Contingency plans and backup files.
5. Determine whether personnel has Access methods e.g., User ID/password for the security of electronic data.

F. Competence of Technical Associate:

1. He/She is conversant with the drug for which he/she is sending the report?
2. Is he/she conversant with the Rechallenge and Dechallenge process?
3. Is this a side effect or “ADR?”
4. Any SAE reported from the centre? How quickly it was forwarded.

G. Authenticity of Data:

1. Mechanism of identifying the patient from the registration number of the case report - random check should be done by the inspecting team
2. How many times TA visits various wards.
3. How quickly he/she sends the report to NCC.
4. Is he/she taking interest in reporting drugs of current interest i.e. from CVS, Psychiatry, Oncology and Diabetes?
5. Interaction with coordinator - frequency and documentation for the same.

H. Core Structural Indicators:

1. Does the AMC have standard accommodation?
2. Whether NCC has given acceptance letter?
3. A regular financial provision for the AMC?
4. Human resources to carry out its functions properly?
5. A standard ADR reporting form?
6. A process in place for collection, recording and entering of ADRs in VigiFlow?
7. Newsletters/NFI/Information bulletin/website for PV information dissemination?
8. A PV advisory committee or expert committee in the setting?

I. Core Process Indicators:

1. Total number of ADR reports reported to NCC last calendar year.
2. Percentage of total annual reports acknowledged by NCC.
3. Percentage of reports subjected to causality assessment in the year.
4. Percentage of reports on therapeutic ineffectiveness.
5. Percentage of reports on medication error.
6. Number of active surveillance activities initiated, on-going or completed, the last 5 years.

J. Core Outcome/Impact Indicators:

1. Number of medicine related hospital admissions/1000 admissions.
2. Number of medicine related deaths/1000 persons served by hospital.
3. Number of medicine related deaths/100000 in the population.
4. Average cost of treatment of medicine-related illness.
5. Average duration of extension of medicine-related hospital stay.
6. Average cost of medicine related hospitalization.

Roles and Responsibilities of Personnel at AMC

Each AMC under PvPI is assigned with a coordinator and a technical associate responsible for its functioning. Their roles and responsibilities are:

• The designated coordinator is responsible for the proper functioning of respective AMC. In absence of the coordinator, the designed deputy coordinator is responsible for the smooth functioning of the centre.
• Other important responsibilities of coordinator checking completeness of a valid case, causality assessment and scrutinizing the ADR reports as per SOPs.
• The technical associate is responsible for collecting and follows up ICSRs. All the scrutinized and signed ADR reports should be entered in VigiFlow by TA. Every report has to be sent for the central assessment at NCC.
• The centre coordinator is responsible for sending the monthly reports of their AMC to NCC.
• The centre coordinator is also responsible for sensitization of the physicians/healthcare professionals/medical students/patient of the catchment hospital for spontaneous ADR reporting by various modes (lectures on ADR reporting, emails, telephone, pamphlets & newsletters).
• Feedbacks to all healthcare professionals involved in reporting are to be sent by the AMC coordinator.

Roles and Responsibilities of Personnel at NCC

NCC is responsible for:

• Preparing standard operating procedures, guidance documents &training manuals.
• Enrolment of new AMC.
• Reviewing and analyzing ICSRs received from AMCs and commit them to WHO-UMC.
• Organising Continuous Medical Education on pharmacovigilance at various zones.
• Conducting periodic training and workshops for all enrolled AMCs.
• Publishing the newsletter (PvPI Newsletter) on timely basis.
• Reporting all concerned issues to CDSCO Headquarters.
• Providing procurement, financial and administrative support to all AMCs enrolled under PvPI.
• Collaborating with WHO-UMC, Sweden.

Roles and Responsibilities of Personnel at Zonal/Sub-zonal CDSCO office

The Zonal/Sub-zonal is responsible for:

• Reporting all drug related issues to the CDSCO headquarter.
• Providing administrative and logistic supports to the AMC at their zone.
• Auditing/inspecting AMC in their respective zonal and submitting the inspection report to CDSCO HQ.

Roles and Responsibilities of Personnel at CDSCO HQ

The CDSCO HQ is responsible for:

• Taking appropriate regulatory decision and actions on the basis of recommendations made by NCC.
• Propagating medicine safety related decisions to stakeholders.
• Providing administrative support to run PVPI.

Roles and Responsibilities of Committees under PvPI

The following committees and panels are constituted by MoHFW, Government of India to give proper direction for efficient functioning of the programme.

• Steering Committee: PvPI is administered and monitored by Steering Committee to supervise and give proper direction to the programme. It is established to provide advice to NCC-PvPI, including its ADR Monitoring Centres for the Drug Monitoring Programme, on safety issues relating to medicinal products. It provides advice related to Pharmacovigilance and technical assistance in PvPI. It is composed of the following members drawn from the Expert Advisory Panels for Drug Evaluation and for Drug Policies and Management.
• PvPI Working Group: It is constituted to approve major technical issues related to establishment, implementation of programme and giving technical inputs to CDSCO for regulatory intervention of medicine.
• Quality Review Panel: It is constituted to review quality, causality assessment and completeness of ICSRs. The panel also makes recommendations to PvPI working group after data analysis and will devise formats and guidance documents for follow up actions after implementation of recommendations.
• Signal Review Panel: It is constituted of experienced scientists and clinical experts affiliated to government and non-government academic institutions, hospitals and pharmaceutical industries to collate and analyze information from ICSRs submitted to NCC. This panel assesses the results of the regular computerized screening of ICSRs in NCC database for the occurrence of signals of possible importance of public health, drug regulation and science. It also defines biostatistical methods to be followed for analysis and creates standardized post analytical reports that will help in understanding the information that is derived from ADRs. It is also responsible to decide on actionable indicators.
• Core Training Panel: The Core Training Panel of PvPI identifies trainers and zone wise training centres for imparting training under pharmacovigilance training programme. Core training panel interacts with international agencies for participation and implementation of training programmes related to pharmacovigilance. It organizes training and projects budgetary requirements. Training modules and training schedules are also develop by this panel.

Risk management is the identification, assessment, and prioritization of risks followed by coordinated and economical application of resources to minimize, monitor, and control the probability and impact of unfortunate events. It is the discipline within pharmacovigilance that is responsible for signal detection and the monitoring of the risk-benefit profile of drugs. At the time of marketing authorisation, the benefit-risk balance is judged to be positive for the target population. A medicinal product is associated with multiple risks and individual risks will vary in terms of severity, effect on individual patients and public health impact. However, at the time when an initial authorisation is sought all the risks (actual or potential) have not been identified and many of the risks associated with the use of a medicinal product will only be discovered and characterised during post-authorisation.

Risk management has three stages which are inter-related as mentioned below:

1. Characterisation of the safety profile of the medicinal product including what is known and not known.
2. Planning of pharmacovigilance activities is to characterise and identify new risks and increase the knowledge in general about the safety profile of the medicinal product.
3. Planning and implementation of risk minimisation, mitigation and assessment of the effectiveness of these activities.

Risk management is a global activity. However the benefits and risk of a medicinal product may also vary between regions as they differ in disease prevalence, severity, population genetics (South Indian, North Indian, East Indian and West Indian). The overall aim of risk management is to ensure that the benefits of a particular medicinal product exceed the risks by the greatest achievable margin for the individual patient and for the target population as a whole.