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Pharmacovigilance By Sandeep . B


Contents Introduction Development of pharmacovigilance WHO Program for International Drug Monitoring Pharmacovigilance Program of India (PvPI) Functions of Pharmacovigilance Current methods of Pharmacovigilance Pharmacovigilance – Data sources Good Pharmacovigilance practice Assessment of pharmacovigilance system Conclusion References


Introduction According to WHO Pharmacovigilance is defined as 'the pharmacological science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem ‘. The etymological roots are: pharmakon (Greek), “drug;” and vigilare (Latin), “to keep awake or alert, to keep watch.” Pharmacovigilance – an umbrella term used to describe the processes for monitoring and evaluating ADRs – is a key component of effective drug regulation systems, clinical practice and public health programs. It is the study of the safety of marketed drugs examined under the practical conditions of clinical use in large communities.

Development of Pharmacovigilance:

Development of Pharmacovigilance No drug which is pharmacologically effective is without hazard. Furthermore not all hazards can be known before a drug is marketed. Once put onto the market, a medicine leaves the secure and protected scientific environment of clinical trials and is legally set free for consumption by the general population. Experience has shown that many adverse effects, interactions (i.e. with foods or other medicines) and risk factors come into light only years after release of the drug.


The greatest of all drug disasters was the Thalidomide Tragedy of 1961–62. The thalidomide disaster led, in Europe and elsewhere, to the establishment of the drug regulatory mechanisms of today. These mechanisms require that new drugs shall be licensed by well-established regulatory authorities before being introduced into clinical use. The Committee on Safety of Drugs in the United Kingdom under the chairmanship of Sir Derrick Dunlop said in its last report (for 1969 and 1970) that ‘ no drug which is pharmacologically effective is without hazard. Furthermore, not all hazards can be known before a drug is marketed ’. The Committee on Safety of Medicines, under the chairmanship of Professor David Grahame-Smith, established a Working Party on Adverse Reactions and published its second report in July 1985. The report supported the continuation of methods of spontaneous reporting by professionals but recommended that post-marketing surveillance (PMS) studies should be undertaken on ‘newly marketed drugs intended for widespread long-term use’.


Similar reviews and conclusions have emerged from the United States since the mid-1970s. The Prescription Drug User Fee Act (PDUFA) of 1992 provided additional resources at the Food and Drug Administration (FDA) for drug reviews through user fees and established target timelines for FDA reviews.

WHO Programme for International Drug Monitoring:

WHO Programme for International Drug Monitoring National pharmacovigilance centres are functioning as an international network coordinated by the WHO Programme for International Drug Monitoring. The WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden manages the international database of adverse reaction reports received from national centres. The Centre has established standardized reporting by all national centres and has facilitated communication between countries to promote the rapid identification of signals. The terminologies developed within the WHO programme for coding adverse reactions to medicines have been widely adopted by national centres, manufacturers and medicine regulators.

Pharmacovigilance Programme of India:

Pharmacovigilance Programme of India The Central Drugs Standard Control Organization (CDSCO), Directorate General of Health Services under the aid of Ministry of Health & Family Welfare, Government of India in collaboration with Indian Pharmacopoeia commission, Ghaziabad has started Pharmacovigilance programme for protecting the health of the patients by assuring drug safety in India. The programme shall be coordinated by the Indian Pharmacopeia commission, Ghaziabad as a National Coordinating Centre (NCC). The centre will operate under the supervision of a Steering Committee headed by the Drug Controller of India.


Objectives of PvPI: To monitor Adverse Drug Reactions (ADRs) in Indian population. To create awareness amongst health care professionals about the importance of  ADR reporting in India. To monitor benefit-risk profile of medicines. Generate independent, evidence based recommendations on the safety of medicines. Support the CDSCO for formulating safety related regulatory decisions for medicines. Communicate findings with all key stakeholders. Create a national centre of excellence at par with global drug safety monitoring standards.

Functions of Pharmacovigilance:

Functions of Pharmacovigilance Collects, records, codes ADEs /ADRs. Analyses and assesses the reports. Promotes the safe use of drugs. Creates appropriate structures and means of communication needed to perform its tasks. Identifying new information about hazards associated with medicines. Preventing harm to the patients.


Goals: Continuous monitoring of the safety of medicinal products (both marketed and investigational) Assessing the risks and benefits of all products and also to ensure that their risks and benefits remain acceptable Providing information to users on safe and effective use of products. To promote rational use of these products by providing information about ADRs. Identification, quantification and improving understanding of previously unknown adverse drug reactions. Identification of patients at particular risk of having an ADR (For e.g. the elderly, children, hepatic and renal compromised patients and terminally ill patients). Monitoring the impact of any action taken.


Objectives: To improve patient care and safety. To improve public health and safety. To contribute to the assessment of benefit, harm, effectiveness and risk of medicines. To pro mote education and clinical training. To promote effective communication to the public. To promote rational and safe use of medicines.

Current Methods of Pharmacovigilance:

Current Methods of Pharmacovigilance Pharmacovigilance is a branch of pharmacoepidemiology but is restricted to the study, on an epidemiological scale, of drug events or adverse reactions. The success or failure of any pharmacovigilance activity depends on the reporting of suspected adverse reactions. Public health surveillance methods are used to identify new signals of possible ADRs. Studies in pharmacoepidemiology are intended to be either ‘ hypothesis-generating ’ or ‘ hypothesis-testing ’. Hypothesis-generating studies , with a recently marketed drug, aim to detect unexpected ADRs. Hypothesis-testing studies aim to prove whether any suspicions that may have been raised are justified.


Hypothesis-Generating Studies: These are generally done by 2 methods – Spontaneous ADR Reporting Prescription Event Monitoring (PEM) 1. Spontaneous ADR Reporting: Spontaneous Reporting is defined as “A system whereby case reports of adverse drug events are voluntarily submitted by health professionals and pharmaceutical companies to the national pharmacovigilance centre.” Doctors (in some countries, other healthcare professionals and patients as well) are provided with forms upon which they can notify a central authority of any suspected ADRs that they detect. In the United Kingdom, the ‘ yellow card ’ has been used for this purpose since 1964. The ‘ blue card’ system is used in Australia and Malasia . In the United States, the MedWatchform is used and is made broadly available to health professionals to encourage reporting.


The great strength of spontaneous reporting is that it operates for all drugs throughout the whole of their lifetime; it is the only affordable method of detecting really rare ADRs. The main weaknesses are that there is gross under-reporting, and the data provide a ‘numerator’ (the number of reports of each suspected reaction) only. 2. Prescription Event Monitoring (PEM): This monitoring is conducted in the United Kingdom and New Zealand, represents a ‘hybrid’ method, combining aspects of public health surveillance and spontaneous reporting with aspects of formal epidemiological studies. In UK, within British National Health Service (NHS), prescriptions written by general practitioners are sent, once they have been dispensed, to a central Prescription Pricing Authority (PPA). The PPA provides confidential copies of certain prescriptions for newly introduced drugs that are being monitored to the Drug Safety Research Unit (DSRU) at Southampton.


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.


3. Other Hypothesis-Generating Methods: In some cases, data being collected for general public health surveillance, such as cause of death files, cancer registries and birth defect registries are used to identify patterns of events that might be associated with medication use. Other methods such as Case-control surveillance, Analytical methods and Data mining techniques are being applied to spontaneous reporting databases, databases on potential drug abuse and diversion and large population-based health records.


Hypothesis-Testing Methods: These are done by three methods- Case-control and Case-Crossover studies Cohort studies Randomized Controlled studies 1. Case-control and Case-Crossover studies: Studies of this type compare cases with a disease with controls susceptible to the disease but free of it. Using this method, the research compares the exposure rate in the cases with the exposure rate in the controls, adjusting statistically for factors that may confound the association. Case–control studies are more efficient than cohort studies, because intensive data need only be collected on the cases and controls of interest. The case–crossover design is a design very useful for the evaluation of events with onset shortly after treatment initiation. In this design, cases, but not controls, are identified. A drug association is evaluated through comparing frequency of exposure at the time of the event with frequency of exposure at a different time for the same individuals. This design is less subject to bias than case–control studies because individuals serve as their as their own controls.


2. Cohort Studies: These are the studies which start by identifying a particular population with a common characteristic (i.e. a cohort), often based on use of a specific drug and follows them forward in time until some individuals have developed the disease of interest. These studies involve a large body of patients followed up for long enough to detect the outcome of interest. Cohort studies generally include an exposed and unexposed group, but there are also single exposure, disease or general population follow-up studies and registries. An advantage of the cohort study is its ability to quantify both an absolute risk and a relative risk. Cohort studies can be conducted prospectively, but such studies are usually expensive and time-consuming. Retrospective cohort studies can be conducted within large existing databases, providing the advantage of the cohort study design and the efficiencies inherent in studies using existing records. Cohort studies are useful when the outcome has not already been identified or when multiple outcomes are of interest.


3. Randomized Controlled Trials: In this method of study, a group of patients is divided into two in strictly random order; one group is then exposed and the other not exposed, so that the outcomes can be compared. The method is of great importance because random assignment of treatment removes some of the biases possible in observational studies. It is of only limited (but important) use as a pharmacoepidemiological tool because most serious ADRs are relatively uncommon; randomized controlled trials (RCTs) used in such contexts can become unmanageably large and expensive.

Pharmacovigilance - Data Sources:

Pharmacovigilance - Data Sources Spontaneous Reporting Systems. National PV Centre / Drug Authority. Published scientific literature and Drug Bulletins. Adverse Reaction Case Reports by the MAHs (Marketing Authorisation Holders) (e.g. collected by sales representatives). Periodic Safety Update Report (PSUR) provided by MAHs. PSUR: The periodic safety update report (PSUR) is a document that allows a periodic, comprehensive assessment of the worldwide safety data of a marketed drug or biological product. The concept evolved from the Council for International Organizations of Medical Sciences (CIOMS) Working Group II report in 1992.


The PSUR process comprises the following steps: intake of ADR information; case processing; data retrieval; data analysis and medical review and risk assessment. Minimum information required for an ADR report: an identifiable source a patient a suspected product a suspected reaction

Good pharmacovigilance practice:

Good pharmacovigilance practice Effective pharmacovigilance relies on contributions by many people with varying educational backgrounds. To attain a coherent pharmacovigilance system it is most important that guidelines and standards are developed, which describe the practical details of the intended information flow. Such standard operating procedures should include information on the following: What constitutes a reportable adverse reaction? Who is expected to report an observation of a suspected medicine-related problem? The availability and practicalities of filling in a reporting form. Procedures for submission or collection of reports. Routines for assessment, follow-up and processing of case reports at the pharmacovigilance centre. Good communication practices.

Assessment of the pharmacovigilance system:

Assessment of the pharmacovigilance system Evaluation and assessment should be built into the monitoring system. The national pharmacovigilance centre, coordinator and review panel should periodically evaluate whether, or to what extent: the reporting is complete, timely and accurate; response has been swift enough; case management has been appropriate; and action has been appropriate to avoid programme error.


Conclusion Current progress in pharmacovigilance is marked by increasing use of databases and by attempts to make the process more proactive and organized. Attempts are being made to augment the spontaneous, random nature of the generation of pharmacovigilance data and to make the process more systematic and structured. There has been a coming together of academic, regulatory and industrial interests across many countries to produce the guidance documents mentioned above as well as good practice guidelines for the conduct of pharmacoepidemiology studies. Health ministries, health professionals and the public can all be reassured by knowing that there is a competent and functional system in place that focuses on the safety of medicines used in the prevention anpld treatment of disease, including vaccines and pharmaceuticals for family planning.


References The importance of pharmacovigilance: safety monitoring of medicinal products. Geneva, World Health Organization, 2002. Dialogue in pharmacovigilance — more effective communication. Uppsala, Sweden, Uppsala Monitoring Centre, 2002. Mann R, Andrews E., eds. Pharmacovigilance. Chichester, Wiley & Sons, 2002. U.S. Food and Drug Administration (2005a) Guidance for Industry E2E Pharmacovigilance Planning, http://www. cder /guidance/6355fnl.htm. CIOMS (1992) International Reporting of Periodic Drug- Safety Update Summaries: Final Report of CIOMS Working Group II. Geneva: Council for International Organizations of Medical Sciences. Pharmacovigilance programme of India for assuring Drug safety, CDSCO, pharmacovigilance_intro_files/pharmacovigilance_intro.htm Mann RD (1987) The yellow card data: The nature and scale of the adverse drug reactions problem. In: Mann RD, ed., Adverse Drug Reactions . Carnforth, UK: Parthenon Publishing, pp. 59–63 International Society for Pharmacoepidemiology (2004) Guidelines for Good Pharmacoepidemiology Practices (GPP), lines_08027.cfm

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