The pharmacovigilance (PV) is defined by the WHO as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problem". An adverse drug reaction (ADR) has been defined as any noxious, unintended and undesired effect of a drug which occurs at a dose used in humans for prophylaxis, diagnosis, therapy or modification of physiological functions (WHO).
Why PV is required?
Adverse drug events lead to significant mortality and morbidity world over. In developing countries, comprehensive information on the safety of drugs used in the patient population is meager and very few studies have been carried out to detect the incidence of ADRs in the young and the elderly population.
Although, the thalidomide tragedy stressed the need for an effective PV system, it was the withdrawal of rofecoxib that renewed interest in drug safety mechanisms. Safety issues with other drugs like erythropetin, rosiglitazone, rimonabant have also highlighted the need for an effective and comprehensive PV system.
The fundamental question that arises is "why drug safety issues do not come to the forefront during clinical trials". Many reasons have been put forward including the fact that data for approving new products are obtained from highly structured clinical trials, carried out on homogenous populations of patients that are carefully screened and preselected and then given new drugs under special protocols. Therefore, it would be unreasonable to assume that such well controlled trials would provide complete information about the safety of a new drug when it is used in much broader populations of patients in real-world clinical settings. Therefore, both clinical trials and post marketing PV are critical throughout the product life cycle.
Early detection of signals from both clinical trials and post marketing surveillance studies have now been adapted by major pharma companies in order to identify the risks associated with the medicinal product and effectively managing the risks by applying robust risk management plans throughout the life cycle of the product.
Brief history of PV in India
Even though PV is still in its infancy, the concept is not new to India. It was not until 1986 that a formal ADR monitoring system consisting of 12 regional centres, each covering a population of 50 million, was proposed for India. In 1989, under the aegis of the drug controller of India, six regional centres were set up in Mumbai, New Delhi, Kolkata, Lucknow, Pondicherry and Chandigarh. In 1997, India joined the WHO Programme for International Drug Monitoring managed by the Uppsala Monitoring Centre, Sweden. The centre in New Delhi (at Dept of Pharmacology, AIIMS) was identified as the national centre, while the centre in Mumbai (at KEM Hospital) was identified as the WHO special centre. Of the six centres, only the centres in Mumbai and New Delhi were active, yet spontaneous reporting of ADRs was poor. The monitoring centres were considered ad hoc and appropriate levels of funding were not, made available, which put severe constraints on them. Recognising the need for improved ADR monitoring in India, the Govt of India sent a proposal to the World Bank for funding. The World Bank approved the proposal with an annual grant of US$0.1 million for 5 years and the National Pharmacovigilance Programme (NPVP) was launched in November 2004.
The NPVP was overseen by the National Pharmacovigilance Advisory Committee based in the Central Drugs Standard Control Organization (CDSCO), New Delhi. Two zonal centres - the South-West zonal centre (located in the Dept of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai) and the North-East zonal centre (located in the Dept of Pharmacology, AIIMS, New Delhi), collated information from all over the country and send it to the Committee as well as to the Uppsala Monitoring Centre in Sweden. Three regional centres reported to Mumbai centre and two to New Delhi. Each regional centre in turn would have several peripheral centres reporting to it. The programme had three broad objectives: the short-term objective was to foster a reporting culture, the intermediate objective was to involve a large number of healthcare professionals in the systems in information dissemination and the long-term objective was for the programme to be a benchmark for global drug monitoring. However, the World Bank funding for the national programme ended in mid 2009 and the programme was temporarily suspended.
The new NPVP - PvPI
Recognizing the need to restart the national pharmacovigilance programme (NPVP), in a brainstorming workshop jointly organized by Dept of Pharmacology, AIIMS and CDSCO in late 2009, the framework of the new programme was formulated. The programme now rechristened as the Pharmacovigilance Programme for India (PvPI) is scheduled to be operational from mid July 2010.
Framework of new programme
The programme is envisaged to be rolled out in three phases. Phase I would include 40 ADR monitoring centres (AMC) and will be rolled out in 2010. The programme would be expanded in phase II to include up to 140 MCI recognized medical colleges by 2011. Phase III would ultimately cover the healthcare system by 2013. Phase I will be further divided into phase Ia and Ib. Phase Ia will involve upgrading 10 centres in terms of infrastructure (computer and auxiliary). Phase Ib will include the rest of the 40 centres by end of 2010. The centres for phase Ia have been shortlisted based on letter of intent received from interested faculty, duly forwarded by the head of the institution. The AMCs will get operational and logistic support from their respective zonal CDSCO centres, situated at Ghaziabad, Kolkata, Mumbai and Chennai. The zonal CDSCO centres will be under administrative control of the CDSCO headquarter at New Delhi.
The coordinating centre of PvPI will be housed at Dept of Pharmacology, AIIMS, New Delhi and will provide technical support to the CDSCO headquarter. All the centres under the programme will function in accordance with the protocol and SOPs developed by expert committees.
ADR data flow
ADR reports will be collected at the AMCs. The PV staff at the AMCs will check for validity of the report and if possible conduct provisional causality assessment. The ADR forms will then be dispatched to the coordinating centre as per the SOPs. The AMC staff will also maintain a log of all the centre activities. Selected AMCs will also carryout focused ADR monitoring of drugs in the focused ADR monitoring watch list.
The coordinating centre will conduct causality assessment and upload the reports into the PV software. The coordinating centre will prepare a consolidated report of ADRs collected at defined time intervals. The coordinating centre will also implement and integrate PV activities into public health programmes involving mass usage of drugs, such as for antimalarial, anti-tubercular and anti-retroviral drugs. Lastly, the integrated ADR data will be transmitted through vigiflow interface into the UMC ADR database where signal processing can be carried out.
Ensuring quality of ADR data
A quality review panel will also be constituted for maintaining quality assurance in the programme. All the centres will be assessed based on the performance metrics criteria such as the number of ADR reports, completeness of reports, training imparted and other parameters mentioned in the PV programme protocol. Following this assessment, performance based incentives will be provided to the centres.
Programme visibility, communication and feedback
A website dedicated to pharmacovigilance will be created by CDSCO headquarters. In phase II of the programme there will be a provision of online reporting of ADRs by healthcare professionals not covered under the programme. The CDSCO headquarters in collaboration with the national coordinating centre will also publish a quarterly 'Medicine Safety Newsletter' comprising of 4-16 pages. Approximately 3000 copies will be printed for a wide circulation in the healthcare institutions across the nation. Further, a Medicine Safety Card will be included in the Medicine Safety Newsletter and will also be included in national medical journals, to ensure that healthcare professionals not covered under the programme can report ADRs directly to any of the centres. This will create awareness about the programme and ensure that the reporters get adequate feedback and remain motivated in the long run. In addition, to enhance the awareness and visibility of the programme focused workshops, symposia and group meetings on ADR reporting and causality assessment will be carried out at regular intervals by all the centres.
To conclude, the new pharmacovigilance programme has been envisaged on practical and feasible experiences drawn from the earlier programme, using established systems and best practices from other global safety programmes. To improve the quality and rate of ADR reporting, special attention has been given in the PvPI to actively involve all the major stakeholders involved in drug safety, and in the process, enhance the overall outreach and effectiveness of the programme.
(The author is with Department of Pharmacology, AIIMS, New Delhi)