The beginning of objective scientific testing and safety monitoring dates back to 1930s, while 1938 is considered as the landmark year when safety requirements for drugs were initiated and legislated following the sulfanilamide disaster. This gruesome disaster, where an elixir of sulfanilamide was prepared in a poisonous solvent (diethylene glycol), killed 107 people, including 100 children.
In 1962 the world heard horrific stories of birth of malformed babies to mothers, who consumed thalidomide as tranquillizer during pregnancy. In response to this, the Kefauver-Harrison amendments were passed to enforce the efficacy requirements. Thereafter, the need to enforce drug safety monitoring was felt worldwide and measures were taken to implement pharmacovigilance programmes with greater emphasis on post marketing surveillance. As a result, quite a few drugs have been withdrawn after being introduced in the market. For instance, Merck withdrew Vioxx from the market in 2004, after a clinical trial found that the drug increased the risk of heart attacks when taken for 18 months or more. Many other drugs, including Cisapride, Troglitazone, Lumiracoxib, Pergolide products followed Vioxx path and Pfizer's inhalable insulin Exubera is the latest in the list.
For the progress of pharmaceutical sciences, it is prerequisite to ensure the availability of drugs for prophylactic, therapeutic and diagnostic purposes with high benefit ratio. A scientifically designed systematic programme for drug safety monitoring is the need of the hour. Although integrated community participation is central to the success of such a programme, major responsibility lies with government, regulatory authorities and pharma industry.
Pharmaco-vigilance
Generally speaking, pharmacovigilance is the science of collecting, understanding, assessing, monitoring and evaluating information related to long term and short term adverse effects of medicines, biological products, herbs and other traditional medicines. The pharmacovigilance is mainly concerned with the adverse drug reactions (ADR) which are defined as 'a response to a drug which is noxious, unintended and occurs at doses normally used for prophylaxis, therapy and diagnosis or for the modification of physiological functions (WHO, 1972)'. The prime objective of pharmacovigilance is to identify all possible hazards associated with the use of such products and to prevent harm to patients.
In the past, very few drugs were discovered or launched in India. The safety profile assessment of a drug to be launched in India was based on the experiences of long term use in western countries, as there was a considerable time gap between the first launch of the new drug in western countries and availability of the same drug in India. Therefore, the regulatory agencies and pharma industry could conveniently assess the safety parameters of drug in question and take appropriate actions. As research activities of Indian pharma companies have grown in recent years, possibilities of discovering and launching new drugs in India have also increased. Besides, the time gap between the first launch and first availability of new drugs in India has narrowed down, leading to decreased availability of long term safety data. This has made the concerned authorities realize the need for developing and implementing pharmacovigilance programme, which is efficient and adequate for collection and monitoring long and short term safety data in the country.
Existing system of pharmacovigilance in India
In 1986, for the first time a formal drug safety monitoring system was proposed in India. The proposal of adverse drug reaction monitoring system of 1986 consisted of 12 regional centres with each centre covering a population of 50 million. More concrete efforts of drug safety monitoring in India began in 1997, in cooperation with World Health Organization (WHO) Adverse Drug Reaction Monitoring Programme based in Uppsala, Sweden.
Under this programme, three ADR monitoring centres were identified, including a national pharmacovigilance centre at AIIMS, New Delhi and two WHO special centres at Mumbai and Aligarh. This programme could not succeed due to multiple reasons and it paved the way for the launch of more ambitious national pharmacovigilance programme (NPP) - central drugs standard control organization (CDSCO) - sponsored by WHO and funded by World bank on January 01, 2005. The objectives of NPP were to involve a large number of health care professionals in the process, inculcate the culture of reporting ADRs and to be a benchmark for global drug monitoring.
The NPP particularly solicits reports of:
1. All adverse events suspected to have been caused by new drugs and drugs of current interest (List published by CDSCO from time to time)
2. All suspected drug interactions
3. Reactions to any other drugs, which are suspected of significantly affecting a patient's management, including reactions suspected of causing:
- Death
- Life threatening reactions (real risk of dying)
- Hospitalization (initial or prolonged)
- Disability (significant, persistent or permanent)
- Congenital anomaly
- Required intervention to prevent permanent impairment or damage
The NPP consists of a pharmacovigilance advisory committee located at CDSCO, New Delhi and two zonal centres - South-West zonal centre (Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai) and North-East zonal centre (Department of Pharmacology, AIIMS, New Delhi). The Mumbai zonal centre collects information from three regional centres, while New Delhi zonal centre collects information from two regional centres. Each regional centre in turn collects information from 24 peripheral centres. To further support the NPP, implementation of Schedule Y has made it mandatory to report all serious adverse events, including suspected unexpected serious adverse reactions from clinical trials. Despite the ongoing efforts, much needs to be done for the success of NPP in India, especially with regard to reporting ADRs from post marketed drugs.
Problems & limitations of current system
Since the need to raise the standards of internal pharmacovigilance system in India is becoming more and more pressing under the present circumstances, the limitations of the current system and associated problems are becoming a major concern for all the involved agencies. Some of the major issues are:
1. As more and more medicines are approved for marketing without long term safety studies, lack of sufficient research on the enormity of the problem and incidence of ADRs and associated morbidity, mortality and financial cost is an important area of concern in India. Lack of adequate assessment of the magnitude of the problem is suspected to lead to failure of not only the planning and development but also arrangement of sufficient funds for effective implementation
2. At present, the system of collecting and forwarding information is poor. The health care professionals involved in pharmacovigilance work at peripheral hospitals and primary care centres are often unaware of exact methods of collecting data and thereby making it difficult to transfer the data to national database and interpret it correctly. The process of collecting information in relation to ADRs by peripheral centres and transfer of this information to zonal centres needs tremendous modification to increase the pace of reporting and contents. An adequate sharing of information between health professionals and regulatory authorities is also poor. The important information collected regarding ADRs at academic institutes and teaching hospitals as part of the thesis work of postgraduate students is often not communicated either to manufacturers or to regulatory and other concerned authorities. On the part of patients, who actually experience the ADRs, some effort is sometimes made to report information. But there is no system in place to check for the validity of such information
3. Scarcity of people with adequate knowledge of science of pharmacovigilance is a pestering issue in India. Shortage of knowledgeable people to handle various aspects of pharmacovigilance at all levels and to train more and more people in this field, right from peripheral areas to the office of Drug Controller General of India (DCGI) is another important issue, which needs attention. Moreover, the ignorance on the part people, health professionals and government departments has made the situation even worse
4. The pharmacovigilance system in India is currently handled by DCGI under the ministry of health & family welfare. The health ministry at present does not sanction any budget for pharmacovigilance programme and the entire program is working with the financial support from World Bank. Poor funding of this extremely important national programme is further posing limitations to its successful implementation.
Future strategies
Looking into the problems that the current system is facing, the future strategies should incorporate some of the proposals, including:
1. Prime importance should be given to strengthening the reporting system from grass roots to the office of DCGI. Reporting of ADRs must be mandatory at all levels. It is important that the training programmes in pharmacovigilance become an integral part of NPP. Incorporating intensive training programmes for health professionals as well as people from other disciplines involved in pharmacovigilance will boost the pace and quality of reporting. If the knowledge of basic concepts of pharmacovigilance can be incorporated within the curriculum for medical, nursing and pharmacy graduates, awareness can be created among health professionals from the very beginning. Workers in rural areas need special training in recognizing ADRs. Further, although it is extremely important to emphasize on the technical aspects of pharmacovigilance such as recognising ADRs, collecting data in required format and sending reports to concerned authorities within the given timelines during training sessions, equally important is the inclusion of methods to motivate people for active participation
2. A uniform format for data collection and reporting needs to be designed and made available to all health professionals in print or through the website of DCGI
3. As the science of pharmacovigilance is extremely complex, it becomes extremely important to train certain groups of health professionals in multiple aspects of pharmacovigilance. These trained professionals can be of immense help in planning and administration of a robust pharmacovigilance programme and advising the DCGI on policy matters
4. To streamline the work and improve the overall efficacy of NPP, the DCGI should take steps to form administrative, technical and financial advisory committees consisting of trained and experienced professionals from industry, academia, regulatory agencies, government and nongovernmental organisations and relevant professional councils, who can help DCGI in effective and speedy decision making
5. Active participation from industry, both domestic and multinational, in the drug safety monitoring during clinical trials and post marketing must be ensured. The companies must submit the reports of surveillance periodically to DCGI
6. All information collected should be assessed and analyzed by trained professionals to create a national database, which should be made available to DCGI and public.
7. All stakeholders must work out a regular schedule for meeting and discussions should be held to point out specific problems encountered, apart from charting out ways to counter them and advise DCGI to take appropriate and speedy action
8. The DCGI must work out a plan to introduce pharmacovigilance inspections at all levels of reporting, so that the requirement of mandatory ADR reporting can be fulfilled. DCGI should also work out a plan for continuous medical education of all concerned health professionals in cooperation with relevant professional councils. A newsletter published periodically by DCGI will help in conveying the recent updates on ADRs, government policies and other relevant information related to pharmacovigilance in the country
9. The importance of pharmacovigilance for the safety of people at large should be spread among government and private hospitals, teaching hospitals, primary care centers, pharmacies, drug information centers, consumer groups, NGOs and patient groups throughout the country, utilizing all possible modes of spreading information
10. Taking inspiration from the working of Uppsala Monitoring Centre, the pharmacovigilance program in India should now look forward for collaboration with several other national and international agencies to strengthen the surveillance program in India. WHO Uppsala centre is an ideal example of international collaboration. This centre has established an extensive database by exchange information on ADRs among national pharmacovigilance agencies of 80 countries around the world. A similar national database can also be established from clinical trials and post marketing surveillance with the help of experienced professional bodies.
(Dr S K Gupta is with Institute of Clinical Research (India), while Dr Renu Agarwal is with Delhi Institute of Pharmaceutical Sciences)