Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 39, Num. 3, 2007, pp. 124-128

Indian Journal of Pharmacology, Vol. 39, No. 3, May-June, 2007, pp. 124-128

Invited Article

Setting standards for proactive pharmacovigilance in India: The way forward

Biswas Pipasha, Biswas ArunK

Symogen Ltd, Bucks

Correspondence Address:Principal Consultant & Director, Pharmacovigilance & Pharmacoepidemiology, Symogen Ltd
Email : b_pipasha@yahoo.co.uk

Code Number: ph07032

Abstract

An increase in drug safety concerns in recent years with some high profile drug withdrawals have led to raising the bar by various stakeholders more importantly by the regulatory authorities. The number of Adverse Drug Reactions (ADRs) reported have also resulted in an increase in the volume of data handled and to understand pharmacovigilance a high level of expertise is required to rapidly detect drug risks as well as to defend the product against an inappropriate removal. Proactive pharmacovigilance throughout the product life cycle is the way forward and the future direction for drug safety. It is a challenge to codify and standardize the act of signal detection and risk management in the context of clinical trials and post-marketing pharmacovigilance. While major advancements of the discipline of oharmacovigilance have taken place in the West, not much has been achieved in India. However, with more clinical trials and clinical research activity being conducted in India, there is an immense need to understand and implement pharmacovigilance. For this to happen in India, the mind set of people working in regulatory agency (DCGI Office) and the Indian Pharmaceutical companies need to change. This article describes and discusses the various strategies and proposals to build, maintain and implement a robust pharmacovigilance system for various stakeholders and eventually make it happen in India!

Keywords: Proactive pharmacovigilance, signal detection, risk management, strategies and Proposals, robust pharmacovigilance system, pharmacovigilance training and knowledge

Pharmacovigilance is defined as the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long-term and short-term adverse effects of medicines. ^[1] Pharmacovigilance is an important and integral part of clinical research. Both clinical trials safety and postmarketing pharmacovigilance are critical throughout the product life cycle. With a number of recent high-profile drug withdrawals, the pharmaceutical industry and regulatory agencies have raised the bar. Early detection of signals from both clinical trials and postmarketing surveillance studies have now been adapted by major pharmaceutical 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. Signal detection and risk management has added a new dimension to the field of pharmacovigilance and as an evolving discipline, it requires ongoing refinement in order to increase its applicability and value to public health.

Pharmacovigilance is still in its infancy in India and there exists very limited knowledge about the discipline. While major advancements of the discipline of pharmacovigilance have taken place in the Western countries, not much has been achieved in India. However, with more and more clinical trials and other clinical research activities being conducted in India, there is an immense need to understand the importance of pharmacovigilance and how it impacts the life cycle of the product. This will enable integration of good pharmacovigilance practice in the processes and procedures to help ensure regulatory compliance and enhance clinical trial safety and postmarketing surveillance.

Brief history of Pharmacovigilance in India

Even though pharmacovigilance is still in its infancy, it is not new to India. It was not until 1986 that a formal adverse drug reaction (ADR) monitoring system consisting of 12 regional centers, each covering a population of 50 million, was proposed for India. ^[2] However, nothing much happened until a decade later when in 1997, India joined the World Health Organization (WHO) Adverse Drug Reaction Monitoring Programme based in Uppsala, Sweden. Three centers for ADR monitoring were identified, mainly based in teaching hospitals: a National Pharmacovigilance Centre located in the Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi and two WHO special centers in Mumbai (KEM Hospital) and Aligarh (JLN Hospital, Aligarh Muslim University). These centers were to report ADRs to the drug regulatory authority of India. The major role of these centers was to monitor ADRs to medicines marketed in India. However, they hardly functioned as information about the need to report ADRs and about the functions of these monitoring centers was yet to reach the prescribers and there was lack of funding from the government. This attempt was unsuccessful and hence, again from the 1 ^st of January 2005, the WHO-sponsored and World Bank-funded National Pharmacovigilance Program for India was made operational. ^[3]

The National Pharmacovigilance Program established in January 2005, was to be overseen by the National Pharmacovigilance Advisory Committee based in the Central Drugs Standard Control Organization (CDSCO), New Delhi. Two zonal centers-the South-West zonal centre (located in the Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai) and the North-East zonal centre (located in the Department of Pharmacology, AIIMS, New Delhi), were to collate information from all over the country and send it to the Committee as well as to the Uppsala Monitoring centre in Sweden. Three regional centers would report to the Mumbai center and two to the New Delhi one. Each regional center in turn would have several peripheral centers reporting to it. Presently there are 24 peripheral centers. The program has three broad objectives: the short-term objective is to foster a reporting culture, the intermediate objective is to involve a large number of healthcare professionals in the systems in information dissemination and the long-term objective is for the program to be a benchmark for global drug monitoring.

Given this background on pharmacovigilance in India to date, nearly two decades later from its origin in 1986, things have definitely changed for the better but at a very slow pace. The Regulatory Authority for India should be commended for introducing and implementing the Schedule Y and for reporting of all serious adverse events (SAEs) including Suspected unexpected serious adverse reactions (SUSARS) from clinical trials. However, much needs to be accomplished in the culture of spontaneous reporting from post-marketed medicines to the centers and in turn, by the National Pharmacovigilance Centers to the WHO Uppsala Monitoring Centre, which at the moment is woefully lacking. Therefore, in these circumstances, the questions that arise are whether the strategy should be changed and if so, how?

The Enormity of the Problem of ADRs

A number of studies conducted throughout the world have demonstrated that ADRs significantly decrease the quality of life, increase hospitalizations, prolong hospital stay and increase mortality. A landmark study by Lazarou in 1998 described ADRs to be the 4 ^th -6 ^th largest cause of death in the USA and ADRs are estimated to cause 3-7% of all hospital admissions. ^[4] More than half of these ADRs are not recognized by the physicians on admission and ADRs may be responsible for death of 15 of 1000 patient's admitted. ^[5] Furthermore, the financial cost of ADRs to the healthcare system is also huge. With more new medicines being approved for marketing more quickly without long-term safety studies by the regulatory authorities and switching of prescription-only medicines (POM) to over-the-counter (OTC) to be used more widely by patients for self-medication, the general public is at risk of exposing itself to ADRs.

In the past, India's regulatory agencies and drug companies based their safety assessments on experiences derived from long-term drug use in the Western markets and there was no real urgency for the government to establish a strong pharmacovigilance system of its own. In recent years, however, the lag between when a drug is placed on the market and its subsequent availability in India has decreased considerably so that the much needed longer-term safety data is no longer available. In addition, India-based drug companies have increased their capacity to develop and launch new drugs through their own research efforts and this has heightened the importance of developing adequate internal pharmacovigilance standards to detect adverse drug events. ^[6]

However, what needs to be more important along with the funding is a focussed vision and effective strategy for developing the pharmacovigilance systems, especially in the DCGI Office, which is lacking. Traditionally, pharmacovigilance was never done in India in Pharmaceutical companies, be it Indian or MNCs, so there is an immense shortage of knowledgeable people who will be able to advice the DCGI on this matter, as pharmacovigilance is a very complex subject, interwined with regulations and complex systems. The need is therefore to engage a completely independent adviser who has an extensive and practical knowledge on pharmacovigilance, who can act as a Pharmacovigilance Advisor to the Government of India to effectively implement the systems and policies on pharmaocvigilance. This will help the DCGI to spearhead the activities and implementation of pharmacovigilance.

India is a vast country and there is a surfeit of drug brands-more than 6,000 licensed drug manufacturers and over 60,000 branded formulations. India is the fourth largest producer of pharmaceuticals in the world and is also emerging as a clinical trials hub. Many new drugs are being introduced in the country, so there is an immense need to improve the pharmacovigilance system to protect the Indian population from potential harm that may be caused by some of the new drugs. However, there are many issues and problems that have prevented building a robust pharmacovigilance system, which are described below:

• Pharmacovigilance systems are not well-funded and organized for a vast country like India to serve patients and the public. The Drug Controller General of India (DCGI) Office which handles the pharmacovigilance system, is embedded within the ministry of health and family welfare. Yet there is little sharing of information on ADRs between the regulatory authority and health professionals. There is also an extreme shortage of qualified trained people to handle pharmacovigilance within the DCGI. The National Pharmacovigilance Program is at present running with the funding obtained from the World Bank, but there is no funding at all from the budget of the Health Ministry. However, what needs to be more important along with the funding is a focussed vision and effective strategy for developing the pharmacovigilance systems, especially in the DCGI Office, which is lacking. Traditionally, pharmacovigilance was never done in India in Pharmaceutical companies, be it Indian or MNCs, so there is an immense shortage of knowledgeable people who will be able to advice the DCGI on this matter, as pharmacovigilance is a very complex subject, interwined with regulations and complex systems. The need is therefore to engage a completely independent adviser who has an extensive and practical knowledge on pharmacovigilance, who can act as a Pharmacovigilance Advisor to the Government of India to effectively implement the systems and policies on pharmaocvigilance. This will help the DCGI to spearhead the activities and implementation of pharmacovigilance.
• The information obtained to date in the zonal centers from various peripheral centers is often poor and not well-analyzed. There is insufficient research on ADRs in India, so the exact incidence of specific ADRs is unknown. There are various local teaching hospitals in India that carry out some work on pharmacovigilance as part of postgraduate theses, but this is hardly shared with the regulatory authorities or other peer groups within the country. Nor do these hospitals inform the pharmaceutical manufacturer regarding the particular product and the ADRs. The reporting forms used by various people engaged in some pharmacovigilance work hugely differ from the reporting form used by the National Pharmacovigilance Program, which in turn becomes extremely difficult to transfer data to the national database, even if this has been shared by the various parties.
• Understanding by healthcare professionals (both in rural areas and urban cities and hospitals) and knowledge and motivation for pharmacovigilance is almost negligible. There is hardly any encouragement from the department of health to provide more training and create more awareness amongst them for better reporting.
• In India, there are several consumers' groups who encourage patients to report any adverse reactions encountered by them, although there is no information for patients to report ADRs directly to the regulatory authority. Direct reports from the patients, who are the ones that actually experience ADRs, are not accepted by the monitoring centers and by regulatory authorities. To add to this is the total lack of any awareness about ADRs in the general population.

With more and more clinical trials and other clinical research activities being conducted in India, there is an immense need to understand the importance of pharmacovigilance and how it impacts the life cycle of the product. Given this situation at present, the DCGI should act quickly to improve pharmacovigilance so as to integrate Good Pharmacovigilance Practice into the processes and procedures to help ensure regulatory compliance and enhance clinical trial safety and postmarketing surveillance.

Proactive pharmacovigilance: The way forward in India [Figure - 1]

A properly working pharmacovigilance system is essential if medicines are to be used safely. It will benefit all parties including healthcare professionals, regulatory authorities, pharmaceutical companies and the consumers. It helps pharmaceutical companies to monitor their medicines for risk and to devise and implement effective risk management plans to save their drugs in difficult circumstances.

Having considered the problems and challenges facing the development of a robust pharmacovigilance system for India, we would like to make the following proposals:

Strategies and Proposals

• Building and maintaining a Robust pharmacovigilance system
• So far, considerable work has been put in place by the dedicated staff at the DCGI to develop a robust pharmacovigilance system. But clearly this is not enough as more needs to be done to meet the challenges of ensuring that all data is captured and analyzed for rapid detection of signals and of putting effective measures in place to overcome the risks. The DCGI should invite experienced private firms to help, train and set up the pharmacovigilance system to combat the problems of inexperience and shortage of trained personnel.
• Making pharmacovigilance reporting mandatory and introducing pharmacovigilance inspections
  The Government of India's Health Ministry will need to pass a law and make Pharmacovigilance reporting mandatory. This should be valid not only for the multinational companies (MNCs) operating within India but also for the Indian Pharmaceutical Companies. A department for Pharmacovigilance Inspections should be incorporated within the DCGI with the view of starting inspections in all pharmaceutical companies operating in India. All pharmaceutical companies should be instructed to maintain and submit to the DCGI the Summary of Pharmacovigilance System document operating within the company, which would serve as the base for future pharmacovigilance inspections.
  
• High-level discussions with various stakeholders
  A high-level discussion with various stakeholders, i.e., Ministry of Health, Indian Council of Medical Research (ICMR), Medical Council of India (MCI), Pharmacy Council, Nursing Council, Dental Council, Pharmaceutical Companies, Consumer Associations, nongovernmental organizations (NGOs) and Patient Groups should be initiated in order to make them aware of how the DCGI is planning to improve and develop a robust system in pharmacovigilance.
  
• Strengthen the DCGI office with trained scientific and medical assessors for pharmacovigilance
  Intensive training should be given in all aspects of pharmacovigilance to officials working within the pharmacovigilance department of the DCGI and the peripheral, regional and zonal centers. This should be an ongoing activity with training scheduled twice a year.
  
• Creating a single country-specific adverse event reporting form to be used by all
  A single countrywide specific adverse event reporting form needs to be designed, which should not only be used by the National Pharmacovigilance Centers, but also by all registered hospitals (both private and government), teaching hospitals, Drug Information Centers and pharmacies throughout the country. It should also be made available to all primary healthcare centers (PHCs) in rural areas and all practicing general practitioners and physicians. This can be done by incorporating approximately ten forms in the monthly index of medical specialities (MIMS), which can be distributed to all healthcare professionals. Also, DCGI needs to make healthcare professionals aware of the website from which the form can be downloaded or filled up electronically and sent to the concerned official.
  
• Creating a clinical trial and postmarketing database for SAEs / SUSARs and ADRs for signal detection and access to all relevant data from various stakeholders
  Create a central database for all protocols and clinical trials run within India along with clinical study reports and results (both for preclinical toxicology studies and clinical trials) across various therapeutic areas with specific registration numbers. Registration numbers should be given at the time of starting the trial and should cover both drug and nondrug therapies and be therapeutically aligned.
  Full complete data should be made available to the DCGI and also publicly from the date of first registration of the trial. This data should comply with consolidated standards of reporting trials (CONSORT) guidelines including overall benefit-risk profile of the product.
  Current standards of safety reporting as outlined in schedule Y and information about all AEs and ADRs per study arm should be systematically included as well as detailed description of cases with previously unknown AEs / ADRs and the reasons for study withdrawals.
  For drugs already in the market, type and frequency of all adverse events (serious and nonserious) should be submitted in periodic safety update reports (PSURs) and also added to the summary of product characteristics (SPCs).
  
• List all new drugs / indications by maintaining a standard database for every pharmaceutical company
  A list should be maintained by the regulatory authorities and pharmaceutical companies for all new drugs / indications in the database. All new issues need to be put under heightened surveillance. Pharmaceutical companies in these circumstances should have meetings set up with the DCGI to outline their risk management plan (RMP) for the safety issues in question and describe how they would put effective strategies in place to mitigate them.
  
• Education and training of medical students, pharmacists and nurses in the area of pharmacovigilance
  There are several courses conducted by various organizations focusing in clinical research, but to date there is no course relevant to pharmacovigilance in the country. The various stakeholders including the MCI should incorporate a pharmacovigilance syllabus within the pharmacology and medicine curricula so that proper theoretical and practical training can be imparted to physicians. This will not only train young minds but also change the mindset for future reporting of ADRs when these doctors go into practice. Similarly, nurses and pharmacists should also be trained in pharmacovigilance so that they are able to recognize ADRs and develop a culture of reporting ADRs in the future.
  For those healthcare professionals in rural areas where the need to recognize ADRs is more important, continuous medical education (CMEs) programs need to be conducted annually by the relevant professional councils. Newsletters developed by the DCGI in conjunction with the relevant councils should be distributed and mailed to doctors, nurses and pharmacists posted to the primary healthcare centers (PHCs).
  An awareness program and a training schedule (both by distance education and face-to-face learning) covering all aspects of pharmacovigilance have now been designed by Symogen Ltd. These are meant for the R &D-based pharmaceutical companies, particularly those involved in new drug research, the medical profession, the pharmacists and chemist-druggist trades and the patients, to be alert in detecting ADRs and reporting them to the Indian regulatory agencies, who in turn will investigate and take timely corrective action.
  
• Collaborating with pharmacovigilance organizations in enhancing drug safety
  With advancements in information technology, there has been the emergence of new opportunities for national ^[7] and international ^[8] collaborations that can enhance postmarking surveillance programs and increase drug safety. The Uppsala Monitoring Center (UMC) is an example for an international collaboration to establish a harmonized postmarketing surveillance database. ^[8] The system is based on the exchange of adverse reaction information among national drug monitoring centers in 80 countries. The information is transferred, stored and retrieved in a timely and secure way through the internet. The UMC database collectively contains over four million records with a large number of data fields.
  The development of large population-based administrative databases has addressed several of the limitations that were associated with other types of data sources previously used in pharmacovigilance systems. These include problems with small sample size, wide variations in sample data and possible misclassification of outcomes. A similar database can be built for the DCGI with the help of experienced private firms from the safety data received from clinical trials and postmarketing surveillance.
  
• Building a network of pharmacovigilance and pharmacopeidemiologists in India
  Pharmacovigilance and pharmacoepidemiology being relatively new fields in India, it is absolutely essential for a group of experts to come together to formulate guidelines for the set-up and implementation of relevant processes within pharmacovigilance. A core group will need to be formed which will have representatives from MNCs, Indian pharmaceutical companies and personnel from the regulatory authority (DCGI). Epidemiologists, pharmacists and other like-minded people can also contribute to the development of the system.
  
• Interaction with the IT sector in building a robust pharmacovigolance system for India
  India boasts of a highly developed IT sector. Since pharmacovigilance and pharmacoepidemiology deal with large numbers of ADRs, it would be wise for pharmacovigilance experts to collaborate with software professionals to develop and build a robust system. Software programs developed can be used for collection and analyses of data sets, determining trends of drug usage in various disease areas, compliance, medication errors and drug interactions leading to ADRs. In specific areas where knowledge is inadequate, i.e., pregnancy, paediatric population, patients with liver and renal dysfunction and the elderly, pharmacokinetic software programs can help in optimizing drug dosages in individuals in various diseased conditions. This will be useful not only in rational drug therapy but would also be an important asset in therapeutics.

Conclusion

Pharmacovigilance is a complex process and robust systems are essential to undertake the activity. The foundation for building a robust pharmacovigilance system has already been done to some extent by the DCGI staff. However, the system needs to be refined with the help of pharmacovigilance experts in collaboration with information technology. With more and more clinical research now being conducted in India, it will be worthwhile for the DCGI to invest in a robust pharmacovigilance system, which will enable assessors and decision makers to analyze safety data and take regulatory decisions without the need to depend on other countries. DCGI should take some tough decisions and make commitments to make pharmacovigilance mandatory and start the culture of pharmacovigilance inspections.

Pharmaceutical companies will need to show both regulators and consumers that they are doing everything possible to assure drug safety, while finding more effective approaches to manage drug safety data. This will require the ability to pull and analyze data from adverse event reporting systems in conjunction with other internal company data or external data sources to respond to any ad hoc safety queries or issues from the regulators. In order to do that, an integrated approach to AE data systems and pharmacovigilance along with appropriate business processes need to be developed and put in place. The companies need to be reassured that by reporting AEs and continuously monitoring for signals and developing risk management plans for products, they can actually still keep marketing their product.

Reporting of ADRs after marketing should be actively encouraged and should involve all those concerned including doctors, pharmacists, nurses, patients and pharmaceutical companies. To enhance and facilitate this, a culture of learning about pharmacovigilance should start early in the professional training of healthcare students. This will help healthcare professionals to understand the subject and also create awareness by giving adequate information to patients at the start of any treatment about the potential benefits and risks of the therapy.

India is now considered to be a hub for clinical research. The DCGI has shown its commitment to ensure safe use of drugs by establishing the National Pharmacovigilance Program. More and more clinical trials are now being conducted in India and business process outsourcing (BPOs) based in India are now also undertaking pharmacovigilance projects from MNCs. Healthcare professionals, consumer groups, NGOs and hospitals should appreciate that there is now a system in place to collect and analyze adverse event data. They should start reporting adverse events actively and participate in the National Pharmacovigilance Program to help ensure that people in India receive safe drugs. The only private company, Symogen Ltd., that deals with all aspects of pharmacovigilance has also started functioning in India. With the help of all stakeholders, let us pledge to make this happen in India and build a world-class pharmacovigilance system. We can surely make this happen if we work together!

References

Copyright 2007 - Indian Journal of Pharmacology

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