INTRODUCTION:

Pharmacovigilance the ongoing assessment of the safety of a marketed medicine has been increasingly appreciated in recent years, Since very few new drugs were discovered in India and hardly any new drug was launched for the first time in India in the past, owing in part to high-profile safety issues with widely used drugs. Pharmacovigilance is pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long term and short term effects of medicine. Pharmacovigilance, a useful tool in post marketing surveillance, is the process of identifying evaluating and responding to adverse drug reactions (ADRs) and safety issues about medicinal products. Pharmacovigilance is a new emerging area in India and there is a need to develop capacity as well as competence.

Pharmacovigilance studies the long term and short term adverse drug reaction or simply stated side effects of medicine. It involves collection, monitoring, researching upon, assigned evaluating information received from healthcare workers such as doctors, dentists, pharmacists, nurses and other health professionals for understanding adverse drug reaction. Because clinical trials involve several thousand patients at most; less common side effects and ADRs are often unknown at the time a drug enters the market. Even very severe ADRs such as liver damage are often undetected because study populations are small. Post marketing pharmacovigilance uses tools such as data mining and investigation of case reports to identify the relationships between drugs and ADRs.¹

Pharmacovigilance is defined as the detection, assessment and prevention of adverse drug reactions in humans. It is the process (Fig-1) of:

• Monitoring medicines as used in everyday practice to identify previously unrecognized adverse effects or changes in the patterns of their adverse effects

• Assessing the risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe use

• Providing information to users to optimize safe and effective use of medicines

• Monitoring the impact of any action taken.²

Need of Pharmacovigilance:

Pharmacovigilance is one of the important post-marketing tools in ensuring the safety of pharmaceutical and related health products. Before a product is marketed, experience of its safety and efficacy is limited to its use in clinical trials, which are not reflective of practice conditions as they are limited by the patient numbers and duration of trial as well as by the highly controlled conditions in which Clinical Trials are conducted.

The conditions under which patients are studied during the pre-marketing phase do not necessarily reflect the way the medicine will be used in the hospital or in general practice once it is marketed. Information about rare but serious adverse drug reactions, chronic toxicity, use in special groups (e.g. pregnant women, children, elderly) and drug interactions is often incomplete or not available. Certain adverse drug reactions may not be detected until a very large number of people have received the medicine.

Since there are considerable social and economic consequences of adverse drug reactions and the positive benefit/cost ratio of implementing appropriate risk management – there is a need to engage health-care professionals and the public at large, in a well structured programme to build synergies for monitoring adverse drug reactions. The purpose of the programme is to collate data, analyse it and use the inferences to recommend informed regulatory interventions, besides communicating risks to healthcare professionals and the public.³

Current Status at Global Level:

To assess current and planned pharmacovigilance activities in low- and middle-income countries, identify gaps and the most urgent pharmacovigilance priorities at national and international levels, and define the elements of a sustainable global pharmacovigilance strategy. The WHO Programme for International Drug Monitoring aims to develop a comprehensive global pharmacovigilance strategy that responds to the healthcare needs of low- and middle-income countries. However, first there is a need to measure and understand existing conditions and pharmacovigilance initiatives intended in these settings. Very few investigations have carried out such a systematic assessment of the pharmacovigilance landscape in recent years in low- and middle-income countries. This study has helped identify some of the special challenges and barriers to promoting pharmacovigilance in low- and middle-income countries. A pharmacovigilance strategy in these settings needs to help build health systems that can serve the purpose of multiple health conditions. It needs to identify and implement feasible systems, governance, infrastructures, human resource, training and capacity building, sustainable methodologies and innovations in pharmacovigilance; a key component will be the dissemination of medicines safety information to policy makers and regulators and knowledge sharing with healthcare professionals through high quality informatics and learning tools, with rational use of medicines and patient safety as the ultimate goal of pharmacovigilance.

National governments are responsible for assuring that medicines sold in their countries are of good quality and are safe and effective. An important component of a country’s ability to monitor medicine safety is a national pharmacovigilance system that is supported by the medicine regulatory authority. A national pharmacovigilance program can be housed in a national pharmacovigilance center or in a tertiary or research-oriented hospital. In the traditional model, a pharmacovigilance system is centralized and consists of one national center collecting reports from health professionals around the country. Internationally, WHO, through its collaboration with the Uppsala Monitoring Centre, has created a global network to share data and information about the benefits and risks of medicinal products. The network membership has grown to include almost 100 countries, including many developing countries.⁴

Key Drivers for Pharmacovigilence:

Regulatory Context:

21 CFR parts 310,312,314,320,600,601,606 of the US FDA mandates the pharmaceutical companies to conduct postmarketing surveillance and reports ADRs within stipulated time frames. Similar regulatory agencies of various other countries also mandates all pharmaceutical manufacturers to conduct adverse drug events monitoring of approved drugs. Typically the pharmaceutical companies are mandated to submit post marketing data periodically. Any serious/ unexpected adverse event occurring in the patient has to be reported within stipulated time frame of 7 to 15 days from the occurrence of the event to the regulators. The regulatory agencies based on the incidence and seriousness of the adverse drug reaction evaluate the risk benefit ratio and then provide appropriate recommendation such as warning insert, change in labeling or even withdrawal of the drug from the market. There have been many instances of pharmaceutical companies getting into litigation quagmire with drugs that have caused serious adverse events. Good pharmacovigilance is based on collection of data from adverse event report also known as case reports. As acknowledged by the FDA, it is very difficult to arrive at a conclusion whether the event was the outcome of the pharmaceutical product. FDA recommends sponsors to search for similar or related cases from the global adverse database (UMC) or other available resources such as FDA AERS or VAERS etc.

When a situation arises wherein one or more cases suggest a safety signal warranting additional investigation, the FDA recommends a case series to be assembled and clinical information to be summarized to characterize the potential safety risk and identify the risk factors. Case series are usually developed based on the information provided on the adverse reports.

The FDA encourages the use of statistical and mathematical models (Data mining). Data mining techniques can provides additional information related to the existence of an excess of adverse events reported for a product.⁵

Involvements of IT companies:

Postmarketing safety data collection and clinical risk assessment based on observational data are critical for evaluating and characterizing a product’s risk profile and for making informed decisions on risk minimization. Information science promises to deliver effective e-clinical or e-health solutions to realize several core benefits: time savings, high quality, cost reductions, and increased efficiencies with safer and more efficacious medicines. The development and use of standard-based pharmacovigilance system with integration connection to electronic medical records, electronic health records, and clinical data management system holds promise as a tool for enabling early drug safety detections, data mining, results interpretation, assisting in safety decision making, and clinical collaborations among clinical partners or different functional groups. The availability of a publicly accessible global safety database updated on a frequent basis would further enhance detection and communication about safety issues. Due to recent high-profile drug safety problems, the pharmaceutical industry is faced with greater regulatory enforcement and increased accountability demands for the protection and welfare of patients. This changing climate requires biopharmaceutical companies to take a more proactive approach in dealing with drug safety and pharmacovigilance.⁶

Benefits and Risks of Pharmacovigilence Technology:

The idea that randomized clinical trials can establish product safety and effectiveness is a core principle of the pharmaceutical industry. Neither the clinical trials process nor the approval procedures of the US Food and Drug Administration (FDA) provide a perfect guarantee of safety for all potential consumers under all circumstances. Despite this fact, there are viable pharmacovigilance technology solutions that biopharmaceutical companies can implement to systematically detect, assess, understand, and prevent adverse drug reactions. When built into clinical research and development practices, pharmacovigilance technologies assist biopharmaceutical firms in enhancing patient safety while reducing or even preventing costly safety-related withdrawals. It is recognized that clinical data mining and signal detection associated with pharmacovigilance technology contribute to potential benefits in providing:⁷

• Systematic, automated and practical means of screening large datasets

• Better utilization of the large safety databases maintained by the FDA, the World Health Organization (WHO) and other organizations

• Improved efficiency by focusing pharmacovigilance efforts on key reporting associations

• Positive contributions to public health by identifying potential safety issues more quickly and/or more accurately than traditional pharmacovigilance methods

• Better decision support for the pharmaceutical industry and regulators

• Potential to clarify the many complex interdependent factors (eg. concomitant drugs and/or diseases) that can play a role in the development of adverse events in a clinical setting

• Value by detecting disproportionalities involving multiple drugs or multiple events that would be too difficult to detect by traditional methods.⁸

Adopting good pharmacovigilance practice in clinical safety monitoring and analysis and having an aptitude to utilize the advantages pharmacovigilance technology solutions provide are key to unlock the power of pharmacovigilance and maximize clinical safety returns in an evolving drug safety environment. One needs to realize that pharmacovigilance is a tool and should be applied into clinical context to achieve its intended functions. One critical component of good pharmacovigilance practice is centered on acquiring complete quality data from reported source on adverse events. Spontaneous case reports of adverse events submitted to the sponsor and FDA, and reports from other sources, such as the medical literature or clinical studies, may generate signals of adverse effects of drugs. The quality of the reports is critical for appropriate evaluation of the relationship between the product and adverse events.⁹

Future of Pharamacovigilence Technology:

The challenges to manage drug safety efficiently and to adhere to regulatory requirements create the strong impression that widespread adoption of pharmacovigilance is inevitable. As an instrument of reform, pharmacovigilance has attributes that ensure its attractiveness to many groups in a politically and economically divided health care system that is struggling with seemingly insurmountable problems of cost and quality and post marketing clinical studies as well. Regulatory bodies such as FDA and European Medicines Agency (EMEA) are intensifying safety regulations, therefore boosting the adoption rates of pharmacovigilance systems by biopharmaceutical firms.(10)However, the apparent certainty of pharmacovigilance adoption needs to be constantly reexamined due to considerations of a number of challenging issues. One is whether the current standardization initiatives in reaching interoperability between differential clinical or e-health systems among several standard consortiums such as CDISC, HL7, NCI, and FDA will have any effect on pharmacovigilance. If so, to what extent such implementation level standard may bring changes and affect ongoing pharmacovigilance monitoring activities? On the technical architecture perspective, will modern pharmacovigilance technology system offer multi-tier web based application framework so that even a new clinical standard definition causes minimum modification behind the scene? This certainly presents a challenge call to pharmacovigilance technology vendors to partner with pharmaceutical firms and health care providers to offer flexible, configurable, scalable, and interoperable pharmacovigilance technology solutions to meet the future pharmacovigilance needs in:¹

a) Increasing globalization

b) Web-based sales and information

c) Broader safety concerns linked to the patterns of drug use within society

d) Collaborative working approach among biopharmaceutical firms, health providers, regulatory agencies, insurance payers, CROs, standards consortiums, and central laboratories.

A second debatable question is whether, if the apparent automation of technical edit checks of pharmacovigilance offers systematic assurance, their definition, range, threshold determination, or data-mining statistical methodology associated with alert or signal triggering requires some level of standardizations to enable consolidated efforts, comparability, and interoperability. If so, achieving this goal requires multiple stakeholders’ contribution and collaboration, among which clinical safety science and statistical modeling matter experts will play ongoing critical roles in ensuring deliverability and objectivity. The primary purpose of these technical autochecks within GPVP are to send alerts or signals, based on pre-defined and configurable thresholds or ranges ,^{11 12} to the reviewers e-mail box for assessment as to whether it is a true signal. It is vital that the clinical safety monitors be assured that any data or sets of data that may have a causal link to one of their drugs be detected as an alert for further evaluation by the clinical risk assessor. A third unanswered question is how, exactly, the modern pharmacovigilance revolution will recruit the majority of small to mid-sized companies, pharmacies, health care providers, and academic communities who still use labor intensive traditional pharmacovigilance tools and prefer not to change due to various reasons, concerns, or skeptics on pharmacovigilance. As yet, no clear strategy has developed to assist these entities with the costs of installing, configuring, and integrating, and maintaining pharmacovigilance] systems or for convincing them that they can effectively function within the new practice regimes that the new pharmacovigilance may offer and support with better improved return on investment as compared to traditional pharmacovigilance. Additionally, convincing top pharmaceutical companies with well established systems and processes to switch to modern pharmacovigilance systems can be both challenging and exciting. One needs to possess at least the following assets to succeed: demonstration of system functionality, understanding business requirement, commitment to customer service, enhancing configurability, assisting with data migration and system knowledge transfer, offer consultation in preparation of new standard operating procedures or modification of existing ones, and prove cost saving advantages in the long-term. The most difficult seems to be aligning existing processes to fit in the new system. Often times, biopharmaceutical firms would want the system to have more configurable features. Perhaps the biggest uncertainty concerning pharmacovigilance is whether it will accomplish dramatic, transformational improvement in accurately and reliably detecting clinical safety signals among the millions of haystack of voluntarily reported data. It seems reasonable that traditional pharmacovigilance approaches are still necessitated for confirming a potential signal from an autofired alert, determining a potential safety risk or any action to be taken from a signal in pharmacovigilance. It would be premature to assume that modern pharmacovigilance technology will offer such critical decision-making capability. Even if it does, a thorough manual confirmation would be required at the detailed clinical data levels. Sponsor management is already grappling with the fact that implementing pharmacovigilance corporate wide will require changing, quite dramatically, the work of many different functional groups including but not limited to: IT, clinical data management, safety, product performance, operations, CROs if applicable, clinical sites in order to create an operational safety framework and foster the gear switch to support the implementation of new technology. In the face of this challenge, the will to improve and prosper will be primary, the technology and innovation secondary, and patience and collaboration critical. Creating standards based and interoperable clinical pharmacovigilance systems in which corporate management and safety staff can find the quality improvement in signal detection and cost reduction essential to accomplishing corporate financial and professional goals will be necessary to widespread adoption of modern pharmacovigilance and to assessing its transformative potential. The modern pharmacovigilance system will have the potential to identify and quantify adverse-event signals with unprecedented power and performance.18–20 Such data-mining capability coupled with improving standards will provide great benefits to optimize medications’ safety and benefit–risk relationships. Setting up the system to function and ensuring its interoperability with multiple other systems such as clinical data management system, coding applications, clinical trial management system, or product performance system will be a daunting task yet achievable, but making sure the alerts or signals it generates are epidemiologically rigorous and clinically valuable will be of paramount criticality. Ultimately, knowing what data mining numbers mean for practice, confirming potential signal or safety risk via further case report or case-series, and communicating that meaning effectively and promptly will present the biggest challenges of all.¹³ Collectively, modern pharmacovigilance system is a tool like all other IT ventures, and one still likely to be driven by humans.

CONCLUSIONS:

The assessment of spontaneous reports is most effective when it is conducted within the defined and rigorous good pharmacovigilance process (GPVP) framework, a functional structure for both public health, health care delivery and corporate risk management strategy. These practices are designed to efficiently and effectively detect and alert the drug safety professional to new and potentially important information on drug adverse reactions. Data mining of adverse event databases is a tool to help with the challenging task of systematically detecting signals among the over 300,000 Med Watch or other similar reports submitted annually to the FDA or similar agencies and is most effectively utilized with full awareness of the limitations and circumstances of voluntary reporting, coding, database characteristics, or quality. Data-mining signals by themselves are not indicators of problems, but indicators of possible problems. Data mining is not intended to replace traditional pharmacovigilance techniques, but to engender improvement and add efficiency. Signals are generated for a relatively small proportion of all distinct drug event pairs in the database. These signals capture a high proportion of the total number of drug–event pairs reported, greatly facilitating more focused follow-up and prioritized risk assessment.³ Such practices and the overall GPVP are supported by modern internet-based systems with powerful analytical engines, workflow, security, and audit trails to allow validated systems support for proactive drug safety signaling efforts. Future technology will have more standardization and interoperability capabilities. It reasons to state that pharmacovigilance has the potential to meet the challenges of the increasing range and potency of medicines (including vaccines); however, there are issues, concerns, challenges and risks involved in implementing and adopting modern pharmacovigilance solutions.

REFERENCES:

1) IT WHO Collaborating Centre for International Drug Monitoring. The Importance of Pharmacovigilance – Safety Monitoring of Medicinal Products. Geneva, Switzerland: World Health Organization; 2002.

2) FDA Clinical Medical Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. Rockville, MD: US Food and Drug Administration; 2005.

3) US Food and drug administration. The sentinel initiative: A National strategy for monitering Medical product safety May 2008. Available from: http://www. fda. gov/safety/ FDAsSentinelInitiative/ucm089474.

4) Shabir Banoo, supporting Pharmacovigilence in developing countries, Strengthing Pharmaceutical system, Available from: http://www. msh. org/project/sps/SPS-Documents/upload/SPS PV paper. pdf, Sept 2009(1), 8-9.

5) Department of Health and Humen Services, Food and Drug Administration 21 and CFR Parts 310, 312 et al. Safety Reporting Requirements for Humen drug and Biological Products; Proposed Rule, March 2003.

6) Zhengwu Lu, Information technology in Pharmacovigilence, Benefits, challenges and future direction from industry perspective, Dove Press Journal, Drug, Healthcare and patient Safety 2009:(1 ) 39-40.

7) FDA Clinical Medical. Guidance for Industry – Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. Rockville, MD: US Food and Drug Administration; 2005.

8) Almenoff J, Tonning JM, Gould AL, et al. Perspectives on the use of data mining in pharmacovigilance. Drug Saf. 2005; 28:981–1007

9) World Health Organization. WHO Programme for International Drug Monitoring. Available from: http://www. who-umc. org/DynPage. aspx?id=13140&mn=1514. Accessed on August 22, 2009.

10) Hochberg AM, Hauben M. Time-to-signal comparison for drug safety data-mining algorithms vs traditional signaling criteria. Clin Pharmacol Ther. 2009; 85:600–606.

11) Sundström A, Hallberg P. Data mining in pharmacovigilance – detecting the unexpected: the role of index of suspicion of the reporter. Drug Saf. 2009; 32:419–427.

12) Hauben M, Aronson JK. Defining “signal” and its subtypes in pharmacovigilance based on a \ systematic review of previous definitions. Drug Saf. 2009; 32:99–110

13) Avorn J, Schneeweiss S. Managing drug-risk information: What to do with all those new numbers. N Engl J Med. 2009; 361:647–649.

Received on 17.02.2011 Modified on 15.03.2011

Research J. Pharm. and Tech. 4(6): June 2011; Page 867-871