About Authors: * Ryali. Jithendra, Dinesh Kumar. Pandurangan, Bandaru. Sowjanya1, Vijayaraj Kumar. Perumal2
1Department of Biotechnology, Acharya Nagarjuna University, Guntur – 522 510, India,
*1-Department of Pharmaceutics, Rahul Institute of Pharmaceutical Science & Research, Chirala-523157, Andhra Pradesh, India.
2-School of Pharmacy, University College Sadaya International,Kuala Lumpur, Malaysia.
ABSTRACT:
Pharmacovigilance is an important and integral part of clinical research. 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. This addresses what exactly is pharmacovigilance? What do we know of its benefits and risks, challenges and the future hold for pharmacovigilance in Indian medicine. Here the main focus on the aims and role of pharmacovigilance in medicines regulation and their Partners. This article describes and discusses the National programme of pharmacovigilance and centre in India. There role in collecting the reports ADRs of medicines. Further effectiveness and risk assessments of therapies are been discussed. The important role played by health care professional, pharmaceutical industries, media, and programmes carried by WHO. Finally the conclusion describes the major challenges and achievements for the future pharmacovigilance programme.
Reference ID: PHARMATUTOR-ART-1005
INTRODUCTION
Pharmacovigilance is an important and integral part of clinical research1. Both clinical trials safety and post marketing pharmacovigilance are critical throughout the product lifecycle. 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.” Pharmacovigilance is still in its infancy in India and there exists very limited knowledge about the discipline.
While major advancements of displine of pharmacovigilance have taken place in the western countries not much has been achieved 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 process and procedures to help ensure regulatory compliance and enhance clinical trials safety and post marketing surveillance.
Pharmacovigilance is not new to India and has infact been going on from 19982. When India decided to join the uppasla centre for adverse event monitoring. The importance of pharmacovigilance is withdrawls the regulatory agencies, media; consumers have become more aware about the benefit and risks of medicines. “An adverse event is defined as any un toward medical occurrence that may present during treatment with a drug but which does not necessarily have a relationship with its use.” “An adverse drug reaction is any noxious, unintended and undesired effect of a drug, which occurs at a dose used in human for prophylaxis, diagnosis, therapy or modification of physiological function.” Spontaneous reporting of adverse drug reaction and adverse events is an important tool for gathering the safety information for early detection. In recent years many Indian companies are increasing the investment in research and development and are enhancing their capacity to develop and market new drugs with their own research efforts.
Further India is becoming a hub for clinical research activities due to its large population, high enrolment rate and low cost 3. Moreover, the lag period when a drug is placed for the first time on the market in USA, Europe, and Japan or somewhere in the world and its subsequent availability in India has decreased considerably. As a result, for such drugs the long term safety data is not available and the time of their marketing in India. This is clear by the fact that all the high profile drugs that have been recently withdrawn were available in Indian market. In such cases, the Indian regulatory agencies cannot count on the experience of other market to assess benefit risk balance of a drug.
There by stressing the importance of developing their own adequately designed pharmacovigilance system in India. For an effective pharmacovigilance system to be functional and efficient, all the stake holders need to be alert and attentive throughout the life cycle of a medicinal product in the market .The office of the Drugs Controller General of India(DCGI) has been making sincere attempts for the implementation the National Pharmacovigilance programme (NPP) in India. To full fill the pharmacovigilance obligations for its marketed products, as per regulations, a generic company in India is mainly to carry out the following activities. Collection monitoring, and reporting of spontaneous adverse reactions, including expedited reporting of serious unexpected adverse reactions and preparations. Pharmacovigilance help to prevent adverse drug effects: Medical science has grown in leaps and bounds since the days of Hippocrates. Modern day pharmaceutical drugs are really life saves. They have increased life expectancy and improved the quality of life for millions of people. But there is the other side of the coin as well; these drugs sometimes have very adverse effects that can even be life threating.
WHAT IS PHARMACOVIGILANCE?
There is a need to monitor the effects of drugs before and after it’s successfully tested and launched in the market. Pharmacovigilance involves monitoring and assessing the quality of drugs, detection and preventing of any adverse effects of drugs. Pharmacovigilance involves evaluating information provided by health care providers, pharmaceutical companies and patients in order to understand the risks and benefits involved with a particular drug. Pharmaceutical companies spend millions of dollars and a considerably long time in developing new drugs.
They again spend a lot of money in conducting clinical trials before the drugs are approved and launched in the market. It is recognized that information technology (IT) has entered and transformed the world of health care and clinical medicine in which the work of doctors and the care of patients proceed with higher quality, efficiency and lower costs. It is also no secret that IT has merged in to clinical safety practice and sparks the creation of worldwide pharmacovigilance systems for safety signal detection.
The IT transformative force and health it adoption have fundamentally changed the conduct of clinical research, practice of medicines, and medicinal safety monitoring. In today’s world, pharmacovigilance pushes new boundaries and it is no longer sufficient to simply report adverse events along with efficacy and quality requirements.
Regulators are demanding proactive surveillance programs that include comprehensive risk management plans and signal detection /analysis throughout a clinical products’ life cycle.
Ø This addresses what exactly is pharmacovigilance?
Ø What do we know of its benefits and risks?
Ø What challenges are out there preventing its wide spread usage?
Ø And what does the future hold for pharmacovigilance in worldwide medicine?
It is now generally accepted that part of the process of evaluating drug safety needs to happen in the post marketing phases through judgment as to whether and how this might happen lies with the regulators. The stronger the national systems of pharmacovigilance and adverse drug reaction (ADR) reporting, the more likely reasonable regulatory decisions will be made for the early release of new drugs with the promise of therapeutic advances. Care full safety monitoring is not restricted, however to new drugs or to significant therapeutic advances. It has a critical role to play in the introduction of generic medicines, and in review of the safety profile of older medicines already available as well, where new safety issues may have arises. While spontaneous reporting remains a corner stone of pharmacovigilance in the regulatory environment, and is indispensable for signal detection, the need for more active surveillance has also become increasingly clear. Without information on utilization and on the extent of consumption, spontaneous reports are unable to determine the frequency of an ADR attribution to a product or its safety in relation to a comparator.
More systematic and robust epidemiological methods that take in to account the limitations of spontaneous reporting or post marketing studies are required to address these key safety questions. They need to be incorporated in to post marketing surveillance programs. This includes the use of pharmaco epidemiologic studies.
These activities are under taken with the goal of identifying adverse events and understanding, to the extent possible, their nature, frequency, and potential risk factor. Pharmacovigilance in principle involves the identification and evaluation of safety signals. Safety signal refer to a concern about an excess of adverse events compared to what would be expected to be associated with products use.
Signals can arise from post marketing data and other sources, such as pre clinical data and events associated with other products in the same pharmacological class4 . Pharmacovigilance is particularly concerned with adverse drug reactions. Many other issues are also relevant to pharmacovigilance science are substandard medicines, medication errors, lack of efficacy reports, use of medicines for indications that are not approved and for which there is inadequate scientific basis, case reports of acute and chronic poisoning, assessment of drug related mortality, abuse and misuse of medicines, adverse interactions of medicines with chemicals, other medicines and food.
AIMS OF PHARMACOVIGILANCE:
Ø Improve patient care and safety in relation to the use of medicines and all medical and Para medical interventions5.
Ø Research the efficacy of drug and by monitoring the adverse effects of drugs right from the lab to the pharmacy and then on for many years.
Ø Pharmacovigilance keeps track of any drastic effects of drugs.
Ø Improve public health and safety in relation to the use of medicines.
Ø Contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use.
Ø Promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public.
The processes involved in the clinical development of medicines. 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. At this point, most medicines will only have been tested for short-term safety and efficacy on a limited number of carefully selected individuals. In some cases as few as 500 subjects, and rarely more than 5000, will have received the product prior to its release.
For good reason, therefore, it is essential that new and medically still evolving treatments are monitored for their effectiveness and safety under real-life conditions post release.
More information is generally needed about use in specific population groups, notably children, pregnant women and the elderly, and about the efficacy and safety of chronic use, especially in combination with other medicines.6 Experience has shown that many adverse effects, interactions (i.e. with foods or other medicines) and risk factors come to light only during the years after the release of a medicine
Table 1 Classical example of serious and unexpected adverse reactions
|
Medicine |
Adverse reaction |
|
Aminophenazone (amidopyrine) |
Agranulocytosis |
|
Chloramphenicol |
Aplastic anaemia |
|
Clioquinol |
Myelooptic neuropathy (SMON) |
|
Erythromycin estolate |
Cholestatic hepatitis |
|
Fluothane |
Hepatocellular hepatitis |
|
Methyldopa |
Haemolytic anaemia |
|
Oral contraceptives |
Thromboembolism |
|
Practolol |
Sclerosing peritonitis |
|
Reserpine |
Depression |
|
Statins |
Rhabdomyolysis |
|
Thalidomide |
Congenital malformations |
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“Role of pharmacovigilance” in medicines regulation”
Robust regulatory arrangements provide the foundation for a national method of medicine safety, and for public confidence in medicines. To be effective the remit of drug regulatory authorities needs to go further than the approval of new medicines, to encompass a wider range of issues relating to the safety of medicines, namely:
Ø Clinical trials;
Ø The safety of complementary and traditional medicines, vaccines and biological medicines;
Ø The development of lines of communication between all parties which have an interest in medicine safety, ensuring that they are able to function efficiently and ethically, particularly at times of crisis.
In order to achieve their respective objectives pharmacovigilance programmes and drug regulatory authorities must be mutually supporting. On the one hand, pharmacovigilance programmes need to maintain strong links with the drug regulatory authorities to ensure that the latter are well briefed on safety issues in everyday clinical practice, whether these issues are relevant to future regulatory action or to concerns that emerge in the public domain. On the other, regulators need to understand the specialized and pivotal role that pharmacovigilance plays in ensuring the ongoing safety of medicinal products.
Partners in pharmacovigilance
The management of the risks associated with the use of medicines demands close and effective collaboration between the key players in the pharmacovigilance7. Sustained commitment to such collaboration is vital if the future challenges in pharmacovigilance are to be met, and if the discipline is to continue to develop and flourish.
Those responsible must jointly anticipate, describe and respond to the continually increasing demands and expectations of the public, health administrator policy officials, politicians and health professionals However, there is little prospect of this happening in the absence of sound and comprehensive systems which make such collaboration possible. The constraints typically include lack of training, resources, political support, and most especially scientific infrastructure. Understanding and tackling these are an essential prerequisite for future development of the science and practice of pharmacovigilance.
Monitoring the safety of medicines: key partners
Ø Government
Ø Industry
Ø Hospitals and academia
Ø Medical and pharmaceutical associations
Ø Poisons and medicines information centres
Ø Health professionals
Ø Patients
Ø Consumers
Ø The media
Ø World Health Organization
NATIONAL PROGRAMME OF PHARMACOVIGILANCE
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.
Pharmacovigilance is therefore one of the important post-marketing tools in ensuring the safety of pharmaceutical and related health products.
• 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 optimise safe and effective use of medicines
• Monitoring the impact of any action taken
Pharmacovigilance in national drug policy
The provision of good quality, safe and effective medicines and their appropriate use is the responsibility of national governments. The establishment of a national medicine regulatory agency and a designated centre for the study of adverse reactions are central to the achievement of these functions.
Multidisciplinary collaboration is of great importance; in particular, links need to be forged between various departments of the ministry of health and also with other stakeholders, such as the pharmaceutical industry, universities, nongovernmental organizations (NGOs) and those professional associations having responsibility for education on rational use of medicines and pharmacotherapy monitoring.
Key elements of pharmacovigilance in national drug policy
Ø Establishment of national pharmacovigilance systems for the reporting of adverse events, including national and, if appropriate, regional pharmacovigilance centres.
Ø Development of legislation/regulation for medicine monitoring.
Ø National policy development (to include costing, budgeting and financing).
Ø Continuing education of health-care providers on safe and effective pharmacotherapy.
Ø Provision of up-to-date information on adverse reactions to professionals and consumers.
Ø Monitoring the impact of pharmacovigilance through process indicators and outcome
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.
Milestones of the Programme:
Ø Short-term objectives: To foster a culture of notification
Ø Medium-term objectives: To engage several healthcare professionals and NGOs in the drug
Ø Monitoring and information dissemination processes.
Ø Long-term objectives: To achieve such operational efficiencies that would make Indian
Ø National Pharmacovigilance Programme a benchmark for global drug monitoring
Ø Endeavours.
OUTLINE OF THE NATIONAL PHARMACOVIGILANCE PROGRAMME
The National Pharmacovigilance Programme aims to provide adverse drug reaction data related to various drugs available in the country to the central drugs regulatory authority i.e. Central Drugs Standard Control Organisation (CDSCO). The programme will be coordinated by the National Pharmacovigilance Advisory Committee [NPAC] constituted by the Ministry of Health & Family Welfare. The Programme would comprise of the following steps:
Step 1 Identifying various centres across the country for capturing ADR related data
Ø Set-up 2 Zonal Pharmacovigilance Centres [ZPC] to coordinate the nationwide programme. [AIIMS for North and East and KEM-Mumbai for South and West]. Zonal Centres shall provide a room and other requisite infrastructure, e.g. a PC with internet facility, access to fax, telecom, etc.
Ø Identify 5 Regional Pharmacovigilance Centres [RPC] across the country
· Ideally medical colleges with interested and initiated pharmacologists
· Can provide a small area (approx. 100 sq. feet)
· Can deploy a pharmacologist for the Programme
Ø Identify Peripheral Pharmacovigilance Centres [PPC]: At least oneteaching hospital in each state and union-territory, and some other leading medical institutions, clinics or pharmacies in the area under each RPC.
· Ideally, centres that have internet facility
· Manned by doctors / pharmacists who are enthusiastic about carrying out research activities e.g. monitoring ADRs
· Visited by not less than a total of 50 patients daily in any/all of the following departments: Medicine, Gynaecology, Paediatrics, Orthopaedics, Cardiology, Oncology
Step 2 Training and Coordination
To ensure harmonized implementation of the Programme efforts shall be made to arrive at a uniform understanding of the operational systems, along with standardized formats to document and analyse ADRs. An induction training programme shall be arranged for healthcare professionals participating in the NPP.
Intensive interaction / training sessions will be organized for all participants to:
Ø i. Clearly define their individual and team roles and responsibilities
Ø ii. Set operational benchmarks e.g.
Each PPC to record at least 30 AEs each month (statistically speaking 30 AEs in about 1500 patients who visit each month would be quite easy to record). Completed AE forms shall be forwarded to the concerned RPC at the end of each month.
Ø Each RPC
· To collate and scrutinize the data received
· To perform the causality analysis of all 120 to 150 forms received every month.
· To submit a monthly report – prepared in a specific form to be forwarded to National Pharmacovigilance Centre (NPC) every month.
· To report any alarming or critical ADRs to NPC along with supporting evidence.
Ø Each ZPC
· To collate the data (approx. 1000-1200 forms) received from RPCs.
· To verify / validate the causality analysis.
· To prepare MIS reports for NPC in a specified format.
· To pass on the final data to WHO Uppsala Centre for their global data pool.
· To publish a periodic newsletter.
Ø iii. Evolve SOPs for generating and forwarding ADR data and for general conduct of the Programme (Zonal centres to prepare SOPs which must ensure that the Programme is conducted in compliance with this Protocol).
Ø iv. Impart relevant skills for carrying out ADR data capture namely
· Appropriate communication skills to elicit ADR related information
· For recording ADR information through hands-on training
· For meticulous collation and completeness of data
· For fostering notification culture.
These training programs and interaction meetings shall be held every 6 months after the initial training. Besides, continuous communication through emails, carrying relevant information related to ADR monitoring methods shall be maintained among the participating centres.
Broad objectives of the Programme
Ø To foster the culture of AE notification and reporting To establish a viable and broad-based ADR monitoring program in India
Ø Specific objectives of the Programme
Ø To create an ADR database for the Indian population To create awareness of ADR monitoring among people To ensure optimum safety of drug products in Indian market To create infrastructure for ongoing regulatory review of PSURs
Coordinator’s eligibility at different tiers of NPP
Ø PPC – Any physician (primary-care or specialist), pharmacist
Ø RPC – A pharmacologist, preferably not below the rank of an assistant professor, attached to a medical college
Ø ZPC – A pharmacologist, not below the rank of a professor, attached to a medical college
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THE NATIONAL PHARMACOVIGILANCE CENTRES
At present, post-marketing surveillance of medicines is mainly co-ordinated by national pharmacovigilance centres. In collaboration withthe Uppsala Monitoring Centre (UMC) the National Centres have achieved a great deal in:
Ø Collecting and analysing case reports of ADRs
Ø Distinguishing signals from background ‘noise’
Ø Making regulatory decisions based on strengthened signals
Ø Alerting prescribers, manufacturers and the public to new risks of adverse reactions.
Ø The number of National Centres participating in the WHO International Drug Monitoring Programme has increased from 10 in 1968 when the Programme started to 67 in 2002. The centres vary considerably in size, resources, support structure, and scope of activities. Collecting spontaneous reports of suspected ADRs remains their core activity.
National pharmacovigilance centres are responsible for:
Ø Promoting the reporting of adverse reactions;
Ø Collecting case reports of adverse reactions;
Ø Clinically evaluating case reports;
Ø Collating, analyzing and evaluating patterns of adverse reactions;
Ø Distinguishing signals of adverse reactions from “noise”;
Ø Recommending or taking regulatory action in response to findings supported by good evidence;
Ø Initiating studies to investigate significant suspect reactions;
Ø Alerting prescribers, manufacturers and the public to new risks of adverse reactions; and
Ø Sharing their reports with the WHO Programme for International Drug Monitoring.
National centres have played a significant role in increasing public awareness of issues relevant to the safety of medicines. As a result, in some countries, pharmacovigilance is increasingly being seen as much more than a regulatory activity as it also has a major part to play in clinical practice and the development of public health policy. This development is partly attributable to the fact that many national and regional centres are housed within hospitals, medical schools or poison and medicine information centres and is in collaboration with a Medicines Regulatory Authority (MRA). The scope of activities of national centres has expanded to include communication of information about the benefits, harm and effectiveness of medicines to practitioners, patients and the public.
The Central Drugs Standard Control Organization (CDSCO) is initiating a country-wide pharmacovigilance programme under the aegis of DGHS, Ministry of Health & Family Welfare, and Government of India. The programme shall be coordinated by the National Pharmacovigilance Centre at CDSCO. The National Centre will operate under the supervision of the National Pharmacovigilance Advisory Committee to recommend procedures and guidelines for regulatory interventions.
RESOURCES FOR PHARMACOVIGILANCE CENTRES
The following books shall be provided to various centres as identified by the NPAC: Current editions of:
Ø Meyler’s Side Effects
Ø AHFS Drug Information hand book
Ø Martindale/online
Ø Davies Text Book of ADR
Ø Physician’s Desk reference
Ø British National Formulary
Each ZPC will be provided funds to deploy a pharmacologist and a data manager. Each RPC will be provided funds to deploy a pharmacologist. Training programmes be arranged for those healthcare professionals who are participating in NPP. All centre coordinators’ will be provided training on the following issues:
Ø Skills to foster notification culture.
Ø Communications skills – for complete and meticulous collection of data.
Ø Methodology of filling up the forms
Terms of Reference for engagement of Regional Pharmacovigilance Centre under the National Pharmacovigilance Programme
With the number of new drugs being regularly approved for marketing in India, there is a need for a vibrant pharmacovigilance system in the country to protect our population from the potential harms that may be caused by some of these new drugs. Besides, with the patent regime coming in force from 2005, it is widely believed that India would become the global hub for new drug trials6.These situations make it pertinent for the Indian central drugs regulatory authority to have a vibrant pharmacovigilance system in the country.
The programme shall be coordinated by CDSCO under the supervision of a National Pharmacovigilance Advisory Committee which would monitor the program and also recommend regulatory interventions based on the generated Adverse Drug Reaction (ADR) data.
Objective of the Assignment
The overall objective as per the National Pharmacovigilance Programme will be:
Ø To monitor safety of the drugs and provide structured inputs for appropriate regulatory interventions
Ø To create awareness about ADR monitoring in India
Regional centres will be the secondary pharmacovigilance centres under the National Pharmacovigilance Programme.
To carry out the functions as envisaged in the “Protocol for the National Pharmacovigilance Programme” a Coordinator will have to be designated who will be in-charge of the pharmacovigilance activities at the designated regional centre.
By accepting to participate in the National Pharmacovigilance Programme all centres explicitly agree that all pharmacovigilance activities at their institutions shall be performed in strict consonance with the National Pharmacovigilance Programme appended here (Coordinators of the centres and heads of the institutions are advised to carefully go through the Protocol prior to joining the programme).
Outline of tasks to be carried out
The National Pharmacovigilance Programme encourages the reporting of all suspected adverse reaction to drugs and other medicinal substances including herbal, traditional or alternative remedies. The reporting of seemingly insignificant or common adverse reactions would be important since it may highlight a wide spread prescribing problem.
Regional Centre is expected to carry out the following tasks:
Ø To maintain a log of all ADE notification forms received and forwarded To receive blank ADE forms and acknowledge receipt To fill or get filled the ADE forms Collect & collate Adverse Drug notifications from Peripheral as well as own centres Receive Adverse Drug Events (ADE) forms and maintain log of all ADE forms received and forwarded.
Ø Correspond with Peripheral Centres, provide them with general technical support, coordinate and monitor their functioning.
Ø Identify and delegate a pharmacologist for management of pharmacovigilance tasks.
Ø Carry out (and/or review) data causality analysis of all ADEs
Ø To forward all duly-filled ADE forms [those generated at the same centre and those received from immediate lower-level centre] as per pre-determined time line
Ø Forward periodic reports to the CDSCO centre as per Sl. No. 9
Ø Liaise with health care professionals in order to inculcate / foster the culture of ADE reporting / notification by acknowledging the cooperation by the notifier and share with the notifier relevant feedback from higher centre.
Ø Organize and attend training programmes / interactive meetings for all peripheral centres falling under the respective regional pharmacovigilance centres
Ø To provide updates, reports and such other information as may be required by the National Pharmacovigilance Advisory Committee and to attend their meetings
Ø To conduct special pharmacovigilance projects on various drugs which may be of special concern or interest to CDSCO / Government of India
Ø To maintain account of the funds provided under this program as per your institution’s systems; to review the account statement received from peripheral centres, and provide a consolidated statement to the zonal centre. Carryout audits to ensure compliance with the program, enlist non-compliance, establish corrective measures and implement them at regional centres and oversee their implications at peripheral centres
In line with the size & patient intake of the institutions where it is based, the regional centre shall ensure a minimum 50 adverse event reporting’s every month and this number must be increased periodically. This number will be in addition to the number of reports generated by the peripheral centres falling under respective regional centres.
What to report
The National Pharmacovigilance Programme (NPP) shall encourage reporting of all suspected drug related adverse events, including those suspected to have been caused by herbal, traditional or alternative remedies. The reporting of seemingly insignificant or common adverse reactions would be important since it may highlight a widespread prescribing problem.
The programme particularly solicits reports of:
Ø All adverse events suspected to have been caused by new drugs and ‘Drugs of current interest’ (List to be published by CDSCO from time to time)
Ø All suspected drug interactions
Ø Reactions to any other drugs which are suspected of significantly affecting a patient's management,
Ø including reactions suspected of causing:
Ø Death
Ø Life-threatening (real risk of dying)
Ø Hospitalisation (initial or prolonged)
Ø Disability (significant, persistent or permanent)
Ø Congenital anomaly
Ø Required intervention to prevent permanent impairment or damage
Who can report
Any health care professionals (Doctors including Dentists, Nurses, and Pharmacists) may report suspected adverse drug events. The Programme shall not accept reports from lay members of the public or anyone else who is not a health care professional.
Where to report
After completion the form shall be returned/forwarded to the same pharmacovigilance Centre from where it was received. Reporting can be done to any one of the country vide pharmacovigilance Centres nearest to the reporter. (Complete list of pharmacovigilance Centres is available at www.cdsco.nic.in) In case of doubt the form may be sent to the national pharmacovigilanc
Centre at:Central Drugs Standard Control Organisation, New Delhi.
What happens to the information submitted
The information in the form shall be handled in strict confidence. Peripheral Pharmacovigilance Centres shall forward the form to the respective Regional Pharmacovigilance Centres who will carry out the causality analysis. This information shall be forwarded to the Zonal Pharmacovigilance Centres. The data will be statistically analysed and forwarded to the global Pharmacovigilance Database managed by WHO Uppsala Monitoring Centre in Sweden. The final report based on the analysed data will be periodically reviewed by the National Pharmacovigilance Advisory Committee constituted by the Ministry of Health and Family Welfare. The Committee is entrusted with the responsibility to review data and suggest any regulatory interventions that may be required with respect to the drug/drugs or class of drugs.
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EFFECTIVENESS AND RISK ASSESSMENT OF THERAPIES
Ø Effectiveness and risk: benefit and harm
Ø Decision-making in risk situations
Ø Good decision-making practices
Effectiveness and risk: benefit and harm
“Estimating the risk and benefit of medicines among the populations exposed to them is essential to promote their rational and safe use and will enhance the tolerability and acceptability of mass-treatment programmes.”
The effectiveness and risk profiles of many of the medicines used in PHPs in the past have been established by long experience rather than on the basis of epidemiological evidence. The modern approach to public health requires that advice be given on the best general ways of approaching the management of diseases, notwithstanding the necessity for considerable freedom to modify therapy according to individual needs9.Because of the need for comparative effectiveness and risk profiles of treatment options to find the most useful medicine at the most reasonable cost, it is necessary to use the correct conceptual and practical approach to assessing the effectiveness and risk of medicines.
When new medicines are marketed, only data on animal pharmacology and toxicology, and limited information on their use in humans are available. The number of subjects who have received the medicine in randomized clinical trials before it is marketed may be as few as 100 and is never more than 5000. Although such trials are an irreplaceable tool for determining the potential benefits of the medicine, they provide only limited insight into the likely responses of patients in whom other medicines are administered concurrently; the effects on diseases other than the target disease; the effects of dose variation; nutrition, and many other factors. In clinical trials, only risks of greater than 1/1000, at best, are likely to be noted. At this stage it is not possible to say that degrees of efficacy and hazard have been established, i.e. the potential for effectiveness and risk. A practical level of knowledge of effectiveness and risk can be achieved only when tens of thousands of unselected patients have been treated, and information on the results has been gathered.
It is also important not to confuse benefit with effectiveness. Benefit, described as an overall good, is difficult to define for a society.
It is common to compare pre-marketing efficacy with the spontaneous reports of harm collected. Because the processes for collecting the information are totally different, great care must be taken in interpreting the results; indeed many assumptions need to be made before any interpretation is possible. Another common problem is the comparison of the efficacy and harm of a new medicine with what is much closer to a set of effectiveness and risk data for an older medicine, derived over years of experience.
Decision-making in risk situations:
In critical public health situations, decisions are made either by the PHP or by the national regulator on the basis of available evidence, informed by prior experience, political context and professional judgement.
The decision could be any of the following:
Ø Stop the programme; investigate effectiveness/risk.
Ø Continue the programme, but investigate effectiveness/risk.
Ø Undertake additional studies.
Ø Issue information of public interest.
Ø Issue new guidelines for the PHPs.
A concept central to decision-making is “acceptable risk”. The fundamental question is, “Acceptable to whom?” Individual patient health lies outside the scope of this document. These decisions are the responsibility of the health practitioner and are taken after discussion with his or her patient. The prescribing physician and the patient must still be at liberty to make their choice, although their decisions should be guided by the public health constraints specific to that locality, and based on reliable information.
Good decision-making practices:
The conventional decision-making process in public health needs to be strengthened to deal with quantitatively and qualitatively more complex issues arising out of new medicines being used in public health programme (PHPs).
Decision-making is the process of determining the actions to be taken, who should take them, and the order and methods of taking action. It also entails judgements on the best means of monitoring, follow-up and of communicating the appropriate information to the parties concerned. Decision making should follow three principles, namely:
Ø Objectivity;
Ø Transparency; and
Ø Accountability.
Moreover, to achieve success, there is a need to consider each decision in terms of the following headings:
Ø Obtaining the best data and information
Ø The context of the decision
Ø De-nition of the steps to be taken to reach a decision, for example, by simplifying into sets of subsidiary decisions, and being able to sum the results of such smaller decisions into an overall strategy
Ø Communication and action
Ø Follow-up
Ø Impact
Ø Revision of the original decision as necessary.
Roles and responsibilities( 9,13,15)
Where established, the national pharmacovigilance centre will be responsible for the development of pharmacovigilance in the public health system, will promote pharmacovigilance in the PHPs and sensitize professionals and public health staff to the reporting of adverse reactions and irrational use of medicines.
Role of pharmacist(10,17,19)
Ø Participate in spontaneous Reporting of Adverse Events.
Ø Also report (even if no adverse event).
Ø Medication errors.
Ø Exposure during pregnancy
Ø Monitor clinical status of patients.
Ø Identify the correct ADRs not side effects.
Ø Get more information.
Ø Investigate at hospital level.
Ø Help doctors to fill-up the forms.
Ø Keep patient’s record if more information needed.
Patients and the public
Public awareness about adverse reactions, early reporting and management are essential for ensuring patient confidence, in and adherence to, pharmacotherapy. In some countries patient reporting is accepted and can add value, but this needs to be separate from involvement of patient interest groups can be sought while formulating the programme and should be part of the feedback–communication link.
Primary health-care workers
It is the responsibility of the primary health-care provider to detect, investigate, manage and report ADRs. These staff will need training on the importance of adverse reactions, diagnosis, basic principles of causality assessment and the important elements of the adverse reactions reporting form.
Patient education is an important role of the primary health-care provider. Educating the public on ADRs is important for promoting adherence. Counselling and explanation about adverse reactions will promote patients’ confidence and adherence.
The reporting of adverse reactions needs continuous stimulation. It is important to achieve a positive attitude towards pharmacovigilance. To encourage reporting, the following steps should be of help:
Ø Easy access to reporting forms;
Ø Training;
Ø Acknowledgement of receipt of a report and provision of feedback to the reporter;
Ø Participation of reporting staff in pharmacovigilance meetings, and of pharmacovigilance staff in professional meetings; and
Ø Collaboration with the national pharmacovigilance centre.
Other health-care workers
Health-care workers outside the government system should also report adverse reactions. These would include, among others, nongovernmental organizations and charitable health facilities.
District investigation team
The district investigation team plays a central role in monitoring adverse reactions. The team should comprise a clinician in the district hospital, head nurse, pharmacist and district health officer or programme manager. The team is responsible for following up adverse reactions reported from all the health facilities within their district.
(In the case of vertical programmes the specific programme manager will be responsible for medicines pertaining to that programme.) The team will play an important role in collaboration with and encouragement of reporting by primary health centre staff and hospital staff. Their detailed follow-up of suspected ADRs will be used to assess causality.
When dealing with reports of ADRs, the district investigation team should:
Ø Seriousness (including all deaths);
Ø Severity; exposure to medicine during pregnancy;
Ø Apparent signals of new reactions; and
Ø Patterns of suspected reactions which although not serious, may affect adherence and the success of the programme.
Refer all reports to the national pharmacovigilance coordinator for processing and review by the Expert Safety Review Panel (ESRP).
National pharmacovigilance coordinator
The coordinator, who should be on the staff of the national pharmacovigilance centre, should function as the focal point for the national pharmacovigilance system in the PHP.
Ideally this should be a full-time position. The responsibilities of the national coordinator would include coordination, communication, integration, training and supervision of the pharmacovigilance-related activities of the district investigation teams. This person would also serve as member or secretary of the national ESRP.
The coordinator should ensure that the ADR reports are processed appropriately for assessment by the ESRP. These would generally fall into one of three categories:
Ø Reports selected for investigation by the district investigation team, which should be considered in detail;
Ø Reports considered to be a signal of a new adverse reaction; and
Ø All other reports, which may be presented in summary format, so that an overall reaction profile of the medicine can be obtained.
National medicines regulatory authority
The regulatory authority will receive reports and recommendations from the ESRP. It will perform risk assessment and consider options for regulatory action which may involve requiring the manufacturers to make changes in the labelling of their product or may be a restriction in the use of the product, a temporary suspension or complete withdrawal. The regulatory authority may liaise with other national MRAs and it should always pass on the information on any action taken to WHO.
Pharmaceutical industry and marketing authorization holders
Pharmaceutical manufacturers are legally responsible for the safety and effectiveness of medicines while the product is available in the marketplace. They should provide medicines of good quality and have stewardship of their products. As essential players in the provision of medicines, they should be kept informed of the results of monitoring and relevant decisions. They also have a duty towards assessing the effectiveness and safety of a PHP and the benefits to patients. They should report adverse reactions both to the national pharmacovigilance centre (and in the absence of such to the MRA) or PHP and, in countries with no MRA they should also report to WHO through the disease control PHP.
Media
It is important that the media are involved from the start of a PHP and that the need for the programme is publicized together with the need for pharmacovigilance. The pharmacovigilance programme should be explained and good lines of communication should be set up between the media and the ESRP or the designated liaison person, to ensure the availability of authoritative information. The need for good information should be anticipated so that potential crises can be dealt with quickly and effectively, and public confidence maintained.
When communicating with the media, the following information should be available:
Ø A complete account of any event of concern and its appropriate context (in terms that will be understood by the lay public), e.g. a clear statement that an event is an isolated occurrence, to prevent concern that it may be widespread.
Ø The likelihood that there will be new cases linked to therapy with the medicine.
Ø An outline of actions taken or planned (depending on the stage, this will range from a plan of action to a completed investigation).
Ø The cause of the event (when identified with reasonable certainty).
Ø The corrective action that has been or will be taken.
Ø Guidance to the public on how to respond to concerns over the medicine including contact information for reporting further adverse events.
It is useful to assess the impact of media communications on public awareness and attitudes as this will assist the development of future communication strategies.
The roles of WHO and the International Advisory Committee:
The role of WHO At an international level WHO will play a key role. While supporting countries to conduct PHPs, WHO and its regional offices have a responsibility to promote the establishment and building of sustainable safety monitoring systems. WHO will take a lead role in supporting Member States in the safe use of medicinal products. WHO will serve as a repository for information from both pharmacovigilance programmes and PHPs, and will disseminate this information appropriately.
WHO will identify areas requiring research and encourage and support initiatives to conduct operational research. It will assist countries to define and develop policy on monitoring the safe use of medicinal products and it will respond to controversial issues on the safety of medicines that threaten the use of medicines in a national or international PHP. It will promote and encourage uniformity of terminology and will promote and develop resource materials and provide leadership in training and capacity development.
Advisory Committee on Safety of Medicinal Products (ACSoMP)
An Advisory Committee has been established by WHO to advise on issues that:
Ø Are important to national or international programmes and have the potential to affect them adversely if not resolved;
Ø Cannot be met by structures and/or institutions and/or systems that are already available;
Ø Respond to identified needs of a country that may be beyond the capability of the country or countries themselves; such responses should be made within an appropriate period of time, taking into account any existing information and the urgency of the issue.
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 Programme has achieved much in improving the activities, support and recognition of individual national pharmacovigilance centres.
It plays a key role as a communication and training centre and clearing-house for information on the safety of medicines. The WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden manages the international database of adverse reaction reports received from national centres. In 2005 this database held over 3.5 million case reports. The majority of contributing national centres has ready electronic access to these. 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.
The WHO Collaborating Centre analyses the reports in the database to:
Ø Identify early warning signals of serious adverse reactions to medicines; evaluate the hazard;
Ø Undertake research into the mechanisms of action to aid the development of safer and more effective medicines.
Through an advisory committee, WHO plays an important role in the provision of expert advice on all matters relating to the safety of medicines. The Committee also exists to facilitate consistent policies and action among member countries and to advise those who may be concerned about action taken in another country.
The success of WHO’s International Drug Monitoring:
It is entirely dependent on the contributions of national pharmacovigilance centres. Such centres provide an essential pool of experience and competence which has been instrumental in the continuous development of the WHO programme and of pharmacovigilance as a whole.
Conclusion:
Despite its 40-year history, pharmacovigilance remains a dynamic clinical and scientific discipline. It continues to play a crucial role in meeting the challenges posed by the ever increasing range and potency of medicines, all of vitamins unpredictable potential for harm. When adverse effects and toxicity do appear especially when previously unknown it is essential that these are reported, analysed and their significance communicated effectively to an audience that has the knowledge to interpret the information. Which carry an inevitable and some-For all medicines there is a trade-off between the benefits and the potential for harm. The harm can be minimized by ensuring that medicines of good quality, safety and efficacy are used rationally, and that the expectations and concerns of the patient are taken into account when therapeutic decisions are made. To achieve this is to:
Ø Serve public health, and to foster a sense of trust among patients in the medicines they use that would extend to confidence in the health service in general;
Ø Ensure that risks in drug use are anticipated and managed;
Ø Provide regulators with the necessary information to amend the recommendations on the use of the medicines;
Ø Improve communication between the health professionals and the public;
Ø Educate health professionals to understand the effectiveness/risk of medicines that they prescribe. This is the important role of pharmacovigilance.
Experience has shown that for a country to be able to rely on its own pharmacovigilance programme a number of elements need to be in place. These are as follows:
Ø A dedicated pharmacovigilance centre, independently funded (usually by the state), and staffed by a person or persons with expert knowledge of drug safety and of the evaluation of reports of adverse events;
Ø Links, electronic and personal, between the pharmacovigilance centre and WHO, specifically with the Uppsala Monitoring Centre;
Ø Close operational ties with the national MRA that fullfil the mutual needs of the MRA and the pharmacovigilance centre for the evaluation and continuous monitoring of the safety of medicines;
Ø Access to comprehensive and unbiased drug information relevant to the medicines available in the country;
Ø To achieve the objective of integrating pharmacovigilance with public health systems the following are necessary. (What follows applies to countries with a minimum national pharmacovigilance system in place. Countries without such a national system will be covered later in this section.)
Ø The national pharmacovigilance programme should have clinical underpinning, and should be known to and be actively supported by the ministry of health, health professionals and the academic sector.
The programme should have ready access to sound and independent drug information (particularly information on drug safety) and it should serve as a robust and dependable reference centre. The public should know of its existence, and have trust in the judgement and expertise of its professional staff. There should be adequate financial support from the state to enable the programme to perform these functions.
Ø The national pharmacovigilance centre may be based physically (but not necessarily so) at the ministry of health, within the national MRA, within a leading state hospital, or at an academic school of pharmacy, medicine or health sciences. Whatever arrangement is made, there should be close collaboration, exchange of information, and mutual technical support between the centre and the MRA.
Ø A national medicines safety review committee (ESRP) for adverse reactions that advises both the MRA and the national pharmacovigilance centre, and that has strong clinical representation in its membership, should provide support and focus for the work of the national centre, and for the MRA.
Ø Finally, there should be regular opportunities for the professional staff of pharmacovigilance centres to upgrade their knowledge and experience through training, study and research
Ø Ideally in conjunction with colleagues in public health.
The following is a summary of some of the serious challenges facing pharmacovigilance programmes in the next ten years, describing in brief the potential implications of such trends on the evolution of the science.
Major challenges are:(6,20,23,24)
Ø Globalization
Ø Web-based sales and information
Ø Broader safety concerns
Ø Public health versus pharmaceutical industry economic growth
Ø Developing and emerging countries
Ø Attitudes and perceptions to benefit and harm
Ø Detection of ADRs
Ø Assessment of ADRs
Ø Communication
Conduct on-going research to assess the cost-effectiveness of contemporary pharmacovigilance systems in contributing to patient welfare and public health. Consider the sensitivity and specificity of current signal detection and assessment methods and the extent to which contemporary pharmacovigilance systems have been successful in detecting and preventing potential disasters while avoiding the premature withdrawal of safe and useful medicines from the market.
Taking medicines, and prescribing them, are among the commonest of activities of people who are unwell and of those who care for them. It makes sense that those medicines should be monitored to equally demanding standards as those evident in the development and evaluation of drugs, and that prescribing habits and the extent of rational and cost- effective use should be reviewed.
Responsibility for the holistic approach to drug safety that is encompassed in the science and practice of pharmacovigilance, as reflected in this report, has to be shared if ideal practice is to be achieved. The scientists, clinicians, pharmaceutical manufacturers, drug developers, regulators, public policy makers, patients and the general public all have their own complementary roles in achieving what is envisaged. Among the important issues are information, information sharing and broader communication. What we need is a continuing and dynamic development of modern professional practice. We must recognize that solutions to the challenges will come from those inspired and committed individuals and institutions round the world with a vision of improved public health and patient safety. Most important in this venture, is the need for a new spirit of sharing of information and intelligence in line with the vision and aspirations of the Erice Declaration.
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