Pharmacovigilance: A Prospective
WHO definition of the term ‘pharmacovigilance’ as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems.” (WHO UMC -2002).
The United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) defines pharmacovigilance as
The process of:
(a) Monitoring medicines as used in everyday practice to identify previously unrecognised or changes in the patterns of their adverse effects;
(b) Assessing the risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe use;
(c) Providing information to users to optimize safe and effective use of medicines;
(d) Monitoring the impact of any action taken.
(http://www.liv.ac.uk/pharmacovigilance/pages/pharmacovigilance.htm
Pharmacovigilance is the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medications, biologicals, herbalism and traditional medicines with a view to:
· Identifying new information about hazards associated with medicines
· Preventing harm to the patients.
Pharmacovigilance require any medicinal product to successfully complete each of three carefully controlled phases in ordered succession from phase 1 to phase 3 before being granted a marketing authorization. These phases are conducted to establish safety, tolerability, quality and efficacy of medicinal product before being made available to general population.
Pre-marketing approval comprises of three phases which are as follows:
Phase I
Phase I defined as the first step of testing a medicinal product in Humans after Pre-Clinical testing. This phase has been conducted in healthy volunteers and among patients who already have the disease (for example, chemotherapy drugs for cancer) with primarily concerned with safety rather than efficacy.
Phase II
This phase of trial aim to determine at which dose the maximal benefit may be delivered with the minimal level of risk. The participants are patients who already have the disease for which the drug may be able to offer a new treatment.
Phase III
This phase of trial has been conducted on a far larger scale (from the hundreds to the thousands of patients) with the final aim of obtaining a Marketing Authorization for the drug.
Pre-marketing trials, however, cannot completely predict the post-marketing effect of use in daily practice due a number of reasons:
- Clinical trials involve relatively small numbers of people exposed to the drug, preventing the detection of rare adverse drug reactions.
- Drugs are evaluated for a defined indication in clinical trials of relatively short duration in restricted categories of people.
- The effects of concomitant disease and drugs are not normally studied during clinical trials.
- Special patient groups such as children (Pediatrics) or the elderly (Geriatrics) or pregnant women are not normally represented in clinical trials.
- The limited periods of the pre-marketing clinical trials will not reveal the long-term effects of the drug.
Therefore, there is a need to monitor the safety of the drug after it has been released for general use. This is the primary function of post-marketing surveillance studies, and is part of the science of pharmacovigilance.
Adverse Drug reaction (ADR)
Any noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions.
Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction
Any untoward medical occurrence that at any dose:
– results in death,
-is life-threatening,
-requires inpatient hospitalization or prolongation of existing hospitalization,
-results in persistent or significant disability/incapacity, or
-is a congenital anomaly/birth defect.
Need for Pharmacovigilance
Pharmacovigilance is needed for the prevention of drug-induced human suffering and to avoid financial risks associated with unexpected adverse effects. In conclusion, medicines on the market need continuous monitoring in every country.
Efficacy and safety of a new drug are generally studied on a few thousand carefully selected and followed up trial subjects and patients according to strictly defined criteria. For this reason only very frequent adverse reactions and mainly those depending on the drug’s pharmacological properties can be observed during its clinical development.
Once the product has been placed on the market, a much larger, and also often polymorbid population will be exposed, which may lead to a change in the drug’s so far known safety profile. Adverse drug reactions can then be observed more frequently, including those occurring only sporadically and independently of the pharmacological properties of the substance. These new adverse reactions should be reported without delay as a contribution to a potentially still incomplete safety profile. If such information is consistently forwarded to the competent authorities they are able to identify and tackle unknown risks related to the marketed drugs. (http://www.swissmedic.ch/).
Pharmacovigilance is needed in every country, because there are differences between countries (and even regions within countries) in the occurrence of adverse drug reactions and other drug-related problems. This may be because of differences in:
• Drug production
• Distribution and use (e.g. indications, dose, availability)
• Genetics, diet, traditions of the people
• Pharmaceutical quality and composition (excipients) of locally produced pharmaceutical products
• The use of non-orthodox drugs (e.g. herbal remedies) which may pose special toxicological problems, when used alone or in combination with other drugs.
Goals of Pharmacovigilance
· improve patient care and safety in relation to the use of medicines and all medical and paramedical interventions;
· improve public health and safety in relation to the use of medicines;
· detect problems related to the use of medicines and communicate the findings in a timely manner;
· contribute to the assessment of benefit, harm, effectiveness and risk of medicines, Leading to the prevention of harm and maximization of benefit;
· encourage the safe, rational and more effective (including cost-effective) use of medicines; and
· promote understanding, education and clinical training in Pharmacovigilance and its effective communication to the public (Kurakowa et al. 2000, 5)
Adverse Drug Reactions Monitoring
An international system for monitoring adverse reactions to drugs (ADRs) using information derived from Member States was established in 1971. WHO Headquarters is responsible for policy issues while the operational responsibility for the programme rests with the WHO Collaborating Centre for International Drug Monitoring, Uppsala Monitoring Centre, (UMC), in Sweden. The system started with 10 countries that had already established national systems for spontaneous adverse reaction reporting and who agreed to contribute data. For an effective international system to become operative, a common reporting form was developed, agreed guidelines for entering information formulated, common terminologies and classifications prepared and compatible systems for transmitting, storing and retrieving and disseminating data were created. (http://www.who.int/medicines/areas/quality_safety, 6)
Adverse Drug Reactions Monitoring in India
In 1997, India joined the World Health Organization (WHO) Adverse Drug Reaction Monitoring Programme based in Uppsala, Sweden. Three centres 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 centres in Mumbai (KEM Hospital) and Aligarh (JLN Hospital, Aligarh Muslim University). These centres were to report ADRs to the drug regulatory authority of India. The major role of these centres was to monitor ADRs to medicines marketed in India. This attempt was unsuccessful and hence, again from January 2005, the WHO-sponsored and World Bank-funded National Pharmacovigilance Program for India was made operational. 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. Now, Adverse Drug Reactions monitoring in India performed according to Pharmacovigilance programme of India (PvPI) which was launched in July, 2010 (Rupesh M. Kumar et al. 2011,7)
- Pharmacovigilance programme of India launched in July, 2010. It is nation-wide programme initiated by Central Drugs Standard Control Organization (CDSCO), Directorate General of Health Services under the aegis of Ministry of Health & Family Welfare, Government of India in collaboration with Indian Pharmacopoeia commission, Ghaziabad for protecting the health of the patients by assuring drug safety and also introduces medical professionals to concept, practice and importance of ADR monitoring.
- The programme shall be coordinated by the Indian Pharmacopoeia commission, Ghaziabad as a National Coordinating Centre (NCC). The centre will operate under supervision of a steering committee. The ultimate goal of PvPI is to ensure that the benefit of use of medicine outweighs the risks and thus safeguard the health of the Indian population.
- In collaboration with UMC National Coordinating Centre with zonal and sub zonal centres has achieved a great deal in collecting and analyzing case reports of ADRs, distinguishing signals from background ‘noise’, making regulatory decisions based on strengthened signals and alerting prescribers, manufacturers and the public to new risks of adverse reactions (CDSCO web domain, 8).
- Pharmacovigilance programme of India emphasize on Focused monitoring of drugs therefore safety of India population can be established before drug being made available to Indian population. In this way occurrence of serious adverse reactions can be prevented.
CURRENT STATUS OF ADR MONITORING CENTRES UNDER PHARMACOVIGILANCE PROGRAMME OF INDIA (PvPI)
Total number of ADR Monitoring Centres are 202 including 9 Regional Training centres and 1 National Coordinating Centre which is Indian Pharmacopoeia Commission, Ghaziabad, Indai.
Requirements for joining the PvPI for Drug Monitoring
The basic requirements to join PvPI are:
1. The Medical Council of India (MCI) approved medical colleges & hospitals or medical/central/autonomous institutes or public health programmes or corporate hospitals.
2. Technical competence to fulfil reporting requirements to NCC-PvPI i.e. well qualified staff to meet the technical requirements of PvPI.
Causality Assessment
Development of an event while taking a medication doesn’t establish that the drug is the source of the problem. The determination of the relationship between drug and event is a difficult, though, essential part of documenting adverse reactions. In order to minimize the suffering of patients from ADRs it is essential, though sometimes difficult, to recognize ADRs and to establish a causal relationship between the drug and the adverse event. To determine the likelihood of a relationship between the drug and an event, assessment of causality is done.
Causality assessment is the evaluation of the likelihood that a particular treatment is the cause of an observed adverse event. It assesses the relationship between a drug treatment and occurrence of adverse event. Causality is the relationship between an event (the cause) and a second event (the effect), where the second event is understood as a consequence of the first.
It is an important component of pharmacovigilance, contributing to better evaluation of the risk-benefit profiles of the medicines and is an essential part of evaluating ADR reports in early warning systems and for regulatory purpose. (Taofikat B. et al. 2008, 10)
It is the method by which extent of relationship between a drug and a suspected reaction is established. Standardized case causality assessment has become a routine at Pharmacovigilance centers around the world. It decreases ambiguity of the data and helps in prevention of erroneous conclusion. It neither eliminates nor quantifies uncertainty but, at best, categorizes it in a semi-quantitative way. There are several step-wise approaches that might be helpful in recognizing and assessing possible drug-related ADRs. Many causality methods have been proposed in order to assess the relationship between a drug and an adverse event in a given patient, ranging from short questionnaires to comprehensive algorithms. Some of these methods are too complex and time consuming and their application in routine clinical practice has been limited. The causality assessment system proposed by the World Health Organization Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (WHO-UMC), and the Naranjo probability scale are the general accepted and most widely used methods for causality assessment in clinical practice as they offer a simple methodology.
Undertaking some form of causality assessment of suspected ADRs is part of routine Pharmacovigilance practice and it contributes to better evaluation of the risk- benefit profiles of medicines and is also an essential part of evaluating ADR reports in early warning systems and for regulatory purposes, but potentially without value if reproducibility and quality of the data are consistently poor.
Different methods of causality assessment
Various methods have been published for assessing ADRs, but because there are no defined diagnostic criteria or categories, inter-rater and intra-rater variability can be large. Currently there is no universally accepted method for assessing causality of ADRs.
Several methods that can be used to make a causality assessment of ADRs reports are:
• The literature (9 points of consideration – Morges, Switzerland , 1981)
• Probability calculation (Bayes’ Theorem)
• Aetiological – Diagnostic Systems (Bénchiou’s group method)
• French imputation systems
• The European ABO Systems
• The US Reasonable Possibility Systems
• The Naranjo ADR Probability Scale
• WHO Causality Categories
Of all these methods, the most commonly used methods are WHO-UMC causalitycategories and Naranjo Probability Scale (Agbabiaka et al, 2008, 10).
WHO-UMC causality assessment system
WHO-UMC system has been developed in consultation with the National Centres participating in the Programme for International Drug Monitoring and is meant as a practical tool for the assessment of case reports. It is basically a combined assessment taking into account the clinical-pharmacological aspects of the case history and the quality of the documentation of the observation with less prominent role of other criteria such as previous knowledge and statistical chance in the system. It is recognized that the semantics of the definitions are critical and that individual judgments may therefore differ. This method gives guidance to the general arguments which should be used to select one category over another (WHO-UMC, 2005, 11).
WHO-UMC SCALE for causality assessment
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Causality term
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Assessment criteria
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Certain
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Event or laboratory teat abnormality, with plausible time relationship to drug intake.
Cannot be explained by disease or other drugs.
Response to withdrawal plausible(pharmacologically, pathologically)
Event definitive pharmacologically or phenomenogically (i.e., an objective and specific medical disorder or a recognized pharmacologic phenomenon)
Rechallenge satisfactory, if necessary.
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Probable/likely
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Event or laboratory test abnormality, with reasonable time relationship to drug intake.
Unlikely to be attributed to disease or other drugs.
Response to withdrawal clinically reasonable.
Rechallenge not required.
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Possible
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Event or laboratory test abnormality, with reasonable time relationship to drug intake.
Could also be explained by disease or other drugs.
Information on drug withdrawal may be lacking or unclear.
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Unlikely
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Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible).
Disease or other drugs provide plausible explanation
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Conditional/unclassified
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Event or laboratory test abnormality.
More data for proper assessment needed, or
Additional data under examination.
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Unassessable/unclassifiable
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Report suggesting an adverse reaction.
Cannot be judged because information is insufficient or Contradictory.
Data cannot be supplemented or verified.
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Naranjo Probability Scale
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NARANJO’s ALGORITHM
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Perhaps the most commonly used causality assessment method, which has gained popularity among clinicians because of its simplicity, is the Naranjo probability scale. It is a structured, transparent, consistent and easy to apply assessment method (Naranjo et al, 1981, 12)
Naranjo CA, Busto U, Sellers EM, et al. (1981). “A method for estimating the probability of adverse drug reactions”. Clin. Pharmacol. Ther. 30 (2): 239–45. doi:10.1038/clpt.1981.154.PMID 7249508