What is Pharmacovigilace?

Pharmacovigilace:

 (ICH-E2A talks about pharmacovigilance)

Introduction:

Pharmacovigilance (PV or PhV), also known as drug safety, is the pharmacological science relating to the 

·        collection,

·        detection,

·        assessment,

·        monitoring, and

·        prevention of adverse effects with pharmaceutical products.

WHO says, “Pharmacovigilance (PV) is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.”

‘WHO established its Programme for International Drug Monitoring in response to the thalidomide disaster detected in 1961. Together with the WHO Collaborating Centre for International Drug Monitoring, Uppsala, WHO promotes PV at the country level. At the end of 2010, 134 countries were part of the WHO PV Programme. The aims of PV are to enhance patient care and patient safety in relation to the use of medicines; and to support public health programmes by providing reliable, balanced information for the effective assessment of the risk-benefit profile of medicines.’

The etymological roots for the word "pharmacovigilance" are: pharmakon (Greek for drug) and vigilare (Latin for to keep watch). As such, pharmacovigilance heavily focuses on adverse drug reactions, or ADRs, which are defined as any response to a drug which is noxious and unintended, including lack of efficacy (the condition that this definition only applies with the doses normally used for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological disorder function was excluded with the latest amendment of the applicable legislation). Medication errors such as overdose, and misuse and abuse of a drug as well as drug exposure during pregnancy and breastfeeding, are also of interest, even without an adverse event, because they may result in an adverse drug reaction.

Information received from patients and healthcare providers via pharmacovigilance agreements (PVAs), as well as other sources such as the medical literature, plays a critical role in providing the data necessary for pharmacovigilance to take place. In fact, in order to market or to test a pharmaceutical product in most countries, adverse event data received by the license holder (usually a pharmaceutical company) must be submitted to the local drug regulatory authority.

Ultimately, pharmacovigilance is concerned with identifying the hazards associated with pharmaceutical products and with minimizing the risk of any harm that may come to patients. Companies must conduct a comprehensive drug safety and pharmacovigilance audit to assess their compliance with worldwide laws, regulations, and guidance.

Common terms used in pharmacovigilance:

·         Adverse drug reaction:

Adverse drug reaction is a side effect (non intended reaction to the drug) occurring with a drug where a positive (direct) causal relationship between the event and the drug is thought, or has been proven, to exist.

·         Adverse event (AE) :

Adverse event is a side effect occurring with a drug. By definition, the causal relationship between the AE and the drug is unknown.

·         Benefits :

Benefits are commonly expressed as the proven therapeutic good of a product but should also include the patient's subjective assessment of its effects.

·         Causal relationship: 

Causal relationship is said to exist when a drug is thought to have caused or contributed to the occurrence of an adverse drug reaction.

·         Clinical trial :

Clinical trial  (or study) refers to an organised program to determine the safety and/or efficacy of a drug (or drugs) in patients. The design of a clinical trial will depend on the drug and the phase of its development.

·         Control group :

Control group is a group (or cohort) of individual patients that is used as a standard of comparison within a clinical trial. The control group may be taking a placebo (where no active drug is given) or where a different active drug is given as a comparator.

·         Dechallenge and rechallenge :

Dechallenge and rechallenge refer to a drug being stopped and restarted in a patient, respectively. A positive dechallenge has occurred, for example, when an adverse event abates or resolves completely following the drug's discontinuation. A positive rechallenge has occurred when the adverse event re-occurs after the drug is restarted. Dechallenge and rechallenge play an important role in determining whether a causal relationship between an event and a drug exists.

·         Effectiveness :

Effectiveness is the extent to which a drug works under real world circumstances, i.e., clinical practice.

·         Efficacy :

Efficacy is the extent to which a drug works under ideal circumstances, i.e., in clinical trials.

·         Implied causality :

Implied causality refers to spontaneously reported AE cases where the causality is always presumed to be positive unless the reporter states otherwise.

·         Individual Case Safety Report (ICSR):

Individual Case Safety Report (ICSR)  is an adverse event report for an individual patient.

·         Life-threatening :

Life-threatening refers to an adverse event that places a patient at the immediate risk of death.

·        Phase refers to the four phases of clinical research and development: I – small safety trials early on in a drug's development; II – medium-sized trials for both safety and efficacy; III – large trials, which includes key (or so-called "pivotal") trials; IV – large, post-marketing trials, typically for safety reasons. There are also intermediate phases designated by an "a" or "b", e.g. Phase IIb.

·         Risk is the probability of harm being caused, usually expressed as a percent or ratio of the treated population.

·         Risk factor :

Risk factor is an attribute of a patient that may predispose, or increase the risk, of that patient developing an event that may or may not be drug-related. For instance, obesity is considered a risk factor for a number of different diseases and, potentially, ADRs. Others would be high blood pressure, diabetes, possessing a specific mutated gene, for example, mutations in the BRCA1 and BRCA2 genes increase propensity to develop breast cancer.

·         Signal :

Signal is a new safety finding within safety data that requires further investigation. There are three categories of signals: confirmed signals where the data indicate that there is a causal relationship between the drug and the AE; refuted (or false) signals where after investigation the data indicate that no causal relationship exists; and unconfirmed signals which require further investigation (more data) such as the conducting of a post-marketing trial to study the issue.

·         Temporal relationship :

Temporal relationship  is said to exist when an adverse event occurs when a patient is taking a given drug. Although a temporal relationship is absolutely necessary in order to establish a causal relationship between the drug and the AE, a temporal relationship does not necessarily in and of itself prove that the event was caused by the drug.

·         Triage :

Triage refers to the process of placing a potential adverse event report into one of three categories: 1) non-serious case; 2) serious case; or 3) no case (minimum criteria for an AE case are not fulfilled).

Adverse event reporting:

One of the fundamental principles of adverse event reporting is the determination of what constitutes an Individual Case Safety Report (ICSR). 

Individual Case Study Report (ICSR) is an adverse event report for an individual patient and is source of data in pharmacovigilance.

The main focus of ICSRs are reports from healthcare providers and patients in member countries of the WHO Programme. A WHO global individual case safety report database (VigiBase) is maintained and developed on behalf of the WHO by the UMC.

During the triage phase of a potential adverse event report, it is important to determine if the "four elements" of a valid ICSR are present: (1) an identifiable patient, (2) an identifiable reporter, (3) a suspect drug, and (4) an adverse event.

If one or more of these four elements is missing, the case is not a valid ICSR. Although there are no exceptions to this rule there may be circumstances that may require a judgment call. For example, the term "identifiable" may not always be clear-cut. If a physician reports that he/she has a patient X taking drug Y who experienced Z (an AE), but refuses to provide any specifics about patient X, the report is still a valid case even though the patient is not specifically identified. This is because the reporter has first-hand information about the patient and is identifiable (i.e. a real person) to the physician. Identifiability is important so as not only to prevent duplicate reporting of the same case, but also to permit follow-up for additional information.

VigiBase:

VigiBase is a World Health Organization’s (WHO) global Individual Case Safety Report (ICSR) database that contains ICSRs submitted by the participating member states enrolled under WHO’s international drug monitoring programme. It is the single largest drug safety data repository in the world. Since 1978, the Uppsala Monitoring Centre (UMC; established in Uppsala, Sweden) on behalf of WHO, have been maintaining VigiBase. Vigibase is used to obtain the information about a safety profile of a medicinal product. These data are used by pharmaceutical industries, academic institutions and regulatory authorities for statistical signal detection, updating periodic reports, ICSR comparisons with company databases and studying the reporting patterns.  The data (pre-dominantly post-marketing serious and non-serious cases) is collected from each of its 110 member states which currently comprises to over 10 million ICSRs (October 2014). About a hundred thousand ICSRs are added each year.

Contributors:

It is mandatory for all the participating countries (125 members states and 28 associate members) to submit ICSRs to UMC via its appointed national centre based in the respective member states, authorized by its competent authority or the health authority itself. These reports are usually sent to the respective national centre by marketing authorization holders, health care professionals (HCP), consumers or any regional centre. Most of participating member have a well established system for collection of ICSRs. These submissions are in ICH E2B format and are reported more than once a month or at least every quarter. For some member states that lack an E2B compatible database for ICSR management, UMC in collaboration with ‘’Swissmedic’’ has developed ‘’VigiFlow’’, a web-based ICSR management system. VigiFlow functions as a national ICSR database management system and analysis tool, through which cases are sent to UMC.

Beneficiaries:

Identify the earliest possible pharmacovigilance signals, the usage of VigiBase is permitted and accessed by the following authorities:

1.  Signal review team and UMC employees have full access to data, including narratives and laboratory values.

2.     Paying customers: Pharmaceutical companies or HCPs can request for the data by paying stipulated fees, provided the data is being used for academic purposes or in public interest.

references:
https://www.ich.org/page/efficacy-guidelines
https://en.wikipedia.org/wiki/Pharmacovigilance
https://www.idmp1.com/wiki/icsr/
https://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/
http://www.vigiaccess.org/