Pharmacovigilance and Drug Safety

Background

The World Health Organization (WHO) defines Pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem (1). Recently, its concerns have been widened to include:

• herbals

• traditional and complementary medicines

• blood products

• biologicals

• medical devices

• vaccines (2).

Over the past 50 years, pharmacovigilance has evolved as an international initiative as well as a scientific practice. The international recognition of the pressing need for worldwide collaboration on medicines safety monitoring came about largely as a result of the thalidomide tragedy in the early 1960s, in which many thousands of congenitally deformed infants were born as the result of in uterus exposure to a medicine (7). Following this tragedy, the Sixteenth World Health Assembly in 1963 adopted a resolution (WHA 16.36) that reaffirmed the need for early action with regard to the rapid dissemination of information on Adverse Drug Reaction (ADR). This resolution led to the creation of the WHO Pilot Research Project for International Drug Monitoring in 1968, which purpose was to develop an internationally- applicable system for detecting previously unknown or poorly understood adverse effects of medicines. The initiative currently has 118 official member states, and 29 associate member states (3).

From these beginnings emerged the practice and science of pharmacovigilance. Systems were developed in Member States for the collection of individual case histories of ADRs and evaluation of them. The collection of international ADR reports in a central database, would serve the important function of contributing to the work of national drug regulatory authorities, improve the safety profile of medicines, and help avoid further disasters2.

Important pharmacovigilance terms

• Adverse Event (AE): Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not (4) considered related to the medicinal product.

• Adverse Drug Reaction (ADR): A response which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function. (WHO, 1972). An adverse drug reaction, contrary to an adverse event, is characterized by the suspicion of a causal relationship between the drug and the occurrence, i.e. judged as being at least possibly related to treatment by the reporting or a reviewing health professional. In the European Union (EU) Directive 2010/84, which became applicable in July 2012 an adverse reaction is defined as: A response to a medicinal product which is noxious and unintended (5).

• Serious adverse event (SAE): An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse (6).

The importance and objectives of pharmacovigilance

Conceptually, pharmacovigilance is most commonly thought of in terms of post- marketing surveillance through ADRs reporting and through so-called phase IV clinical trials, however, pharmacovigilance is actually an integral part of a biopharmaceutical product’s entire life cycle, from clinical development to the introduction of follow-on generic products (2).

Therefore, pharmacovigilance is a much wider practice than simply monitoring ADRs. In fact, pharmacovigilance encompasses all the aspects within a biopharmaceutical product or technology’s life-cycle which concerns its safety and quality. As such, an effective pharmacovigilance system necessitates the active involvement of regulatory authorities, manufacturers and distributors, healthcare institutions and professionals, as well as patients (3).

The specific aims of pharmacovigilance are to:

• 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;

• contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use, and

• promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public (2).

In countries and regions such as the United States, Europe, Japan, Canada and Australia, pharmacovigilance is not a new concept but an established and essential part of the drug regulatory framework. However, even for the most advanced drug regulatory authorities, new gaps and challenges are constantly emerging which necessitate closer attention, as these gaps potentially (3) pose patient safety and public health concerns.

References

1. Pharmacovigilance. World Organization Health website.

http://www.who.int/medicines/areas/qualit y_safety/safety_efficacy/pharmvigi/en/. Accessed on 07/28/16.

2. The Importance of Pharmacovigilance - Safety Monitoring of medicinal products. Essential Medicines and Health Products Information Portal - World Health Organization. apps.who.int/medicinedocs/pdf/s4893e/s48 93e.pdf. Accessed on 07/28/16.

3. Pugatch M, Torstensson D, Laufer M. The Evolution of Pharmacovigilance - Labeling, Packaging and Pharmacopeia Standards. 2015; http://www.pugatch- consilium.com/reports/The%20Evolution% 20of%20Pharmacovigilance.pdf.

   Accessed on 07/28/16.

4. ICH Topic E2A Clinical Safety Data

   Management: Definitions and Standards for Expedited Reporting. European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/do cument_library/Scientific_guideline/2009/ 09/WC500002749.pdf. Accessed on 07/28/16.

5. Glossary ofPharmacovigilance.Organizationumc.org/graphics/25301.pdf. Accessed on 07/28/16.

6. CFR - Code of Federal Regulations Title 21 - Sec. 312.32 IND safety reporting. US FDA website. http://www.accessdata.fda.gov/scripts/cdrh /cfdocs/cfcfr/CFRSearch.cfm?fr=312.32. Accessed on 07/22/16.

7. Authoral work: Ferreira F. (2016). Define Pharmacovigilance. Explain the meaning of ADR, AE, and SAEs. On the basis of your own internet research explain why pharmacovigilance is important in drug discovery and healthcare"; James Lind Institute.

Assessed and Endorsed by the MedReport Medical Review Board