Pharmacovigilance: An Emerging Trend in Dental Practice of India

Introduction

The etymological origin for the word "pharmacovigilance" are: Pharmakon (Greek word for ‘drug’) and vigilare (Latin word for ‘to keep watch’).^1,2 WHO defines Pharmacovigilance as, it is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drugrelated problem.³ Pharmacovigilance is an important and essential part of clinical dental field.⁴ Pharmacovigilance mailny give emphasis on adverse drug reactions which are defined as any reaction to a drug which is harmful and unintended including lack of efficacy used for the prophylaxis, analysis or therapy of illness or for the modification of physiological function.¹

With an increase in number of newer highprofile drug withdrawals, the pharmaceutical industry and regulatory agencies have raised the standards of pharmacovigilance. Early detection of signals from both clinical drug trials and post marketing surveillance reporting have now been adapted by all leading pharmaceutical companies in order to identify the risks associated with the medicinal product and effectively manage the risks by applying strong risk management plans throughout the lifecycle of the drug.⁴ Signal detection and risk management of drug has added a new extent to the field of pharmacovigilance and as an evolving authority in dental field, it requires ongoing refinement in process to increase its applicability and value to public health.⁵

History of Pharmacovigilance

Pharmacovigilance started on 29 Jan about 170 years ago, when a young girl (Hannah Greener) from the north of England died after receiving chloroform anesthetic. As a result of other deaths and questions raised by the clinicians and the public about the safety of anesthesia, a commission was established to take a note on this problem. The commission exhorted English doctors, including the doctor in colonies, to report deaths caused by the anesthesia, later results were published.⁶

The US Federal Food and Drug Act were formed on June 30, 1906, and it established that drugs must be pure and free of any contamination. Furthermore, in 1911, this organization forbade false therapeutic indications of drugs. Later in USA (1962), the amendment, requiring safety and efficacy data of drugs before premarketing submission, was approved while in 1964, the “Yellow card” (YC) was structured in the UK, which was a specific form to compile a spontaneous report of drug toxicity.^7,8

Meanwhile many studies of observed adverse drug reactions were conducted between 1968 and 1982. In 1992, the European Society of Pharmacovigilance (ESoP) was funded, turned into the International Society of Pharmacovigilance (IsoP) with the aim to promote Pharmacovigilance, and enhance all aspects of the safe and proper use of medicines.⁹ In 1995, the European Medicines Agency (EMA) was formed.¹⁰ In 2001, EudraVigilance was funded. It is the official European database for managing and analyzing information on suspected adverse reactions to medicines which have been authorized for the market or being studied in European clinical trials.¹⁰ The main changes in the new legislation were.¹¹

• Modification of the definition of adverse drug reactions (ADR);

• Greater involvement of patients and citizens in Pharmacovigilance activities;

• Strengthening of the Eudravigilance database containing reports of suspected reactions reported by all EU Member States;

• Increasing transparency and timeliness of important information on Pharmacovigilance problems;

• Obligation of “additional monitoring” for the products contained in the specific list kept by the European Medicines Agency;

• Possibility to impose further safety and/or efficacy studies on the certificates of marketing authorization at the time of granting the trust;

• Establishment within the European Medicines Agency of the Pharmacovigilance Risk Assessment Committee (PRAC).The new legislation set-up measures to facilitate the performance of PV, called the Good Pharmacovigilance Practices (GVP). The guideline on Good Pharmacovigilance Practices is divided into two categories: modules covering major Pharmacovigilance processes and product- or population-specific considerations and second category were available for vaccines and biological medicinal products.¹² In November 2017, the new Eudra Vigilance format was launched; in particular, the marketing authorizations will have extended access to the EudraVigilance database to support the fulfillment of their Pharmacovigilance obligations.¹¹

History of Pharmacovigilance in India

Pharmacovigilance in India started from 1986. A formal Adverse Drug Reactions monitoring system was initiated with 12 regional centres, each covering a population of 50 million.¹ In year 2005 WHO supported and World Bank – funded National Pharmacovigilance Programme of India was made operational.^13-15

Pharmacovigilance in dentistry

Dentist’s advice a wide range of drugs in their routine clinical practice for treatment of various oral conditions; mainly include antibiotics, analgesics, anti-inflammatory, and antipyretics.^16,17 Safe use of Drug in dentistry is an important aspect in patients life.¹⁸ In the year 2005, report of bisphosphonate-associated osteonecrosis of the jaws made adverse drug reaction and dental pharmcovigilance is important to notice and take action by Food and Drug Admistration.¹⁹ Certain drugs have the ability to cause adverse oral reactions; a list of drugs that mainly cause various adverse oral cavity reactions, enabling dentists to be observant in reporting any side effects is mentioned in Table-1.^20,21 In day to day practice usually dentists are familiar with adverse drug reactions caused by drugs that they prescribe for treatment of mucosal conditions, still dentists also need to be aware of the other drugs that can cause oral reactions that require dental involvement.

The wider range of therapeutic options from different group of drugs makes dental practitioners to provide therapeutic interventions that previously were not possible. Dentists are responsible for understanding the common advantages and adverse effects of available drug choices and must dentist should self report any unexpected side effects from those drug treatments. Drug safety depends mainly on the monitoring of medicines once they have been marketed and prescribed. In order to make drugs more safe and effective in dental procedures, it is important to advise a culture of safe drug usage and immediate reporting to avoid major drug disasters.²² Post marketing adverse drug reactions reporting is important because tests in animals are insufficient to predict human safety, because clinical trials use a selective and limited number of patients for a short duration with different conditions than those involved in clinical dental practice.²³ Information about rare but serious adverse reactions, chronic toxicity of drugs, use of certain drugs in special groups such as children, pregnant women, or the elderly, or drug interactions often is incomplete or not reported. Clinical trials may be a better method to check drug’s efficacy than its safety during day to day clinical usage. Lack of knowledge and less interest of dentist may be the reason for a lack of vigilance in slow reporting of adverse drug reaction.²⁴

The pharmacovigilance process in dentistry

The basic component of the pharmacovigilance process in dentistry starts with adverse-event data generation from patients. Data collected through various methods from patients should be evaluated by manufactures for seriousness, expectedness, and causality.²⁵ Manufacturers are also required to maintain a database of all reports of adverse events regardless of their seriousness, expectedness, or causality.25 A strong regulatory framework with dental organizational support is important for introducing and implementing a robust pharmacovigilance program at a national level. Dental schools can collaborate and integrate organizational approaches to patient safety through the initiation of a medical safety team at an institutional level.²⁶ A medication safety team can be a stand-alone entity that reports directly to the institution’s board of directors or dental board or it can be a subcommittee of a larger group, such as a patient safety committee or a pharmacy and therapeutic committee.²⁷

Dentists need to be trained in pharmacovigilance programs. The mutual exchange of information regarding adverse drug reactions between the dentist, clinical pharmacist, pathologist, or microbiologist is crucial. Collaboration with clinical pharmacologists and clinical pharmacists can play a key role in the medication safety team, as professionals from a pharmacology/ pharmacy background have a focused knowledge in regard to drug therapy. By being part of a medication safety team, these specialists can play an important role in promoting a culture of safe drug usage via adverse drug reaction reporting (to establish a causal relationship between a drug and an adverse drug reaction, education through seminars/ workshops for drug safety, and surveillance.²⁸

Dentists need to be trained in pharmacovigilance programs. The mutual exchange of information regarding adverse drug reaction between the dentist, clinical pharmacist, pathologist, or microbiologist is crucial. Collaboration with clinical pharmacologists and clinical pharmacists can play a key role in the medication safety team, as professionals from a pharmacology/ pharmacy background have a focused knowledge in regard to drug therapy. By being part of a medication safety team, these specialists can play an important role in promoting a culture of safe drug usage via adverse drug reactions reporting (to establish a causal relationship between a drug and an adverse drug reactions), education through seminars/ workshops for drug safety, and surveillance.²⁸

Dentist and Adverse Drug Reaction

Adverse drug reaction may be difficult to recognize, as they can act via the same physiological and pathological pathways as other diseases. When evaluating a possible drug-related adverse drug reaction, confirm that the drug and the prescribed dosage are correct. The onset of an adverse drug reaction should be verified; it should manifest only after the drug is administered. The amount of time that elapses between the administration of the drug and the onset of the reaction must be established. After discontinuing the drug or reducing the dose, evaluate the suspected adverse drug reaction and monitor the patient’s status.²⁹ Restart the drug treatment and monitor the recurrence of any adverse events; alternative conditions (other than the drug) that might have caused the reaction should be analyzed as well. Using relevant evidence-based literature and dental experience, determine whether there are any conclusive reports that match or mirror this patient’s reaction. National pharmacovigilance centers and drug information centers are important resources for obtaining information on adverse drug reactions.²⁹

For new drugs, all suspected reactions including minor ones must be reported. For established or well-known drugs, all serious or unusual adverse drug reactions should be reported. In addition, a report should be filed whenever there is a given reaction with increased frequency, when suspected adverse drug reactions are associated with drug withdrawal, when adverse drug reactions result from an overdose or error in administering medication, when a lack of efficacy or suspected pharmaceutical defects (such as contamination during formulation and use of additives/ preservatives) are observed, and when there is a suspected adverse drug reactions in special fields of interest such as drug abuse and drug use during pregnancy and lactation.³⁰ The proper evaluation/ decision must be made while establishing a causal relation between a drug and an adverse drug reaction. Medication safety data can be aggregated and analyzed using tools that measure how changes in drug prescription trends and safety measures have modified the medication use process and affected the potential for patient harm. Adverse Drug Reaction Reporting is the most commonly associated with Pharmacovigilance and consumes a considerable amount of resources of government agencies or drug regulatory authorities or drug safety departments in pharmaceutical organizations. Adverse drug reaction reporting should be done within seven days and it includes the receipt, triage, data maintaining, evaluation, distribution, reporting of AE data.³¹ The foundation of adverse drug reactions reports may include solicited reports from patient support programs, reports from clinical or post-marketing studies, spontaneous reports from healthcare professionals or patients or other intermediaries, reports from literature sources, reporting is a regulatory requirement in most countries, reports from the media including social media and websites and reports reported to drug regulatory authorities themselves.³¹ For pharmaceutical companies adverse drug reaction reporting also provides data that play an important in assessing the risk-benefit profile of a given drug.³²

The ADR form can be collected through any pharmacovigilance centre. The filled ADR form can be submitted to the peripheral pharmacovigilance centre. After reviewing the form, the centre forwards it to the regional centre and after that it is propelled to the zonal centre.^33,34 The details are then statistically evaluated and forwarded to WHO-Uppsala Monitoring Committee (UMC).³⁵ It is the most important duty of any pharmacovigilance centre to report ball suspected adverse events of the drug if found.³⁵ ADRs and the type of ADRs that should be reported as mentioned in table-2.^36,37

The WHO has highlighted severe deficiencies in the culture of reporting adverse drug reaction. The method of generating a signal from adverse drug reaction is useful only if the signal is taken seriously and the action taken is immediate and addresses the level of concern. The drawback of pharmacovigilance today remains that drug companies continue to invest large sums of money in promotional launches instead of committing a portion of their funds to propagating training and awareness programs that would promote early reporting of advers drug reaction.³² Increasing and updating the awareness of pharmacovigilance in dental therapeutics requires proactive participation among health care professionals in general and especially among dentists.

Conclusion

While major advancements in the discipline of pharmacovigilance have taken place in the West, not much has been achieved in India. However, with more clinical trials and clinical research activity being conducted in India, India's pharmaceutical industry is now the third largest in the world in terms of volume, 14th in terms of value and now emerging as an important clinical trial hub in the world still there is a massive need to understand and implement pharmacovigilance. Developments in dental pharmacotherapeutics require dentists to constantly update their knowledge of new drugs, drug safety, and therapeutic trends. Dentists must acknowledge the reporting benefits the practice of adverse drug reaction in dentistry as a whole. Early and more proper documentation of adverse drug reaction will directly influence the speed with which problematic drugs can be withdrawn from the market, directly affecting the lives of patients and more safety will be achieved by the dental fraternity as well.