For the benefit of those hearing the term ‘Pharmacovigilance’ (PV) for the first time, let me rephrase what is already available in the public domain, the word “Pharmacovigilance” is a neoclassical compound derived from “pharmakon” (Greek for ‘drug’) and “vigilare” (Latin for ‘to keep watch’).
What does it really mean?
In lay terms, PV entails all the steps that could lead to making drugs safer (for consumption) by studying the side effects of drugs. Undesired side effects which can be attributed to the consumption of drugs are called ‘Adverse Drug Reactions’ or ADRs. (scroll down for the acronym guide) Some of the key steps involved in PV are collection of reports on side-effects of drugs, assessment of reported side effects, classification of reports into ADRs and non- ADRs, and finally implementation of corrective regulatory actions (nationally or globally) based on the analysis of ADRs. Medication errors such as drug overdose, drug interaction, Drug Misuse/Abuse by patients and the sale of Counterfeit Medicines are also areas of interest for PV. It is important to know that PV programs apply not only to drugs but also vaccines and herbal products.
Studies indicate that approximately 4% (non-elderly patients) to 16% (elderly patients) of all hospitalizations are due to ADRs [i] and that 88% of ADR-related elderly hospitalizations are preventable. In the USA, ADRs occur during approximately 10–20% of hospitalizations i.e., in-patient cases [ii]. It is estimated that the total cost of drug related illness and mortality is between US $30 billion and US $130 billion annually [iii].
An ‘Adverse Event’ (AE) is another important concept in PV. It is basically an unexpected medical event that occurred while a drug was being consumed. ADR cases are a subset of AE cases, where it can be established that the AE actually occurred due to a drug and that the AE was not due to some external reason. With increasing awareness about drug safety, the number of AE reports being received by the US FDA has almost doubled from 2010 to 2015 (see figure below).
With the advent of social media, mobile applications and SMS-based reporting, the volume of AE reports is going to increase at a much faster rate, indicating a positive development for drug safety.
Who are the different stakeholders and how does PV benefit them?
We have six major stakeholders in PV:
- Pharmaceutical Companies
- Contract Research Organisations (CROs)
- National Drug Regulatory Authorities (e.g., FDA, TGA, CDSCO) and Public Health Institutions (e.g., WHO)
- Healthcare Providers (Physicians, Hospitals etc.)
- Pharmacies, and
Drugs are manufactured by pharmaceutical companies, but they cannot be released in the mass market until manufacturers demonstrate the efficacy and safety of the drug through several types of clinical trials. Pharmaceutical companies usually outsource the management of clinical trials to specialized agencies known as CROs. Once the clinical trials are complete, the findings are then analysed and submitted to the respective National Drug Regulatory Authorities for approval to release the drugs in the respective market. The onus is now on regulatory bodies to assess whether to release the drugs in the market. They assess if the benefits of releasing the drug significantly outweigh the risk of any adverse side-effects from this drug. Once the drug is approved and available in the market, the drug can be prescribed by physicians and sold to consumers/patients via pharmacies. Finally, the regulatory bodies in conjunction with pharmaceutical companies carry out an important exercise called Post-Marketing Surveillance (PMS) to monitor the safety of a new drug. While PMS is the responsibility of the sponsor for newly released drugs, PV is a much broader area that includes PMS and places the onus on everyone (physicians, patients, healthcare providers) to proactively report AEs to their respective regulatory bodies for all drugs available in the market. Maintaining patient safety through the active monitoring of drugs is the primary objective of establishing drug regulatory bodies in a country.
For patient safety, any of the following corrective steps can be taken by regulatory bodies depending on the findings from ADR analysis:
- Ban the drug from the respective market;
- Allow limited release of the drug with certain conditions;
- Mandate that an additional warning of the risk of adverse effect be conveyed to patients: a. directly through guides in the form of paper handouts in the drug packet; or b. through physicians and healthcare providers.
Below are some statistics on drug recalls by the US FDA[iv]
Due to the risk of heavy financial losses, as a result of above mentioned corrective steps, it is also in the business interests of pharmaceutical companies to implement and support effective and efficient PV programs on an on-going basis. Healthcare providers and pharmacies too have a lot at stake since they interact directly with patients who unquestionably are the largest stakeholder in the PV process.
Why do Adverse Drug Reactions (ADRs) occur despite the clinical trials?
Clinical trials carry a high degree of risk and patients volunteer to be a part of the process mostly because conventional medicine did not work for them. It is logical to expect that most patients would prefer to avoid participating in clinical trials due to the risks involved. As a result of this, it is difficult to get a representative sample of patients whose response/reaction to a new drug would be representative of what would be seen in the mass population. Moreover, every individual has a unique genetic makeup and hence their bodies are bound to respond differently to not just different medicines but also different food items. Thereby, sample selection and accurate statistical analysis are two major challenges in ensuring that the efficacy and safety of the drug during trials will generalize to the mass markets.
Post-Marketing Surveillance (PMS) and how it is done
Effective PMS requires a concerted effort from all of the stakeholders. Today, almost every country has a PMS program that allows healthcare providers and patients to report AEs through online/paper-based forms or through mobile applications to either pharmaceutical companies or directly to regulatory bodies. The image below depicts the reporting workflow in the USA [v].
The reporting statistics on direct regulatory reporting vs reporting through manufacturers differ for each country. However, by leveraging commonly used tools (SMS, mobile apps) and with the advent of advanced technology (NLP, AI etc.) to analyse reports in natural language (or free-text), direct reporting is set to become a disruptive process in PV. As a matter of fact, Nigeria is one of the few (or only?) countries to implement a national level SMS based AE reporting system called ‘PRASCOR’ [vi].
The potential of spontaneous ADR reporting by consumers, its challenges and possible solutions is a topic that requires a separate blog post in itself! Signing off this post with a list of countries that have simplified consumer ADR reporting through mobile applications:
ADR: Adverse Drug Reaction
ADR PvPI: ADR Pharmacovigilance Programme of India
AE: Adverse Effect
AI: Artificial Intelligence
CDSCO: Central Drugs Standard Control Organization
CRO: Contract Research Organization
FDA: Food and Drug Administration
NLP: Natural Language Processing
PMS: Post-Marketing Surveillance
PRASCOR: Pharmacovigilance Rapid Alert System for Consumer Reporting
SMS: Short Messaging Service
TGA: Therapeutic Goods Administration
WHO: World Health Organization
Note: This article was originally posted on the blog Common Sciense