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.” Although pharmacovigilance is an important concept throughout the drug development process, the term is most frequently used within the context of monitoring the effects of medical drugs after they have been released to the market.
Some may wonder why we need post-market pharmacovigilance when drugs are heavily studied before ever becoming generally available. To understand the need for ongoing monitoring of adverse effects long past a drug is officially approved, it is important to understand the limitations of clinical trials in predicting the full breadth of drug interaction among widespread, general population usage:
- The population of patients receiving the drug in a clinical trial is a relatively small number, generally hundreds or a few thousands of patients, which may be too small of a sample to uncover patterns or trends for outliers; in contrast, in general use, the drug could be prescribed to many thousands or hundreds of thousands of patients, making it highly likely that additional reactions will make an appearance.
- Clinical trials are designed to control for unknown variables and protect high risk patients so, some patients, such as the elderly, are often not candidates for clinical trials, but may be candidates for general use of the drug.
- By design, clinical trials are rigorous and heavily monitored including restrictions on dosage, duration, and so on. With general use, monitoring is less stringent allowing for more flexible use of the drug which inherently introduces more variables (and risk).
In summary, as more and more patients adopt drug usage in the “real world,” there is a very real possibility that previously undetected adverse reactions will occur as the drug is exposed to patients and situations not controlled for during the clinical trial.
The Evolution of Pharmacovigilance
It may seem obvious that follow-up monitoring is critical to ensuring the safety of any new drug, but the concept wasn’t formalized until the 1960s, after it came to light that a drug known as thalidomide, which had been marketed as a mild sleeping pill, was responsible for the deformity of more than 20,000 infants.
Thalidomide first entered the market in 1957 as an over-the-counter sedative to combat the sleeplessness that was common in this post-war era. Advertisements for the drug stated that it was safe for everyone, including pregnant women. In fact, because the drug seemed to relieve morning sickness, it became popular among pregnant women. By 1960, thalidomide was being distributed and marketed in 46 countries and it has been estimated that one in seven people were taking the drug. It wasn’t until 1962 that the devastating effect of the drug was revealed.
Prior to the thalidomide disaster, new drugs were welcomed by the market without much additional scrutiny. After the tragedy, views changed dramatically and programs were put into place to formalize the monitoring of adverse drug reactions. One such program is the WHO PV Programme, which is now widely adopted across the globe, extending to over 134 member countries. The Food and Drug Administration (FDA) also heeded the lessons from the thalidomide incident, amending its Federal Food, Drug, and Cosmetic Act to require data on both safety and efficacy.
Over the years, there have been numerous other approved drugs that have been withdrawn from the market due to adverse events. Fortunately, in many cases, improved pharmacovigilance has led to faster recognition of adverse reactions. An example of this is bromfenan, a nonsteroidal anti-inflammatory drug (NSAID) that was withdrawn from general use just a year after approval due to serious hepatotoxic effects discovered as a result of pharmacovigilance activities.
Pharmacovigilance in Clinical Trials
According to the National Institutes of Health (NIH), clinical trials are “research studies that explore whether a medical strategy, treatment, or device is safe and effective for humans.” Clinical trials are mandated in the United State’s drug development process, which the Food and Drug Administration (FDA) outlines as having five broad steps:
- Discovery and development
- Preclinical research
- Clinical research
- FDA review
- FDA post-market safety monitoring
Pharmacovigilance is crucial during the clinical research (i.e. clinical trials) phase of drug development to determine whether a potential new drug is safe and effective. It is the practice of pharmacovigilance (i.e. detection, assessment, understanding and prevention of adverse effects) that enables researchers, drug developers, and the FDA to rigorously assess the safety of the new drug. Many drugs never make it past the clinical step because patients have adverse events early on.
Pharmacovigilance in Post-Market Safety Monitoring
As was discovered in the aftermath of the thalidomide tragedy, it is not sufficient to limit pharmacovigilance efforts to clinical trials only. In the thalidomide case, birth defects did not occur during the clinical trial phase as that was a variable that was controlled for in the study. What would have been helpful in reducing the sheer number of affected babies is continued surveillance after the drug became available for general use. The growing recognition that came after the thalidomide tragedy that it is impossible to have complete information about the safety of a drug at the time of approval is the reason why, today, pharmacovigilance is a crucial part of the final phase (step 5) in the drug development process, referred to as FDA post-market safety monitoring.
Post-market safety monitoring, also known as post-market surveillance, takes many forms. Below are a few examples:
- Voluntary (spontaneous) reporting: The FDA operates a program, called MedWatch, that allow manufacturers, health professionals, and consumers to report adverse events and problems associated with approved drugs. To maximize the benefits of this reporting system, it is important that there is thorough understanding in the marketplace of the differences between a drug’s known side effects and an adverse event. Side effects are a result that is in addition to the desired effect; adverse events are an unintended reaction. All too often, adverse events are assumed to be side effects, causing them to be under reported. This underscores the need for comprehensive training and collaboration among drug developers, practitioners, and patients.
- Patient registries: According to the Agency for Healthcare Research and Quality (US), a patient registry is “an organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure, and that serves one or more predetermined scientific, clinical, or policy purposes.” Some registries are mandated by public health authorities, such as is the case with drug product registries for thalidomide, clozapine, and isotretinoin; many more registries are instituted by patient advocate and medical associations, hospitals, specialized treatment centers, and even pharma industry. Regardless of the source, disease, medication or even medical device being tracked, post-approval studies and registries are excellent tools in the arsenal of post-market tracking and pharmacovigilance, although there are still significant challenges to overcome in terms of universally (and easily) sharing the electronic health record (EHR) and other research data that is vital to ensuring the comprehensiveness of any study.
- Active surveillance: According to the FDA’s website, it is developing a new national system to more quickly spot possible safety issues. Called the Sentinel Initiative, the system “will use very large existing electronic health databases—like electronic health records systems, administrative and insurance claims databases, and registries—to keep an eye on the safety of approved medical products in real time.”
- Sentiment monitoring: Drug developers have a vested interest in spotting potential drug complications. Their reputations and profits are at stake and so they also take an active role in pharmacovigilance. One method growing in popularity due to the rise of social media is sentiment monitoring. Sentiment monitoring closes the loop between consumers and pharmas by tracking what consumers are saying about drugs via Facebook, Twitter, Instagram, and other social networks. By analyzing social media feeds and the occurrence of drug names with correlating keywords, pharmas can look for trending mentions of adverse events on a macro level.
The Future of Pharmacovigilance
Technology plays a huge role in pharmacovigilance—both before and after a drug is released to the market. Effective sharing, aggregating, and mining of large data sets for the purpose of discovering unintended drug effects is key to the success of today’s—and future—pharmacovigilance efforts. Liaison Technologies’ data solutions for the life sciences and healthcare industries are at the forefront of this technology, providing innovative ways to manage patient registries, improve clinical trial collaboration, and harmonize data coming from any number of sources (e.g. EHR records, registries, federal databases, claims databases, etc.) into a quality whole ready for analysis and modeling.