Post-marketing Surveillance of Prescription Drugs

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What is post-marketing surveillance of prescription drugs? How is it done? What does it mean for clinicians? 

As prescription drug abuse continues to be a problem, new technologies are being developed to track prescription drug abuse around the country. In this roundtable, clinicians and researchers will discuss post-marketing surveillance of prescription drugs, how it is done, and what the implications are for clinicians.

Nathaniel Katz, M.D., M.S.,:

Nathaniel Katz, M.D., M.S., is the Senior Consulting Advisor at Inflexxion Inc. in Newton, MA. Dr. Katz is an Adjunct Assistant Professor of Anesthesia at Tufts University School of Medicine. Dr. Katz was an Associate Editor at the Clinical Journal of Pain, and Associate Editor (Pain) for the Encyclopedia of Neurological Sciences.

Nathaniel Katz will be answering the question, what does post-marketing surveillance mean to clinicians?

Post marketing surveillance allows regulatory, pharmaceutical industry, clinicians, and public health community to continually evaluate the safety of a product in a "real-world setting". Clinical trials conducted prior to the launch of a product cannot fully assess the effects of drugs in specific subgroups (minorities, geographic areas, age groups, etc.), interactions with other drugs, nor interactions among patients with complicated medical histories. Additionally, such trials may not be able to detect uncommon, but serious life threatening adverse events or events that require a long time period to manifest. Surveillance data provides supplementary safety information that may not be uncovered in homogenous conditions of pre-market clinical trials.

In regards to prescription opioid abuse, post marketing surveillance provides clinicians information needed to better assess the risk benefit ratios for particular opioids in their area. The prevalence of prescription opioid abuse varies among particular populations and geographic locations. Post marketing surveillance can detect "hot spots"of abuse across the country in order to guide the implementation of interventions and inform clinicians of issues in their area to guide appropriate prescribing. For clinicians, post marketing surveillance provides a linkage between drug safety information and prescribing guidelines.

What is post-marketing surveillance of prescription drugs? How is it done? What does it mean for clinicians? 

As prescription drug abuse continues to be a problem, new technologies are being developed to track prescription drug abuse around the country. In this roundtable, clinicians and researchers will discuss post-marketing surveillance of prescription drugs, how it is done, and what the implications are for clinicians.

Stephen F. Butler, Ph.D:

Stephen F. Butler, Ph.D is the Senior Vice President and Chief Science Officer at Inflexxion, Inc. in Newton, MA.

Stephen Butler will answer the question what is post-marketing surveillance of prescription drugs?

Post-marketing surveillance of potentially addictive medications (generally Schedule II or III) began in earnest following the OxyContin outbreak in 1999 or 2000. In his book, Pain Killer, the New York Times reporter, Barry Meier (2003) documented this so-called "epidemic." The book portrays the frustration of providers, law enforcement officials, FDA officials, and the pharmaceutical company in early efforts to determine whether an outbreak was occurring and the role played by a particular product. At that time, no one had any data to which they could turn. Reports from physicians, addiction counselors, coroners, and police were sent to the FDA about an upsurge of abuse and deaths in local, often rural communities. These reports typically mentioned OxyContin as the problem. Up to that point, OxyContin, an extended release version of oxycodone, was thought to be less abusable, since the formulation's gradual release of the opioid was supposed to be associated with less "high" than the traditional versions (such as Percocet), where the all the opioid is released immediately. However, what appeared to be happening was that abusers could simply chew or crush the OxyContin and get an immediate release of 12 hours worth of active ingredient—leading to rapid addiction and overdoses.

In the early months of 2000, FDA officials were literally sifting through dueling anecdotes from local health and safety authorities, on the one hand, and those compiled by the pharmaceutical company on the other. The pharmaceutical company maintained that there was a general increase in opioid abuse, not just OxyContin. There was no particular problem with their product. Rather, the outbreak was due to a media frenzy. A later study, published in 2003 by the US Government Accountability Office (GAO), concluded that they could not assess the relationship between the increased availability of OxyContin and locations where it was abused and diverted because the data on abuse and diversion were not reliable, comprehensive, or timely. This lack of data resulted in ambiguity that not only fostered a lag in the authorities' ability to respond, but to this day prevents resolution as to whether the OxyContin "epidemic" was truly a product-specific epidemic or was merely a media construction.

Several groups, including a taskforce of the College on Problems of Drug Dependence (CPDD), recommended a series of actions, among which was establishing comprehensive post-marketing surveillance systems. This notion was based on the concept of public health disease surveillance. Public health surveillance has a long history of monitoring various diseases (especially infectious diseases) to determine whether and where an outbreak is occurring to give public health officials time to develop plans and to implement interventions. The Centers for Disease Control tracks 52 diseases and reports on these weekly. Following the anthrax attacks/scares that occurred in the wake of 9/11, larger and more systematic efforts were made to set up systems that can provide early detection of an outbreak of symptoms that might indicate a bioterrorism attack. Development and testing of these surveillance systems continues today.

Post-marketing surveillance of prescription medications builds on an analogy to disease surveillance and has adopted many of its designs and methods. That is, as a case of abuse, addiction, or death related to prescription opioids comes to the attention of some authority, that case is noted in some database and tracked to determine whether and where there is an increase in rates of abuse of a particular medication. In the case of medications, that can be an increase in a particular compound (such as hydrocodone or oxycodone) or a particular product (e.g., Vicodin or OxyContin). To be useful, post-marketing surveillance should have good geographic specificity and spread, and collect and analyze data in a "real-time" or "near real-time" fashion. As the GAO noted, databases on abuse rates that were in place in 2000 regularly took two years or more before data were ready to be analyzed—too late to be of much public health use. Modern surveillance systems are working out how to collect data that can be immediately analyzed and tracked, even on a daily basis.

Usually, surveillance involves determining if a target condition (in this instance, abuse cases) is increasing over a baseline rate or what would ordinarily be expected. For instance, if influenza is being tracked, the public health question is whether the number of cases this year is greater than would be expected in a normal year. In this way, the outbreak is defined in relation to some baseline occurrence of the disease. When the number of cases is significantly greater than the baseline, a "signal" is detected and reported to public health authorities. Likewise, abuse surveillance assumes that each community has a "baseline" level of abuse (since abuse of abusable substances does occur) and that a signal will entail a significant increase over this level of abuse. A signal could then lead to intervention. Obviously, and we have found this in our work, even the baseline abuse rates of some communities are extremely high. A surveillance system should be able to identify such high risk areas and track ups and downs in this baseline rate as well.

A major difference between surveillance of abuse and surveillance of disease is that, while cases of illness are usually detected in medical settings (hospitals, doctor offices, emergency departments), cases of abuse come into contact with authorities through a variety of points, including hospitals and emergency departments, but also admissions to substance abuse treatment, calls to poison control centers, or criminal justice agencies. Which of these provides an early warning is not yet clear, and systems have been developed to track data in all of these areas. One might ask about admissions to substance abuse treatment. If admission to treatment occurs at the end stage of an addiction, shouldn’t treatment admissions be a following indicator? Yet, many long-time addicts who enter treatment are connoisseurs of the various opioid products, and if a particular opioid product is increasing in availability and abuse in a local community, there is reason to believe that new admissions will report using it and allow a signal to be detected. What types of data should be monitored, that is, which data (hospital or emergency room admissions, arrests, substance abuse treatment, etc.) are leading indicators and which are following indicators remains an empirical question and an intense focus of current research.

Theresa Cassidy, MPH:

Theresa Cassidy, MPH is an epidemiologist working at Inflexxion Inc. in Newton, MA.

Theresa Cassidy will be answering the question, how is post-marketing surveillance of prescription drugs done?

Post-marketing surveillance of prescription opioids employs both a system of watchfulness and investigation. In general, surveillance activities involve comparison of available data sources and the use of statistical tools to present a "picture" of the data that allows monitoring for atypical patterns or "signals." The signals may be indicators of emerging patterns or trends in prescription drug abuse. It is the epidemiologist's job to track the data and review the results of statistical analyses to see what kind of picture emerges. In this way, researchers who conduct surveillance are akin to data detectives. We are trained to examine the results of statistical analyses and answer the five W"s (who, what, where, when and why) of the data. Although we have many tools in our statistical "toolbox" to attempt to answer these questions, there is no standard or "one size fits all" approach. Some statistical methods are more powerful than others in detecting patterns and some perform better in analyzing certain types of data. Time-series analysis and spatial cluster detection techniques are two types of statistical tools that can aid in pattern recognition and signal detection. In time-series analyses, abuse rates can be tracked by day, week, month or any other temporal frequency. Spatial scan statistics can look to see if abuse rates cluster in an atypical way in a certain geographic location or time span or both.

The effectiveness of any surveillance system is its ability to identify important patterns as "signals" and disregard unimportant events. The challenge to surveillance of prescription drug use and abuse is that there are multiple data sources that can be monitored for indicators of abuse patterns. Each data source has unique attributes that can add a different piece of the puzzle. The integration of computer technology and geographic information systems (GIS) promotes automated data analysis and visualization for real-time or near real-time detection of emerging patterns of opioid abuse. Although automated surveillance systems have been developed to track public health emergencies such as infectious disease outbreaks and bioterrorism attacks, no such system exists for prescription drug abuse. Through the National Addiction Vigilance, Intervention, and Prevention Program (NAVIPPRO), a program being developed at Inflexxion, Inc., we are working to create the technology for this type of automated real-time monitoring of prescription opioids.