It is a widely accepted concept that pre-approval drug clinical trial programs often fail to uncover serious and life threatening side effects.

In fact, many adverse events (AEs) only become evident well after a regulatory body has approved a drugDrug-prescribing information documents (‘labels’ or ‘inserts’) are widely used sources of safety information for the healthcare industry. In theory, this information is supposed to provide comprehensive and continually updated information regarding AEs potentially associated with the use of a given prescription drug.

However, in practice, discrepancies occur between safety data disclosed in label inserts and side effects that occur in the real world because (1) there is often a significant discrepancy between AEs observed in clinical trials compared with those reported in corresponding publications on the same trials, and (2) publication and industry bias can obstruct the disclosure of relevant adverse reactions. Therefore, fundamental evidence regarding drug safety data appears to be routinely missing from drug inserts that are a main information source relied upon by healthcare providers.

Accordingly, the analysis of real-world, post-approval safety data appears vital to comprehensively assess a drug’s true safety profile. US FDA collects post-marketing AE data in the FDA Adverse Event Reporting System (FAERS). FDA uses these data internally to issue safety warnings, update drug information labels, and restrict the use of or remove medications from the market.

The use of these data in new and innovative ways within both pharmaceutical pharmacovigilance teams and the broader healthcare community is a growing trend.

FAERS Background Information

When FDA approves a drug, that means its safe right?

The mantra that is repeated over and over about the FDA drug approval process is “for a drug to win approval it must prove to be both safe and efficacious by rigorous clinical testing.” To a large extent that mantra rings true on the efficacy side of the equation, but with regard to safety, FDA-mandated clinical testing regimes oftentimes fall shortA member of the FDA’s Office of Drug Safety summed up the issue by stating:

...“the complete adverse event profile of a drug is not known at the time of approval because of the small sample size, short duration, and limited generalizability of pre-approval clinical trials”...  “since most trials exclude the elderly, children, pregnant women, patients with multiple diseases, and those on medications suspected of interaction with the study drug, the studies’ participants may not be representative of the real world where the drug is eventually used.”

Accordingly, clinical testing typically uncovers common side effects such as gastrointestinal discomfort, flu-like illnesses, nausea, etc. Oftentimes, however, serious and life-threatening side effects that were not exposed during the screening programs become evident only after the drug wins FDA approval.


How are post-approval adverse events data obtained? 

The centralized computerized information database for post-marketing drug safety surveillance is the FDA Adverse Event Reporting System (FAERS), which is currently growing by approximately 1.2 million new cases per year. In 1993, FAERS (then referred to as AERS) launched with a simple, and worthy, goal: facilitate the reporting of post-approval ADEs.

FDA does not make the data publicly searchable, but it can be downloaded and mined from a relational database. The database structure and data within are considered by many to be a data nightmare.


Is reporting adverse events to FAERS mandatory?

For healthcare professionals and consumers reporting is voluntary, but drug manufacturers must report all known ADEs to the FDA. In 2007, in order to enhance post-approval drug safety analysis even further, the FDA began to require drug companies to enact Risk Evaluation and Mitigation Strategies (REMS) to better manage, track, and report ADEs.

In order to increase reporting, many believe that the health system must change dramatically, and that patient care and outcomes need to be the central focus. In order for this to happen, more data needs to be gathered, tracked and analyzed to ensure that the treatments and paths of care are effective and necessary. If data submission and gathering is not mandatory, then actionable steps need to be taken to ensure that there is a concerted effort to marshall resources to encourage the daily discovery and reporting of pertinent drug safety information. 


What is the real-world impact of post-approval adverse events? 

During clinical trials, an average of 48 adverse events per drug come to light. At the time of approval an average of 70 adverse events per label. Research has shown that drug adverse events cost the healthcare system $27 billion each year.


The State of Drug Safety Systems

FAERS is the gold standard for post-market surveillance

When it comes to surveillance of drug safety issues in post-marketed drugs, FAERS has been, and will continue to be, the gold standard for regulators and industry. Even though FDA has invested over $200M into "active surveillance" systems like Sentinel they have very little to show for it over the past 7-8 years.

Recently, FDA launched a public dashboard for FAERS (the FDA Adverse Event Reporting System).  The dashboard is intented to make the data more easily accessible for consumers, however it is not a solution geared for the enterprise.

Several years earlier, FDA released OpenFDA. It is delivered in a search-based API that should enable software developers to more easily build applications based on adverse event data from the FDA Adverse Event Reporting System (FAERS) dataset. While API access to the data is a step in the right direction, many in the industry have pointed out OpenFDA's faults. 


Reporting to FAERS is Accelerating

In 2016, there were 1.2 million new case reports added to FAERS. With another year of drastic increases in reporting, it is important to identify what is behind the growth over the past few years.  It’s not prescription growth.  We know from Quintiles/IMS data that prescription rates are growing at about 1% per year, which is far lower than the 15-20% annualized growth that we have seen for FAERS.  Moreover, t’s not that medications have suddenly become less safe and are now causing more adverse events. The bottom line is that while direct reporting by patients and healthcare providers is hugely important, pharma is still the primary driver of FAERS reporting volume.  With the increased importance that pharma has placed on gathering these data, the more reports we’ve seen. 


Issues with FDA and FAERS

There have been reports over the past several years that have highlighted FDA's problems when it comes to its drug safety systems. a study published in JAMA Internal Medicine that documented delays in the disclosure of serious adverse events to FDA. The study reviewed 1.6M case reports filed in FAERS between 2004 and 2014 and found that 9.94% of serious and unexpected cases were not reported to FDA within the required 15-day window. The authors also found that adverse event cases reported with death outcomes had a slightly higher rate of failing to comply with the 15-day reporting window. The release of FAERS data has often been delayed and slow, leading organizations to have to file Freedom of Information Act Requests. And a report by the U.S. Government Accountability Office (GAO), filed at the request of Representative Rosa DeLauro on December 15, 2015 was made public. The report’s focus was to better understand the rate at which drug applications were expedited using “fast track” and “breakthrough therapy” designations and if FDA was fulfilling its duty to properly track and analyze post-marketing monitoring for those drugs. The answer was no. They have even failed in their duty to make the analysis of the FAERS data public in a timely manner. 

However things seem to be changing. When FDA Released their Q1 2017 Safety Signals, some have commented that it was in fact boring, and that's good. FDA did their job by further analyzing the potential risks and communicating their findings in a timely manner. And manufacturers did their job by efficiently collecting and submitting the reports to the agency. 

FAERS Myths vs. Realities

The use of the FDA’s Adverse Event Reporting System (FAERS) for broad post-approval drug safety studies has long been curtailed due to three assumed limitations of the dataset. Advera Health has systematically set out to debunk these assumed limitations through the use of peer-reviewed studies in major academic journals. 

The Weber Effect

The ‘Weber Effect’ was described in a paper in 1984 and has become gospel in the industry for the past thirty years. . The ‘Weber Effect’ is the notion that after approval of a drug, the adverse event reporting for that drug increases over the first two years, peaks near the end of year two, and then reliably, and rapidly, diminished with further time on the market. However, an Advera Health research study firmly shows that the ‘Weber Effect’ does not actually exist in modern FAERS data.


Stimulated Reporting

“Stimulated reporting,” is the concept that public disclosure of a safety issue by the issuance of an FDA alert or warning, or the clustering of adverse event reports triggered by consumer-based “support group” and/or litigation, will result in substantially increased reporting rates for the affected drug.

It has important implications regarding the utility of post-marketing adverse events data, as alert-driven shifts in reporting could impact the accuracy of comparative research and related analytical methods such as disproportionality analysis. refutes this widely held assumption.

Published in the premier drug risk assessment journal, Drug Safety, Stimulated Reporting: The Impact of US Food and Drug Administration-Issued Alerts on the Adverse Event Reporting System (FAERS) refutes this widely held assumption.


Underreporting: Calculating the reporting rate of adverse events in FAERS

Despite the significant reporting increase, limitations in the use of FAERS data for post-market surveillance remain.  One of the biggest limitations is that not all adverse events are reported.  As a spontaneous (i.e., voluntary) reporting system, it’s simply not possible for every adverse event to be recorded.  This is different from a controlled clinical trial where all adverse events and outcomes are recorded.

Nonetheless, FDA and industry rely on FAERS as an early warning system for emerging safety issues in the real world.  And as the size of the FAERS database grows, and the analytic tools to parse and interpret these data mature, the reliance on FAERS will only continue to grow as well. 

How can the growing reliance on FAERS with the very real limitation caused by the lack of complete reporting be reconciled?  For Advera Health, the answer was to figure out a validated method to estimate the reporting rate of adverse events in modern FAERS. Not only is the rate of adverse event reporting in FAERS vastly different from the old 1% - 10% estimate range, but it varies widely by indication and class. See the full report. 

FAERS Use Cases

Signal Detection Utilizing FAERS

One of the key benefits of a drug safety data aggregation platform is the data source flexibility it provides. Historically, smaller organizations have put off automating aggregate signal detection on FDA Adverse Event Reporting System (FAERS) data to avoid the cost and time commitment needed to implement traditional signal detection software. And those organizations that do have traditional software installed, have typically limited use to specific functional areas within drug safety and “expert” users, making FAERS data and analytics hard to access. A drug safety data aggregation platform makes these data and the related analytics easy and provides for a robust source of insight. Read more...

A drug safety data aggregation platform can provide an easy-to-use interface to access both qualitative data such as labeling information, seriousness, and disease related classifications, as well as sophisticated data mining analytics such as reporting odds ratios (ROR), proportional reporting ratios (PRR), and other safety specific statistical calculations. The flexibility of the platform allows for on-demand add-ons of other datasets such as curated clinical study outcomes data, their own internal data from safety systems, or other real world data like claims and social listening, thus scaling with the organization as it grows. Read more about signal detection in FAERS data in Pharmacovigilance Signal Detection: A Complete Guide.


Using FARES to determine medical costs - A payer perspective. 

WEA Trust is a not-for-profit health insurer serving Wisconsin public employers, their staffs and families.  In Alan Lukazewski's, RPh – Director of Clinical Pharmacy at WEA Trust role as Director of Clinical Pharmacy, he manages pharmacy benefits for WEA Trust, including prior authorization management, clinical program design, and specialty pharmacy management.  Within those areas, he focuses attention on adverse drug event detection and prevention, especially in older adults. 

Last year, WEA Trust partnered with Advera Health on a unique project to determine whether the Trust could use data from theFDA Adverse Event Reporting System (FAERS) to determine total medical costs for a particular class of medicines.  Previously, Advera Health published a study detailing their methodology for calculating medical costs from FAERS data, but this would be the first study to pair FAERS data with specific claims data to determine downstream medical costs. Read more...


How Memorial Hermann uses FAERS data 

Healthcare systems are generally slow to adopt new technologies. For all the talk about leveraging “Big Data,” the industry has been even slower to adopt analytics to make those data actionable. In fact, not one state Medicaid agency currently uses an evidence aggregation platform with post-approval adverse drug events intelligence when creating preferred drug lists, writing prior authorization criteria, negotiating supplemental rebates, educating prescribers and dispensers, or performing prospective, concurrent, or retrospective drug utilization reviews. This is in spite of the fact that millions of patient lives are put at risk and billions of dollars are spent every year from adverse drug events. Yet there is no mandate to use readily available, reliable data to inform making decisions about prescription medicines. Read more...


Mitigating drug litigation with FAERS data 

Product liability insurers protect pharmaceutical companies from legal actions associated with their drugs.  They have a significant economic incentive to scientifically assess and understand the scope of litigation risk.   Experienced underwriters use an evidence aggregation platform to better understand if a manufacturer’s drug is causing severe side effects that could lead to potential litigation. They also use an evidence aggregation platform to adopt and employ a simplified and unified process of assessing side effect risk with proven statistical measures via a simple interface that deploys in minutes. Read more...


Use clinical trial results linked to FAERS data to support formulary reviews

Managed Care Organizations are reviewing drugs well before a product is approved. According to a survey conducted by Dymaxium (the company behind the AMCP eDossier System) and presented in a recent webinar, two out of three healthcare decision makers begin to evaluate a drug at least six months prior to approval. The survey also indicates that the primary source of information that payers are using for these pre-approval evaluations is (, and that manufacturers are not always responsive to requests for information pre-approval. Read more...

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