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FDA’s Drug Safety Report

In October, FDA published a 40-page report on their procedures in place to monitor drug safety, called Drug Safety Priorities. Initiatives & Innovation. It is a well-written and detailed report on what FDA is doing to ensure and enhance post-marketing drug safety. It’s definitely worth the read.

I will summarize some of the key areas and some of the lesser known initiatives.



After an introduction by Dr. Janet Woodcock, the Director of CDER, there is a brief summary of FDA’s goal of drug safety oversight across the entire product life cycle. The report traces the history of change at FDA since the 2006 Institute of Medicine report on FDA. This report was requested by FDA and done by a blue-ribbon panel that was gracefully critical of FDA. It made many recommendations that FDA took to heart and has begun implementing.  The contents of this section are fairly well known but it is worth the read.  A chart on page 6 summarizes the entire safety monitoring process up to postmarket monitoring.

Another chart on page 7 details the postmarketing system which includes:

Some of the highlights focusing on less well-known aspects of FDA’s safety world:


Safety First Initiative

This began in 2008 and was largely an internal change in policies and procedures to increase postmarketing safety which was perceived to be less rigorous than the premarket safety review leading to NDA approval. This led to many changes including FDA’s requiring/requesting additional clinical trials after marketing, Risk Evaluation & Mitigation Strategies (REMS) as well as the creation of multi-disciplinary teams to better evaluate and track risk. The goal of the teams is to determine whether the benefit-risk evaluation remains positive and whether new requirements (e.g. label changes, additional studies, new or modified REMS, market withdrawal) are needed.  Much of the change was behind the scenes at FDA and less visible.

Jump Start is a program that is being put in place to enhance computerization and electronic review of data and safety issues. It is a software platform for early assessment of data quality and product safety. Basically, it is meant to allow reviewers to spend more time on medical and safety review and less time on data manipulation. It includes a data warehouse for clinical trial data, as well as building analysis libraries and other tools for data analysis.



This is the FDA’s Adverse Event Reporting System and replaced an earlier system called AERS. FDA now gets about 1.4 million MedWatch (or equivalent) reports, of which 95% come from sponsors and manufacturers; the remainder come directly from the public. FDA monitors data from FAERs on a weekly basis as well as further reviews, quarterly, bi-annually and annually. Additional reviews are done on drugs 18 months after approval.  These reviews may lead to further evaluation using data from other systems and databases (Sentinel, Medicare/Medicaid, VA etc.).

FDA reiterates the important concept that because…

“AEs are substantially underreported, FAERS data cannot be used to calculate the incidence of a specific AE…reports submitted to FAERS are a highly selective sample of the events observed in real-world medical practice, which are frequently confounded by factors such as multiple drug use and worsening of pre-existing disease.  As a result, it is rarely, if ever, certain that a reported AE was actually caused by an associated drug product. Despite these limitations, FAERS remains a very useful surveillance tool.”

Interestingly, FDA’s workload is skyrocketing with very significant growth in the number of reports received.  FAERS now has over 12 million reports.


The Sentinel System

This is FDA’s move into “big data.” This is a national, integrated electronic system using shared health care databases outside FDA including academic centers, healthcare systems, health insurers and patient advocacy groups. The system allows the agency to actively, and often in real-time, monitor specific products and “product scenarios” and to access healthcare data on 193 million members of health care plans. The document stresses several times that patient privacy controls are in place.


Safety Research Interest Group

This group was put in place after 2011 to identify “regulatory science and research needs and priorities.” They have identified seven key needs:

  1. Improve access to postmarket data sources and explore the feasibility of their use in analyzing safety signals.
  2. Improve risk assessment and management strategies to reinforce the safe use of drugs.
  3. Evaluate the effectiveness of risk communications of drug safety information to health care providers and the public.
  4. Improve product quality and design, manufacturing processes, and product performance relating to safety.
  5. Develop and improve predictive models of safety in humans.
  6. Improve clinical trial statistical analyses for safety, including benefit-risk 
  7. Investigate clinical biomarkers of safety, including standards for biomarker qualification.

Research projects underway include: “electronic healthcare data to better determine risk of suicide related to use of approved drug products; consumer reactions to drug product labeling; computer modeling to better predict ADEs and identification of factors explaining new safety signals in pre- and post-marketing settings.”


Division of Applied Regulatory Science

This is the division that handles the less directly clinical areas such as toxicology, pharmacology, biophysics, chemistry, genomics and computational modeling. They’re looking at such areas as the Stevens-Johnson Syndrome and have conducted analyses that identified a protein mediator of SJS; why autopsies cannot specify whether cardiac impairments were due to drug products; developing industry standards for biomarker discovery and evaluation as well as other complex projects.


Public-Private Partnerships

This is a mechanism whereby FDA can work with external groups including industry, academia, patient advocacy groups, ex-US health agencies, and others.  It has led to several initiatives:


Management Operations

This area covers items noted in a “2015 GAO Report: A call to improve data on drug safety.” Congress asked the Government Accountability Office (GAO) to review CDER’s postmarket monitoring activities particularly in regard to tracked safety issues and postmarket studies. The report issued in December 2015 noted:

CDER has responded saying, basically, that they are aware of this and that improvements are underway. They are focusing on areas such as Post-Marketing Requirements (PMRs) and Post-Marketing Commitments (PMCs) which are studies or trials to be done after marketing.

CDER also noted that “tracked safety issues” (some might call these “signals”) were being identified and followed but not actually entered into FDA’s database. FDA has indicated that they’ve entered 154 new and 171 retroactive issues into the database and new ones are now being entered rapidly.

CDER further notes that they are moving forward in various programs to increase post-marketing safety oversight.


Other Sections of the Report

There are further sections in the document covering:

The reader is referred to the report for further information on these sections.


This is a fairly comprehensive report, though it does not go into much depth on each topic, nor are there many URLs allowing one to find the detailed information. Nonetheless, it is a good and quick review of FDA’s post-market safety surveillance functions and initiatives.

What is lacking is whether these programs — many of which have been in place for some years dating back to 2006 or so — have produced any positive results. Has FDA done outcome measurements to see whether these changes are picking up SAEs, signals, safety problems earlier? Whether there is some measure of success that can be evaluated? Whether collecting twice as many AEs per year in 2015 compared to 2010 has made any difference?

In other words, is post-marketing surveillance better now than in 2010 or 2005?

There does not seem to be an initiative for “markers for safety surveillance.” This is actually not a trivial issue. We really don’t know how to measure how well we are doing in drug safety. Key performance indicators often just measure on-time reporting to FDA of expedited reports or similar operational parameters. We don’t measure, or even know how to measure, whether we’re doing better. It would be most important to know if all of these efforts have helped the public health.

Several critical safety issues were not addressed: counterfeiting, how biosimilar safety will be monitored (this may be more CBER than CDER though one would certainly hope both groups are working together closely) and medical marijuana (which FDA says is largely out of their scope since it is not an approved drug). All of these are “hot” topics.

The relatively recent phenomenon of the US drug supply now being sourced largely from abroad (namely, India and China) to the tune of 70-80% is not addressed except indirectly under generics and quality. How the US should handle the situation that most of our medical drug supply comes from abroad is worth a discussion at the highest level.

So this report is, to a certain degree, almost a “report card.” Although FDA does not give itself a grade, it seems that they view themselves as roughly a “B to ‘B+”.  They are clearly trying. But it is now more than a decade since the big 2005 IOM report and we do not clearly know whether our post-marketing surveillance is doing better.


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