Drug Safety Priorities: Initiatives and Innovation

Center for Drug Evaluation and Research 2015-2016
DRUG SAFETY PRIORITIES

Initiatives and Innovation
www. fda.gov
CONTENTS
Drug Safety Oversight Across the Product Lifecycle............................................................4
Advancing Drug Safety Science.............................................................................................9
• JumpStart – Enhancing Pre-Market Drug Review with Digital Tools...................................... 9
• Postmarketing Safety Surveillance and Oversight...................................................................11
• Improving Drug Safety through Research ............................................................................. 15
• Advancing Drug Safety Science through Public-Private Partnerships................................... 20
Improving Operations and Management in Support of Drug Safety................................22
• The 2015 GAO Report: A Call To Improve Data on Safety Issues........................................ 22
• Opioid Addiction and Abuse: Addressing a National Crisis................................................... 25
• Safe Use Initiative................................................................................................................... 28
• Working to Ensure Drug Product Quality............................................................................... 30
• Compounded Drugs and Drug Supply Chain Security .......................................................... 32
Communicating Drug Safety: A Global Public Interface...................................................34
• Expert Responses to Public Queries ...................................................................................... 34
• Social Media and Online Tools............................................................................................... 35
• Drug Safety Communications................................................................................................. 37
• Safety Labeling Changes........................................................................................................ 37
• Risk Communications Research............................................................................................. 39
2 | CDER DRUG SAFETY PRIORITIES 2015-2016

INTRODUCTION
For more than a century, the safety of medicines

approved for use in the United States has been one
of the mission cornerstones of the Food and Drug
Administration (FDA). From the Food and Drug Act
of 1906, through legislation enacted over the years,
FDA’s regulatory authorities and resources have
been progressively enhanced, allowing the Agency to
consistently strengthen and modernize its drug safety
initiatives and programs.
With millions of Americans taking more medicines

than at any time in history, an unanticipated drug
safety problem can rapidly escalate to become a major
public health threat—demanding a multifaceted safety
effort based on interdisciplinary scientific teamwork
that enables rapid but balanced regulatory and public
health decision making. CDER Drug Safety Priorities: Initiatives and Innovation describes
a number of programs that help ensure the safety of drug products, depicting the extensive,
interrelated, and cooperative nature of our drug safety enterprise, while also reporting on key
safety milestones achieved over 2015 and to date in 2016.
This report goes beyond previously issued safety-related reports to offer a broader picture
of FDA’s safety efforts, highlighting the critical advantages gained through a range of
multidisciplinary collaborations and partnerships. From innovative computing platforms that
support new drug reviews, to the ongoing implementation of existing programs like Safety
First and the Safe Use Initiative, the active surveillance capacities of the Sentinel System,
improvements in drug product quality oversight, and state-of-the-art communications tools that
exploit new opportunities in social media and mobile device applications, FDA is evolving
a drug safety enterprise that leverages gains achieved within the Agency as well as through
alliances with our federal partners and with numerous stakeholder organizations.
Janet Woodcock, M.D.

Director, Center for Drug Evaluation and Research
INITIATIVES AND INNOVATION | 3

DRUG SAFETY OVERSIGHT
ACROSS THE PRODUCT
LIFECYCLE
A key component of the FDA mission is to protect the public health by assuring
The Food, Drug and the safety of human drug products. Supporting this objective, FDA is also
Cosmetic Act defines responsible for advancing public health by facilitating the scientific innovations
drugs, in part, by their that can help make medicines safer while assuring that the public receives clear,
intended use, as “articles accurate, science-based drug safety messages.
intended for use in the
In 2006, recognizing that the complexities of drug safety oversight had entered
diagnosis, cure, mitigation,
a new and challenging era, FDA requested that the Institute of Medicine (IOM)
treatment, or prevention
evaluate the Agency’s existing drug safety system.
of disease” and “articles
(other than food) intended The Institute’s study, published in 2007, noted a range of concerns, including
to affect the structure or ambiguous legislative authorities and a lack of reliable postmarket data about
any function of the body of the risks and benefits of drugs. These and other barriers limited the FDA’s
man or other animals”. capacity to assess the safety of drugs once they entered the marketplace, or,
at times, to take specific regulatory actions when needed. Responding to the
IOM’s recommendations, the Agency identified three primary areas of focus
that would operate in tandem to support a broad-based drug product safety
This report uses the terms program:
“drug” and “drug product”
to refer to prescription
• Drug Safety Science. Strengthening the science that supports the medical
and over-the-counter
product safety system at every stage of the product life cycle, from pre-
(OTC) medicines in their
market testing and development through postmarketing surveillance and risk
finished, FDA-approved
management.
and marketed form. A
• Operations and Management. Improving operations and management to
drug product’s finished
ensure implementation of the review, analytical, and communication processes
form is often a single
needed to strengthen the U.S. drug safety system.
drug, but may include
two drugs manufactured • Safety Communications. Expanding and improving communication and
in combination. A drug information flow among all stakeholders engaged in promoting the safe use of
product may have medical products.
different routes of
administration, such as oral These focal areas, as they continue to guide and inform FDA’s drug safety
(tablets and capsules), enterprise, function in tandem in leveraging assets and delivering benefits
liquid solutions and through contributions from across the Agency.
suspensions, or injection.
The central responsibility for managing, overseeing, and coordinating drug
safety efforts rests with the Center for Drug Evaluation and Research (CDER).
CDER evaluates new drugs before they can be marketed and maintains a
rigorous postmarketing safety surveillance program, monitoring the use of
marketed drugs for unexpected health risks.

CDER also implements safety oversight by regulating the manufacture of drugs
and by setting standards for drug quality, and holds numerous public meetings
to facilitate expert and consumer input on pending drug safety decisions and
priorities.
CDER’s assessment of a drug’s safety profile begins early in the drug

development process—long before a product is approved for marketing. A The “sponsor” of a drug
pharmaceutical company or other “sponsor” that is developing a new drug product’s development is
will have first invested several years in laboratory research and animal studies. typically a pharmaceutical
If early data supports further product development, a sponsor may elect to company, but can also
submit an Investigational New Drug Application (IND) to CDER. An IND will be a medical institution,
include results from animal studies, toxicity data (information about side effects university, foundation, a
that cause harm), drug manufacturing data, and plans for human studies to be Federal research agency
conducted (clinical trials). such as the National
Institutes of Health, or
Collaboration and consultation supports and enhances drug product safety from even (rarely) an individual
the time an IND is submitted. CDER assigns a multidisciplinary review team to physician or researcher.
an IND, comprised of project management and scientific review staff, including
physicians, pharmacologists, toxicologists, chemists, and statisticians. This
team has 30 days to review an IND submission, a process that not only assesses
interim findings to determine their acceptability, but protects volunteers who will
participate in clinical trials from unreasonable and significant risk. Although an
IND can be placed on a “clinical hold” for various reasons, it is usually approved
if the technical data is acceptable and proposed clinical trials meet Federal
standards.
If the resulting evidence from early development (laboratory tests and animal
studies), and all human clinical trials support a drug’s safety and efficacy for its
intended use, a company can file a New Drug Application (NDA) to market the
drug.
An expanded multidisciplinary team is formed at this point, including staff with

expertise in epidemiology, drug surveillance, and risk management. These review
teams evaluate the available information about a drug’s safety and efficacy to
make determinations about whether the drug can be marketed for use—but
also to identify what additional activities, if any, a sponsor must perform in the
postmarketing period to further ensure the safety of the drug.
Drug approval decisions are based on a comprehensive assessment of the benefits

of the drug and its known and potential risks. In some cases, these decisions
are informed by discussions with CDER’s external expert advisors, such as an
Advisory Committee or the Drug Safety Oversight Board, which provide input
on uniquely challenging drug issues.

The Drug Lifecycle
PREMARKET REVIEW TO POSTMARKET MONITORING
DRUG DEVELOPED
Drug sponsor develops a new drug compound and seeks to have it approved by FDA for sale in the United States.
ANIMALS TESTED PRECLINICAL

Sponsor must test new drug on animals for toxicity. Multiple species are Drug Sponsor’s Discovery
used to gather basic information on the safety and effectiveness of the and Screening Phase
compound being investigated or researched.
IND APPLICATION
The sponsor submits an Investigational New Drug (IND) application to FDA. The
application includes information about the drug’s composition and manufacturing,
results from initial testing, and a plan for testing the drug on humans.
PHASE 1 CLINICAL
Phase 1 studies are usually conducted in healthy volunteers. The Phase 1 Drug Sponsor’s Clinical
emphasis is safety. The goal is to determine what the drug's most frequent Studies/Trials
side effects are and, often, how the drug is metabolized and excreted. The
number of subjects typically ranges from 20 to 80.
PHASE 2
Phase 2 studies begin if Phase 1 studies don't reveal unacceptable
toxicity. The Phase 2 emphasis is effectiveness. The goal is to obtain
preliminary data on whether the drug works in people as a treatment for
a certain disease or condition. Safety continues to be evaluated, and
short-term side effects are studied. The typical number of subjects in
Phase 2 studies ranges from a few dozen to about 300.
PHASE 3
Phase 3 studies begin if evidence of effectiveness is shown in Phase 2,
gathering more information about safety and effectiveness, studying the
drug in different populations and at different dosages, and in combination
with other drugs. The number of subjects in Phase 3 studies usually
ranges from several hundred to about 3,000 people.
REVIEW MEETING PREMARKET

FDA meets with a drug sponsor prior to submission of a New Drug Application (NDA). FDA’s New Drug Application
NDA APPLICATION
The drug sponsor formally asks FDA to approve a drug for marketing in the United
FDA DRUG
SPONSOR
States by submitting an NDA. An NDA includes all animal and human data and analyses
of the data, as well as information about how the drug behaves in the body and how it
is manufactured.
APPLICATION REVIEWED
After an NDA is received, FDA has 60 days to decide whether to file it so it can be reviewed.
If FDA files the NDA, the FDA Review Team is assigned to evaluate the sponsor’s research on
the drug’s safety and effectiveness.
DAY
DRUG LABELING
FDA reviews the drug’s professional labeling and assures appropriate information is
communicated to health care professionals and consumers.
60
FACILITIES INSPECTED
FDA inspects the facilities where the drug will be manufactured.

MANDATORY REPORTING
Industry’s periodic
safety reports
SAFETY FIRST INITIATIVE VOLUNTARY REPORTING

Equal attention given to FDA’s MedWatch program for
postmarket drug safety as health care professionals
is given during premarket and consumers
drug review
POSTMARKETING
Safety surveillance, tracking of safety issues,
10001010001001
postmarketing requirements and commitments,
01000100011100
risk assessment and mitigation strategies,
SENTINEL SYSTEM DATA ANALYSIS
10001010001001
safety communications. 01000100011100
Intergrated electronic FDA’s adverse event 10001010001001
system for monitoring Once FDA approves a drug, the reporting system 01000100011100
medical product safety postmarketing monitoring stage begins and 10001010001001
01000100011100
continues for the life of the drug.
Through several post-approval systems, FDA
works to assure there is ongoing safety and
effectiveness of drug products currently
marketed in the United States.
COMMUNICATIONS
SAFE USE INITATIVE Drug Safety Communications,
Combating medication Webinars, blogs, podcasts,
misuse and errors videos, and social media
POSTMARKETING SURVEILLANCE
Tracking of safety issues, required
postmarketing studies or clinical trials
FDA
APPROVED
DRUG APPROVAL
FDA approves the application or issues a complete response letter.
www.fda.gov

Safety First in Action
The Safety First Initiative, launched in 2008, provides CDER’s overarching
framework for identifying, assessing and acting upon drug safety issues in the
postmarket period.
Through an amalgam of internal policies and organizational procedures, Safety

Drug approval decisions First’s primary objective is to support and reinforce drug safety by bringing
are based on a equal focus and attention to the performance of new drugs after they are on
comprehensive assessment the market as is given during premarket review, helping improve the safe use
of the benefits of the of drugs throughout their lifecycle. Safety First directs that multidisciplinary
drug and its known and teams within CDER assess postmarket drug safety signals as they arise,
potential risks. identify appropriate actions for the Center and/or pharmaceutical companies
to take, and monitor those actions. All these activities have become integral
aspects of CDER’s overall drug safety program.
In mandating and supporting team-based multidisciplinary collaborations,

“The agency continually Safety First supports the alignment of safety processes and policies and serves
evaluates the safety of as a foundation for FDA’s safety initiatives, programs, and projects. Based
drug products, and CDER’s on safety data collected during development of a new drug or new safety
ongoing commitment to information identified after a drug is approved and marketed, CDER may
rigorous and continued find that additional studies are needed to better characterize a drug safety
drug safety evaluation in concern and may require further studies as a condition of continued marketing
the postmarket period is approval. CDER’s review teams may also consider whether a Risk Evaluation
reflected in its Safety First and Mitigation Strategy (REMS) is necessary. (A REMS is a safety strategy to
Initiative—which outlines manage a known or potential serious risk associated with a medicine, to ensure
CDER’s policies and that its benefits outweigh its risks, and to enable patients to have continued
procedures to ensure that access to the medicine by managing its safe use.)
equal attention is given to
postmarket drug safety as Postmarketing safety oversight always involves multidisciplinary and
is given during premarket collaborative assessment of reports of unwanted or dangerous side effects
drug review.” associated with the use of specific drug products (known as “adverse events”),
reported medication errors, and findings from REMS and postmarketing
-Mwango Kashoki, MD, MPH, studies. Based on safety information that emerges during the postmarket
Associate Director for Safety, period—particularly as a new drug is used among more people for longer
Office of New Drugs, CDER periods of time—CDER may determine there is an identified risk that alters
the benefit-risk balance of the drug and may make regulatory decisions to
minimize or manage that risk. The nature of these decisions will vary based
on the impact of the risk, and can include safety labeling changes, additional
safety studies, a new or modified REMS, or withdrawal of a drug from the
market.
In providing the operational structure for evaluating and acting on drug safety
issues in the postmarket period, Safety First supports and reinforces safety
oversight across the product lifecycle and serves as an integral aspect of
CDER’s overall drug safety program.

ADVANCING DRUG SAFETY SCIENCE
Drug safety
science includes
the development of
Drug safety science, which includes the development of tools, techniques, tools, techniques,
and data sources that help CDER to better identify and manage safety issues and data sources that
related to drug effects and product quality, is an integral component of FDA’s help CDER to better
regulatory science portfolio. As profound new insights into disease processes
at cellular and molecular levels operate in the technologically advanced
identify and manage
environments of distributed digital networks, data mining, custom-built safety issues.
software platforms, and mobile device applications, drug safety science is
taking on ever more powerful potential to predict, detect, and prevent drug-
related adverse events.
JumpStart – Enhancing Pre-Market Drug Review with Digital Tools

Drug applications submitted in electronic form are easier for CDER to store and manage than paper-based
submissions, which can exceed many thousands of pages. CDER has encouraged drug companies to submit INDs
and NDAs in electronic format for over 10 years. (Electronic submission of most INDs and NDAs will be required
by May 2017.)
As pharmaceutical developers and manufacturers submit electronic product applications in ever greater numbers,
the applications have also grown in complexity. In turn, CDER’s workload has increased, and digital tools used to
analyze large amounts of data are critical to consistent, reliable, and expeditious assessments of drug safety and
efficacy.
The scientists and physicians who serve on CDER’s review teams, although experts in their respective specialty
areas, may have difficulties and spend valuable time navigating the digital intricacies of electronic drug product
submissions. JumpStart, a vital new service in CDER’s portfolio, is meeting this challenge.

Created by CDER’s Office of Computational Science (OCS), housed within the Office of Translational
Sciences (OTS), JumpStart was recognized as a Health and Human Services (HHS) Secretary’s Pick
for the 2014 HHS Innovates program, for advancing the modernization of the drug review process.
JumpStart represents a first step in the creation of a modern integrated review environment that supports
FDA’s 21st Century regulatory review goals.
JumpStart is a software platform that provides an early assessment of data quality and product safety to
CDER’s review staff, enabling reviewers to spend less time manipulating complex data and more time
applying their expertise to identify safety and efficacy concerns and support informed decision making.
More computing tools have been incorporated into the JumpStart service—combining automated
analyses for data fitness and safety. Next steps include the piloting of additional tools and services,
expanding data fitness assessment capabilities, and building analysis “libraries” to include more
analyses aligned with specific areas of drug review.
JumpStart Updates—2015-2016
JumpStart has been offered to CDER’s drug review teams for the third year, providing reviewers
with better understanding of submission data earlier in the review process, highlighting areas of
potential concern and facilitating the efficiency of safety signal identification and risk analysis.
• Thirty full service JumpStart training sessions were provided for drug reviewers. Based on
feedback, the JumpStart team improved the data fitness sessions to better meet the needs of
reviewers.
• Work proceeded on assessing the feasibility of integrating clinical trials data with JumpStart.
The Janus Clinical Trials Repository (CTR) is a data warehouse that can provide access to study
data in ways that reviewers need, whether as an individual study or a set of studies integrated
for safety assessments. OCS also explored the use of CTR to facilitate analyses of safety risk across
classes of drugs or focused on specific treatment indications.
• A robust training program continues to ensure that newly developed digital tools are
seamlessly adopted across the review community to improve pre-market safety assessments.

Postmarketing Safety Surveillance and
Oversight: MedWatch, FAERS and the
Sentinel System
After a newly-approved drug enters the marketplace, postmarketing experience
can reveal adverse events (AEs) not detected during clinical trials or pre- MedWatch is FDA’s
approval review. FDA maintains two major systems for postmarketing drug system for the reporting
surveillance, a “passive” system known as FAERS (FDA Adverse Event and collection of
Reporting System) and an “active” system known as the Sentinel System. clinically important
safety information about
FAERS – FDA Adverse Event Reporting System marketed human medical
products.
One key tool employed to characterize and evaluate adverse effects (AEs) is
FAERS, an electronic data base of spontaneously submitted adverse events
(AEs) associated with drugs and biologic products. For the past 47 years,
spontaneous reporting has been the cornerstone of CDER’s postmarketing
drug safety monitoring, based on voluntary MedWatch reports from the
public, healthcare professionals, and others, of AEs, drug quality problems, or
medication errors they observe during the use of a marketed drug product.
How Drug Postmarketing Reports Get to FDA
Patients, Consumers and

Healthcare Professionals
Voluntary Voluntary
FDA MedWatch Manufacturer
Regulatory Requirements
FAERS
Database FDA
5% of all reports 95% of all reports

About 95 percent of the 1.4 million MedWatch reports received annually come from drug product
sponsors or manufacturers; the remainder come directly from the public. The objective of CDER’s
review of spontaneous reports is to identify serious, rare, or unexpected AEs in order to spot “safety
signals”—indicators of new or unanticipated drug safety concerns. The public can use a variety of
methods to submit reports, including electronically, on paper, via phone calls or via fax.
FAERS helps to bridge the gap between known AEs seen in pre-approval clinical trials and those seen
once an approved drug is used in the general population. If a potential safety concern is identified in
FAERS, further evaluation is conducted on a systematic basis. Monitoring of individual spontaneous
reports and aggregate data from the FAERS database for all marketed products is conducted weekly.
Reviews of AE reports and benefit-risk evaluation reports occur at quarterly, bi-annual and annual
intervals, and full drug product safety reviews are conducted 18 months after approval. CDER employs
data mining techniques to efficiently identify FAERS reports of greatest value, and is continuously
working to update these approaches.
When reviewing reports, particular attention is paid to those AEs that are both serious and unexpected.
An important part of the review focuses on the narrative submitted by the person reporting the AE. The
more complete a report’s medical and clinical information is, the more useful the report will be, and
reporters are encouraged to include as much detail as possible in their narratives.
When a safety concern is detected, further evaluation might include studies conducted using other large
databases such as those housed in the Sentinel System, the Centers for Medicare and Medicaid Services,
and the Veterans Health Administration, among others. Depending on the results of additional evaluation,
CDER may take regulatory action to improve product safety and protect the public health, such as
updating a product’s labeling information, called a Safety Labeling Change, communicating new safety
information to the public, or, in rare cases, removing a product from the market.
Even though CDER receives more than one million AE reports every year, not all AEs associated with
a given drug are reported. Many factors influence whether or not an event will be reported, such as the
time a product has been on the market or the nature of publicity about a drug-related event. Because
AEs are substantially underreported, FAERS data cannot be used to calculate the incidence of a specific
AE or other problem in the U.S. population. It is also understood that 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. CDER does
not require that a causal relationship between a product and event be proven before reporting, and reports
may not always contain enough detail to properly evaluate the event. Despite these limitations, FAERS
remains a very useful surveillance tool that CDER is actively working to improve.
In 2016 alone, the FAERS database will have logged nearly two million AE reports, and now contains
more than 12 million reports.

Number of Adverse Event Reports
1,400,000
Non-Expedited
1,200,000
15-Day
Direct
1,000,000
Number of Reports
800,000
600,000
400,000
200,000
0
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
This graph shows the number of direct, 15-day, and non-expedited (also known as periodic) reports received and
entered into FAERS from 2004 through 2015. FDA receives direct reports from the public while 15-day and non-
expedited reports are submitted by industry. The 15-day reports describe AEs from spontaneous reports that are
serious and unexpected, as well as AEs from clinical trials that are serious, unexpected and judged to be reasonably
associated with the drug. Industry submits all other adverse event reports as non-expedited reports.
The Sentinel System:

Transforming How We Monitor
FDA-Regulated Products “The Sentinel System offers
The Sentinel System is a national, integrated electronic the exciting possibility
system for monitoring drug safety through shared health of not waiting for safety
care databases (with care taken to protect personal health
information to come to us
information). Sentinel leverages “big data” and broad
networks across many data partners to systematically detect in the form of reports, but
and respond to emerging risks associated with FDA-regulated rather enables us to go out
medical products—allowing evaluation of safety issues and get that information,
more rapidly than has been possible in the past. As an active
digital surveillance infrastructure focused on recognizing and
adding greatly to our safety
characterizing drug safety issues, Sentinel enables FDA to monitoring capability. This
proactively assess medical product safety under real-world is active surveillance.”
conditions and thus complements existing FDA postmarketing
monitoring capabilities, including FAERS. In the words of – Janet Woodcock, MD,
CDER Director Janet Woodcock, “FAERS is an invaluable
Director, CDER
asset, and we’re not seeking to replace it. However, the
Sentinel System offers the exciting possibility of not waiting

for safety information to come to us in the form of reports, but rather enables us to go out and get that
information, adding greatly to our safety monitoring capability. This is active surveillance.”
An important foundation of the Sentinel System is its collaborative nature and active engagement with
a broad range of stakeholders, including academic medical centers, healthcare systems, health insurers,
and patient advocacy groups. With data analytics leveraged across broad digital networks, and with
access to information provided by data partners, including electronic health record systems (EHRs),
administrative and insurance claims databases, and registries, Sentinel enables FDA to obtain vital
data to help evaluate safety issues—and demonstrates the benefits that can be achieved through broad
collaboration.
In addition to its vital contribution to drug safety surveillance, the Sentinel System is also an invaluable
national scientific resource for a broad range of other applications. A current goal is that, working with
other scientific groups, a National Data Infrastructure can be created that enables many users (such
as other governmental agencies or researchers from academia or industry) to access various types of
digital data for various purposes, including evaluating medical product performance and healthcare
quality improvement.
Sentinel System Updates

In 2015-2016, Sentinel’s pilot project, “Mini-Sentinel”, transitioned to the fully up and running
Sentinel System.
Other milestones in this time period include:
• The Active Risk Identification and Analysis (ARIA) System was integrated into FDA’s day-
to-day regulatory and review activities. A subcomponent of the Sentinel System, ARIA
leverages existing analysis methods and Sentinel’s Common Data Model to evaluate safety
signals identified during both premarketing and postmarketing settings.
• CDER used Sentinel’s rapid query capability in ARIA to run nearly 2,000 different medical
product scenarios, and to access the electronic healthcare data (with privacy controls in
place) of over 193 million health plan members.
• CDER continued to coordinate with the Center for Biologics Evaluation and Research to
expand their vaccine and blood products surveillance capabilities under their Postmarket
Rapid Immunization Safety Monitoring (PRISM) and Blood Surveillance Continuous Active
Network (BloodSCAN), and with the Center for Devices and Radiological Health to
complement the National Evaluation System for Medical Devices (NESMD).
• Blue Cross/Blue Shield of Massachusetts and the Hospital Corporation of America (HCA)
came aboard as Sentinel data partners. HCA provides access to data from inpatient
hospitalizations, including inpatient medications and transfusions, expanding Sentinel’s
reach and capabilities.

Improving Drug Safety through Research: A Biomarker is a factor
The Safety Research Interest Group and that can be objectively
measured and serves as
Division of Applied Regulatory Science an indicator of normal
Safety Research Interest Group or abnormal biological

processes or responses to
Since the 2011 report Identifying CDER’s Science and Research Needs was a therapeutic intervention
developed by CDER’s Science Prioritization and Review Committee, activities such as taking a medicine
to identify regulatory science and research needs and priorities have continued. or receiving a treatment.
CDER is engaged in many drug safety-related regulatory science efforts as
well as activities by CDER’s Safety Research Interest Group (SRIG) to identify Biomarkers can help
priority gaps that could be addressed through targeted research projects. These to confirm a diagnosis,
priorities are assessed within the broad framework of FDA’s overall regulatory predict a likely medical
science objectives and evolving needs which help guide development of outcome, or monitor a drug’s
CDER’s science and research agenda. effectiveness, among other

uses. Familiar examples are
After developing and implementing a process to help guide priorities for safety- measuring blood pressure to
related research needs, CDER’s SRIG identified seven major areas of safety- measure the effectiveness of
related needs: a blood pressure medication,
or blood sugar levels to
• Improve access to postmarket data sources and explore the feasibility of
measure the effectiveness
their use in analyzing safety signals.
of a diabetes medication. In
these cases, blood pressure
• Improve risk assessment and management strategies to reinforce the safe use
measurement or blood
of drugs.
sugar level are biomarkers.
• Evaluate the effectiveness of risk communications of drug safety Common biomarkers also
information to health care providers and the public. include liver function studies,
cholesterol levels, or an
• Improve product quality and design, manufacturing processes, and product electrocardiogram.
performance relating to safety.
Other Biomarkers are more
• Develop and improve predictive models of safety in humans. complex, such as specific
genes or proteins that may
• Improve clinical trial statistical analyses for safety, including benefit-risk be linked to specific or rare
assessments. conditions. Biomarkers can
also be used in the drug
• Investigate clinical biomarkers (see sidebar) of safety, including standards
development process for a
for biomarker qualification.
variety of purposes including
monitoring drug safety
during the investigational
period, or identifying the
optimal dose of a medicine.

The SRIG reviewed research activities within each of the seven research needs, focusing on potential
public health and regulatory impact, feasibility, and the need for CDER involvement or external
collaboration or resources. To connect priority projects to resources, the SRIG met with relevant CDER
staff to better understand and discuss the scope of needed research. Selected current and ongoing safety-
related research projects include:
Electronic health care data to better determine risk of suicide

related to use of approved drug products.
In recent years there have been regulatory actions with various drugs and drug classes involving
increased risk of suicide related to use of those drugs. CDER must enhance its ability to determine
if suicide is a potential adverse event of a specific drug therapy. However, suicidal outcomes are
infrequent and difficult to measure in clinical trials. Electronic healthcare database studies can measure
outcomes for large populations at lower costs than other forms of data-gathering, but their ability to
accurately measure suicidal outcomes is uncertain. CDER investigators are therefore conducting a
systematic review to investigate which data resources and methods have been most informative for
determining suicidal outcomes in populations of interest. Available data are being assessed for their
suitability to determine suicide as an outcome of drug therapy, and possibilities for enhancing future
data collection on completed and attempted suicide will be explored.
Consumer reactions to drug product labeling.

This research focuses on generating systematically collected and robust information on consumer
reactions to drug labeling, to inform ongoing regulatory action and future guidance development around
over-the-counter (OTC) proprietary (brand) drug naming and the front label panel of a drug product’s
box or packaging (the “principal display panel presentation”).
Computer modeling to better predict adverse drug events.

Innovative approaches in computer science are being explored to better predict drug-related adverse
reactions, by integrating medical and laboratory data with other data based on current medical
knowledge and published research. These tools aid in understanding timing and association of drug
safety signals with specific enzymes following certain anticancer treatments. As a result, investigators
developed novel approaches such as machine learning and neural networks (in which computers can
“learn” as new data is collected) to aid regulatory agencies, industry, academia and others to understand
adverse events and guide drug development and regulatory reviews.
Identification of factors explaining new safety signals in

pre- and postmarket settings.
This project will identify factors that might explain the emergence of drug safety issues in the pre-
and postmarket settings—and the extent to which scientific evidence, along with approaches used in
precision or “personalized” medicine (where drugs or treatments are tailored to an individual based
on that person’s genetic make-up and other personal factors) can be used to predict and manage safety
issues. This project will compile a “catalog” of past decisions made by CDER to place a drug approval
on hold or when postmarketing safety label changes were needed. Researchers plan to map that data to
possible risk management strategies, which can assist drug product reviewers and safety surveillance as
well as regulatory decision-making in the postmarketing period.

Other FDA
Centers,
Federal
Agencies
CDER
Intramural Consortia
Funding and
Programs Academia
Mechanisms
for CDER
Safety
Research
CDER Fellowships
Offices
Contracts
and Grants
Mechanisms facilitating and supporting CDER safety research efforts include contributions from other Federal
agencies, public-private partnerships, academic collaborations, funding through grants and contracts, and
the ongoing expertise provided by CDER’s scientific offices and divisions.

Division of Applied Regulatory Science
Science evolves rapidly—and CDER must stay abreast of that evolution to maintain 21st Century drug
review and safety surveillance capacities. In the Division of Applied Regulatory Science (DARS),
researchers using state-of-the-art equipment and technologies are applying a wide range of expertise in
areas such as toxicology, pharmacology, biophysics, chemistry, genomics, and computational modeling,
in the service of developing new and innovative approaches that will improve CDER’s drug product
review capabilities.
DARS scientists provide:
• Improved lab assays for predicting drug safety
• Better understanding of the mechanisms underlying drug toxicity
• Insights into the links between a drug’s chemical structure and its potential to induce adverse events
• Research-based predictions that can be used to support decisions for new and generic drugs when
safety data are limited
DARS conducts studies that cannot or will not be done by industry or other Federal agencies, with a
staff that provides technical capabilities using a range of tools to predict such safety-related outcomes
as genotoxicity, carcinogenicity, cardiotoxicity and drug-induced liver injury. DARS consultations assist
CDER safety reviewers in the interpretation of data submitted in INDs and NDAs—which are often
followed by new research conducted to address knowledge gaps in key areas.
DARS scientists are currently involved in over 30 projects that advance drug development and safety
assessment to help inform regulatory decision making. Some highlights are presented below.
• Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) are serious and potentially
life-threatening skin reactions that can occur in individuals treated with a variety of drugs, and are
therefore of significant concern to CDER and the larger medical community. To better understand
underlying mechanisms, DARS researchers conducted analyses that identified a specific protein as
a significant mediator of SJS/TEN. Leveraging a genomics database, DARS found that the drug
carbamazepine disrupted several genes, including one associated with carbamazepine-induced SJS/TEN.
This information can be applied in future drug reviews as well as postmarket safety oversight.
CDER’s research scientists use state-of-the-art equipment and

technologies in the service of developing new and innovative approaches
that improve CDER’s drug product review capabilities.

• While autopsy findings can identify cardiac impairment, they cannot specify if impairments were caused
by drug products. DARS uses a number of laboratory and computer-based approaches to measure the impact
of specific sets of drugs on heart function. These combined approaches will allow better prediction of both
the functional effects and scope of injury associated with cardiotoxic drugs, thereby enhancing the safer use
of medications.
• In another effort to investigate drug-induced cardiac toxicity, DARS is part of a research consortium
of worldwide regulatory agencies, industry, and academic centers evaluating the possibility of predicting
drug-induced cardiac toxicity using a computer model of the human ventricular (heart muscle) cell. This
project involves evaluating drugs and then simulating their effects on electrical activity in the heart under
a wide range of conditions. The study seeks to develop a new regulatory pathway that will change current
cardiovascular safety testing guidelines and potentially eliminate the need for certain kinds of clinical
testing during drug development.
• DARS is pursuing development of industry standards for biomarker discovery and evaluation, including
gene-based research methods and reference data sets, to develop consistent criteria to measure tissue
damage in pathology samples.
• DARS is evaluating digital tools that may help to predict and explain drug-related adverse events. These
tools can be used to generate possible explanations for why an adverse event might occur, and have the
potential to help modernize drug safety analyses, to improve product labeling, and guide development in the
pre-market phase as well as supporting pharmacovigilance in the postmarketing period.
• DARS is evaluating a software program that generates adverse event profiles based on a drug’s
molecular targets in the human body, to predict adverse events not previously seen in clinical trials and
therefore not included in the original product label. Predictions of drug-related adverse events have already
been made using this approach. Planning is underway to perform similar analyses on many more drugs now
under review.
DARS research is tightly linked to current and emerging drug product reviews and
is customized to answer specific questions. The value of DARS’ resident expertise to
CDER regulatory science is enhanced through targeted collaborations across FDA
and with industry and academia, providing additional opportunities to build on its past
research successes and improve the way drugs are developed and reviewed.

Advancing Drug Safety Science through
Public-Private Partnerships
Drug safety science—the development of methods, tools, and data sources
employed to better identify, predict, assess, and manage safety issues related to
drug products—is an essential component of CDER’s regulatory science portfolio.
Creating the cutting-edge scientific knowledge base needed to support 21st Century
safety science requires an understanding of the knowledge gaps in product safety, the
resources that can be leveraged to address those gaps, and the necessary expertise of
internal and external partners.
This effort cannot be done alone but rather requires partnerships between FDA and
Creating 21st Century multi-sector stakeholders sharing the common goal of promoting drug safety and
safety science requires effectiveness to protect and improve public health.
the necessary expertise
of internal and external The Critical Path Initiative (CPI), launched in 2004, is FDA’s keystone initiative to
partners and scientific forge stakeholder collaborations to tackle various drug safety and drug development
collaborators. issues.
These strategic partnerships help to enhance the efficiency and quality of medical
product development, evaluation, and manufacture through scientific advances—
the “critical path”. When a new or growing public health concern is identified
that cannot be effectively addressed by a single organization, CDER and other
organizational components in FDA, operating within the framework of the CPI,
can ask a non-profit stakeholder organization to serve as a neutral convener that can
then leverage the expertise of numerous other stakeholders through a public-private
partnership (PPP).
PPP stakeholders may include industry, academic institutions, patient advocacy

groups, government agencies, and others.
PPPs come together pre-competitively to provide a platform to bring new insights to

regulatory and drug safety science questions. CDER staff members currently serve
as liaisons to several PPPs, providing a regulatory perspective and assisting with the
development of public health objectives, which may take various forms including
white papers, registries, databases, disease models, and biomarker development.
The products of PPP efforts are shared in the public domain for all stakeholders with
the goal of streamlining drug development, increasing the efficiency of regulatory
decision-making, and enhancing public health.

Some examples of drug safety goals and objectives from current and ongoing CDER-facilitated PPPs are
outlined below.
Predictive Safety Testing Consortium (PSTC)

PSTC’s mission is to scientifically validate or “qualify” new biomarkers for the detection and monitoring
of drug-induced toxicities (side effects). To date, PSTC has achieved qualification for kidney injury
biomarkers seen in rats, and PSTC members are currently engaged in discussions with FDA and its
European counterpart, the European Medicines Agency, to qualify clinical (tested in humans) safety
biomarkers for drug-induced liver, muscle, cardiac and blood circulatory system, kidney, testicular, and
pancreatic injury. PSTC’s efforts on additional kidney and muscle injury biomarkers have been recognized
for their public health potential by CDER through Letters of Support, which enhance the visibility of
PSTC’s work, encourage data sharing, and stimulate additional studies for further evaluation of these
biomarkers. Once such safety biomarkers are developed and well understood, they can be used widely
during drug development to make risk/benefit decisions—both by regulators who will have fresh insights
into the safety implications of new drugs, and later by patients and health care providers who can make
more informed health decisions regarding the potential consequences of taking a drug.
International Serious Adverse Event Consortium (iSAEC)

The iSAEC mission is to identify variations in human genes that predict the risk of drug-related serious
adverse events. Some patients are genetically predisposed to certain responses to drugs, including certain
side effects. The iSAEC’s research examines the impact of genetic variation on how individuals respond to
a large variety of medicines. iSAEC’s initial studies have successfully identified genetic variants associated
with drug-related liver toxicity and serious skin rashes. Through better understanding of the genetic
basis for such adverse events in patients, informed health decisions can be made regarding an individual
patient’s predisposition to the risk of taking specific medications.
Cardiac Safety Research Consortium (CSRC)

and Health and Environmental Sciences Institute (HESI)
Cardiac Safety Technical Committee
CSRC is advancing scientific knowledge on cardiac safety for new and existing drug products by building
a collaborative research environment based on the principles of the CPI as well as other public health
priorities. The HESI Cardiac Safety Technical Committee seeks to improve public health by reducing
unanticipated drug-related cardiovascular adverse effects and developing new approaches for early
detection and prediction of cardiovascular side effects. The potential for new drugs to cause heart rhythm
changes (known as arrhythmias) is one of the batteries of safety tests performed during drug development.
Currently, this safety evaluation of drug-induced arrhythmias is measured through changes seen in an
electrocardiogram. CDER is collaborating with CSRC and HESI’s Cardiac Safety Technical Committee to
develop an innovative laboratory test that can serve as a much improved drug toxicity assessment of new
drugs.
Through the expertise and resources of external scientists working in the PPP model, vital new information
is shared in a pre-competitive space that is defining the path forward for drug safety and drug development
science. Through the products of such partnerships, CDER is better positioned to ensure that new drugs
are safe and effective prior to marketing, to continue to assess and monitor safety once drugs are on the
market, and to help patients and health care providers make better decisions about the drugs they use.

IMPROVING OPERATIONS
AND MANAGEMENT IN
SUPPORT OF DRUG SAFETY
CDER has undertaken a number of program and policy enhancements over

As new drug safety the last 18 months, enlisting Center operational and management initiatives
challenges emerge, in the implementation of new or revised policies. These include internal
including concerns related reorganizations that maximize CDER’s rich human capital resources and
to tracking of postmarketing better align those resources on behalf of a state-of-the-art drug quality and
drug safety issues and the safety program. As new challenges emerge and are addressed—including
call for a rigorous response concerns related to tracking of postmarketing drug safety issues and
to the national opioid studies and the call for a rigorous response to the national opioid abuse and
abuse and addiction crisis, addiction crisis—CDER continues its focus on reducing preventable harms
CDER focuses on reducing from medication use, enhancing drug product quality efforts, and improving
preventable harms from oversight of generic drugs, compounded drugs, and drug supply chain
medication use, enhancing security.
drug quality efforts, and
improving drug safety The 2015 GAO Report:
oversight.
A Call To Improve Data on Safety Issues
CDER monitors and reviews safety information about all drugs throughout
their lifecycles, interacting with pharmaceutical companies during product
development and clinical investigation of the drug, closely reviewing
safety issues during consideration for marketing approval, and, if approved,
monitoring safety reports after the drugs are marketed. After approval,
CDER may learn of new, more serious, or more frequent adverse drug

reactions from, for example, post-approval voluntary or mandatory reporting of adverse drug reactions
during use of the drug, post-approval clinical trials exploring new uses of the drug, or other post-approval
studies including active surveillance evaluations.
CDER integrates information from these sources with its own evaluations into an overall system of
postmarket surveillance and risk assessment, and uses this aggregated information when a drug’s identified
risks indicate a need to undertake any of a number of actions. These actions can include providing
additional safety information to the public, updating drug labeling, requiring postmarket studies or trials or
other risk management interventions, and, rarely, withdrawing approval of a drug.
When there is an unmet need for the treatment of a serious medical condition, CDER may use one or more
of its expedited programs, including the “fast track” or “breakthrough therapy” designations, intended to
bring drugs to market and expedite their availability to patients. CDER is also responsible for monitoring
the safety of these marketed drugs and reporting on those efforts.
In December 2015, the Government Accountability Office (GAO) issued a report responding to a
Congressional request that GAO provide information about aspects of CDER’s postmarket monitoring
activities.
GAO was tasked with providing information on CDER’s expedited programs and its postmarket monitoring
of expedited and nonexpedited drugs. GAO’s report examined the number and types of requests for fast
track or breakthrough therapy designation that CDER received, and the number and types of approved drug
applications that used an expedited program, focusing on “the extent to which FDA’s data on tracked safety
issues and postmarket studies allowed the agency to meet its reporting and oversight responsibilities.”
GAO analyzed CDER data on requests for fast track or breakthrough therapy designation and approved
drug applications that used an expedited program between October 1, 2006 and December 31, 2014.
GAO also interviewed relevant CDER staff and reviewed CDER information on tracked safety issues and
postmarket studies, concluding that:
• “FDA lacks reliable, readily accessible data on tracked safety issues and postmarket studies needed to
meet certain postmarket safety reporting responsibilities and to conduct systematic oversight.”
• “While internal control standards for the Federal government specify that information should be
recorded in a form and within a time frame that enables staff to carry out their responsibilities, and that
relevant, reliable, and timely information should be available for external reporting purposes,” GAO
found that CDER’s “data on postmarket safety issues and studies were incomplete, outdated, contained
inaccuracies, and was stored in a manner that made routine, systematic analysis difficult.”
GAO acknowledged that CDER has supported efforts to shorten development and streamline review of drug
applications through expedited pathways, but noted problems with “efforts to oversee and track potential
safety issues and postmarket studies once those drugs are on the market.”
In responding to the GAO report, CDER clarified that, to be approved, all drugs must meet the same
standards for safety and effectiveness—whether or not a particular drug has been the subject of an expedited
review program. CDER also noted that, based on continuous improvement processes launched prior to
the initiation of the GAO study, the challenges related to administrative tracking of the two aspects of the
Center’s postmarket safety work noted above had already been recognized and remedies were underway.
Consistent with GAO’s recommendations, CDER is continuing to address those issues through ongoing
improvement efforts.

Postmarketing Requirements and Commitments
TSIs
Using an internal database, CDER is continuing with efforts to improve its ability to maintain accurate and
CDER tracks postmarket drug timely data on the status of PMRs and PMCs. A recent internal audit of CDER
safety issues to ensure their timely data, which began in 2014 and continued into 2015 (and was ongoing at the
evaluation and management. start of and during GAO’s investigation), resulted in multiple data updates and
These issues are referred to as corrections, allowing the Center to implement additional oversight mechanisms
tracked safety issues, or TSIs. to ensure the timeliness and accuracy of PMR and PMC data.
PMRs CDER’s most recent annual assessment found that most open PMRs and PMCs
CDER may require drug are progressing on schedule.
companies to conduct
postmarketing studies or clinical Tracked Safety Issues
trials to further characterize
TSIs are one of the many ways in which information about significant safety
known or potential serious risks
issues is shared within CDER and across the Agency, joining the larger system
of a drug. These studies and
of safety oversight programs and resources described in this report. At the time
clinical trials are referred to as
the GAO report issued, CDER had already noted that its administrative tracking
postmarketing requirements,
of TSIs needed re-evaluation and updating. The Center recognized that the
or PMRs.
overall number of TSIs entered into the system established for tracking safety
PMCs issues was low compared to the number of postmarketing safety issues already
Drug companies frequently identified and, therefore, TSIs were not being effectively recorded in the database
recognize the importance of in a timely manner. CDER addressed this issue and continues to do so: As of
certain other postmarketing June 30, 2016, 154 new TSIs have been created and 171 retroactive TSIs have
studies and, at FDA’s request, been added to the database. New TSIs are being entered into the tracking system
commit to conducting those immediately or shortly after they are identified.
studies. A postmarketing
study that is agreed to, but
Optimizing Drug Safety Oversight
not required, is called a
CDER needs every available tool in its efforts to maintain a robust, versatile,
postmarketing commitment,
and technologically optimized drug safety oversight program. In response to
or PMC.
the GAO report and based on CDER’s own program assessments, the Center
continues to implement new processes and procedures to correct data and
address gaps in information. CDER is also engaged in activities to increase and
streamline the capture of specific information into its database and is facilitating
additional analyses for oversight of postmarket studies and safety issues—
reflections of the Center’s commitment to completing implementation of these
and other new safety monitoring processes and procedures in a timely manner.

Opioid Addiction and Abuse:
Addressing a National Crisis
Rates of opioid use and abuse

began to accelerate in the
late 1990s and continued to
chart a steep increase over
the next 15 years. While the
reasons for this phenomenon
are varied and complex, three
key facts illustrate the breadth
and seriousness of the crisis:
• According to the Centers

for Disease Control and
Prevention, 259 million
prescriptions were written
for opioids in 2012—more
than enough to provide
every American adult
Another kind of drug safety issue emerges when drug products are misused— with a prescription.
not used as directed, or used inappropriately after being prescribed. This is
the case with the national opioid abuse and addiction crisis. The nation is • The 2014 National
experiencing a devastating epidemic of prescription opioid misuse and abuse, Survey on Drug Use and
including a large number of overdose deaths. Health reported that
an estimated 4.3 million
Department of Health and Human Services statistics tell us that, on an average people aged 12 or older
day in the U.S., more than 650,000 opioid prescriptions are dispensed, 3,900 were current nonmedical
people initiate nonmedical use of prescription opioids, and 78 people die from users of pain relievers.
an opioid-related overdose.
• The National Center
As this public health problem has grown in scope, FDA has taken a number for Health Statistics
of significant actions aimed at doing our part to address it. Consistent with the identified drug overdose
Comprehensive Addiction and Recovery Act of 2016, signed by The President as the leading cause of
on July 22, the Agency is committed to using all available tools to continue its accidental death in the
focus on the following goals: United States, with 18,893
overdose deaths related
• Improve the safe use of opioids through careful and appropriate regulatory
to prescription pain
activities and policy development, and through communication, partnership and
relievers as of the end of
public discussion.
2014.
• Improve the treatment of pain through improved science.

As a part of this work, FDA recently developed a comprehensive action plan
CDER facilitates additional
to take concrete steps toward reducing the impact of opioid abuse on American
analyses for oversight of
families and communities. A pivotal element of this plan commits many elements
postmarket studies and
within CDER and the Agency to seek outside input, including advice from
safety issues on an ongoing
Advisory Committees on many opioid-related issues. At the same time, FDA is
basis—reflections of the
committed to re-examining the risk-benefit paradigm for opioids and to ensure
Center’s commitment to
that the Agency is considering the wider public health effects of its decisions
implementation of safety
regarding opioids.
monitoring processes and
procedures in a timely Actions that FDA is committed to taking
manner. include the following:
Expanded use of Advisory Committees. The FDA will convene an expert
Advisory Committee before approving any new drug application for an opioid
that does not have abuse-deterrent properties. Additionally, the Pediatric
Advisory Committee will offer expert advice regarding a framework for pediatric
opioid labeling before any new labeling is approved. The FDA will also convene
an Advisory Committee on abuse-deterrent formulation (ADF) opioids when
those medicines raise unexpected issues.
Development of warnings and safety information for immediate-release

(IR) opioid analgesic labeling. In order to better inform doctors about the
risks of opioid analgesics and how to prescribe them safely, CDER is requiring
changes to IR opioid analgesic labeling to include prominent warnings and safety
information. These safety labeling changes incorporate elements similar to the
extended-release/long-acting (ER/LA) opioid analgesics labeling changes that
were finalized in 2014.
Strengthening of postmarket requirements. The scientific evidence needed

to guide the use of opioid analgesics—particularly in the setting of long-term
use—is substantially lacking. CDER is strengthening requirements for ER/LA
opioid analgesic sponsors to conduct postmarket studies and generate data on the
long-term impact of using ER/LA opioid analgesics, developing better evidence
on the serious risks of misuse and abuse associated with long-term use of opioid
analgesics and predictors of opioid addiction.
Updating Risk Evaluation and Mitigation Strategies (REMS). CDER

can require a REMS from manufacturers to ensure that the benefits of a drug
outweigh its risks. (REMS are safety strategies designed to manage known or
potential serious risks associated with a medicine. A REMS may be required
as part of the approval of a new product or for an approved product when
FDA becomes aware of new safety information.) ER/LA opioid analgesics are
currently subject to a REMS program that requires drug companies to fund
professional medical education on the appropriate use of these products, which
they must offer to health care providers at low or no cost. CDER will update

the REMS program requirements for ER/LA opioid analgesics after considering Advisory Committee
recommendations, with a goal of increasing the number of prescribers who receive training on pain
management and safe and appropriate prescribing of ER/LA opioid analgesics.
Expanded development and use of effective abuse-deterrent formulations (ADFs) to discourage

abuse. The pharmaceutical industry has shown significant interest in developing ADFs as the technology
to do so has continued to rapidly progress. ADFs hold promise as their abuse-deterrent qualities continue
to improve and as they become more widely available. CDER has recently issued draft guidance with
its recommendations for the approval standards for generic abuse-deterrent formulations. Release of
this guidance is a high priority, as the availability of less costly generic products should accelerate
prescriptions written for ADFs, while also fueling innovation and generic ADF product development.
We are also working to assess the real-world impact of these new formulations to make certain they are
having the positive effects on abuse we anticipate based on the pre-market testing.
Support for better treatments for pain and for opioid overdose. Naloxone is a drug used to
counteract the effects of opioid overdose. CDER recently approved naloxone in an intranasal form
(administered by spraying into the nose). Building on this approval, CDER is reviewing options,
including over-the-counter availability, to make naloxone more available. While CDER continues its
assessment, the Agency actively supports the Centers for Disease Control and Prevention guidelines
for prescribing opioids for the treatment of pain, and will facilitate the development of evidence and
improved treatments to bring broader access to overdose treatment, safer prescribing and use of opioids,
and ultimately, new classes of pain medicines without the same risks as opioids.
Reassessment of the risk-benefit approval framework for opioid use. CDER received advice from
the Agency’s Science Board in March 2016, and has engaged the National Academies of Sciences,
Engineering, and Medicine on how to take into account our evolving understanding of the risks of
opioids—not only for patients but also the risks of misuse by other persons who obtain them. Both
activities will generate publicly available reports serving to incorporate the broader public health
impacts of opioid abuse in CDER’s drug product approval decisions.
Each of these action items is keyed to specific outcomes, such as:

• Facilitating opportunities for expert advice from external medical and scientific authorities, and for
public input before approval of any new opioid that does not have abuse-deterrent properties.
• Developing, and providing doctors with, better information about the risks of opioids and how to
prescribe these drugs safely.
• Improving scientific evidence to guide the use of opioid medications, particularly in long-term use
settings, by strengthening requirements for drug companies to generate postmarket data on the long-term
impact of using extended-release/long-acting opioids.

Safe Use Initiative
As many as 1.5 million Americans are injured or killed each year by inappropriate use of FDA-regulated
drugs, including intentional or accidental misuse, or errors such as receiving the wrong drug or wrong
dose from a pharmacy or doctor. Many of these deaths or injuries are preventable.
As an external public outreach complement to Safety First, CDER instituted the Safe Use Initiative
(SUI) to develop solutions within the broader healthcare environment that go beyond standard
regulatory methods to enhance the safe and appropriate use of drugs for all Americans. SUI seeks to
reduce preventable harm from medications by developing, implementing, and evaluating cross-sector
interventions with partners committed to safe and appropriate medication use. As part of this long-
term initiative, SUI brings together various parts of the health care system to develop interventions that
measurably reduce preventable harm from medications.
Selected 2015-2016 program updates include:

Opioid Patient-Prescriber Agreement. SUI’s facilitation of open collaboration with a multidisciplinary
group of federal and non-federal stakeholders was launched in 2012 and continued through 2015 and into
2016. Collaborators include addiction specialists, pain management specialists, primary care physicians,
dentists, pharmacists, medical malpractice insurer, third party insurers, patients previously addicted
to opioids, and caregivers of patients taking opioids. The working group’s goal is to develop a model
opioid patient-prescriber agreement (PPA) designed to be a shared decision-making tool regarding pain
treatment as well as a mechanism to support discussion of critical information about opioids. The Opioid
PPA was piloted for acceptability, feasibility and usability with 14 prescribers and 117 patients. Data
analysis has been completed and a report describing the results of the pilot is currently in development.
Multi-state Prescription Drug Monitoring Program Surveillance Database. In 2015 the SUI team
partnered with the Bureau of Justice Assistance and Brandeis University to develop a surveillance
database using state Prescription Drug Monitoring Programs that will enable CDER to identify opioid
use patterns.

Post-Surgical Opioid Intervention. Kaiser Foundation Research Institute and
the Kaiser Permanente Center for Health Research, with support from the SUI,
are developing a prediction tool to identify patients at high risk for opioid use
following surgery, adapting an opioid-sparing educational intervention and
estimating the efficacy of the intervention in a randomized controlled trial.
(Enrollment underway.)
Development of a risk score for severe hypoglycemic events. SUI partnered with
Kaiser Permanente to provide health care providers with a practical way to identify
patients at high risk of severe hypoglycemia and guide shared decision-making
with respect to modifications of glucose-lowering therapy in out-patient clinical
settings. The prediction model has been completed and validation is underway.
Healthy People 2020 – Medical Product Safety Topic Area Working Group.
Healthy People provides science-based, 10-year national objectives for improving
The Safe Use Initiative works
the health of all Americans. SUI team members are leading the Medical Product
to support the safe use of
Safety Topic Area Working Group as part of the HHS Healthy People 2020
prescription medicines and
Initiative. This group is revising a developmental objective focused on reducing
spans federal partnerships,
deaths from the use of pain medicines.
public-private workgroups,
Standardizing the preparation of medications to reduce errors. With SUI collaborations throughout
support, the University of Michigan gathered information on current practices health communities including
involving preparation of oral liquid medications in pharmacies, and developed patients and patient
voluntary standard concentrations in compounding medications to reduce the risk caregivers, as well as funding
of errors when patients change pharmacies or transition their care. This study original research to better
ended May 2015 and received the annual Cheers Award from the Institute for understand the nature of
Safe Medication Practices, recognizing superlative standards of excellence in the prescription medicine misuse
prevention of medication errors and adverse drug events. One of the investigators and errors.
is now working on a national standardization effort with SUI and the Association
of Health-Systems Pharmacists.
SUI’s ongoing efforts, working across a spectrum of activities to support and facilitate
the safe use of prescription medicines, spans federal partnerships, public-private
workgroups, collaborations throughout health and medical communities outside of
government, the enlistment of experts beyond medical providers and administrators
to include insurers, patients, and patient caregivers, as well as the funding of original
research to better understand the nature of prescription medicine misuse and errors.

Working to Ensure Drug Product Quality
What can go wrong with drug products after approval, but before and during
CDER’s drug quality oversight distribution to pharmacies, clinics, and hospitals across America? Many
streamlines regulatory things, from inherent defects in product design, to failures in drug product
processes by integrating manufacturing related to outmoded equipment or aging manufacturing facilities
review, inspection, pressed beyond capacity, or inadequate or ineffective on-site quality management
surveillance, policy, and systems. In addition to these sorts of direct concerns related to manufacturing
research activities to problems, production slow-downs or failures can create drug shortages—many
strengthen pharmaceutical of which involve critically needed life-saving medicines used in hospital
quality on a global scale. emergency departments and operating rooms.
The quality of drug products is a pivotal aspect of drug safety, making product
quality oversight a vital asset in CDER’s drug safety portfolio. In facilitating
needed growth in CDER’s product quality programs, Center Director Janet
Woodcock spearheaded the stand-up of the new CDER Office of Pharmaceutical
Quality (OPQ) in January 2015.
CDER’s drug quality oversight is now structured to streamline regulatory

processes and align areas of expertise by integrating review, inspection,
surveillance, policy, and research activities to strengthen pharmaceutical quality
on a global scale.
Supporting this central objective is a systematic approach to product quality

knowledge and informatics that brings parity to the oversight of brand name
and generic drugs and domestic and international manufacturing facilities, while
also promoting emerging technologies to enhance pharmaceutical quality. These
efforts are moving toward a reinvigoration of the pharmaceutical manufacturing
sector in the United States by, among a number of activities, centralizing
regulatory review, policy, research and science functions, project management,
quality management systems, and administrative activities, and establishing a
uniform approach to pharmaceutical quality across all manufacturing facilities,
domestic or foreign, and across all drug product areas—new drugs, generic
drugs, and over-the-counter drugs.
These tenets establish “One Quality Voice” for patients, providers, and industry,
creating the “critical mass” that ultimately assures the availability of safe,
effective, high-quality medicines to the American public.
OPQ recently celebrated its first anniversary, marking several milestones and
achievements including:
• Establishment of the CDER Emerging Technology Program featuring a cross-

function team that will provide drug companies with opportunities to discuss
design and development issues related to their proposed new technology prior to
the submission of drug applications. The program also published a draft guidance
that will help drive the pharmaceutical industry toward a more efficient, agile,
and flexible manufacturing sector.

• Development of a risk communication dashboard that will complement or
even possibly replace the existing drug product quality review infrastructure,
which is based upon subjective, unstructured and lengthy text narratives.
• Establishment of a risk-based approach in quality assessment to capture

knowledge of risks over a product lifecycle. This risk-based approach will
enhance quality, transparency and consistency of assessment of drug products
and will lead to more efficient and effective regulatory decisions and clear
expectations for industry.
• Establishment of new policies to ensure that drug quality activities support

the availability of quality medicines for all Americans by developing and
clearly communicating science and risk-based policies and standards related to
drug product quality, including application review and inspection.
Generic Drug Safety Oversight:

A Coordinated Effort
CDER’s Office of Generic Drugs (OGD) established its Clinical Safety and
Surveillance Staff (CSSS) in 2014. The CSSS facilitates broad collaborative
surveillance projects with various Offices throughout CDER, establishing
coordinated partnerships that further CDER’s commitment to the surveillance
CDER’s Office of Generic
of generic drug quality and therapeutic equivalence.
Drugs safety and surveillance
The CSSS continues with tracking and evaluation of reports of potentially activities facilitate broad
inferior generic product quality, adverse events and other safety concerns, collaborations—establishing
and reports of different therapeutic effect compared to the relevant reference coordinated partnerships that
listed drug (also known as the “brand name” drug). The results of these further CDER’s commitment
investigations are further evaluated by an interdisciplinary team and, if a to the surveillance of generic
significant safety issue is identified, that team works collaboratively with other drug quality.
relevant CDER offices to resolve the issue.
The interdisciplinary CSSS structure facilitated evaluation of several high

profile surveillance efforts, integrating the efforts of all contributors to
the CDER Generic Drug Program. A recent example is the evaluation of
therapeutic non-equivalence of generic versions of methylphenidate (indicated
for treatment of adult attention deficit/hyperactivity disorder and narcolepsy),
thorough reviews of formulation differences, bioequivalence criteria, and
clinical use of the brand-name product (Concerta), which led to a downgrade
of therapeutic equivalence ratings for two generic versions, a multidisciplinary
workgroup recommendation for changes to the bioequivalence criteria, and
a major change to the product-specific bioequivalence criteria. The Office of
Generic Drug’s Regulatory Science Program also launched a prospective study
to further evaluate therapeutic differences between brand-name and generic
versions of Concerta.

Compounded Drugs and Drug Supply Chain
Security: Critical Aspects of Product Safety
Compounded Drugs
Compounding is a
Compounding is a practice in which a licensed pharmacist, a licensed physician, or,
practice in which a
in certain cases, a person under the supervision of a licensed pharmacist, combines,
pharmacist or doctor
mixes, or alters ingredients of a drug to create a medication tailored to the needs of
combines, mixes, or alters
an individual patient. Compounded drugs can serve an important role for patients
ingredients of a drug to
whose clinical needs cannot be met by an FDA-approved drug product, such as a
create a medication
patient who has an allergy and needs a medication to be made without a certain dye,
tailored to the needs of an
or an elderly patient or a child who cannot swallow a tablet or capsule and needs a
individual patient.
medicine in a liquid dosage form that is not otherwise available. But drugs that are
compounded improperly, or that are compounded under substandard conditions,
can pose serious health risks. For example, compounded drugs that are produced
under insanitary conditions can become contaminated, and errors made during
compounding can result in sub- or super-potent products.
CDER has responded to many serious adverse events, including infections and
deaths, associated with compounded drugs that were contaminated or otherwise
compounded improperly. The most serious in a long history of outbreaks associated
with contaminated compounded drugs was an outbreak of fungal meningitis in late
2012. Over 750 patients in 20 states were diagnosed with a fungal infection after
receiving injections of the contaminated drugs, and 64 patients in nine states died.
Since the 2012 fungal meningitis outbreak, FDA has identified insanitary conditions
at many of the compounding facilities it has inspected. Among many other insanitary
conditions that put patients at risk, examples include dog beds and dog hairs in close
proximity to a sterile compounding room, pharmacies with dead insects in ceilings,
renovations made without any evidence of controls to protect sterile drugs from
contamination, use of coffee filters to filter particulates, compounding by personnel
Compounded drugs serve with exposed skin during sterile production, toaster ovens used for sterilization, and
an important role for a kitchen dishwasher used to clean sterile compounding equipment and utensils.
patients whose medical
Congress enacted the Drug Quality and Security Act (DQSA) in 2013. The DQSA
needs cannot be met by
removed certain provisions from section 503A of the Federal Food, Drug, and
an FDA-approved drug
Cosmetic Act (FDCA) that were found to be unconstitutional and created a new
product—such as a patient
section, 503B, in the FDCA. Under this new section, a compounder can become
who needs a medication
an “outsourcing facility.” Outsourcing facilities must comply with current good
to be made without a
manufacturing practice requirements, are inspected by FDA according to a risk-
certain dye to avoid an
based schedule, and must meet certain conditions, including reporting adverse events
allergic reaction. But drugs
to FDA associated with their compounded drugs.
that are compounded
improperly, or that are CDER has worked quickly to implement the compounding provisions of the DQSA,
compounded under while directing inspection and enforcement initiatives to protect the public from
substandard conditions, poor quality compounded drugs. In 2015 and so far in 2016, CDER:
can pose serious health
risks. • Continued inspection and enforcement efforts, as well as policy development,
related to human drug compounding.

• Directed and evaluated findings from over 110 inspections of compounders throughout the United States –
with problems identified in a majority of inspections, prompting numerous compounders to initiate voluntary
product recalls and, in some cases, to stop sterile production.
• Issued more than 35 warning letters to compounders. In addition, in 2015, two compounders entered into
consent decrees of permanent injunction (a legal agreement to permanently comply with FDA regulatory
policies).
CDER has also continued to make significant progress in implementing the compounding provisions of the
FDCA by publishing policy documents applicable to compounding pharmacies and outsourcing facilities. In
2015 and so far in 2016, CDER has published twelve draft guidance documents, four final guidances, and a
draft memorandum of understanding with the states, and also held the first five meetings of the reconstituted
Pharmacy Compounding Advisory Committee.
As problems are identified at compounding pharmacies and outsourcing facilities across the country, CDER will
continue to vigorously pursue inspection and enforcement efforts.
Drug Supply Chain Security

The U.S. drug supply chain remains one of the safest in the world—but has also become increasingly complex
as the supply chain reaches beyond U.S. borders. Threats to the supply chain such as counterfeiting, theft, and
importation of unapproved or otherwise substandard drugs, could result in unsafe and ineffective drugs in U.S.
distribution.
FDA has been actively engaged in efforts to improve the security of the drug supply chain for many years
to protect patients from unsafe, ineffective, and poor quality drugs. Since the formation of the first FDA
Counterfeit Drug Task Force in 2003, the Agency has advocated for a multi-tiered approach to securing the
supply chain and protecting consumers from the threats posed by counterfeit or compromised drug products.
The ability to trace prescription drugs also plays a significant role in providing transparency and accountability
in the drug supply chain.
The Drug Supply Chain Security Act (DSCSA) was signed into law in 2013, providing for a uniform Federal
framework to be in place by 2023. This framework will identify and trace certain prescription drugs by outlining
critical steps to build an enhanced electronic, interoperable system to trace drug products as they are distributed
within the United States. This critically important system expands and improves FDA’s ability to protect the
public from exposure to drugs that may be counterfeit, stolen, tainted, or otherwise potentially harmful.
Since January 1, 2015, the law placed new requirements on drug manufacturers, repackagers, and wholesale
distributors, followed by dispensers (primarily pharmacies), to have systems and processes in place to
exchange product tracing information, conduct verification to identify suspect product, including steps such as
quarantining and investigating suspect product, notify FDA and trading partners when an illegitimate product is
found, and keep records.
FDA has issued several guidances for industry and continues to work with stakeholders on implementation
through public workshops and other meetings. To help inform the enhanced system of 2023, FDA is
coordinating with members of the supply chain and developing a pilot project program that will explore and
evaluate methods to enhance the safety and security of the pharmaceutical distribution supply chain. This pilot
project program will focus on utilization of the product identifier, which will enable product tracing down to the
level of an individual package.

COMMUNICATING DRUG SAFETY:
A GLOBAL PUBLIC INTERFACE
As CDER’s preeminent resource for communicating human drug information, the Center’s Office
of Communications (OCOMM) serves at the nexus of virtually every drug safety issue, question,
or crisis that CDER faces. With nearly 100 staff members including health professionals,
communications specialists and web and graphic designers, OCOMM fulfills CDER’s internal
and external communication needs, including providing strategic communication advice to
Center and Agency leadership, developing and coordinating overarching public communication
initiatives and educational activities, and employing comprehensive communication approaches
to ensure consistent branding, messaging, and strategic direction of CDER’s communication
products—all critical aspects of drug product safety.
Expert Responses to Public Queries

A team of pharmacists, consumer safety officers and nurses respond to public inquiries from
around the world, providing expert guidance and responses to questions about human drug
products.
More than 65,000 requests for information are received annually, many of which involve some
aspect of drug safety, from how much or how little of a medicine to safely use, to safe prescribing
or dispensing practices, to responses on media-trending drug safety concerns. Queries arrive via
phone, electronic mail, and letter, from an array of stakeholders, including consumers, health care
professionals, academia, foundations and research organizations, and the pharmaceutical industry.
Safety inquiries can involve complex scientific or regulatory issues; in those cases OCOMM
coordinates extensive research and consultation needs with the subject matter experts needed to
craft accurate and balanced responses.
Another variation in public inquiry are national write-in campaigns, which are frequently
organized around a particular facet of medication safety. OCOMM organizes and manages
CDER’s response to these campaigns—in the last 18 months alone, OCOMM has sent over 2,000
emails and letters to 16 different campaigns.

Social Media and Online Tools
OCOMM serves as CDER’s public interface in using multiple digital tools and platforms to provide
drug safety outreach and education. The highlights below reflect 2015-2016 milestones in these
communications arenas.
Facebook. CDER became the first Center to engage the public on FDA’s Facebook
page, with 128 drug-related posts reaching over 4 million Facebook users.
Twitter. CDER became the first FDA Center with a Twitter account (@FDA_Drug_
Info). 616 Tweets were sent, and 40,764 new followers were gained over the last 18
months to reach a total of more than 200,000 Twitter followers. OCOMM organized
and led the first CDER Twitter Chat, #LungChat, which engaged major oncology
organizations, patients, advocates and health care professionals about lung cancer
treatments, and live-tweeted three of Center Director Janet Woodcock’s recent
Congressional testimonies.
Podcasts. FDA Drug Safety Podcasts provide Drug Safety Communications in audio
form and are available on iTunes and ReachMD radio—46 Drug Safety Podcasts
have seen 31,846 transcript visits and 135,388 audio downloads in 2015 and through
the first quarter of 2016.
The Director’s Corner is an audio podcast

series featuring Dr. Janet Woodcock
commenting on a number of CDER priorities
including drug safety issues and advances.
• Celebrating 30 years at FDA. Dr. Woodcock reflects on breakthroughs in drug research and
regulation and makes some predictions for the future of drug products.
• Talking Translational Science. Dr. Woodcock defines translational science and how it can
positively affect drug development and review.
• Looking Back and Moving Forward in 2016. Dr. Woodcock discusses major events of 2015 and
priorities for 2016.
• Drug Compounding. Dr. Woodcock discusses drug compounding from both a safety and regulatory
standpoint.
• Working with Patient Advocacy Groups. Dr. Woodcock discusses regulatory guidances drafted and
submitted to FDA by patient advocacy groups.

Webinars. OCOMM hosted 27 webinars over 2015 and to date in 2016, several of which offered
information and training on drug safety programs and initiatives:
• Introduction to Postmarketing Drug Safety Surveillance: Pharmacovigilance in FDA/CDER
• Introduction to FDA’s MedWatch Adverse Reporting Program
• Professional Labeling: The Prescribing Information
• FDA Online Drug Information Resources for Students and Clinicians
• Introducing the REMS@FDA Website
• Know Your Source: Protecting Patients from Unsafe Drugs
Video. FDA Drug Info Rounds Videos target pharmacists ond other health care providers and are
promoted to State Boards of Pharmacy, pharmacy schools, and posted on YouTube. Many of the Drug
Info Rounds Videos produced in 2015 and 2016 focus on aspects of drug safety.
• REMS@FDA Tutorial presents the new and improved REMS website called REMS@FDA.
• Emergency Preparedness – Keeping Medications Safe discusses the importance of having a plan in
place for keeping medications safe as part of emergency preparedness.
• MedWatch Tips and Tools presents resources available to health care professionals to make reporting
to MedWatch easier than ever.
• Breakthrough Therapy discusses the breakthrough therapy designation, an exciting new program to
expedite drug development while maintaining safety oversight in the development process (Bronze Telly
Award).
• FAERS provides background information about the FDA Adverse Event Reporting System (FAERS)
database.
• REMS presents the many components of Risk Evaluation and Mitigation Strategies (REMS) and how
they can help manage a drug product with known or potential serious risks.
• Disposal of Unused Medicines discusses safe medication disposal options.
Drug Information Update. The FDA Drug Information Update email subscription service sends
bulletins to stakeholders with safety information about drug products including Drug Safety
Communications, drug approvals, CDER Statements, and industry guidances. The Drug Information
Update email service gained 28,999 new subscribers in 2015 (with a current total of 155,447), and the
service sent out 208 email messages.

Drug Safety Communications (DSCs)
Patients, caregivers, health care professionals, and the public are updated on
CDER’s Drug Safety
new drug safety information with Drug Safety Communications (DSCs). These
Communications web page
messages and announcements can range from new or emerging risks associated
is the most visited page on
with concurrent conditions (for example, pregnancy or existing liver or kidney
the FDA’s web site, with more
disease), or cautions about potential medication errors. DSCs contain actionable
than a million page views
recommendations for patients and health care professionals that can help them
over the last 18 months
make more informed decisions, and prevent or mitigate drug-related harm.
DSCs are usually issued in conjunction with regulatory actions such as Safety
Labeling Changes for a number of reasons, including issues affecting a large Drug Safety Communications
number of patients, potentially serious or life-threatening adverse events, or are broadly circulated
medication errors that may result in serious or life-threatening adverse reactions. through a variety of channels,
including email newsletters,
The Drug Safety Communication web page is the most visited page on the FDA’s
podcasts, social media
web site. Forty-six DSCs were issued between January 1, 2015, and July 26, 2016,
and targeted outreach to
and during that time the DSC home page and the 46 individual DSC web pages
healthcare professionals,
received over a million page views. Outreach was significantly greater than that,
advocacy groups and other
however, as DSCs are much more broadly circulated through a variety of other
stakeholders.
channels, including several large listservs, email newsletters, podcasts, social
and traditional media, and targeted outreach to media, healthcare professionals,
advocacy groups and other stakeholders.
Safety Labeling Changes (SLCs):

New and Improved Access to Safety Information
When a drug is approved for marketing, not every safety concern or risk potential
can be identified. As this report highlights, postmarket safety oversight is therefore
essential to learning more about the effects of a medicine when used by a large
number of people over a long period of time. If new safety concerns emerge after
a medicine is used in a real-world setting, CDER may require a “Safety Labeling
Change,” or SLC. These changes can focus in one or more specific sections of
a drug label, including contraindications, warnings and precautions, adverse
reactions, or boxed warnings (widely known as “black box warnings”).
Although SLCs have been available online for many years, they were aggregated
and posted on a monthly basis. This meant that if a new safety concern was
reflected in an approved labeling change early in a month, that information was
not publicly posted until early in the following month—three to four weeks later.
As web and database technologies evolved, CDER recognized a need to apply
new digital functionalities that would not only shorten the time between an SLC’s
approval and when its safety information becomes available on the FDA’s website,
but to generally enhance an online visitor’s experience by improving the SLC web
platform’s clarity, access, and navigability.

As of August 1, 2016, CDER’s SLC data and web access functions migrated to a
The “labeling” of a medicine new platform and database managed by OCOMM, making drug safety labeling
is the detailed information information available in real time and in a user-friendly format for relevant
on the package insert that stakeholders, including health IT and information vendors, health care providers,
accompanies a drug, be and patients. Searchability along with ease in downloading data, whether for one
it inside the product box or drug or several, are both features that can now be used on the newly designed
folded and glued to the lid SLC Web platform.
of a bottle—not simply the
information printed on a As health IT vendors are able to gather SLCs more efficiently, they can more
bottle or box. The product effectively organize and distribute data related to those SLCs. In turn, this
labeling includes a summary furthers CDER’s primary goal in redesigning the SLC database and Web
for the safe and effective interface: To deliver drug safety label changes to health care providers as quickly
use of the drug and is as possible. In turn, this facilitates “downstream” data integration into drug
generally intended for use by information systems, and will carry SLC data into other communication venues
prescribers and pharmacists. such as social media, news feeds, and web sites with vast reach among health
FDA-approved patient care professionals, patients, and consumers, including WebMD, Medscape, PDR.
information is written for a lay net, Epocrates, FirstDataBank, and Yahoo Health.
audience and is generally
included at the end of the
The new CDER website database will be populated with SLCs from January
product label.
2016 forward. Data from earlier than January 2016 will continue to be available
on the MedWatch website.
The table below details the number of SLCs approved between January 2015 and
July 2016�more than 1,500 in all.
Boxed Warnings 87
Contraindications 83
Warnings 452
Precautions 548
Adverse Reactions 362
PPI / MG / PCI 144
TOTAL 1,676

Risk Communications Research
OCOMM houses a number of ongoing research studies that will allow better understanding of CDER
audiences’ knowledge, perceptions, needs, desires, and behaviors related to a variety of drug safety
information. Evidence now being generated will provide data that can be used to improve CDER
communications and expand dissemination of content and materials in order to help target audiences
understand the health and safety information that CDER provides. These research efforts also provide
the public, including people with limited health literacy or who face disparities in accessing health
services, opportunities for input on the effectiveness of CDER drug safety information.
In late 2015, a study of medical countermeasures messaging (launched in 2012) was completed,
offering insight and recommendations for developing effective communication initiatives for public
health emergencies. A second phase of this study will be undertaken in 2016 to test the various medical
countermeasures messages that were developed as a result of the initial study findings.
Other OCOMM risk communication research conducted in 2015 and through early 2016 included:
• A study to enhance FDA communications addressing opioids and other potentially addictive pain
medications, scheduled to be completed in 2017
• Research exploring issues of uncertainty and unintended consequences associated with prescription
drug communications
• A survey project building on prior focus group research that tests Drug Safety Communications
to better understand consumer recall, understanding of risk, and behavioral intentions related to DSC
content and formatting

The work highlighted in this report—projects, initiatives, partnerships, and original research—is
not a complete list of CDER’s safety programs, but represents many of the most dynamic
efforts to reinvent and advance the Center’s drug safety enterprise. CDER’s drug safety
work capitalizes on team-oriented and multidisciplinary methodologies, tapping synergies
within the FDA while also reaching outside the Agency to partner with industry, academia,
independent research institutions, and advocacy organizations in the drive to reach critical
safety objectives.
As with all areas of science and technology, drug safety science is constantly evolving. CDER
recognizes that ongoing success in safety oversight and surveillance requires a continuing
ability to adapt to new information, new technologies, and new developments. CDER has
created a safety system that directs scientific expertise and rigor across the lifecycle of FDA-
approved drugs, building the Agency’s ability to navigate the inevitable changes to come
in medicine and health care.
Moving forward, all CDER’s safety efforts, as they remain thorough and systematic, will
continue to be designed to support parallel efforts to advance innovation and help ensure
that safe and effective new therapies are available to the American public as efficiently and
rapidly as possible.

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Center for Drug Evaluation and Research 2015-2016

DRUG SAFETY PRIORITIES

Drug Safety Oversight Across the Product Lifecycle............................................................4

Advancing Drug Safety Science.............................................................................................9

• JumpStart – Enhancing Pre-Market Drug Review with Digital Tools...................................... 9

• Postmarketing Safety Surveillance and Oversight...................................................................11

• Improving Drug Safety through Research ............................................................................. 15

• Advancing Drug Safety Science through Public-Private Partnerships................................... 20

Improving Operations and Management in Support of Drug Safety................................22

• The 2015 GAO Report: A Call To Improve Data on Safety Issues........................................ 22

• Opioid Addiction and Abuse: Addressing a National Crisis................................................... 25

• Safe Use Initiative................................................................................................................... 28

• Working to Ensure Drug Product Quality............................................................................... 30

• Compounded Drugs and Drug Supply Chain Security .......................................................... 32

Communicating Drug Safety: A Global Public Interface...................................................34

• Expert Responses to Public Queries ...................................................................................... 34

• Social Media and Online Tools............................................................................................... 35

• Drug Safety Communications................................................................................................. 37

• Safety Labeling Changes........................................................................................................ 37

• Risk Communications Research............................................................................................. 39

2 | CDER DRUG SAFETY PRIORITIES 2015-2016

For more than a century, the safety of medicines

With millions of Americans taking more medicines

Janet Woodcock, M.D.

INITIATIVES AND INNOVATION | 3

4 | CDER DRUG SAFETY PRIORITIES 2015-2016

CDER’s assessment of a drug’s safety profile begins early in the drug

An expanded multidisciplinary team is formed at this point, including staff with

Drug approval decisions are based on a comprehensive assessment of the benefits

INITIATIVES AND INNOVATION | 5

ANIMALS TESTED PRECLINICAL

REVIEW MEETING PREMARKET

6 | CDER DRUG SAFETY PRIORITIES 2015-2016

SAFETY FIRST INITIATIVE VOLUNTARY REPORTING

INITIATIVES AND INNOVATION | 7

Through an amalgam of internal policies and organizational procedures, Safety

In mandating and supporting team-based multidisciplinary collaborations,

8 | CDER DRUG SAFETY PRIORITIES 2015-2016

JumpStart – Enhancing Pre-Market Drug Review with Digital Tools

INITIATIVES AND INNOVATION | 9

10 | CDER DRUG SAFETY PRIORITIES 2015-2016

How Drug Postmarketing Reports Get to FDA

Patients, Consumers and

FDA MedWatch Manufacturer

5% of all reports 95% of all reports

INITIATIVES AND INNOVATION | 11

12 | CDER DRUG SAFETY PRIORITIES 2015-2016

The Sentinel System:

INITIATIVES AND INNOVATION | 13

Sentinel System Updates

Other milestones in this time period include:

14 | CDER DRUG SAFETY PRIORITIES 2015-2016

Safety Research Interest Group or abnormal biological

CDER’s science and research agenda. effectiveness, among other

INITIATIVES AND INNOVATION | 15

Electronic health care data to better determine risk of suicide

Consumer reactions to drug product labeling.

Computer modeling to better predict adverse drug events.

Identification of factors explaining new safety signals in