Drug Safety Priorities 2021: Center For Drug Evaluation and Research

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CENTER FOR DRUG EVALUATION AND RESEARCH
DRUG SAFETY
PRIORITIES
2021
January 2022
www.fda.gov
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DRUG SAFETY PRIORITIES 2021
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Table of Contents
Introduction from Center Director .....................................................................................5
COVID-19 .....................................................................................................................................6
Safety Surveillance and Oversight of Marketed Drug Products .......................... 14
Nitrosamine Impurities in Medicines: FDA’s Continuing

Multidisciplinary Response................................................................................................ 22
Continued Efforts to Address the Misuse and Abuse of

Opioid Drugs and Other Substances ............................................................................. 24
Ensuring Quality, Safety, and Effectiveness of Generic Drugs............................... 28
Safe Use Initiative: Collaborating to Reduce Preventable

Harm from Medications ...................................................................................................... 33
Compounded Drugs: Continuing Oversight and Stakeholder Outreach ......... 38
Communicating Drug Safety: Global Outreach Through Diverse

Tools and Technologies ....................................................................................................... 41

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Drug Safety
DRUG SAFETYPriorities 2019 2021
PRIORITIES
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Introduction
The past year had its challenges with much of our focus still directed
toward the response to the Coronavirus Disease 2019 (COVID-19)
pandemic. During this period, we continued to advance the Food and
Drug Administration’s (FDA) public health and consumer protection
mission. CDER Drug Safety Priorities 2021–our seventh annual
report–illustrates the broad range of safety efforts undertaken based on
multidisciplinary collaborations and partnerships, and presents updates
on the year’s safety-related achievements and milestones.
In addition to assessing the safety of drug products used for COVID-19

and protecting consumers from unsafe, unapproved, and fraudulent
products, we maintained our robust postmarket surveillance and risk
evaluation programs. We were able to rapidly analyze and resolve drug
safety issues when they arose through coordinated activities that included Patrizia Cavazzoni, M.D.
experts across multiple scientific disciplines. We continued to protect the Director, Center for Drug
public from contaminated products by inspecting facilities to the extent Evaluation and Research (CDER)
we were able during the pandemic, issuing warning letters and risk alerts,
and working to improve the quality of compounded drugs. On the heels of
historic highs in the number of drug overdose deaths, we redoubled our
efforts to address the opioid crisis and to reduce inappropriate use and
the harm from controlled substances abuse or misuse. We also continued
our work on other drug safety initiatives and programs, including the
Sentinel System, our electronic safety surveillance system; the Safe Use
Initiative that works to minimize preventable harm from medications;
and work to address unexpected, and potentially cancer-causing impuri-
ties in medicines. We continued outreach to transparently communicate a
broad variety of drug safety information to the public. Our many accom-
plishments over the past year reflect the best of CDER’s commitment to
public health and safety.

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COVID–19
COVID-19 continued to present a major threat to public health world-
wide in 2021. The FDA recognized the increased demand for certain
products during this emergency and remained committed to facilitating
access to safe and effective medical products to help address criti-
cal needs of the American public. The Agency’s safety focus included
monitoring and evaluating drugs for COVID-19; taking actions against
unsafe, fraudulent, and unapproved products; and keeping the public
informed. The latest COVID-19 news from the FDA can be found here.
The highlights below detail key drug safety actions CDER worked on
in 2021.
Assessing the Safety of Products Used for

COVID-19
To protect the public during the pandemic, CDER monitored and
assessed the safety of novel and repurposed medicines used for
COVID-19. We conducted surveillance using multiple data sources for
safety concerns and medication errors related to products used to treat
or prevent COVID-19, provided guidance on how to adapt risk evalua-
tion and mitigation strategies (REMS) programs during a pandemic, of-
fered recommendations for labels and labeling to minimize medication
errors, and collaborated with other agencies and organizations to study
the effects of drugs used to treat COVID-19. The Agency also enhanced
communications with the public and industry.

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Surveillance
FDA continued to support
• Reviewed safety data, including adverse event reports and
public-private partnerships of
observational studies, as part of the overall benefit-risk
assessment for products submitted for COVID-19 under an EUA clinical trials conducted through
and new drug application (NDA) approval the Coronavirus Treatment
• Conducted surveillance on case reports in FAERS, medical Acceleration Program (CTAP) that
literature, the National Poison Data System, prescription and were testing new treatments
nonretail sales, and other data sources; and evaluated newly
identified safety concerns and medication errors related to for COVID-19 to gain valuable
products used to treat or prevent COVID-19 knowledge about their safety
• Conducted searches and reviews of observational study literature and effectiveness and enable
on the impact of drugs used to treat or prevent COVID-19 treatments supported by research
• Reviewed and provided feedback on the quality and feasibility to be available as quickly as the
of proposals for Real World Data (RWD) analyses to inform the
scientific evidence supported
effectiveness of COVID-19 therapies
them.
• Reviewed proprietary names (commonly known as brand names),
container labels, carton labeling, Fact Sheets, and Dear Health
Care Professional letters related to multiple COVID-19 therapies
• Undertook an in-depth research project exploring the effects the

COVID-19 pandemic was having on opioid use and addiction
Safety Assessment in Population-Based Data Sources

• Examined use of systemic corticosteroids and concomitant
therapies, clinical and demographic characteristics, COVID-19
severity, and outcomes in COVID-19 outpatients using data from
Sentinel System and three other large U.S. databases
• FDA’s Sentinel System initiated activities designed to:
• Describe racial and ethnic distribution of testing, hospitalization,

and death from COVID-19, and evaluate associations between
race and ethnicity and COVID-19 severe disease and in-hospital
death among patients younger than 65 years
• Inform safety surveillance activities by characterizing

utilization patterns and baseline characteristics of patients
receiving products under EUA, including monoclonal
antibodies, baricitinib, and tocilizumab
• FDA’s Sentinel System also continued to carry out activities in the

following areas:
• Built and enhanced infrastructure to analyze health care claims

and electronic health record data to support epidemiological
studies of COVID-19

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• Developed and applied new capabilities to conduct near real-

time monitoring of critical drugs in the inpatient setting to assess
changes in utilization over time and by geography to inform the
potential for drug shortages
To assist the public in searching
• Described the course of illness among hospitalized COVID-19
for information related to patients, including their characteristics, health care utilization,
adverse events with drugs and disease progression, and outcomes
therapeutic biological products • Assessed the occurrence of coagulopathy and its risk factors
approved under an Emergency among hospitalized COVID-19 patients
Use Authorization (EUA) during
• Examined the natural history of COVID-19 disease in pregnant
COVID-19, FDA launched in 2021 women, including medication utilization, disease severity, and
the COVID-19 EUA FAERS Public clinical outcomes of COVID-19
Dashboard, which provides weekly • Completed two studies describing risk factors for COVID-19-
updates. During public health related deaths and hospitalizations in Medicare beneficiaries,
emergencies, the FDA may in one in community-dwelling beneficiaries and another in those
certain circumstances use an EUA residing in nursing homes
to authorize use of unapproved • Completed a study to examine whether the active use of
drugs or unapproved uses of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin
receptor blockers (ARBs) to treat high blood pressure at the time
approved drugs for life-threatening
of SARS-CoV-2 infection was associated with an increased risk of
conditions when there are no COVID-19 hospitalization or more severe COVID-related outcomes
adequate, approved, and available
options and other conditions Collaboration with Other Organizations and
are met. FAERS, the FDA Adverse Communication with the Public and Industry
Event Reporting System, is a
• Led collaboration with the American College of Medical
database containing adverse event Toxicology (ACMT) to create a Toxicology Investigators
reports, medication error reports, Consortium (ToxIC) COVID-19 Sub-Registry, an enhanced data
and product quality complaints collection tool within the ToxIC network, to focus on identifying
potential adverse events related to COVID-19 drug products
resulting in adverse events
submitted to FDA and supports • Led collaboration with the Veterans Administration (VA) and CMS
the Agency’s postmarketing safety to develop infrastructure and conduct near real-time surveillance
of EUA products in the CMS Medicare and VA populations
surveillance program.
• Contributed to the FDA’s Center for Biologics Evaluation and
Research (CBER)-led guidance called Policy for Certain REMS
Requirements During the Tocilizumab Shortage
• Responded to Congressional and media inquiries related to the

safety of products used to treat or prevent COVID-19, multiple
inquiries on individual approved REMS requirements during
COVID-19, and multiple inquiries on the feasibility of conducting
remote human factors studies during COVID-19

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Warnings about Hand Sanitizers

Hand sanitizer is recommended for use when soap and water are not avail-
able, and since the beginning of the pandemic, the FDA has remained vigi-
lant and continued to take action when safety and quality issues arose with
certain hand sanitizer products. The Agency is especially concerned with:
• Products contaminated with harmful or poisonous ingredients,

such as methanol or 1-propanol. Methanol, also known as wood
alcohol, is used to make rocket fuel and antifreeze and is very
toxic. 1-Propanol is used to make industrial solvents and can also
be toxic when swallowed.
• Products contaminated with unacceptable levels of benzene,

acetaldehyde, and acetal impurities. Benzene may cause certain
types of cancer in humans. Animal studies show acetaldehyde may
cause cancer in humans and may cause serious illness or death.
Acetal can irritate the upper respiratory tract, eyes, and skin.
• Products contaminated with micro-organisms. Use of contaminated

hand sanitizer could lead to serious infections, including infection
of the skin, soft tissues, lungs, or bloodstream. Individuals with
compromised immune systems are at increased risk.
• The dangers of drinking any hand sanitizer under any condition.

While hand sanitizers with possible methanol contamination are
more life-threatening, the FDA urges consumers not to drink any
of these products.
• Certain hand sanitizers that may not contain sufficient

concentrations of ethyl alcohol or isopropyl alcohol.
• Hand sanitizers sold or offered for sale with false and misleading,
unproven claims that they can prevent the spread of viruses such
as COVID-19, including claims that they can provide prolonged
protection (e.g., for up to 24 hours).
• Products fraudulently marketed as “FDA-approved” since no hand

sanitizers are approved by FDA.
• Products packaged to appear as drinks, candy or in liquor

bottles, and those marketed as drinks or cocktails because their
appearance could result in accidental ingestion or encourage
ingestion. Children are particularly at risk with these products
since ingesting only a small amount of hand sanitizer may be
lethal to them.

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In 2021, the FDA worked to protect the public from poor-quality,

In 2021, the FDA worked to protect unsafe, and unapproved hand sanitizer products, in particular, those
the public from poor-quality, unsafe, contaminated with methanol and associated with deaths in the United
and unapproved hand sanitizer States, including by:
products, in particular, those • Creating the first-ever country-wide import alert for Mexican firms
contaminated with methanol and • Seeking the voluntary recall of more than 190 hand sanitizer
associated with deaths in the United products
States, including by:
JANUARY 19 | FDA issued a guidance outlining the Agency’s policy for
drug manufacturers and compounders to test alcohol or isopropyl
• Creating the first-ever country-wide alcohol for methanol contamination prior to using the alcohol to
import alert for Mexican firms produce drugs, including hand sanitizer products.
JANUARY 26 | FDA placed all alcohol-based hand sanitizers from Mexico

• Seeking the voluntary recall of on a countrywide import alert to help stop products that appear to be
more than 190 hand sanitizer in violation from entering the United States until the Agency is able to
review the products’ safety.
products
MARCH 25 | FDA warned consumers and health care professionals not
to use Durisan Antimicrobial Solutions Hand Sanitizer manufactured by
Sanit Technologies LLC doing business as Durisan in Sarasota, Florida,
due to microbial contamination. Durisan voluntarily recalled its hand
sanitizer product on March 24 and expanded the recall on April 16.
JUNE 16 | FDA issued a Drug Safety Communication warning that

symptoms such as headache, nausea, and dizziness can occur after
applying alcohol-based hand sanitizers to the skin. These symptoms
are likely to have occurred because of vapors from the hand sanitizer,
potentially from exposure in enclosed spaces or places with poor air cir-
culation. FDA received increasing reports of these side effects since the
start of the COVID-19 pandemic and alerted consumers and health care
professionals to use hand sanitizers in a well-ventilated area or if using
in an enclosed area such as a car, to open a window to improve ventila-
tion until the hand sanitizer is dry and the vapors have cleared.
OCTOBER 4 | FDA tested certain ArtNaturals Scent-Free Hand Sanitizer

labeled with “DIST. by ArtNaturals Gardena, CA 90248” and found
unacceptable levels of benzene, acetaldehyde, and acetal impurities.
FDA urged consumers not to use this product.
NOVEMBER 2 | FDA issued a Drug Safety Communication warning

that getting alcohol-based hand sanitizer in the eyes from splashing or
touching the eyes can result in serious injury, including severe irritation
and damage to the surface of the eye. Such eye injuries had become
much more frequent, especially in children, likely due to the marked
increase in the use of alcohol-based hand sanitizer during the
COVID-19 pandemic. FDA recommended mitigating alcohol-based

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hand sanitizer in the eyes by immediately and thoroughly rinse them

under gently running water such as from a sink tap, water bottle, or Methanol, or wood alcohol, is a
emergency shower for at least 15-20 minutes. substance that can be toxic when
A more complete timeline of FDA announcements, statements, and absorbed through the skin and can
actions related to hand sanitizers, including those products consumers be life-threatening when ingested;
should not use, can be found online. 1-propanol can cause skin irritation
or serious damage to the eyes, and
Taking Actions Against Fraudulent Unapproved may be harmful if inhaled and life-
Products for COVID-19 threatening when ingested.
The FDA has continued to actively monitor for any firms marketing
products with fraudulent COVID-19 prevention and treatment claims.
The Agency exercised its authority to protect consumers from firms
selling unapproved products and making false or misleading claims,
including by issuing warning letters or pursuing injunctions against
products and firms or individuals that violate the law.
• Issued 26 warning letters to companies marketing products

fraudulently claiming to treat COVID-19 and to internet pharmacies
selling unapproved medications claiming to treat it. More than 80
percent of the recipients complied with these warning letters.
• Worked with the Department of Justice and the FDA’s Office of the
Chief Counsel to successfully obtain injunctive relief against one
company that did not comply with our warning letters.
FDA Issued Specific Compounded Drug Concerns

Related to COVID-19
Compounded drugs are not FDA-approved, which means they have not
undergone premarket review for safety, effectiveness, or manufacturing
quality. The Agency recommends FDA-approved drugs be used to treat
patients whenever possible; compounded drugs should only be used to
meet the needs of patients whose medical needs cannot be met by an
FDA-approved drug. The FDA had concerns about the use of the follow-
ing drugs prepared by compounders to treat patients with COVID-19:
• The FDA was aware of products containing thymosin being offered

to patients for the treatment of COVID-19; however, thymosin
is not approved to treat any condition, including COVID-19.
Therefore, the Agency warned that it would take appropriate action
against compounders that produced thymosin. Thymosin alpha-1 is
not a component of an approved drug, and thymosin does not meet

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• FDA recommended that the approved drug Veklury (remdesivir)

be used to treat patients who were prescribed remdesivir
rather than a compounded version of the drug. The FDA
was concerned that complexities related to the quality and
sourcing of the remdesivir active pharmaceutical ingredient
(API) and formulation of the drug product could make these
drugs particularly challenging to compound. The Agency was
concerned that patients would receive substandard or low-quality
compounded remdesivir products which could result in harm.

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Postmarketing Drug Surveillance
Once a medication is available for prescription or

over-the-counter use, FDA continues to monitor its safety,
efficacy, and quality so the Agency can take action if needed.
Manufacturers must evaluate received adverse

event reports associated with their marketed
products and report certain serious adverse
health effects to FDA for evaluation.
FDA periodically inspects drug manufacturing plants

and continues to monitor drug quality.
FDA monitors the FDA Adverse Event Reporting System

(FAERS) and reviews MedWatch reports submitted by
health care professionals, patients, and drug
manufacturers to investigate concerns related to drug
product quality and safety.
To help FDA track safety issues with medicines, FDA

urges patients, consumers, and health care professionals
to report side effects involving medicines to the FDA
MedWatch program by completing and submitting the
report Online or calling 1-800-332-1088 to request a
reporting form that can be mailed or faxed.
Visit www.fda.gov/drugs
to learn more.

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Safety Surveillance and Oversight

of Marketed Drug Products
Pharmacovigilance
The FDA maintains a wide-ranging practice of postmarketing surveil-
lance and risk evaluation programs to identify and evaluate new adverse
events that did not appear during the drug development and approval
process or to learn more about known adverse events. These reviews and
evaluations are based on detailed assessment of a variety of data. For ex-
ample, FAERS is a database that contains adverse event and medication
error reports that have been submitted to the Agency by patients, family
members, and health care professionals through the MedWatch pro-
gram. It also includes information required to be submitted by regulated
industry under the Code of Federal Regulations and the FD&C Act. The
reports allow the FDA to identify safety concerns and develop recom-
mendations to improve product safety and protect the public.
The FDA’s risk evaluation program includes:
• Surveillance, assessment, and review of epidemiologic data using

various data sources, including Sentinel
• Review of protocols and studies submitted by industry
• Surveillance and review of the published scientific literature

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When information is uncovered that may change the benefit-risk profile of a

product, the FDA will investigate the issue and consider appropriate action,
including requesting or requiring labeling changes, issuing Drug Safety
Communications and other safety information, requiring postmarketing
studies, requiring a REMS, or rarely, requesting a market withdrawal of
the product. The FDA continuously monitors the safety of all drug products
FDA maintains other searchable
while they are being marketed, even if the Agency has determined that one safety-related databases available
of these actions is not necessary at a specific point in time. to the public, including REMS
(REMS@FDA), Drug Safety-
FAERS Public Dashboard related Labeling Changes (SrLC),
Improving data access and transparency are core concepts underlying Medication Guides (MedGuides),
the FDA’s work and they are key factors driving the development of the and Postmarket Requirements
FAERS Public Dashboard. This dashboard is an interactive, user-friendly,
and Commitments. FDA also posts
web-based tool that allows the public to access information about adverse
drug event reports received by FDA and contained in the FAERS data- quarterly reports that list potential
base. Data is updated quarterly, and may be searched and viewed in a signals of serious risks/new safety
customizable format. Dashboard users can view a summary of the adverse information that were identified
event reports received on specific drugs during time periods dating from
using the FAERS database.
1968 to the present.
Medication Error Prevention and Analysis

The FDA works to increase the safe use of drug products by minimizing
use errors related to product naming, labeling, design, and packaging.
The FDA’s Office of Surveillance and Epidemiology (OSE) focuses on
how proprietary names (commonly known as brand names) can contrib-
ute to confusion in the marketplace. OSE also is a member of the NDA/
Biologics License Application (BLA) review team and evaluates labels
and labeling, applying learning from postmarketing surveillance activi-
ties to minimize the risk for medication errors. Furthermore, OSE serves
as CDER’s lead on the evaluation of human factors data and information
to ensure the safe and effective use of medical products that fall under
CDER’s jurisdiction.
Selected Updates
• OSE and the Reagan-Udall Foundation for the FDA convened a
public meeting to explore perspectives on the risk of medication
errors related to the content and format of information on
investigational drug container labels, the prevalence and nature
of medication errors, and practices that might minimize the
potential for such errors.

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• OSE collaborated with the Center for Devices and Radiologic

A REMS is a drug safety program Health (CDRH) and the Center for Veterinary Medicine (CVM)
that the FDA can require for a to analyze and mitigate medication errors associated with device
certain relatively small number of incompatibility and pet exposure to human drugs that result in
animal fatalities.
drugs with serious safety concerns
to help ensure the benefits of the Risk Management
drug outweigh its risks. REMS are
Risk management is a critical consideration in assessing the benefit-
designed to reinforce drug use risk balance of a drug, including:
behaviors and actions that support
• Development of strategies to minimize risks while preserving
that drug’s safe use.
benefits
• Evaluation of the effectiveness of such strategies and reassessing

benefit-risk balance
• Adjustments to risk minimization strategies when appropriate to

further improve the benefit-risk balance
The FDA’s primary risk management tool is FDA-approved product

labeling, often referred to as the “package insert” or the “prescribing
information,” and the required “Drug Facts” labeling of nonprescription
drugs, which includes a summary of the essential information needed
by health care professionals or nonprescription drug consumers for the
safe and effective use of the drug. Medication Guides are also part of drug
labeling and they contain FDA-approved information that can help pa-
tients avoid serious adverse events. Labeling is sufficient for most drugs
to ensure that the benefits outweigh the risks. In a limited number of
cases, the FDA may determine that a REMS will also be needed.
REMS Public Dashboard

The FDA launched the REMS Public Dashboard, an interactive, web-
based tool that allows analysis of REMS data in a user-friendly fashion.
The intention of this tool is to expand access to data and report-gen-
erating capabilities on REMS programs for research organizations,
academia, and industry. Improving data access and transparency are
core concepts that drove the development of this dashboard. The FDA
anticipates this increased transparency will help meet the policy and
regulatory needs of existing and future REMS programs. Data used in
this dashboard are pulled from existing REMS data files submitted by
drug companies and REMS program administrators. The dashboard
does not include all data about REMS drugs, for example, risk informa-
tion and the indication for use. The FDA is continuing to explore other
data sources to augment the information in this database.

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Modernizing and Improving REMS Assessments

The FDA continues its efforts to modernize and improve REMS assess-
ments. The improvement efforts focus on: (1) improving REMS assess-
ment planning; (2) clarifying FDA expectations by expanding the review
of REMS assessment methodological approaches, study protocols, other
analysis plans and assessment approaches; (3) improving the efficiency
of our reviews; and (4) enhancing our enforcement actions and tools.
Additionally, the FDA launched improvements to the review processes

for REMS Assessment Reports and REMS Assessment Methodologies,
which were incorporated into CDER’s workflow management system in
2021. Highlights include automated workflow steps and data collection,
improved collaboration across offices, divisions, teams and disciplines,
and improved transparency of the review process.
New REMS Approvals

The FDA approved a REMS for three separate NDAs in 2021:
APRIL 6 | FDA approved a shared system REMS for macitentan because

it has a risk of serious birth defects if used during pregnancy. Maciten-
tan is a prescription medication used to treat pulmonary arterial hyper-
tension, which is high blood pressure in the arteries of the lungs.
MAY 14 | FDA approved a REMS for Empaveli (pegcetacoplan) because

the medication can increase the chance of having serious infections,
which may quickly become life-threatening and cause death if not rec-
ognized and treated early. Empaveli is a prescription medication used to
treat adults with a disease called paroxysmal nocturnal hemoglobinuria.
MAY 21 | FDA approved a shared system REMS for lenalidomide be-

cause the medication can cause birth defects or death to unborn babies
if used during pregnancy. Lenalidomide is a prescription medication
used to treat multiple myeloma and other types of cancer of white blood
cells, and a condition called myelodysplastic syndromes.
The Sentinel System

The Sentinel Initiative, launched in 2008, began as a Congressional
mandate for the FDA to establish a public-private partnership to devel-
op an electronic medical product safety surveillance system using exist-
ing data. The principal operational component of the Sentinel Initiative
is the Sentinel System, a network of databases (technically known as a
distributed database) that included 13 partner institutions with 14 data
marts as of October 2021.

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Sentinel collaborators include data and academic partners that provide

access to health care data and scientific, technical, and organizational
expertise. Distributed data networks allow secure access to multiple
data sources, achieving far larger sample sizes than could be achieved
through a single source, while assuring that data is collected securely
with full patient privacy safeguards in place.
When safety concerns arise, FDA staff can use Sentinel to assess poten-
tial risks that may be associated with FDA-regulated medical products,
enabling product safety assessment under real-world conditions. Sen-
tinel provides unparalleled capabilities for investigation of new safety
signals that arise from spontaneous reporting systems like FAERS and
other sources of safety information. FDA is developing Sentinel’s capac-
ity to detect unsuspected potential safety concerns using new approach-
es that scan thousands of health outcomes, looking for unexpected safe-
ty signals after product exposure. Such analyses mine large amounts of
health care data without prespecifying a specific target medical product.
Sentinel also supports inquiries on many different regulatory questions,
including those related to medication errors, risk mitigation strategies,
generic drugs, biosimilars, and drug safety in specific patient groups
such as children and pregnant patients.
The Sentinel System has transformed the way researchers monitor

FDA-regulated medical products. Now one of the FDA’s leading ev-
idence-generation platforms, Sentinel proactively monitors medical
product safety and serves to advance the science of RWD and RWE.
The Sentinel System Five-Year Strategy 2019–2023 is a roadmap charting the development of the
Sentinel System through five strategic aims intended to expand the Sentinel System’s operational
foundation, augment its safety analysis and signal detection capabilities, and leverage the system to
accelerate access to and broader use of RWD for real world evidence (RWE) generation. To advance
these aims, the FDA established three centers as part of the Sentinel System: the Sentinel Operations
Center (SOC), the Sentinel Innovation Center (IC), and the Community Building and Outreach Center
(CBOC). The SOC continues to focus on conducting medical product assessments and enhancing the
infrastructure of the Sentinel System to support FDA’s regulatory needs. The IC carries out work to
advance analytic tools and accelerate novel data source acquisition and evaluation, and the CBOC
focuses on building the Sentinel System user community and engaging stakeholders.

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FDA routinely uses RWD made available through the Sentinel System
to generate evidence about drug safety, drawing on data from insurance
claims, hospital stays, outpatient doctor visits, and pharmaceutical
dispensing data. Sentinel also queries data from partners with electron-
ic health record information to address questions in the context of the
COVID-19 pandemic. By making it possible to analyze emerging risks
associated with FDA-regulated medical products and to study medical
care more broadly, Sentinel enables the FDA to assess medical product
safety, describe medical product utilization, and characterize medical
events under real-world conditions.
2021 Highlights
In 2021, FDA’s Sentinel System supported numerous activities to pro-
tect and promote public health during the COVID-19 pandemic (see the
COVID-19 section of this report). To support these activities, Sentinel
has enhanced its data infrastructure by building a database with near
real-time data from six Data Partners and incorporating use of several
additional data sources derived from electronic health records. Sentinel
is also collaborating with the Reagan-Udall Foundation and Friends of
Cancer Research on the COVID-19 Evidence Accelerator, a forum for
stakeholders across the health care spectrum to share RWD and gener-
ate ideas on COVID-19. Additional Sentinel highlights include:
MAY | On May 13th, the Sentinel System deployed a fully redesigned pub-
lic website to improve the usability and findability of information and to
better serve the Sentinel community. Some major new features include:
• A Google Search engine directly integrated into the website

interface to improve the relevancy of results for the site’s global
search.
• Sentinel Training Center: A single location for easy access to

the video recordings and materials of key Sentinel trainings and
workshops.
• Engage with Sentinel: A dedicated space that encourages the

community to stay informed, get involved, and engage with the
Sentinel Initiative.
• Drug Assessments: Information is now provided on drug

assessments conducted in the Active Risk Identification and
Analysis (ARIA) system and other Sentinel data resources in
a new table structure that consolidates analytic code, results,
communications, and regulatory outcomes for all queries
associated with the same underlying safety question.

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• Sentinel Initiative YouTube Channel: Incorporates major

FDA published in September 2021 webinars, trainings, and workshops into a single, publicly
a draft guidance document on available repository.
Benefit-Risk Assessment for New AUGUST | Investigators disseminated Sentinel work at the 37th
Drug and Biological Products. International Conference on Pharmacoepidemiology and Therapeutic
The guidance clarifies for drug Risk Management (ICPE), leading two symposia and providing 14 oral
sponsors and other stakeholders presentations and scientific posters.
how considerations about a SEPTEMBER | FDA enhanced the Sentinel System infrastructure by
medication’s benefits, risks, and releasing a new version of the Sentinel Common Data Model (SCDM):
v8.0.0. This improvement expands Sentinel’s data capture and preci-
risk management options factor
sion and allows for its use by international partners. Key enhancements
into certain premarket and in this new version include the addition of a prescribing table and a
postmarket regulatory decisions provider table. This SCDM upgrade also introduces technical efficien-
that the Agency makes about cies designed to ensure the Sentinel System will match the growing
NDAs and BLAs. volume of health care data provided by data partners.
NOVEMBER | The Thirteenth Annual Sentinel Initiative Public Work-

shop was held virtually on November 8 and 9, bringing together stake-
holder communities on a variety of topics on active medical product
surveillance and current and emerging Sentinel activities. Sessions
featured key leads from each CDER Sentinel coordinating center to
discuss past and current activities as well as to advance and transform
Sentinel’s data infrastructure into a national resource for evidence
generation. Sessions also highlighted the past, present, and future of
Sentinel and RWE.
DECEMBER | Throughout the year, the Sentinel Innovation and Methods

Seminar Series brought leading experts to present on various topics,
including feature engineering, natural language processing, advanced
analytics, and data interoperability. This seminar series engaged Senti-
nel’s scientific community by sharing information on emerging technol-
ogies and advances in methods relevant to Sentinel’s work.

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Drug Safety Modernization

In November 2021, the FDA
CDER’s Drug Risk Management Board (DRMB) is a cross-CDER board released FAERS II to replace the
responsible for three key objectives: (1) facilitating and coordinating
previous version of FAERS to
decisions around major product safety issues; (2) providing clear and
consistent guidance enabling an appropriate response to major safety support our internal postmarket
issues; and (3) systematically communicating decisions and resulting stakeholder community. FAERS
actions across the Center and to other stakeholders as appropriate. In II is a one-stop shop solution for
addition, the DRMB facilitates and coordinates all new and existing case intake and processing, safety
marketed product safety initiatives across CDER, including the modern-
surveillance, and analytics for
ization of the Center’s framework capabilities for safety surveillance of
marketed products. approved drugs. This modernized
pharmacovigilance toolkit will
CDER continues to support implementation of the Newly Identified
Safety Signal (NISS) process, a major modernization initiative achieved
improve regulatory processes and
in April 2020, which allows for a standardized, interdisciplinary ap- data quality to better support
proach to systematically identify, evaluate, and resolve both clinical- lifecycle safety tracking.
and quality-related safety signals. The Lifecycle Signal Tracker (LiST)
workflow tool was developed to support the NISS process, providing
the ability to capture and manage all safety signals for marketed drugs.
The NISS Manual of Policies and Procedures (MAPP) and LiST not only
support CDER’s commitment to drug safety, but also its commitment
under Prescription Drug User Fee Act (PDUFA) VI for timely and effec-
tive evaluation and communication of postmarketing drug safety issues.
In March 2021, FDA contracted with a third party to assess how data
systems and processes support the review, oversight, and communica-
tion of postmarketing drug safety issues to meet this commitment. The
NISS MAPP and LiST also address recommendations made in the 2015
Government Accountability Office report.

22
Nitrosamine Impurities in
Medicines: FDA’s Continuing
Multidisciplinary Response
After learning in June 2018 that certain generic versions of valsartan,
a high blood pressure and heart failure drug, contained unexpected
impurities that posed a potential safety concern, the FDA investigated
and took regulatory action with respect to some drug products, and
continues to monitor valsartan and other drug products for these impurities.
These impurities, known as nitrosamines–including, for example,
N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), and
other nitrosamine drug substance related impurities (NDSRIs),
for example, N-nitroso-varenicline–are potentially cancer-causing
substances that can be generated in the drug manufacturing process when
certain other chemicals, and reaction and processing conditions are present.
Since then, several more drug products have been found to contain
unacceptable levels of nitrosamines, including the heartburn drugs ranitidine
and nizatidine, the type 2 diabetes drug metformin, the tuberculosis drugs
rifampin and rifapentine, and the smoking cessation drug varenicline. On
November 18, 2021, FDA provided information to industry on possible
mitigation strategies to reduce the risk of NDSRIs in drug products.

23
Varenicline
All FDA updates and actions on varenicline in 2021 are available online.
Key actions addressing N-nitroso-varenicline impurities in varenicline
products include:
JULY 2 | FDA alerted the public about Pfizer’s voluntary recall of nine lots
of the smoking cessation drug varenicline to the warehouse level because it
may contain levels of a nitrosamine impurity, called N-nitroso-varenicline,
above FDA’s acceptable intake limit of 37 ng per day.
JULY 16 | To ensure patient access to varenicline, FDA announced it would

not object to certain manufacturers temporarily distributing varenicline
tablets containing N-nitroso-varenicline up to the FDA’s interim intake
limit of 185 ng per day until the impurity could be eliminated or reduced to
acceptable levels. The agency continues to evaluate data.
JULY 19 | Pfizer expanded its voluntary recall of varenicline to 12 lots to

the consumer level.
AUGUST 18 | Pfizer expanded its voluntary recall to include four

additional lots of (16 total) to the consumer level.
AUGUST 23 | FDA posted its laboratory results showing N-nitroso-

varenicline levels in varenicline products currently available for the
U.S. market.
SEPTEMBER 17 | FDA alerted the public that Pfizer expanded its voluntary
recall to the consumer level to include all lots of varenicline 0.5 mg and
1 mg tablets. Pfizer recalled these lots due to the presence of unacceptable
N-nitroso-varenicline levels.
Nitrosamines are common contaminants found in water and foods, including cured and grilled meats,
dairy products, and vegetables. Everyone is exposed to some level of nitrosamines. The FDA does not
expect nitrosamines to cause harm when ingested at low levels. Although nitrosamines may increase
the risk of cancer if people are exposed to them above acceptable levels and over long periods of
time, a person taking a drug that contains nitrosamines at or below the acceptable daily limit every
day for 70 years is not expected to have an increased risk of cancer.

24
Continued Efforts to Address the

Misuse and Abuse of Opioid Drugs
and Other Substances
The misuse and abuse of illicit and prescription opioids and the risks of ad-
diction, overdose, and death are a public health crisis in the United States.
From 1999 to 2019, approximately 500,000 people died from an overdose
involving any opioid, including prescription and illicit opioids. In 2020, 191
people died every day in the United States from opioid overdose, according
to provisional data from the Centers for Disease Control and Prevention
(CDC). The estimated number of overdose deaths from opioids increased
from 50,963 in 2019 to 69,710 in 2020. The COVID-19 pandemic has exac-
erbated the opioid crisis and the FDA has continued to prioritize address-
ing this public health crisis. Actions, activities, and updates from 2021 are
highlighted below.
Support Recovery from Substance Use Disorder (SUD)

and Reduce Overdose Deaths
MARCH 4 | FDA approved changes to the prescribing information for
all opioid pain relievers and medicines indicated to treat opioid use
disorder (OUD) to add new recommendations about patient access
to naloxone for the emergency treatment of opioid overdose. These
changes were instituted to help ensure that health care professionals

25
discuss the availability of naloxone and assess each patient’s need for a
naloxone prescription when opioid pain relievers or medicines to treat
OUD are being prescribed or renewed. This information was originally
announced in a Drug Safety Communication.
APRIL 30 | FDA announced the approval of a higher dose naloxone

hydrochloride nasal spray product to treat opioid overdose. The new-
ly approved product delivers 8 milligrams (mg) of naloxone into the
nasal cavity. FDA had previously approved 2 mg and 4 mg naloxone
nasal spray products. A higher dose of naloxone provides an additional
option in the treatment of opioid overdoses.
OCTOBER 18 | FDA announced the approval of Zimhi (naloxone) injec-

tion as an additional option to treat opioid overdose. Zimhi is adminis-
tered using a single-dose, prefilled syringe that delivers 5 mg of nalox-
one solution through injection in the muscle or under the skin.
OCTOBER 18 | The FDA, in partnership with the Reagan-Udall Foun-

dation for the FDA and the National Institute on Drug Abuse, held a
public workshop called A Practical Research Agenda for Treatment
Development for Stimulant Use Disorder. The workshop allowed
stakeholders to provide input on a proposed practical research agenda
that focuses on innovation in clinical trial design and endpoints for the
evaluation of potential treatments for stimulant use disorder.
Strengthen Enforcement Against Illicit Opioids and

Inappropriate Opioid Use
FEBRUARY 1 | FDA provided an update on the pilot program with the
National Telecommunications and Information Administration (NTIA)
and three domain name registries to help reduce the availability of
unapproved opioids illegally offered for sale online. The 120-day pilot
program ended in 2020, and the update reported that nearly 30 web-
sites illegally offering opioids for sale became inaccessible to the public.
Naloxone is a medicine that can be administered by individuals with or without medical training to
help reduce opioid overdose deaths. If naloxone is administered quickly, it can counter the opioid
overdose effects, usually within minutes. Currently, most states allow pharmacists to dispense nalox-
one through a standing order from the state health department. This allows a pharmacist to dispense
naloxone without a prescription for an individual patient.

26
The pilot program was an effective tool in maximizing the impact of

FDA’s efforts to limit the illegal sale of unapproved opioids online and
the collaboration will continue to help prevent illegal online opioid sales.
FEBRUARY 16 | FDA issued a warning letter to AcelRx Pharmaceuticals,

Inc. for the false and misleading promotion of Dsuvia (sufentanil sub-
lingual tablet), a potent opioid pain medication. AcelRx disseminated
promotional communications that undermined key prescribing condi-
tions required for the safe use of this opioid. Dsuvia was approved with
a REMS with special restrictions requiring that it only be prescribed
in a certified medically supervised setting by health care professionals
trained to properly administer it. However, the promotional commu-
nications at issue promoted the product as simple to administer: just
“Tongue and Done.” This promotion dangerously undercut FDA-
required conditions on the proper administration of the drug, which
requires particular diligence to minimize the risk of serious or even fatal
adverse events.
SEPTEMBER 9 | FDA hosted its third summit to continue to enhance collab-

oration with internet stakeholders, government entities, academia, and oth-
er important partners to maximize the scope of our efforts to address the
illegal availability of opioids online. Discussions at the summit focused on
new ways to continue to combat the online component of the opioid crisis.
Supporting Safe Use of Opioids and Other Substances

MARCH 1 | FDA approved hydrocodone bitartrate, the first FDA-
approved generic opioid with an abuse-deterrent formulation. This
means that product has properties that are expected to reduce, though
not totally prevent, abuse of the drug when chewed and taken orally, or
crushed and snorted or injected.
MARCH 25 | FDA issued a Drug Safety Communication warning that the

abuse and misuse of the over-the-counter (OTC) nasal decongestant
propylhexedrine (Benzedrex) can lead to serious harm such as heart and
mental health problems that could result in hospitalization, disability,
or death. Propylhexedrine is safe and effective when used as directed;
however, reports of individuals abusing and misusing it have increased
in recent years.
JUNE 7–8 | FDA held the public workshop Morphine Milligram Equiva-
lents: Current Applications and Knowledge Gaps, Research Opportuni-
ties, and Future Directions. The purpose was to bring stakeholders to-
gether to discuss the scientific basis of morphine milligram equivalents
(MME) for opioid analgesic prescribing, with the goals of providing an
understanding of the science and data underlying existing MME calcula-
tions, considering gaps in these data, and discussing future directions to
refine and improve the scientific basis of MME application.

27
JUNE 28–29 | Through a cooperative agreement with FDA, the

Duke-Margolis Center hosted the private workshop called Exploring The FDA is involved in ongoing
Options for Safe and Effective In-Home Opioid Disposal. The purpose education and outreach campaigns
was to bring together regulators, academic researchers, clinicians, to help support the safe use of
patient advocates, and other stakeholders to explore available in-home
opioids. Remove the Risk aims to
opioid disposal options, and the potential benefits and impact of FDA
requiring opioid manufacturers to provide a safe, in-home disposal raise awareness among patients
option when opioids prescriptions are dispensed. and consumers about the serious
dangers of keeping unused
JULY 12–13 | Through a cooperative agreement with FDA, the
Duke-Margolis Center hosted a public workshop called Safe Use of prescription opioids and to provide
Benzodiazepines: Clinical, Regulatory, and Public Health Perspectives. information about safe disposal of
Its purpose was to bring together regulators, academic researchers, these medicines. Through a CDER
clinicians, patient advocates, and other stakeholders to discuss epide-
collaboration with Partnership
miological and abuse liability data of polysubstance use, patient and
clinician perspectives and experiences, and gaps in data and under-
to End Addiction, Search and
standing about the safe use. Rescue aims to provide health
care professionals with the tools
JULY 21 | FDA issued a Consumer Update, Accidental Exposures to
Fentanyl Patches Continue to Be Deadly to Children, to warn patients, and resources they need to help
caregivers, and health care professionals about the dangers of acci- patients avoid prescription drug
dental exposure to the fentanyl patch, and how to properly store and misuse, abuse, and addiction.
dispose of the product.
AUGUST 4 | Researchers from FDA published a systematic review titled

Patient-Reported Opioid Analgesic Use After Discharge from Surgical
Procedures: A Systematic Review. It describes published literature on
patient-reported opioid analgesic use after surgical procedures and
gives methodologic recommendations for future studies to help support
their use in condition- and procedure-specific evidence-based opioid
analgesic guidelines.
OCTOBER 13–14 | Through a cooperative agreement with FDA, the

Duke-Margolis Center for Health Policy convened a public workshop,
Reconsidering Mandatory Opioid Prescriber Education Through a Risk
Evaluation and Mitigation Strategy (REMS) in an Evolving Opioid Crisis.
The purpose was to give stakeholders an opportunity to provide input on
aspects of the current opioid crisis that could be mitigated in a measur-
able way by requiring mandatory prescriber education as part of a REMS.

28
Ensuring Quality, Safety, and

Effectiveness of Generic Drugs
The FDA’s generic drug program continued to substantially increase the
availability of affordable, high-quality drugs in the United States. More than
10,000 generic drugs are currently approved by the FDA, and nine of 10
prescriptions filled are for generic drugs. Importantly, generic drugs have
saved the health care system more than $2 trillion in the past decade.
Increasing the availability of generic drugs helps to create competi-

tion in the marketplace, which helps reduce the cost of treatment and
increase access to medicines for more patients. The Office of Generic
Drugs (OGD) follows a rigorous review process to ensure that, compared
to the brand-name drug, a generic drug has the same:
• Active ingredients (the ingredients that treat a condition or

symptoms)
• Strength
• Dosage form (e.g., tablet, capsule, cream, patch, or liquid)
• Route of administration (e.g., oral, topical, inhalation, or

injection)
• Conditions of use
• Labeling (with certain exceptions)

29
OGD evaluates generic drug safety before these drugs are approved and
continues to monitor and evaluate their safety throughout the time they
are available for sale in the United States. Effective postmarket sur-
veillance is essential to making sure that FDA-approved generic drugs
provide the same therapeutic effect and safety as brand-name drugs.
Presenting Generic Safety Surveillance Activities to

Stakeholders in 2021
In 2021, OGD presented its scientific approach to conducting safety
evaluations and postmarketing surveillance, and engaged with several
major stakeholder audiences.
JANUARY 27 | Presented Update on Safety Surveillance for Generic

Drugs at the Drug Information Association Pharmacovigilance and Risk
Management Strategies Conference: FDA Updates in Pharmacovigi-
lance session.
APRIL 29 | Presented and participated in panel discussions at the CDER

Small Business and Industry Assistance (SBIA) Generic Drugs Forum
2021: Lifecycle of a Generic Drug for the following sessions:
• Postmarketing Safety Surveillance of Generic Drug Products –

An Update
• Premarket Review of Expedited Serious Adverse Event Reports

from IND-Exempt BA/BE Studies
• Risk Evaluation and Mitigation Strategies (REMS) for Generic

Drugs
SEPTEMBER 22 | Presented Comparative Analyses for Generic Oral

Inhalers at the CDER Small Business and Industry Assistance Advanc-
ing Generic Drug Development: Translating Science to Approval.
Safety Surveillance of Generic Drugs: OGD’s Division

of Clinical Safety and Surveillance
OGD’s Office of Safety and Clinical Evaluation’s (OSCE) Division of
Clinical Safety and Surveillance (DCSS) consists of a multidisciplinary
staff of physicians, pharmacists, epidemiologists, nurses, and other
scientists who perform and facilitate broad preapproval and postmar-
ket generic drug safety and surveillance activities for OGD. OSCE was
newly established in 2021 as part of a reorganization within OGD and
was formed through the realignment of certain clinical, pharmacology/
toxicology, and safety review staff. This realignment of these suborga-
nizations places scientists and other staff with expertise in drug safety
under one group within OGD for resource efficiency.

30
Together, the DCSS staff support CDER’s Postmarket Safety Moderniza-

tion efforts, including through identifying, evaluating, and resolving newly
identified safety signals consistent with CDER’s MAPP 4121.3 Collaborative
Identification, Evaluation and Resolution of a Newly Identified Safety
Signal. They also initiate Generic Drug User Fee Amendments (GDU-
FA)-related postmarket safety research, and perform generic drug safety
and surveillance outreach through presentations and publications to gener-
ic drug stakeholders, including patients, health care providers, pharmacists,
and drug safety-focused organizations.
DCSS Safety and Surveillance Highlights in 2021

JANUARY | The DCSS was instrumental in the publication of the CDER
Alert, FDA updates vinca alkaloid labeling for preparation in intra-
venous infusion bags only. Throughout 2021, the DCSS, along with
colleagues in OGD’s Office of Regulatory Operation’s Division of Label-
ing Review continued work on requesting that all ANDA holders of the
chemotherapy drug products vincristine sulfate, vinblastine sulfate, and
vinorelbine tartrate remove instructions for using them with a syringe
and add use with minibags in order to address the risk of fatal neuro-
logic injury or death related to the accidental spinal rather than intrave-
nous administration of these cancer medicines.
JUNE | The DCSS collaborated with CDER’s Office of Medical Policy in

updating the “Safety Reporting Requirements for BA and BE Studies”
portion of the draft guidance for industry, Sponsor Responsibilities —
Safety Reporting Requirements and Safety Assessment for IND and
Bioavailability/Bioequivalence Studies.
SEPTEMBER | The DCSS contributed to the investigation that supported

FDA’s public notification to pharmaceutical companies regarding data
integrity concerns with clinical and bioanalytical studies conducted by
Synchron Research Services and Panexcell Clinical Lab in support of
ANDAs and NDAs.
The DCSS collaborated with CDER’s Office of Medical Policy in

updating the draft guidance for industry, Investigator Responsibilities –
Safety Reporting for Investigational Drugs and Devices.
The DCSS Clinical Team reviews Bio-Investigational New Drug Applications (Bio-INDs) and serious
adverse events from Bio-INDs and non-IND bioequivalence/bioavailability studies that support
Abbreviated New Drug Applications (ANDAs). In addition, the clinical reviewers are responsible for
assessing Health Hazard Evaluations for potential recalls. The DCSS Data Team analyzes generic
drug quality and therapeutic equivalence adverse event reports and trends, follows generic drug
distribution patterns, and identifies emerging safety issues. The DCSS REMS Team assists generic
drug applicants in developing and maintaining REMS for applicable generic drugs.

31
DCSS Risk Evaluation and Mitigation Strategies

(REMS) Highlights in 2021
The DCSS REMS Team assists in developing, implementing, managing,
and evaluating REMS-related activities submitted to ANDAs. For OGD,
a generic drug that is the subject of an ANDA is subject to certain ele-
ments of the REMS required for the applicable listed drug. The DCSS
REMS Team serves as experts on the statutory and regulatory require-
ments and recommendations in FDA guidance documents related to
ANDAs containing a REMS or subject to a REMS. Throughout 2021,
the DCSS REMS Team actively participated in CDER’s cross-office
efforts to:
• Evaluate and approve 3 separate system REMS
• Evaluate established REMS materials to aid in the approval of 25

ANDAs subject to REMS
• Evaluate and approve various REMS modifications, ultimately

affecting 135 approved ANDAs
Information on approved REMS for NDAs and ANDAs is available at

FDA REMS.
Generic Substitution and Safety of Generic vs Brand-

Name Drugs: OGD’s Office of Research and Standards
As part of GDUFA-funded research projects, the FDA is conducting
ongoing research to evaluate generic substitution, including clinical
studies of substitution in patients, medical informatics data analysis to
evaluate generic utilization and substitution, and patient and provider
perceptions impacting generic substitution.
In 2021, the FDA completed a study investigating the bioequivalence of

a generic immunosuppressive drug product tacrolimus and its refer-
ence product. The FDA is currently analyzing the results of this study to
determine its impact on generic substitution. The FDA also investigated
the feasibility of using Sentinel data to investigate generic performance
in terms of therapeutic equivalence with the reference product and
compared the outcomes of solid organ transplantation between these
two formulations.

32
During 2021, ongoing research efforts were focused on evaluating the

substitutability of approved generic products and their corresponding
reference products. Research in collaboration with the Yale University-
Mayo Clinic Center of Excellence in Regulatory Science and Innovation
(CERSI) was completed to characterize whether users of different gener-
ic levothyroxine products used to treat underactive thyroid had equiva-
lent clinical outcomes, in particular thyroid stimulating hormone (TSH)
levels. Preliminary results showed there were no significant differenc-
es among the various generic levothyroxine products and no need to
caution against switching between different generic products. A second
study with the Yale-Mayo CERSI was designed to control for unobserved
confounding that is ubiquitous in observational studies. Previous efforts
had successfully controlled for observed confounding factors such as
age and other demographic factors. The preliminary results showed the
global treatment effect was not significantly different between generic
levothyroxine and brand levothyroxine products following adjustment
for confounding effects.
Other ongoing research efforts include monitoring postmarket perfor-

mance of a first generic, Wixela Inhub, an approved generic version of
Advair Diskus used to treat asthma and chronic obstructive pulmonary
disease (COPD). Research has also been initiated to evaluate the appli-
cation of pharmacogenomic (PGx) information for BE purposes. PGx
information can be applied in BE studies for generic drug development to
further enhance subject safety and BE study design. The ongoing research
will help determine when PGx information should be used to identify sub-
jects vulnerable to serious adverse events, minimize carryover effects in a
crossover study, and ensure balanced groups in a parallel study.

33
Safe Use Initiative: Collaborating

to Reduce Preventable Harm from
Medications
Millions of Americans depend on prescription and OTC medications to
sustain their health on a daily basis, with more than four billion pre-
scriptions written annually. However, too many people suffer unneces-
sary injuries and some die as a result of preventable medication errors,
which can include medicines dispensed in error, medicines taken for
too long or not long enough, or inappropriately mixed with other medi-
cines or foods that can increase the risk of side effects.
The FDA believes that many of these medication-related risks are

manageable if partners committed to their safe use work together.
FDA’s Safe Use Initiative (SUI) works to create and facilitate public and
private collaborations within the health care community that can help
to reduce preventable harm by identifying specific, preventable medica-
tion risks and developing, implementing, and evaluating interventions
along with partners and collaborators. Current and potential partners
in Safe Use programs and projects include federal agencies; health care
professionals and professional societies; pharmacies and hospitals; and
patients, caregivers, consumers, and their representative organizations.
SUI enables many of its collaborations through funding and actively par-
ticipating in research projects that seek to reduce preventable drug harm.

34
Safe Use maintains an open and continuous announcement to solicit

research proposals and its projects target many kinds of preventable harm
and involve a range of approaches.
Projects Completed in 2021

Manganese Contamination in Neonatal Parenteral Nutrition.
Parenteral nutrition (PN), which is the administration of nutrition
through a vein, has become standard and essential to the care of preterm
newborns in the neonatal intensive care unit. Health benefits of PN
include positive nitrogen balance, weight gain, and reduced neurodevel-
opmental impairment. However, the daily provision of PN to preterm
newborns involves numerous safety risks, including side effects from
ingredient formulations not ideally suited for this vulnerable population.
One example is the trace element manganese, which is added to PN. How-
ever, the first part of this project found neonatal PN contains significant
quantities of manganese not intentionally added during its preparation.
In the second part of the project, a prospective clinical trial was conduct-
ed to determine whether preventing potential harm from PN manganese
overexposure can be done reliably and safely through creative product
selection during the PN compounding process. Data collection has been
completed and reporting is underway.
Projects Ongoing in 2021

A Scalable, Patient-centered Approach to “Right-sizing” Opi-
oid Prescriptions. Patient-reported data on the use of opioid pain
medications after specific procedures are lacking, and many studies
have found that more pills are prescribed than are actually needed.
This project is collecting data from patients undergoing elective surgi-
cal procedures and those seen in an emergency department for acute
pain. Information on the number of doses of opioid pain medication
used, the number of days of medication used, and how patients feel
about their ability to treat their pain is being collected. Understanding
how much medication most patients actually used will enable standard
orders for surgeries to be revised to reflect actual need. The project will
ensure patients are provided enough medication to treat their pain,
while attempting to minimize the number of leftover pills that could be
diverted, misused, or abused. To date, several thousand patients have
been enrolled and data collection is ongoing. Two articles have been
published, which can be viewed here and here.
In a second phase of this project, prescriber “report cards” are being

tested to further “right-size” prescribing. This aim will test the effect of
providing prescribers comparative feedback on their patients’ quantity
of unused pills using a stepped-wedge cluster randomized trial. Report
cards will contain information on pills prescribed and those actually

35
used by patients for each surgical provider for each common procedure.
The hypothesis is that compared with usual care, monthly feedback will
prompt prescribers to reduce the amount of opioid tablets prescribed,
thereby reducing the amount of pills left over, but will not impact abil-
ity to manage pain. Multiple surgical subdivisions are participating in
this phase of the project.
Suicide-Related Risks Associated with Prescription Opioid

Deprescribing. Concerns exist that abrupt discontinuation or rapid/
unsupported tapering of opioid pain medication may result in unin-
tended consequences, including suicides. However, the scope of
suicides and suicide attempts after opioid deprescribing, as well as
which patients are most vulnerable, are largely unknown. This project
assesses overdose and suicide-related outcomes associated with pre-
scription opioid deprescribing in a large, multisite, nationally represen-
tative, observational study using data from six health systems. A further
aim of the study is to identify factors that can reduce associated risks
and reduce preventable harm related to opioid deprescribing.
Perioperative Medication Safety Self-Assessment for Hospitals

and Ambulatory Surgical Centers (ASCs) and Targeted Risk-
Reduction Tool Development. Preventable harmful medication errors
in perioperative settings are a common cause of morbidity and mortality in
the United States, with the frequency of medication errors varying widely
depending on detection and measurement strategies. Systematic identifi-
cation and characterization of perioperative medication errors is essential
to enable targeted interventions such as resources that enable health care
providers and institutions to identify and manage shortcomings to reduce
preventable harm. This project involves the development, testing, and
implementation of a perioperative medication safety evaluation of systems
and practices in U.S. hospitals and ambulatory surgical centers using a
self-assessment instrument. Additionally, the Institute for Safe Medica-
tion Practices (ISMP) will apply findings to create a tool for general use by
health care providers and institutions to perform these self-assessments.
Data collection is currently underway. Results will be presented at a future
national meeting.
Leveraging the Electronic Health Record (EHR) to Promote

Pharmacy Adoption of Dosing Best Practices and Reduce Par-
ent Errors in Administering Pediatric Liquid Medications. This
project is examining whether an instruction to pharmacists incorporated
into the EHR as part of the electronic prescription will reduce errors in
administering pediatric liquid medications. These instructions specify

36
that the prescription should be in “mL only” units and that an appropri-
ate-sized dispensing device should be given to the patient. Follow-up with
patients checking that the appropriate dispensing device was given will
assess the effectiveness of the instructions to the pharmacist and if the
intervention reduces dosing errors made by parents.
Evaluation of Stimulant Abuse in the United States: A Mosa-

ic Epidemiology Study. Stimulant abuse is increasing dramatically;
however, compared to opioid abuse, little is known about this emerging
public health issue. This project will use several databases to characterize
stimulant abuse, including examining demographics, drugs of interest,
motivations, and behaviors, as well as trajectories of use.
Mentored Implementation and Dissemination of Anticoagula-

tion Stewardship (MIDAS) Program. Anticoagulants are essential
medicines to reduce the risk of blood clots and strokes, but they are also
a major source of preventable harm due to the risk of excessive bleeding
and the challenge they pose for health care professional management.
This project is examining the ability of an anticoagulation stewardship
program to reduce preventable harm from anticoagulants using a Men-
tored Implementation Program, using a Stewardship Guide and Self-
assessment developed in a previous FDA-funded project. In this new
effort, paired physician-pharmacist teams will serve as mentors for five
diverse hospitals that will conduct self-assessments at the beginning of
the program, create an interdisciplinary team, and work with the mentors
to create an individualized implementation plan. Mentoring will take
place monthly over a 12-month period. The hospitals will share lessons
learned with each other and provide updates quarterly. A content devel-
opment committee will use the implementation plans and lessons learned
to create a “playbook” which other institutions can use to create and carry
out their own Anticoagulation Stewardship Implementation Program.
Preventable Harm from Pediatric Outpatient Medication Errors:

Measure Development. This project seeks to develop an understanding
of current measures in outpatient pediatric medication safety and assess
the gap between current measures and needs. Measure development is a
necessary step in defining and establishing quality improvement programs.
Quality measures in pediatrics have lagged behind measure development in
other areas. The project will include a systematic literature review and input
from stakeholders such as health care providers, parents, and patients. The
literature review has been completed and a manuscript is in preparation.

37
New Projects in 2021

Assessment of a Pharmacist-led Interprofessional Transition of
Care Program Targeting Patients with Multiple Recent Hospital
Admissions: the ICARE Program. Transitions of care (TOC) pro-
grams can decrease the rate of 30-day hospital readmission and 30-day
emergency department utilization in high-risk patients. Previous studies
have examined the impact of TOC services on outcomes related to specific
disease states. One gap in the current literature is an examination of the
impact of a TOC program on patients at high risk for readmission due to
a history of multiple admissions. In order to decrease the rate of 30-day
readmissions and improve patient care during care transitions, the investi-
gators are implementing the ICARE (Identify at admission, Counsel before
discharge, secure Access to medications, Reach out for follow-up, Engage
community providers) TOC program. Using this approach, the investiga-
tors will develop a pharmacist-led hospital-community collaborative TOC
program to decrease medication-related harm in patients at high risk for
hospital readmission due to multiple recent admissions.

38
FDA’s compounding program Compounded Drugs:

aims to protect patients from Continuing Oversight
unsafe, ineffective, and poor-
quality compounded drugs, while and Stakeholder Outreach
preserving access to lawfully Human drug compounding is generally a practice in which a licensed
marketed compounded drugs for pharmacist or a licensed physician combines, mixes, or alters ingredients
patients who have a medical need of a drug to create a medication tailored to the needs of an individual pa-
for them. tient. Although compounded drugs can serve an important role, they also
can present a risk to patients.
Compounded drugs do not undergo FDA premarket review for safety, ef-
fectiveness, and quality, and therefore may present a greater risk of harm
to patients than FDA-approved drugs. To help mitigate these risks, the
FDA has developed a novel approach to engage facilities that compound
sterile drugs and help them produce the highest quality drugs.
The Compounding Quality Center of Excellence, launched in 2019, is

designed to enhance collaboration with outsourcing facilities, compound-
ers, and other stakeholders with the goal of improving the overall quality
of compounded medicines. An FDA Voices article published in 2021
highlighted the Agency’s continued collaboration with drug compound-
ers. One area of engagement includes supporting in-person and online
trainings on current good manufacturing practice (CGMP) requirements.
These requirements for outsourcing facilities are particularly important
because their compounded drugs reach many patients across the country.

39
In 2021, the FDA advanced the implementation of the Compounding

Quality Center of Excellence, including by:
• Developing and holding multiple instructor-led virtual and

self-guided online CGMP and compounding policy trainings for
outsourcing facilities
• Holding the second annual conference in September 2021 to

convene outsourcing facilities and other stakeholders to enhance
collective learning in areas that can help to bolster the quality of
compounded drugs
• Engaging in research to better understand the outsourcing

facility sector and its needs to inform current and future program
areas for the Center
The FDA also took important steps to implement and enforce federal
law related to drug compounding. In September 2021, the FDA’s actions
led to a consent decree against a Florida-based compounder, Premier
Pharmacy Labs Inc., prohibiting it from manufacturing and distribut-
ing drugs due to insanitary conditions. The FDA inspected the firm and
found it manufactured and distributed drugs, including those intended
to be sterile, that were adulterated because they were made under insani-
tary conditions and in violation of good manufacturing practice require-
ments under the FD&C Act.
In September 2021, the FDA alerted patients and health care profes-
sionals not to use products intended as sterile from Prescription Labs
Inc., doing business as Greenpark Compounding Pharmacy in Houston,
Texas. During an inspection, FDA investigators observed conditions that
could cause compounded drugs to be contaminated or otherwise pose
risks to patients.
In October 2021, the FDA issued a Compounding Risk Alert highlighting

concerns with compounding of drug products by medical offices and
clinics under insanitary conditions. Adverse events have been reported,
but it is likely that these events are underreported. The FDA also noted
increasing awareness of businesses such as intravenous (IV) hydration
clinics, medical spas, and mobile IV infusion services that are com-
pounding drugs under conditions that may not meet section 503A of the
FD&C Act or comply with state regulations.
The FDA also advanced development of the lists of bulk drug substances
that may be used in compounding though a meeting of the Pharmacy
Compounding Advisory Committee and publications in the Federal
Register. Additionally, the FDA published a revised draft guidance on
compounding in hospital and health-system settings.

40
The following resources related to human drug compounding can be

found on FDA’s website:
• Compounding: Inspections, Recalls, and other Actions
• Compounding Risk Alerts
• Consumer and Health Care Professional Information
• Compounding and the FDA: Questions and Answers

41
Communicating Drug Safety:

Global Outreach Through Diverse
Tools and Technologies
CDER’s Office of Communications (OCOMM) supports the FDA’s mission
to protect and promote public health through a broad range of commu-
nication tools and technologies. Throughout 2021, OCOMM continued
to develop and expand this mission through the expertise and efforts of a
multidisciplinary staff of health care professionals, science and medical
communications specialists, researchers, web and graphic designers, and
senior strategists and advisors. These professionals enable OCOMM to:
• Provide strategic communication advice to CDER and FDA
leadership
• Develop and coordinate overarching public communication
initiatives and educational activities
• Devise and deploy comprehensive communication strategies
that ensure consistent branding, messaging, and direction of
communication initiatives and tools
• Offer expertise on communication products across a variety of
media
• Respond to inquiries from the public about a range of topics
related to human drugs
• Conduct social science and risk communications research

42
Communicating Drug Safety Across Multiple Audiences

Drug Safety Communications (DSCs)
support more informed decision Drug Safety Communications (DSCs) provide important new or emerg-
ing safety information about marketed prescription and OTC drugs to
making by patients and health care
patients, caregivers, health care professionals, and the public. DSCs
professionals and help prevent or communicate safety issues that, for example, may affect a large number of
mitigate drug-related harm. patients, describe potentially serious or life-threatening adverse events or
certain other cautions related to use of a drug or class of drugs, and con-
tain actionable recommendations for patients and health care profession-
als. DSCs also support more informed decision making by patients and
health care professionals and help prevent or mitigate drug-related harm.
The DSC home page is consistently a highly visited page on the FDA’s
web site. The key safety information contained in the DSCs is also
broadly circulated through many other channels, including large email
listservs, including a DSC-specific list that allows patients and health
care professionals to request email alerts about medicines or medical
specialties of specific interest to them; social and traditional media;
podcasts; and targeted outreach to media, health care professionals,
advocacy groups, and other stakeholders. Throughout 2021, DSC
information was widely reported, including by Bloomberg, Reuters,
WNYT, and multiple trade press publications.
Eight DSCs were issued in 2021, generating nearly 206,000 unique

pageviews. Among the DSCs issued, several involved high-profile issues
or drug products, including:
• Xeljanz, Xeljanz XR (tofacitinib): Preliminary safety clinical trial

results showed an increased risk of serious heart-related problems
and cancer with this arthritis and ulcerative colitis medicine
compared to tumor necrosis factor (TNF) inhibitors.
• Xeljanz, Xeljanz XR (tofacitinib), Olumiant (baricitinib), Rinvoq

(upadacitinib)—Janus kinase (JAK) inhibitors that treat certain
chronic inflammatory conditions: Increased risk of serious heart-
related events such as heart attack or stroke, cancer, blood clots,
and death communicated based on FDA review of the completed
safety clinical trial results.
• Alcohol-based hand sanitizers (two DSCs): Symptoms such as

headache, nausea, and dizziness can occur after applying alcohol-
based hand sanitizers to the skin and breathing in the vapors.
Splashing or touching the eyes after use of alcohol-based hand
sanitizer can result in serious injury, including severe irritation
and damage to the surface of the eye.
More than a year after the OCOMM launched a distribution listserv that
allows health care professionals, patients, and consumers to sign up to
receive email alerts about DSCs on medications and medical specialties of
specific interest to them, the listserv has over 31,000 subscribers across the
43
78 different DSC medication and medical specialty topics offered. Addi-

tionally, the DSCs are distributed through the MedWatch Safety Alerts Across all DSCs issued during 2021,
listserv, the Division of Drug Information listserv, and to various targeted visitors spent an average of over
stakeholder organizations. DSCs issued in 2021 were also widely shared via two and a half minutes on DSC
social media on FDA’s Facebook page, Twitter feeds, and LinkedIn page.
content. In comparison, most users
LinkedIn, which has greater potential for targeting health care profession-
als, saw more than 2,000 “click-throughs” to the full DSCs. Across all DSCs
generally stay on websites for less
issued during 2021, visitors spent an average of over two and a half min- than 15 seconds.
utes on DSC content. In comparison, most users generally stay on websites
for less than 15 seconds.
Drug Safety Podcasts of each DSC provided an additional format for this
this emerging safety information. The eight podcasts issued in 2021, which
generated more than 21,000 engagements, are available on the FDA web-
site and on Apple Podcasts, Google Podcasts, Spotify and ReachMD.
Drug Information Webinars offer free, live online continuing education

(CE) for physicians, physician assistants, nurse practitioners, nurses,
pharmacists, and pharmacy technicians. The webinars often center on
drug safety or safety-related topics. Recordings of these webinars are
posted online after the live session for home study.
MAY 18 | Safety Labeling Changes for Leukotriene Receptor Antago-

nists and Decisions Behind a Boxed Warning
JUNE 1 | Enhanced Drug Distribution Security: 2023 and Beyond
OCTOBER 19 | How FDA and ISMP Utilize Medication Error Reports to

Improve Drug Safety
NOVEMBER 16 | Fraudulent Products – Hidden Ingredients and Un-

proven Claims in Products Marketed as Dietary Supplements
New Home Study CE Courses posted in 2021 include:
• Overview of Risk Evaluation and Mitigation Strategies (REMS)

for Health Care Providers
• An Overview of Naloxone and FDA’s Efforts to Expand Access
The FDA also issued several Consumer Updates related to drug safety
information.
NOVEMBER 3 | Safely Using Hand Sanitizer
OCTOBER 28 | Should You Give Kids Medicine for Coughs and Colds?
JULY 21 | Accidental Exposures to Fentanyl Patches Continue to Be

Deadly to Children
JUNE 14 | Older Therapies Aren’t Necessarily Better for Thyroid Hor-

mone Replacement

44
DRUG SAFETY COMMUNICATIONS OUTREACH
REACHED OVER
8 DSCS VIEWED NEARLY 31,000 DSC LISTSERV SUBSCRIBERS
206,000 TIMES 117,000 DRUG INFORMATION LISTSERV SUBSCRIBERS
400,000 MEDWATCH LISTSERV SUBSCRIBERS
PUSHED TO OVER
493,000 783,000 331,100

FOLLOWERS FOLLOWERS FOLLOWERS
LINKEDIN FACEBOOK TWITTER
129,538 505 163

IMPRESSIONS LIKES LIKES
712 232 180

REAC TIONS SHARES RET WEETS
2,072
CLICKS TO THE DSC

45
Responding to Public Inquiries PUBLIC INQUIRIES MANAGED

BETWEEN OCTOBER 1, 2020–
OCOMM responds to public inquiries about all human drugs. These
SEPTEMBER 30, 2021
inquiries are received via phone, email, letters, and through social
media platforms such as Facebook and LinkedIn. Expert responses
are developed and facilitated by a team of pharmacists, nurses, and
Letters Social Media
other health professionals who field questions from consumers, health
1% 1%
care professionals, journalists, research and nonprofit organizations,
regulated industry, other government agencies, academia, and from
international stakeholders in government and research institutions.
OCOMM received and managed more than 43,000 public inquiries
between October 1, 2020, and September 30, 2021, mostly by phone. Email
35%
Phone
Social Media Engagement 63%
The CDER Social Media team has significantly expanded CDER’s commu-
nications outreach by ‘meeting people where they already are’ on numer-
ous social media platforms, including Twitter, Facebook, LinkedIn, and
YouTube. Drug safety information is now actively pushed to more than
756,000 FDA Facebook followers, 327,000 Twitter followers, and 476,000
LinkedIn followers, facilitating exponential growth in the distribution of *Facebook and LinkedIn
FDA’s public health messages, safety communications, and drug safety
warnings. In addition to posting content and engaging in two-way commu-
nication, the Social Media Team also performs social listening, monitoring
the comments and questions users post on FDA’s social media channels to
obtain immediate feedback on FDA actions and decisions. The team also
oversees ‘live’ tweeting of discussions occurring at meetings and work-
shops, providing real-time highlighted content to many more people than
those attending in person.
On November 9, 2020, the team launched the @FDACDERDirector TOP 10 PUBLIC INQUIRIES
Twitter account to provide a head of Center perspective on CDER
actions and initiatives, including those regarding drug safety. This COVID-19 9,081
account issued 187 tweets and has 2,503 followers from media, current Opioids 1,334
and former FDA officials, consumers, health care providers, industry, Nitrosamines 1,182
stakeholder groups, health organizations, and other health and govern-
Investigational New 1,053
ment leaders.
Drugs (IND)
Between October 1, 2020, and September 30, 2021, the CDER Social Personal Import 1,047
Media Team: Electronic Registration 1,010
and Listing
• Actively disseminated FDA information to followers on Twitter
through 956 tweets and Facebook through more than 320 posts Expanded Access/Right 941
to Try
• Provided information to more than 117,000 subscribers on Clinical Trials 865
our Drug Information Listserv through 262 messages sent,
Import/Export 567
generating more than 1.9 million URL “click-throughs” to FDA
website content OTC Monograph 491

46
• Expanded social media outreach for COVID-19 communications,

Facebook Events, and the Remove the Risk opioid disposal
campaign, BeSafeRx online pharmacy campaign relaunch,
information about Biosimilars, and Sunscreens.
SOCIAL MEDIA OUTREACH

FACEBOOK
Facebook followers 756,252
CDER posted content 320
Replied to comments 319
Public Likes/Shares 40,991
LINKEDIN
FDA page followers 476,704
Small Business and Industry Assistance (SBIA) Showcase 15,350
page followers
Global Alliance of Drug Information Specialists (GADIS) 1,094
Group members
TWITTER
Total followers 326,305
Tweets 956
Retweets 5,850
Likes 9,885

47
Drug Safety-related Labeling Changes

Not every safety concern can be identified at the time a drug product is
approved for marketing. If new safety concerns emerge after a drug is
marketed, the FDA may require a drug safety-related labeling change
(SrLC). The SrLC database includes safety labeling changes FDA
requires or orders drug manufacturers to make as well as labeling
changes voluntarily submitted by product sponsors.
The database makes safety information available in near real-time and

can be easily searched through a user-friendly portal by stakeholders
such as health care professionals, patients, and health IT and infor-
mation vendors. Stakeholders accessing the database provide valuable
feedback that assists the FDA in continually upgrading how safety
labeling information is organized and presented.
SAFETY-RELATED LABELING CHANGES*
Adverse Reactions 1,204

Boxed Warnings 374
Contraindications 506
Drug Interactions 754
Patient Counseling information and/or Medication Guides 1,206
Use in Specific Populations 1,178
Warnings and Precautions 1,280
TOTAL 6,502
*Between October 1, 2019–September 30, 2021

48
BeSafeRx Campaign
FDA’s BeSafeRx campaign helps consumers learn about how to safely buy prescription medicines
online. Between October 1, 2020, and September 30, 2021, the BeSafeRx campaign received more
than 2 million airings/placements, yielding an estimated 295 million impressions across TV, radio,
and medical office and hospital waiting rooms.
• The campaign’s TV public service announcements (PSAs) aired 21,471 times on

194 television stations and 10 television networks across the country, yielding
approximately 113 million impressions.
• The radio PSAs aired approximately 53,229 times on 940 radio stations nationwide
(including Nielsen, non-Nielsen and TTWN affiliates), 13 networks (including TTWN)
and 1 program, yielding an estimated 167 million impressions.
• The video PSAs aired approximately 1,964,902 times in the waiting rooms of medical
offices and hospitals across the country, yielding an estimated 14 million impressions.

49
Online Communications WEB TRAFFIC BETWEEN

JANUARY 1–
Drug safety news, announcements, and information are distributed to
SEPTEMBER 30, 2021
multiple audiences using a variety of digital and electronic media sup-
ported by a broad portfolio of services, including video production and
TRAFFIC VOLUME SESSIONS*
photography, web graphics, online publications, posters, infographics,
illustrations, and other materials. The online communications team Mobile 72,525,385
also maintains web content such as drug safety information and safety- Desktop 42,951,654
related regulatory policy documents on FDA web pages; manages public Tablet 2,737,580
databases; and develops web and mobile applications, including optimiz- * Number of individual online sessions initiated
ing applications for viewing formats such as smart phones and tablets. by all users with periods of inactivity less than
30 minutes.
Between January 1 and September 30, 2021, the traffic to CDER’s web
pages amounted to more than 19 million individual sessions. The metrics % OF
in the tables below depict the extent of this online engagement, including TRAFFIC SOURCES SESSIONS
the platforms from which the traffic is coming; the 10 most-viewed CDER Search Engines 67%
web pages – collectively accounting for more than five million online vis- Direct (URLs) 16%
its; and the topics, questions, and documents generating the most online
Referrals 9%
traffic for the period. Also tracked are trending topics on social media,
Email 4%
as well as the leading subjects of news stories and other informational
outlets, and those carried via newsfeeds and social media. Social Media 4%
TEN MOST VIEWED CDER PAGES TOP 10 GOOGLE SEARCHES

LEADING TO FDA
Unique
Pageviews*
SAFETY CONTENT
1. Drugs 1,447,039 1. Hydroxychloroquine
2. Drug Approvals and Databases 835,899 2. Benadryl
3. FDA updates on hand sanitizers consumers should not use 806,789 3. Hand sanitizer
4. Drug Safety Communication: FDA cautions against use of 540,315 4. Metformina*
hydroxychloroquine or chloroquine for COVID-19 outside 5. Metformin
of the hospital setting or a clinical trial due to risk of heart 6. Loperamida*
rhythm problems
7. Montelukast
5. High Blood Pressure–Understanding the Silent Killer 527,434
8. Ketoconazole
6. National Drug Code Directory 494,979
9. Clopidogrel
7. Q&A for Consumers | Hand Sanitizers and COVID-19 369,377 10. Difenhidramina*
8. Disposal of Unused Medicines: What You Should Know 309,431
* Spanish language searches.
9. FDA authorizes REGEN-COV monoclonal antibody therapy 271,163
for post-exposure prophylaxis (prevention) for COVID-19
10. Drug Disposal: Drug Take Back Locations 238,498
* Number of sessions during which the page was viewed one or more times in the same session.

50
Risk Communications Research

OCOMM undertakes a range of social and behavioral science research
studies to gather evidence directly from health care professionals,
patients, caregivers, and consumers related to numerous drug and drug
safety-related issues.
• The goal of this research is to enhance understanding of our

stakeholders’ knowledge, perceptions, needs, desires, and
behaviors.
• Findings from these studies provide detailed and comprehensive

evidence to inform communication, regulatory, and policy
decisions aimed at enabling health care professionals, patients,
and the public to make informed health decisions.
• These studies involve qualitative, quantitative, and mixed

methods, including detailed, in-depth research, testing of FDA
materials and messages, and exploratory pharmacovigilance
studies conducted through monitoring and analysis of open-
source data available online and through social media.
Highlights of 2021 Research Programs and Projects

Studies related to opioids and other abused drugs
Abuse-deterrent Formulation Opioids. Throughout 2021,
OCOMM social scientists and CDER opioid subject matter experts
continued work on a three-phase project exploring and assessing the
knowledge, attitudes, and understanding regarding abuse-deterrent
formulation (ADF) opioids among prescribers and dispensers/phar-
macists, including related to the ADF terminology. Based on findings
from focus groups with opioid prescribers and pharmacists in the first
project phase, a follow-up survey was completed in 2021 to obtain more
representative data, including related to the terminology. The final third
phase, which involves an experimental study, is underway.
Substances Used as Adjuncts or Alternatives to Prescription

Opioids. Two additional studies are in progress exploring substances that
may be used as adjuncts or alternatives to prescription opioids among both
consumers with opioid/substance use disorder and health care profession-
als who prescribe these substances. Among the substances being explored
are three classes of prescription drugs – opioids and benzodiazepines
(among patients undergoing treatment and separately among prescribers)
and gabapentinoids – and other substances often used with opioids –
kratom and cannabidiol (CBD) (among patients undergoing treatment).

51
Proactive Pharmacovigilance Through Social Media Monitoring

and Analysis. This novel research method aims to obtain an under-
standing of the social contexts and trends surrounding opioids and other
prescription drugs, particularly their use for nonmedical or recreational
purposes, being discussed in publicly available online discussion forums
and on social media. In addition to developing monthly social media
research reports concerning the misuse and abuse of prescription opioids,
OCOMM completed an in-depth project exploring the effects the early days
of the coronavirus pandemic had on opioid use and addiction, the findings
from which were presented in several public meetings.
Other Studies
Biosimilar Products. This project focuses on assessing educational
materials FDA developed to most efficiently and effectively communi-
cate with patients about biological products that are demonstrated to
be biosimilar to an FDA-licensed biological product. The educational
materials consist of an infographic, fact sheet, and a video public ser-
vice announcement to be posted on FDA’s website or disseminated to
patients through other methods. This study is a follow-up to a related
study that collected information about knowledge, awareness, and
understanding of biological products and biosimilars from patients and
health care professionals.
Message and Materials Testing. Several studies were undertaken

in 2021 assessing a variety of FDA messages and materials, includ-
ing sample drug safety announcements about the misuse and abuse
of OTC medicines, proposed updates to the FDA’s DSC web page and
the communications’ question-and-answer format, a draft Consumer
Update article about children’s OTC and homeopathic cough and cold
products, and 20 commonly used technical regulatory terms and their
plain language alternatives to determine comprehension by lay health
consumers.
Information about these research efforts were presented publicly in

2021. This includes presentations at the Drug Information Association’s
(DIA’s) Biosimilar Conference and the FDA Science Forum.

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Silver Spring, MD 20993
www.fda.gov

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CENTER FOR DRUG EVALUATION AND RESEARCH

CENTER FOR DRUG EVALUATION AND RESEARCH

Safety Surveillance and Oversight of Marketed Drug Products .......................... 14

Nitrosamine Impurities in Medicines: FDA’s Continuing

Continued Efforts to Address the Misuse and Abuse of

Ensuring Quality, Safety, and Effectiveness of Generic Drugs............................... 28

Safe Use Initiative: Collaborating to Reduce Preventable

Compounded Drugs: Continuing Oversight and Stakeholder Outreach ......... 38

Communicating Drug Safety: Global Outreach Through Diverse

CENTER FOR DRUG EVALUATION AND RESEARCH

In addition to assessing the safety of drug products used for COVID-19

CENTER FOR DRUG EVALUATION AND RESEARCH

Assessing the Safety of Products Used for