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30 Cobert’s Manual of Drug Safety and Pharmacovigilance
3. Development and Approval Process
for Drugs: This provides information on how
drugs are developed and approved.
4. Guidance, Compliance, and Regu-
latory Information: For industry, this
key page for pharmacovigilance (PV) pro-
fessionals has links to information on laws,
acts, rules, good review practices, enforce-
ment activities, surveillance, post-marketing
commitments requirements, warning letters,
enforcement actions, new guidance documents,
cyber letters, and the CDER manual of policies
and procedures.
5. Information for Industry: This is a page
for the pharmaceutical industry with links to
guidance, post-marketing information, the Pre-
scription Drug User Fee Act (PDUFA, which
is renewed every 5 years), industry fees, warn-
ing letters, electronic submissions, the Orange
Book (approved drug products with therapeu-
tic equivalence evaluations), abbreviations, and
types of applications.
6. JumpStart: This is a tool for FDA reviewers to
gain insights on data fitness in an application
and which analytical tools might be appropri-
ate for use in the review. This was spawned by
CDER’s 21st Century Review Process, which
is an integrated review process that partitions
work into IT functions and scientific analysis.
JumpStart is intended to be applied to elec-
tronic data between submission of a marketing
application by industry and filing of the appli-
cation by CDER.
7. MedWatch: See below for more detailed
information.
8. Drugs at FDA: This is a link to the page that
has an alphabetical list and search engine to
find approved drugs by name, active ingredient,
or application number.
9. openFDA: This is a software tool designed to
facilitate public access and use of public FDA
data.
10. Recalls, Market Withdrawals and
Safety Alerts.
The Safety Reporting Portal
FDA has launched a “one-stop shopping” safety por-
tal in which electronic case safety reports for nearly all
products regulated by FDA (and NIH) can be submit-
ted. Food (human or animal), drugs, biologics, blood
products, gene-transfer research issues, and more can
be reported by sponsors/applicants/manufacturers/dis-
tributors, healthcare professionals, researchers, public
health officials, and “concerned citizens”. The features
and functionalities of this portal evolve as experience
is gained. It allows for initial and follow-up reports.
One can enter a case as a “guest” or one can establish
an account and use it repeatedly. It is not meant for
emergency reporting when a company’s safety system is
down. See the Safety Reporting Portal FAQ page. Other
pages of interest include the following:
1. Potential Signals of Serious Risks/New
Safety Information Identified from the
FDA Adverse Event Reporting System
(FAERS): This page contains information
about ongoing signals. Along the same lines,
the 2007 legislation generally required FDA
to perform extensive safety analyses of new
drugs at 18-months following approval or after
10,000 individuals had been exposed to the
drug, whichever was later. However, the 21st
Century Cures Act abolished this requirement
because a study showed that these assessments
had little value and the requirement was redun-
dant to other FDA safety activities. Results were
largely the same as those from established safety
surveillance practices and they did not reveal
important safety issues any sooner. These activ-
ities were not a good use of FDA resources so
they were curtailed by the 2016 legislation.
In January 2024, FDA published a final docu-
ment titled, “Best Practices for Food and Drug
Administration Staff in the Postmarketing
Safety Surveillance of Human Drug and Biolog-
ical Products.” This document segregates prod-
ucts into three categories for safety screening
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The United States Food and Drug Administration 31
and gives FDA staff general guidance on the
recommended cadence of ICSR reviews for
each category. The document updates an earlier
version (2019) and, among other things, pro-
vides reference to CDER’s “Manual of Policies
and Procedures for Collaborative Identification,
Evaluation, and Resolution of Newly Identified
Safety Signals.”
2. Post-market Drug Safety Information
for Patients and Providers: This site
contains information on post-market study
requirements and commitments, a link to the
clinical trials registry, and other safety-related
information.
3. Approved Risk Evaluation and Mitiga-
tion Strategies (REMS): This site contains
summary information and links to REMS sum-
maries that are in place and dates of modifica-
tions or release. There is a separate link to a
repository of released (previously approved, but
inactive) REMS.
4. Guidances: This site contains FDA’ s new,
current, revised, and withdrawn guidance in
all areas, including Drug Safety, ICH, OTCs,
Good Review Practices, the FDAAA Food and
Drug Administration Amendments Act (2007),
the FDA Safety and Innovation Act (2012), the
21st Century Cures Act (2016), and the FDA
Reauthorization Act of 2017.
5. Post-market Drug Safety Information
for Patients and Providers: Selected
Safety Regulations: This page has links to
the relevant sections of the Code of Federal
Regulations covering safety matters for drugs
and biologics, as well as INDs, NDAs, BLAs,
STNs (submission tracking numbers), and
labeling.
6. Warning Letters: A site with many years of
warning and untitled letters for all matters, not
just safety, that are searchable by company (or
investigator, etc.), issuing office, and so forth.
7. Pregnancy and Lactation Labeling.
8. Prescription Drug User Fee Act
(PDUFA): The main web page for information
on PDUFA, including the current version, with
several links.
9. Office of Surveillance and Epidemiol-
ogy (OSE).
10. Guidance, Compliance, and Regulatory
Information: This page has links to the vari-
ous laws, acts, guidance, and so forth.
11. Surveillance: Post-drug Approval
Activities: Links to the staff guide, regula-
tions and policies, advertising, and promotional
information.
12. FDA Adverse Event Reporting Sys-
tem (FAERS): This site has the description
of the main FDA drug safety database, with
post-marketing data files and statistics for chem-
ical drugs and therapeutic biologics, includ-
ing data migrated from predecessor databases.
There is a fairly user-friendly “Public Dash-
board” that supports navigation of redacted
FAERS data (additional details at www.fda.gov).
13. Vaccine Adverse Events Reporting Sys-
tem (VAERS): This site contains post-mar-
keting reports for vaccines regulated by CBER.
The database is housed by a vendor and scien-
tific access is shared by CBER and the Centers
for Disease Control.
14. Electronic Medical Device Reporting
(eMDR) System: This site has post-market-
ing safety (“incident”) data for medical devices
regulated by Center for Devices and Radiologic
Health (CDRH) and reported by manufacturers
and user facilities.
15. MedWatch to Manufacturer Program:
The system whereby FDA informs applicants of
SAEs that are received directly by FDA for the
first 3 years after a new product is marketed.
This is activated only on request of the applicant
(see “MedWatch” below). Note: The MHRA in
the United Kingdom has a similar program.
16. DailyMed: This is actually an NIH website
that provides “high quality information about
marketed drugs”. It is not a complete listing
but does have information on more than 7,000
drugs. See the Drugs@FDA site.
32 Cobert’s Manual of Drug Safety and Pharmacovigilance
17. Medication Guides.
18. Medication Errors.
19. Safe Use Initiative: FDA’s program to reduce
preventable harm from medications. This FDA
website is extensive, and almost everything that
one wants to find relating to the FDA, drugs,
and drug safety are present, though often not
easy to find. In addition, FDA changes its web-
sites frequently, and pages may jump or be
moved, or URLs may be dead links. It may be
necessary to search for the new URL using the
FDA search engine on the home page. Note that
most, but not all, of the drug safety information
is in the CDER section of the website.
Risk Management
On the FDA website there is extensive information on
risk management initiatives. Other FDA activities are
covered elsewhere in this chapter and in other chapters
of this manual.
In 1997, the federal government put forth a global
framework for federal risk management of drug prod-
ucts. The fundamental concepts include the following:
Risk assessment is the estimation and evaluation
of a risk in the pre- and post-marketing areas.
Risk confrontation determines the acceptable level
of risk in the large context, including social and
community values and the technical judgments
of professionals. This includes the use of advi-
sory committees, which get input from various
concerned independent experts and stakehold-
ers. In addition, the FDA has relationships with
various groups of health professionals, consumer
and patient advocacy groups, industry organiza-
tions, and other governmental agencies to gather
information and advice.
Risk intervention is the evaluation of alternative
risk control actions, selection among them, and
their implementation. After the risks are iden-
tified and assessed, they must be managed or
minimized. The FDA can refuse to allow the
product to be marketed if the Agency concludes
that the product’s risk outweighs its benefits.
If the product is permitted on the market, the
FDA minimizes risk by various mechanisms,
including the review and approval of the origi-
nal labeling and any subsequent changes. FDA
also regulates the advertising and promotion
of marketed products. Promotional materials
must not be false (i.e., they must conform to
the label and be substantiated), and they must
not be misleading (i.e., they must be balanced
and include the material facts). FDA also tracks
medication errors and can act on issues there.
FDA also can require other risk minimization or
mitigation measures, including mandating edu-
cation for product users, limiting product distri-
bution (e.g., to specific hospitals or specialists),
requiring prescriber qualifications, training, or
informed consent, etc. The FDA may also require
post-approval clinical or epidemiologic studies
after marketing. In urgent situations, there are
various mechanisms to remove products from
the market. In January 2024, FDA issued a final
guidance document Titled, “Best Practices for
Food and Drug Administration Staff in the Post-
marketing Safety Surveillance of Human Drug
and Biological Products
Risk communication is aimed at conveying the
needed information to the public. There are
ongoing and rapidly changing risk communi-
cation mechanisms using traditional and social
media mechanisms to convey information to
consumers and healthcare practitioners. The
Internet and various new means of wireless com-
munication challenge all parties to get the cor-
rect message out and make it visible in the large
sea of available information. The product label-
ing (Package Insert) has been the classic mech-
anism of communication. The FDA has redone
and revised how labels are made and how the
information is communicated both to patients
and practitioners. This is a controversial area as
some feel the changes make labeling more com-
plete but less useful and more ponderous. Med-
ication guides for patients are also provided for
some products in lay language to communicate
how consumers should use products. Whether
these changes lead to lowering risks for particu-
lar products remains to be seen.
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The United States Food and Drug Administration 33
Another controversial area is Direct-to-Consumer
advertising, which is allowed in the United
States but not in many other developed coun-
tries. Whether this promotes product use that is
safer or more dangerous is a much-debated topic,
with no clear answer.
MedWatch
The MedWatch program is the FDA’s national pharma-
covigilance program for marketed products. It collects
safety information and provides clinical informa-
tion about safety issues involving prescription and
OTC drugs, biologics, medical and radiation-emitting
devices, and special nutritional products (e.g., medical
foods, dietary supplements, and infant formulas). See
the MedWatch site at www.fda.gov.
The website provides “one-stop shopping” for
information or links to information on medical prod-
uct safety alerts, recalls, withdrawals, current new and
hot topics, educational materials, and a glossary, the
NIH Daily Med site (hosted by the National Library of
Medicine with up-to-date drug labeling information),
Medication Guides, drug-specific information (more
labeling), drug shortages, and more.
There is also a set of links to receive periodic e-mail
notifications and RSS feeds (which you can have auto-
matically sent to your Internet home page, if it accepts
such feeds). There are also social media broadcasts pro-
duced by FDA on Facebook, Twitter, etc.
Another little-known MedWatch function is the
MedWatch to Manufacturer Program (see above), which
allows drug and biologics manufacturers to receive cer-
tain serious AEs submitted directly to FDA that would
not otherwise be known to the manufacturer. An appli-
cant can subscribe at any time within 3 years after
product approval; FDA will send reports for a period of
about 3 years after approval.
The other key part of the MedWatch site is information
on reporting serious AEs to the FDA using the MedWatch
form, which comes in three very similar variations —
the 3500-form for the public to voluntarily submit AEs,
the 3500B-form that is more consumer-friendly than the
3500-form, and the 3500A-form for mandatory reporting.
Manufacturers usually use the 3500A-form only for expe-
dited reporting from clinical trials; structured electronic
reporting is required for marketed products.
An information page for health professionals and
the public describes the systems used for safety report-
ing, which then has links to the other pages giving fur-
ther information. There are links to downloadable PDF
versions of the MedWatch forms. There is also a link to
an online reporting form for the public.
There is a page with information for industry on
the three key serious AE reporting areas. Information
and links to the appropriate regulations and forms are
included:
OTC Products and Dietary Supplements;
Drug/Biologic/Human Cell, Tissues and Cellular
and Tissue-Based Product Manufacturers, Distribu-
tors, and Packers;
Human Cell & Tissue Products (HCT/P) Adverse
Reaction Reporting.
Safety Databases
The FDA maintains several databases that contain safety
information:
FDA Adverse Event Reporting System
(FAERS): This is a computerized information
system for FDA’ s post-marketing safety surveil-
lance program for drugs and biologics. It is com-
pliant with the data elements specified in the ICH
E2B guideline. This database is one of the largest
of its kind and contained over 15-million ICSRs as
of mid-2024. More than half of these are classified
as serious. Quarterly (non-cumulative) data files
since January 2004 are available for downloading
as zipped SGML or ASCII files. The data in these
files are not cumulative and not searchable online.
However, there is a “Public Dashboard” that sup-
ports searches of FAERS data. It is also possible to
request FAERS cases (redacted) using Freedom of
Information (FOI) requests.
Data freely available for querying via the “Pub-
lic Dashboard” include patient demographics, the
suspect drug(s) reported, the adverse reaction(s),
34 Cobert’s Manual of Drug Safety and Pharmacovigilance
patient outcome, and the source of the reports. It
is possible to stratify and organize data by product,
patient age, type of adverse event, the timeframe in
which the event occurred, etc.
Post-marketing Requirements (PMRs) and
Commitments (PMCs): This database contains
information on studies and trials that applicants
have committed to carrying out after drug approval.
Vaccine Adverse Event Reporting System
(VAERS): VAERS is a cooperative database run
by the CDC and the FDA. VAERS collects informa-
tion about AEs that occur after the use of licensed
vaccines, or adverse events following immunization
(AEFI). See below under CBER.
Manufacturer and User Facility Device
Experience Database (MAUDE): This data-
base contains selected safety information for medi-
cal device reports since 1991 and is updated weekly.
See below under CDRH.
Clinical Trials Database: This is not a safety
database but has information about governmental
and private clinical trials under way in the United
States and globally. There are tens of thousands of
trials in more than 170 countries on file. Some con-
tain safety information. The PDUFA/FDAAA laws
require safety information to be put online and this
has been a gradual process. See: www.clinicaltrials.
gov.
Other databases include such topics as poisonous
plants.
Other Useful FDA Web Pages
Post-market Drug Safety Information for Patients
and Providers: A one-stop shopping page for just
about everything you want to know about safety.
FDA guidance for FDA-regulated products.
Office of Non-prescription Drugs (OTCs).
Potential Signals of Serious Risks New Safety Infor-
mation Identified from the FDA Adverse Event
Reporting System (FAERS).
Prescription Drug User Fee Acts (PDUFA), which
are on 5-year cycles. PDUFA legislation specifies
deadlines for the FDA to review new drug appli-
cations (normally 10-months for new drugs or
6-months for priority review, beginning on the date
that FDA accepts the application).
Food and Drug Administration Amendments Act
(FDAAA) of 2007.
Warning Letters.
Summaries of approved Risk Evaluation and Miti-
gation Strategies (REMS).
Global Health Agencies (links).
Dietary Supplements.
Code of Federal Regulations.
Drugs@FDA — the US labeling for most approved
drugs.
Finally, there is a very useful page that covers man-
datory post-marketing reporting by drug and biologic
manufacturers, distributors, and packers. There are
hyperlinks to the applicable federal regulations:
Labeling
201.56 — Requirements on content and format
of labeling for human prescription drug and
biological product
Other labeling regulations
208 — Medication Guides for Prescription
Drug Products
310.501 — Patient package inserts for oral
contraceptives
310.515 — Patient package inserts for estrogens
312 — Investigational New Drug (IND)
Application
312.32 — IND safety reports
312.33 — Annual reports
312.88 — Safeguards for patient safety
314 — Applications for FDA Approval to mar-
ket a New Drug (NDAs)
314.80 — Post-marketing reporting of adverse
drug experiences
314.81 — Other post-marketing reports
314.97 — Supplements and other changes to an
approved abbreviated application (ANDA)
314.98 — Post-marketing reports
314.520 — Approval with restrictions to assure
safety use
314.540 — Post-marketing safety reporting
314.630 — Post-marketing safety reporting
601 — Biological Licenses
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The United States Food and Drug Administration 35
601.12 — Changes to an approved application
601.32 — General factors relevant to safety and
effectiveness
601.35 — Evaluation of safety
601.93 — Post-marketing safety reporting
610 — General Biological Products Standards
610.11 — General safety
In addition, other key documents such as FDA
instructions for field staff, E2B ICSR submission infor-
mation, ICH documents, and others are available.
Center for Biologics
Evaluation and Research
The CBER website contains less information regarding
product safety than the CDER site because the regu-
latory responsibility for approval and post-marketing
evaluation of many CBER products was transferred to
CDER in 2003. The products remaining in CBER include
cellular products (e.g., pancreatic islet cells for trans-
plantation, whole cells, cell fragments, or other com-
ponents intended for use as preventative or therapeutic
vaccines); allergenic extracts used for diagnosing and
treating allergic diseases and allergen patch tests; anti-
toxins; antivenins/antivenoms; venoms; blood; blood
components; plasma-derived products (e.g., albumin,
immunoglobulins, clotting factors, fibrin sealants, pro-
teinase inhibitors), including recombinant and trans-
genic versions of plasma derivatives (e.g., clotting
factors); blood substitutes; plasma volume expanders;
human or animal polyclonal antibody preparations,
including radiolabeled or conjugated forms; certain
fibrinolytics, such as plasma-derived plasmin; and red
cell reagents.
More extensive information on this subject can be
found at the CBER website. In regard to safety, there
is information covering recalls, shortages, biological
product deviation reporting (i.e., errors and accidents
in manufacturing), AE reporting, and specific informa-
tion about safety issues on various products, such as
flu vaccines, HIV test kits, tissue products, and blood
products. As noted, most AEs are reported via Med-
Watch using the 3500-voluntary reporting form. One
exception is vaccine AEs (e.g., Adverse Events Fol-
lowing Immunization (AEFI)). These are reported to
the Vaccine Adverse Event Reporting System (VAERS),
which is sponsored by the FDA and the CDC. As with
drugs, the goal is to collect and analyze safety sig-
nals and vaccine AEs. In particular, compared with
drug products, vaccines are given to large numbers
of children (FDA notes on its website that more than
10 million vaccinations are given yearly to children
younger than 1 year old). As with all other products,
the full safety picture is not known at the time of vac-
cine approval. Most of the VAERS reports are mild and
include fever and injection site reactions, but some
15% are more severe AEs.
The VAERS website has sections for consumer and
healthcare professional reporting of AEs online, by fax,
or by mail.
The VAERS database, unlike the drug database,
FAERS, has a system called CDC WONDER for obtain-
ing data and producing tables, maps, charts, and var-
ious extracts regarding the incidence of vaccine AEs.
For example, one can produce a report grouped by
symptoms or medical problems (e.g., gastroenteritis)
and various other criteria, such as age, gender, manu-
facturer, US location, date vaccinated, onset interval,
seriousness, and outcome. The data are immediately
available and are largely up to date. Data downloads are
also available. This is a very useful tool. However, many
discrepancies have been introduced by the application
of SMQs to add an extrapolated diagnosis to the data-
base when a diagnosis was not provided by the reporter.
SMQs were not designed or tested for this and, e.g.,
sometimes age-inappropriate diagnoses are added. Use
caution.
Center for Devices
and Radiologic Health
Device regulation became much more formalized start-
ing in 1976 with amendments to the Food, Drug and
Cosmetics Act, in 1982 when the CDRH was formed and
in 1990 when the Safe Medical Devices Act was passed.
This is the center that deals with medical devices and
36 Cobert’s Manual of Drug Safety and Pharmacovigilance
radiologic agents. There are three sections in the CDRH
website that are worth examining.
The first is the Medical Device Safety section, which
covers alerts and notices, recalls, and emergencies.
There is a large section on Medical Device Reporting
(MDR) of adverse events from manufacturers, import-
ers, and user facilities (e.g., hospitals, nursing homes).
Consumer and healthcare professionals report via
MedWatch (as with biologics and drugs) using either
the 3500- or 3500B-voluntary reporting form. With
the introduction of electronic reporting, eMDR was
launched and mandatory reports must be sent to eMDR
according to CDRH technical specifications.
The second is the Device Advice: Regulations &
Guidance section. This is a very useful section that
explains the regulations on marketing, standards, guid-
ance, compliance, and post-market requirements. Note
that the entire process of approval, marketing, and
safety for devices is markedly different from the pro-
cesses for drugs and biologics.
The third is the section on medical device data-
bases. There are several, but the key one for safety is
MAUDE (Manufacturer and User Facility Device Expe-
rience). This database contains AE reports involving
medical devices. It contains data submitted by manda-
tory reporters (manufacturers, importers, and device
user facilities) and voluntary reporters (healthcare
professional, patients, and consumers). Data goes back
to 1991 for device user facilities, to 1993 for distrib-
utor reports, and to 1996 for manufacturer reports. It
is online and searchable by product problem, product,
class, manufacturer, event type (death, injury, mal-
function, other), brand name, registration number,
and time frame. The focus is on medical devices which
may have malfunctioned or caused a death or serious
injury.
Some of the MAUDE data are downloadable. These
files consist of voluntary reports since mid-1993, user
facility reports since 1991, distributor reports since
1993, and manufacturer reports since mid-1996. The
searchable portion of the data contains records for the
most recent 10 years and is refreshed weekly. Note that
MAUDE may not include reports made under waiv-
ers, exemptions, variances, or alternative reporting
requirements. There also is a separate database for pre-
1996 reports from manufacturers. A detailed review of
medical device safety or drug-device combination prod-
ucts is not in the scope of this manual.
Over-the-Counter Products
OTC products are regulated by CDER’s Office of
Non-prescription Drugs and are drug products that can
be sold in the United States without a prescription and,
thus, without any medical professional intervention.
That is, they are sold without a clear medical diagno-
sis being made by a medical professional and, thus, are
purchased largely for symptoms as self-diagnosed by the
lay public. Some products are not truly over the counter
and are held by the pharmacist “behind the counter”
such that the consumer must speak with the pharma-
cist, who will/should assess the need and appropriate-
ness of the patient and product. OTC products have
benefits that outweigh their risks, have low potential
for misuse and abuse, can be adequately labeled, and
do not require a health practitioner for their safe and
effective use.
Drugs can enter the OTC market in several ways.
A drug may be approved via the usual NDA process
and then may be moved to OTC status through vari-
ous routes. One is the “Rx to OTC switch”. Other drugs
that are “generally recognized as safe and effective
(GRAS/E)” are listed in the FDA’ s “OTC monograph(s)”
that specify which drugs may be marketed without fur-
ther studies, FDA review, or approval. There are also
so-called negative monographs that limit specific indi-
cations for certain drug ingredients. The monographs
are very detailed specifications in the Code of Federal
Regulations that specify ingredients, doses, formula-
tions, indications, and labeling.
The FDA can act quickly to restrict marketing or
remove a product from sale if there is significant risk or
lack of evidence for effectiveness, or if the FDA finds that
the usual notice and public procedure method are imprac-
ticable, unnecessary, or contrary to the public interest.
The FDA can, thus, issue a rule requiring immediate
label changes and marketing restrictions. In non-urgent
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The United States Food and Drug Administration 37
situations, the FDA can use the notice and comment
rulemaking mechanism to change marketing status.
Regarding safety reporting, OTC reporting by indus-
try was not required until December 2007 for OTCs
that did not have NDAs. That is, there was no require-
ment for AEs to be collected, analyzed, or submitted by
manufacturers. This changed in 2007 when FDA issued
a guidance that required reporting of serious AEs for
OTC products found to be “associated with the drug”.
These were to be reported via MedWatch by manufac-
turers, packers, and distributors, using the 3500A-form.
This essentially required that all serious AEs (whether
in the label or not) must be reported to FDA within
15 calendar days. Requirements for minimal validity
criteria are essentially the same as for drugs. Manufac-
turers are now required to submit reports electronically,
but others are not yet required to use electronic means
to make OTC case reports.
Drug Safety Oversight Board
The FDA created an internal Drug Safety Oversight
Board (DSB) in 2005. The DSB was subsequently
mandated by the FDA Amendments Act of 2007 and
advises CDER Center Director on handling and com-
municating important and emerging drug safety issues,
especially regarding how such issues impact federal
healthcare delivery and payment systems. The DSB is
composed of representatives from two FDA Centers and
eight other federal government agencies, the Agency
for Healthcare Research and Quality (AHRQ), Centers
for Disease Control and Prevention (CDC), Centers for
Medicare and Medicaid Services (CMS), Department of
Defense (DOD), Health Resources and Services Admin-
istration (HRSA), Indian Health Service (IHS), National
Institutes of Health (NIH), and Department of Veterans
Affairs (VA). An important role of the DSB is to help FDA
assess the impact of their safety decisions on the health-
care systems of its Federal Partners. The Board, with its
broad representation from federal healthcare organiza-
tions, can provide valuable input and allows FDA to hear
varied perspectives on drug safety issues.
Monthly meeting minutes and outcome reports are
available online.
Prescription Drug User
Fee Act
In 1992, the Prescription Drug User Fee Act (PUFA)
was passed and then renewed 5 years later in 1997
(PDUFA II), and again in 2002 (PDUFA III), 2007
(PDUFA IV), 2012 (PDUFA V), and 2017 (PDUFA VI).
This Act allows the FDA to collect a fee from an appli-
cant whenever the applicant submits an NDA or BLA.
In addition, companies pay annual fees for each manu-
facturing establishment and for each prescription drug
product approved for marketing. Previously, taxpayers
alone paid for product reviews for regulatory action by
the FDA, through congressional appropriations.
In the program authorized under PDUFA, industry
provides the funding in exchange for FDA agreement
to meet drug-review performance goals, which empha-
size timeliness without a loss of scientific quality of the
review. As examples, the PDUFA fee rate for FY 2018
was $2,421,495 for an application requiring review of
clinical data and was $1,210,748 for an application not
requiring review of clinical data. The fees are adjusted
on an annual basis. The typical allowed review time for
an NDA under PDUFA is 10-months (or 6-months for
priority reviews). Questions have been raised about the
appropriateness of what is, in effect, industry funding of
the government process for approving a medical prod-
uct for entry into the commercial marketplace. In real-
ity, user fees are for application review, not approval.
Approval is not guaranteed.
Prescription Drug User Fee
Act: Five-Year Plan
The FDA created multiple action plans to address the
requirements of the law. In particular, FDA issued a
“Prescription Drug User Fee Act Five-Year Plan” with
each sequential renewal of PDUFA. Each plan includes
steps to address the requirements in the legislation.
Details and milestones are posted on the FDA website.
Other FDA initiatives under way are briefly men-
tioned below. The landscape changes frequently and
38 Cobert’s Manual of Drug Safety and Pharmacovigilance
FDA’ s website should be checked periodically for
updates and new initiatives.
Food and Drug
Administration Act (FDAAA)
of 2007
In 2007, PDUFA was actually a part of major new leg-
islation known as the Food and Drug Administration
Amendments Act (FDAAA) of 2007.
The FDAAA has multiple parts. The ones that deal
with post-marketing safety are known as Title IX and
give enhanced authority to the FDA regarding safety. In
particular, it created the concept of Risk Evaluation and
Mitigation Strategies (REMS), which are briefly outlined
in this chapter and described in more detail elsewhere.
Another section strengthened the FDA’ s authority
to unilaterally modify product labeling. Before 2007,
the FDA did not clearly have the power to force labeling
changes and most changes were done on a “voluntary”
basis, though the FDA, in practice, could force most
changes they desired. FDAAA formally empowered
FDA to “notify” the applicant of new safety informa-
tion that the agency “believes should be included in the
labeling”. The applicant then has 30 days to submit an
amendment proposing new labeling that reflects FDA’s
communication or to notify the FDA that it disagrees
and why. FDA may then have discussions with the
applicant that usually last no more than 30 days, after
which time the FDA may force the applicant to make
labeling changes that the agency “deems appropriate”.
The FDA has used this new authority on several occa-
sions, including the addition of a black box regarding an
increased risk of death in elderly patients treated with
antipsychotics for dementia, the addition of a black box
regarding an increased risk of tendon injury with fluo-
roquinolone antibiotics, and the addition of a black box
regarding the risk of histoplasmosis and other fungal
infections with TNF alpha-blockers.
Other sections deal with the following:
1. Pre-approval review of proprietary names;
2. Modernization of information technology;
3. Medical devices, including enhancements in
the device review program, inspections by third
parties, new requirements for certain single-use
devices, and user fees;
4. More studies in the pediatric population;
5. Development of products for tropical diseases,
rare diseases, and other “neglected” diseases;
6. The Reagan–Udall Foundation, made up of senior
advisers from outside the federal government, to
advise FDA on innovation and enhanced food
and drug safety. (the foundation was not initially
funded by Congress, but sustainability models
are evolving):
More transparency regarding possible con-
flicts of interest is required for potential Advi-
sory Committee participation; and
The clinical trials database was expanded.
21st Century Cures Act
The 21st Century Cures Act was passed by Congress
and then signed into law on December 13, 2016. The
stated intent of this legislation was to accelerate innova-
tive medical product development and get advances to
patients who need these products more efficiently.
The law encourages FDA to consider the perspec-
tives of patients in FDA’ s decision-making process
in medical product development. This encompasses
innovation in drugs, therapeutic biologics, vaccines,
and medical devices. The legislation encourages new
approaches to scientifically-sound clinical trial designs
and clinical outcome assessments.
The law also provides new authority to facilitate
recruitment and retention of a broad base of highly
qualified personnel to execute these innovative pro-
grams. The legislation contemplates new approaches to
expedite innovation, including the following:
Regenerative Medicine Advanced Therapy
(RMAT): This describes an expedited option for
certain eligible biologics products;
The Breakthrough Devices Program: This is
intended to speed the review of certain innovative
medical devices.
https://avxhm.se/blogs/hill0
The United States Food and Drug Administration 39
In addition, this legislation directs FDA to create
cross-center initiatives to coordinate activities in stra-
tegic areas, e.g., diseases with a major public health
impact. These activities cascade to the regulation
of combination products. It also establishes an FDA
Oncology Center of Excellence (OCE), which sup-
ports patient-centered decision-making and an inte-
grated approach to the evaluation of drugs, biologics,
and devices medical products for the treatment of can-
cer. The OCE works with centers and offices across
the FDA.
This Act authorized an additional US$ 500 mil-
lion for FDA over 9 years to implement the legal
requirements.
FDA Reauthorization Act
of 2017
FDA Reauthorization Act (FDARA) was signed into law
on August 18, 2017 and it extended the user fee pro-
grams for drugs, medical devices, generic drugs, and
biosimilar biological products through FY 2022 (and
added other obligations). It reauthorized PDUFA for
the fifth time. In addition, the Medical Device User Fee
Amendments (MDUFA) was reauthorized for the third
time, and included both the Generic Drug User Fee
Amendments (GDUFA) and the Biosimilar User Fee Act
(BsUFA) for the first time.
Selected provisions of FDARA include the following:
An enhanced ability to capture patient preferences
in drug development;
Flexibility to inspect medical device facilities based
on risk, while encouraging predictability and trans-
parency in the inspection process;
A focus on treatment of rare diseases (especially in
pediatrics);
Additional resources for review of breakthrough
therapies;
“Real world evidence” to inform decision-making
(including use of the Sentinel System);
Enhanced partnerships with patients;
More flexibility in the regulatory pathway for cer-
tain medical device accessories;
New opportunities for scientific advice on surrogate
endpoints;
Cross-center coordination of combination product
review;
Enhanced hiring and retention of well-qualified
staff.
Bottom line: The reauthorization of PDUFA,
MDUFA, GDUFA, and BsUFA support FDA’s organi-
zational ability to focus on improved health outcomes
while promoting biomedical innovation.
The Sentinel System
and ARIA
Launched by FDA in 2008 as a result of 2007 legisla-
tion, the Sentinel System is a US National medical prod-
uct safety monitoring system that taps into electronic
medical records across the country. It is an active elec-
tronic safety surveillance system that strengthens FDA’s
ability to monitor the safety of marketed medical prod-
ucts. The program began as a pilot, which reached a
milestone of 100 million covered lives by 2011. As of
June 2018, the Agency had 17 distributed data partners
with 178 million covered members, each of whom had
pharmacy and medical coverage. It is a large system
with longitudinal medical records and an analytic cen-
ter in Boston which handles coordination among the
data partners. Data partners retain control of the med-
ical records to protect privacy and maintain security;
FDA prepares analytic queries to explore questions,
but they do not have a centralized data repository for
this system. Queries can be developed by FDA and ano-
nymized results from more than 178 million covered
lives can be obtained from these distributed datasets in
a matter of days.
All of FDA’s centers have access to the Sentinel Sys-
tem through OSE.
To strengthen FDA’s ability to better utilize the
Sentinel System, the 2007 legislation required FDA to
establish an analysis tool, ARIA (Active Risk Identifi-
cation and Analysis). ARIA contains validated modular
programs that have re-usable analytical tools for rapid
safety analyses of healthcare data. There are three levels