Bright Ponte2017

C H A P T E R
8
Postmarket Surveillance and Regulatory
Considerations in Reproductive and
Developmental Toxicology: A Food and Drug
Administration Perspective
Susan Bright-Ponte
O U T L I N E
Introduction 145 Vaccines Intended for Use in Humans 154

Brief History of the Food and Drug Administration 145
Drugs Intended for Use in Animals 158
Overview of the FDA’s Postmarket Surveillance and
Pharmacovigilance 147 Disclaimer 161
Drugs Intended for Use in Humans 149 References 161
INTRODUCTION
Agriculture (USDA) Division of Chemistry, began con-
Brief History of the Food and Drug ducting research into the misbranding and adulteration
of food and drug products in US commerce. Wiley pub-
Administration
lished the Division’s findings and lobbied for new fed-
The US Food and Drug Administration (US FDA) is a eral laws to set uniform standards for food and drugs
regulatory, science-based federal agency responsible for entering into interstate commerce (FDA, 2015a). This
protecting and promoting the public health through the came at a time when the American public had already
monitoring and regulation of a number of items neces- been awakened to hazards in the marketplace by jour-
sary for the health and well-being of consumers. The nalists such as Upton Sinclair, who in 1906 published
FDA’s jurisdiction includes most food products (other the novel The Jungle, which exposed appalling condi-
than meat, poultry, and some egg products); pet food tions in the US meat packing industry. The resulting
and animal feed; human and animal drugs; medical de- public uproar contributed in part to the passage a few
vices; veterinary devices; therapeutic agents of biologic months later of the 1906 Food and Drugs Act and the
origin (e.g., vaccines, blood, and blood products) for Meat Inspection Act. The Food and Drugs Act pro-
humans; radiation-emitting products for consumer, hibited the interstate transport of adulterated or mis-
medical, and occupational use; cosmetics; and tobacco branded food, drink, and drugs, and was administered
products. The history of the FDA can be traced back to by the USDA’s Bureau of Chemistry (FDA, 2009a). The
the latter part of the 19th century, when Harvey Wash- Bureau of Chemistry’s regulatory powers were reorgan-
ington Wiley, chief chemist of the US Department of ized under a new USDA body, the Food, Drug, and
Reproductive and Developmental Toxicology

http://dx.doi.org/10.1016/B978-0-12-804239-7.00008-1 145 2017 Published by Elsevier Inc.
146 8. POSTMARKET SURVEILLANCE AND REGULATORY CONSIDERATIONS
Insecticide organization, which later was shortened to to include the product name, expiration date, address,
the Food and Drug Administration. The Food and Drugs and license number of the manufacturer. Today, bio-
Act of 1906 was later replaced by broader legislation, in logics are regulated under the Public Health Service
light of the “Elixir Sulfanilamide” tragedy, in which over Act (PHS Act), which provides for their licensing, as
100 people died after using a drug formulated with a well as under provisions of the FFDCA (FDA, 2012b).
toxic solvent (diethylene glycol). The new Federal Medical devices were subject to some degree of moni-
Food, Drug and Cosmetic Act (FFDCA) was signed toring by the FDA between 1938 and the early 1970s. The
into law by President Franklin D. Roosevelt in 1938. Agency could bring charges against products that were
This law significantly increased regulatory authority found to be adulterated or misbranded, but no require-
over drugs by mandating a premarket review of the ment for premarket testing, review, or approval existed
safety of all new drugs, as well as banning false thera- during that time. In 1972 and 1973 pacemaker failures
peutic claims in drug labeling. The law also authorized began to be reported, and in 1975 certain intrauterine
inspections of factories and expanded enforcement shield devices caused thousands of reported injuries.
powers, in addition to setting new regulatory standards These incidents helped reinforce the need for medical
for foods, and brought cosmetics and therapeutic de- device regulation, and the Medical Device Amendments
vices under federal regulatory authority. In 1940, the were passed in 1976. Medical devices were now subject
FDA was transferred from the USDA to the Department to classification requirements, and Class III device man-
that would ultimately become today’s Department of ufacturers were required to notify the FDA prior to mar-
Health and Human Services (FDA, 2012a). keting. In addition, good manufacturing practice
In 1959, concerns were brought to the forefront by regulations were authorized (FDA, 2010a).
Senator Estes Kefauver about pharmaceutical industry Under the FFDCA of 1938, manufacturers of human
practices, such as high cost and uncertain efficacy of or animal drugs only had to demonstrate that their prod-
many drugs. A tragedy involving thalidomide pushed ucts were safe. The 1962 amendments to this Act
Congress to lend support to expansion of FDA authority. required their products also be shown effective; howev-
The use of thalidomide, marketed in Europe for the er, the 1962 amendments generally did not distinguish
treatment of nausea during pregnancy, led to thousands between human and animal drugs. In 1968, Congress
of European babies being born deformed. The drug had passed legislation to strengthen provisions of the Act
not been approved in the United States, but trial samples that pertained to regulation of animal drugs. The Ani-
had been sent to American doctors during clinical inves- mal Drugs Amendments of 1968 required that animal
tigations of the drug, a process that at the time was drugs, medicated feeds, and food additives be safe for
entirely without regulation. The thalidomide tragedy the animal for which they were intended for use; and
prompted the passage of the 1962 Kefauver-Harris for food-producing animals, safe for human consump-
Amendment to the FFDCA. Now the law required that tion and safe for the environment. Effectiveness studies
all new drug applications demonstrate substantial evi- were also required (FDA, 2010b). A number of other
dence of the drug’s efficacy for a specific indication, in amendments have been made to the FFDCA related to
addition to the existing requirement for premarket various areas of FDA regulatory responsibility. Informa-
demonstration of safety. Drugs approved between 1938 tion about significant amendments is available on the
and 1962 were also subject to FDA review of efficacy. FDA’s Website (FDA, 2015b).
The 1962 amendments also placed some restrictions on The FDA’s current organization consists of the Office of
drug advertising and expanded the FDA’s authority to the Commissioner and four major directorates overseeing
inspect drug manufacturing facilities (FDA, 2009b). the core functions of the agency: Medical Products and To-
Prior to the 1906 passage of the Food and Drugs Act, bacco, Foods and Veterinary Medicine, Global Regulatory
Congress enacted the Biologics Control Act of 1902, Operations and Policy, and Operations. In addition, the
which gave the government control over production FDA is organized geographically into Regional Offices
processes used for biological products, such as vaccines, and component Districts, where field staff are assigned.
serum, and antitoxins. This Act was also brought about The Office of the Commissioner provides centralized
by a tragedy, involving the death of 13 children who had agency-wide program direction and management ser-
been given diphtheria antitoxin derived from a horse vices to support effective administration and FDA’s con-
infected with tetanus. The horse serum was manufac- sumer protection efforts within its regulatory framework
tured locally, with no central or uniform production con- and to put available resources to the most efficient use.
trols. The Biologics Control Act required that The Office of Medical Products and Tobacco provides
manufacturers of vaccines be licensed annually for the high-level coordination and leadership across the centers
manufacture and sale of vaccines, serum, and antitoxins. for human drugs, biologics, and medical devices, and to-
Manufacturing facilities were also required to undergo bacco products. The office also oversees the agency’s spe-
inspections. In addition, all product labels were required cial medical programs. The Office consists of the Center
II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

INTRODUCTION 147
for Drug Evaluation and Research (CDER), the Center for early biomarkers of toxicity using quantitative risk
Devices and Radiological Health, the Center for Biologics assessment methods. The NCTR also represents the
Evaluation and Research (CBER), and the Center for To- FDA on key committees of the National Toxicology Pro-
bacco Products. The Office of Foods and Veterinary Med- gram, a program that evaluates the effects of chemicals
icine has a wide range of responsibilities related to on health (FDA, 2016a). Of particular application to
protecting the safety and security of foods for humans reproductive and developmental toxicity assessments,
and animals, regulating the safety and effectiveness of an- the NCTR maintains an endocrine disruptor knowledge
imal drugs, and ensuring that food labels contain useful database (EDKB) program, a major element of which has
and reliable information. The Center for Food Safety and been the development of computer-based predictive
Applied Nutrition, the Center for Veterinary Medicine models to predict affinity for binding of compounds to
(CVM), and the Office of Regulatory Affairs (ORA) work estrogen and androgen nuclear receptor proteins
together to carry out FDA’s food safety, nutrition, and an- (FDA, 2015d). NCTR has also developed an Estrogenic
imal health activities. The Office of Global Regulatory Op- Activity Database, which assembles a comprehensive
erations and Policy (also known as GO) comprises the set of estrogenic activity data from a variety of data sour-
ORA and the Office of International Programs. The GO Of- ces and is a component of the enhanced EDKB program
fice provides executive oversight, strategic leadership, (FDA, 2015e).
and policy direction to FDA’s domestic and international
product quality and safety efforts, including global collab-
oration, global data sharing, development and harmoni-
Overview of the FDA’s Postmarket Surveillance
zation of standards, field operations, compliance, and
enforcement activities. The Office of Operations is respon-
and Pharmacovigilance
sible for various Agency functions, including finance and The safety of the medical products regulated by the
budget, facilities engineering, information management FDA has been a key focus of the Agency since it was
and technology, human resources, crisis management, established more than a century ago as the nation’s first
and emergency operations (FDA, 2015c). consumer protection agency. Drugs and biologics are
The National Center for Toxicological Research approved after the FDA determines in the premarket
(NCTR), established by executive order in 1971, is an phase that a product’s benefits outweigh the risks asso-
important research component of the FDA that plays a ciated with its labeled use for the intended population.
critical role in the FDA’s mission to promote and protect Although the FDA has a rigorous preapproval process
public health. The NCTR, in partnership with re- for medical products, well-conducted, randomized,
searchers from elsewhere in the FDA, other government controlled clinical trials cannot uncover every safety
agencies, academia, and industry, provides innovative problem, nor are they expected to do so. In most cases,
technology, methods development, vital scientific clinical trials are not large enough, diverse enough, or
training, and technical expertise. The unique scientific long enough in duration to provide all of the informa-
expertise of the NCTR is critical in supporting FDA tion on a product’s performance and safety. In addition,
product centers and their regulatory roles. The NCTR clinical trials are unlikely to reliably detect rare, serious
conducts FDA mission-critical, peer-reviewed, critical adverse events that occur with long latency or in sub-
path research targeted to developing a scientifically populations that have not participated in studies.
sound basis for regulatory decisions and reducing risks Furthermore, as new medical products enter the market,
associated with FDA-regulated products. Research is the potential for interactions with other drugs, biologics,
aimed at evaluating the biological effects of potentially medical devices, and foods increases. Important addi-
toxic chemicals or microorganisms, defining the com- tional information about medical product safety can be
plex mechanisms that govern their toxicity, understand- obtained during postapproval use.
ing critical biological events in the expression of toxicity, The use of medical products brings both benefits and
and developing methods to improve assessment of hu- risks. Although marketed medical products are required
man exposure, susceptibility, and risk. Customized by federal law to be safe for their intended use, safety
assessment of chemicals of vital interest to the FDA in- does not mean zero risk. A safe product is one that has
volves the coordination of expertise in the areas of acceptable risks, given the magnitude of the benefit ex-
biochemical and molecular markers of safety and pected in a specific population and within the context
toxicity, neurotoxicology, microbiology, chemistry, ge- of alternatives available. The FDA carefully considers
netic or reproductive/developmental toxicology, and all of the available safety information submitted to the
systems-biology assessments for characterizing bio- agency during the preapproval process. However, unex-
markers. The NCTR has developed and is standardizing pected and sometimes serious safety problems can
technologies, such as genomics, proteomics, metabolo- emerge once a product goes on the market and is used
mics, and nanotechnology, to identify and characterize by millions of people.

A cornerstone of the FDA’s safety surveillance and automated computer algorithms to analyze data in
monitoring efforts are regulations that require firms large, complex databases are now being employed at
who market medical products to report to the FDA FDA to more efficiently identify safety signals. These
adverse events associated with the product’s use that signals can then be evaluated with case review and
are reported to the firm. Usually firms learn of these potentially with further epidemiologic investigations,
adverse events from health professionals or patients for intervention as appropriate.
who experience serious problems that they suspect are In the postmarketing phase of a product’s life cycle,
associated with the drugs, biologics, and medical de- once a safety issue has been identified, and evaluation
vices they prescribe, dispense, or use. Healthcare profes- has resulted in a judgment that the product may in
sionals and patients may also inform the FDA directly fact pose a significant threat to public health, a thorough
about these events. Case reports published in the medi- riskebenefit assessment should be conducted. Riske
cal literature and results of postapproval and other clin- benefit assessments consider the disease or condition be-
ical studies are also important to the FDA’s safety ing treated, the population being treated, the purpose of
surveillance and monitoring efforts. In recent years, the intervention (treatment, prevention, etc.), availabil-
rapid scientific advances as well as advances in informa- ity of therapeutic alternatives, the frequency of the
tion technology have created new opportunities for adverse event and the overall adverse event profile of
monitoring the performance of medical products, the product. After a riskebenefit assessment is conduct-
including active surveillance methods. ed, some action may be necessary to increase the benefit
The monitoring of the safety of marketed drug prod- of the product or reduce the risk. These actions may
ucts is known as pharmacovigilance, defined by the include healthcare practitioner and consumer education,
World Health Organization (WHO) as “the science and or on occasion, restricting the use of a product. If the
activities relating to the detection, assessment, under- overall balance of risks and benefits is determined to
standing, and prevention of adverse effects or any other be negative, then the product may be withdrawn, unless
drug-related problems” (WHO, 2016). Pharmaceutical risk minimization strategies can reasonably be put into
companies have obligations to collect all data relevant effect that would change the overall riskebenefit
to the safety of their products and submit such data to balance.
regulatory agencies in line with guidance and legisla- In addition to passive and active postmarket surveil-
tion. Regulators monitor these data for signals but also lance activities, postmarketing study commitments may
collect and screen safety data on medical products for be required of or agreed to by a sponsor, which are con-
signal detection independently of pharmaceutical com- ducted after the FDA has approved a product for mar-
panies. A signal is defined by the WHO as reported in- keting. The FDA uses postmarketing study
formation on a possible causal relationship between an commitments to gather additional information about a
adverse event and a drug, the relationship being un- product’s safety, efficacy, or optimal use. Agreements
known or incompletely documented previously with sponsors to conduct postmarketing studies can be
(WHO, 2013). Historically, most safety signals come reached either before or after FDA has granted approval
from spontaneously reported adverse drug experiences to a sponsor to market a product. The Food and Drug
(ADEs), but major safety issues may be detected from Administration Modernization Act of 1997 (FDAMA)
any relevant data sources, including postapproval clin- amended the Food, Drug and Cosmetic Act by adding
ical studies and case reports in published scientific liter- a new section 506B (21 USC 356b). This section provides
ature. Limitations of utilizing spontaneous ADE additional authority for monitoring the progress of post-
reporting databases for pharmacovigilance activities marketing studies that drug and biologic applicants
include the significant underreporting of ADEs, limited have agreed to conduct to address potential safety con-
detail in submitted reports, and reporting bias. The fre- cerns. Congress enacted this section in response to con-
quency of reporting for a given medical product varies cerns expressed by the Food and Drug Administration
over time, with time from first marketing, and with pe- and the public about the timeliness of completing post-
riods of media activity surrounding a product. Given the marketing studies and about the need to update drug la-
variability in reporting and the many factors that affect beling with information obtained from such studies.
it, reporting rates cannot be used to reliably estimate This provision requires sponsors of approved human
incidence rates of adverse events and comparison of drugs and biologics to report to the FDA annually on
reporting rates between products or between countries the progress of their postmarketing study commitments.
cannot be used to determine risk. In the past, sponta- In addition, the FDA publishes annually in the Federal
neous adverse event reports were examined by FDA Register a report that provides information on the status
staff performing systematic manual review of every of postmarketing studies that sponsors have agreed to
report received. With the increase in ADE reporting conduct and for which annual reports have been submit-
over time, data mining strategies involving the use of ted. The FDA also provides basic information about the

DRUGS INTENDED FOR USE IN HUMANS 149
status of each postmarketing study commitment to the information related to marketed drugs throughout
public on the FDA Website (FDA, 2016b). each product’s life cycle. When a drug is approved,
This chapter describes postmarket surveillance and the product labeling includes, among other things, avail-
pharmacovigilance activities that the FDA conducts to able information about the benefits and risks of the drug.
monitor the safety of drugs and vaccines intended for After drug approval, the FDA may learn of new, or
use in humans and drugs intended for use in animals, more frequent, serious ADEs from postapproval clinical
and provides a brief overview of some of the methods studies or from clinical use. For example, additional
the FDA uses to communicate important safety informa- ADEs may be identified as a drug is more widely used
tion to health professionals and the public about mar- and under more diverse conditions. 21 CFR 314.80 de-
keted FDA-regulated medical products. Information fines an “adverse drug experience” as “any adverse
about the FDA’s postmarket surveillance activities event associated with the use of a drug in humans,
regarding food safety and medical devices are beyond whether or not considered drug related, including the
the scope of this chapter, but may be found on the following: an adverse event occurring in the course of
FDA’s Website (www.fda.gov). Throughout this chapter, the use of a drug product in professional practice; an
reference may be made to the Code of Federal Regula- adverse event occurring from drug overdose whether
tions (CFR) and certain guidance documents. The CFR accidental or intentional; an adverse event occurring
is a codification of the general and permanent rules pub- from drug abuse; an adverse event occurring from
lished in the Federal Register by the Executive depart- drug withdrawal; and any failure of expected pharma-
ments and agencies of the federal government. Title 21 cological action”. Furthermore, this regulation defines
of the CFR is reserved for rules of the FDA. Each title a “serious adverse drug experience” as “any adverse
(or volume) of the CFR is revised once each calendar drug experience occurring at any dose that results in
year. A revised Title 21 is issued on approximately any of the following outcomes: death, a life-
Apr. 1 of each year and is usually available on the threatening adverse drug experience, inpatient hospital-
FDA’s Website several months later. Guidance docu- ization or prolongation of existing hospitalization, a
ments represent the FDA’s current thinking on a partic- persistent or significant disability/incapacity, or a
ular subject. These documents are prepared for FDA congenital anomaly/birth defect. Important medical
review staff and regulated industry to provide guide- events that may not result in death, be life-threatening,
lines for the processing, content, and evaluation or or require hospitalization may be considered a serious
approval of applications and also for the design, produc- adverse drug experience when, based upon appropriate
tion, manufacturing, and testing of regulated products. medical judgment, they may jeopardize the patient or
They also establish policies intended to achieve consis- subject and may require medical or surgical intervention
tency in the FDA’s regulatory approach and establish in- to prevent one of the outcomes listed in this defi-
spection and enforcement procedures. Because nition..” An “unexpected adverse drug experience”
guidance documents are not regulations or laws, they is “any adverse drug experience that is not listed in
are not enforceable, either through administrative ac- the current labeling for the drug product. This includes
tions or through the courts. An alternative approach events that may be symptomatically and pathophysio-
may be used if such approach satisfies the requirements logically related to an event listed in the labeling, but
of the applicable statute, regulations, or both. differ from the event because of greater severity or spe-
cificity. ‘unexpected,’ as used in this definition, refers
to an adverse drug experience that has not been previ-
DRUGS INTENDED FOR USE IN HUMANS ously observed (i.e., included in the labeling) rather
than from the perspective of such experience not being
Drugs intended for human use are approved and anticipated from the pharmacological properties of the
monitored by the FDA’s CDER. Among CDER’s many pharmaceutical product”.
regulatory activities are programs related to oversight The FDA depends upon the recognition and volun-
of new drug development and review of drug marketing tary reporting of adverse events by healthcare providers
applications, oversight of postmarket drug safety, and and patients, and on the mandatory reporting of adverse
oversight of drug manufacturing and quality. events by firms holding approved drug applications,
One of CDER’s primary objectives is to ensure that drugs manufacturers, and drug distributors as required
marketed prescription and over-the-counter (OTC) by law and regulation. Unsolicited reports from
medications are safe and effective when used as healthcare professionals or consumers received by the
directed. All drugs have risks, and healthcare profes- FDA are called spontaneous reports. Spontaneous re-
sionals and patients must balance the risks and benefits ports of adverse drug reactions, medication errors, and
of a drug when making decisions about medical therapy. product quality problems are sent directly to the FDA
The FDA monitors and reviews available safety by healthcare professionals and consumers through

the MedWatch program or through the application reports and alerts safety reviewers to serious and unla-
holders to the FDA. Application holders are required to beled events, and serious medical events generally
report adverse experiences that they learn about to the known to be drug related (e.g., toxic epidermal necroly-
FDA under 21 CFR 314.80, within certain time frames. sis). Data mining of the FAERS database using auto-
Adverse experiences that are both serious and unex- mated signal detection methods, such as
pected, whether foreign or domestic, must be reported disproportionality analysis, aids reviewers in detecting
as soon as possible but not later than 15 calendar days signals more quickly than would be possible with
of initial receipt of the information. Application holders manual review of reports. When potential signals are
must promptly investigate all adverse experiences that identified, further evaluation is performed. Further eval-
are the subject of these postmarketing 15-day reports uation might include conducting studies using other
and submit follow-up reports within 15 calendar days large databases, such as those available in the FDA’s
of receipt of new information, or as requested by the Sentinel System, evaluating published medical litera-
FDA. Fifteen-day alert reports based on information ture, and further review of adverse event reports
from the scientific literature are required to be accompa- contributing to the signal, to look for common trends
nied by a copy of the published article. Firms that are and potential risk factors. FAERS data do have limita-
identified on the drug label as its manufacturer or distrib- tions. First, there is no certainty that the reported event
utor are also required to report serious and unexpected was actually due to the product. The FDA does not
adverse events that they learn about, either by notifying require that a causal relationship between a product
the FDA or the drug’s application holder. Adverse events and event be proved, and reports do not always contain
that are not serious and unexpected are reported in peri- enough detail to properly evaluate an event. Further-
odic ADE reports, which are submitted by the application more, the FDA does not receive all adverse event reports
holder at quarterly intervals for the first 3 years after that occur with a product. Many factors can influence
approval, then annually. Adverse experiences are also re- whether or not an event will be reported, such as the
ported from postmarketing studies. time a product has been marketed and publicity about
In 1993, the FDA launched its MedWatch Adverse an event. Therefore the FAERS database cannot be
Event Reporting Program, to facilitate and support the used to calculate the incidence of an adverse event in
voluntary adverse event reporting process by healthcare the US population (FDA, 2016d).
professionals and consumers. MedWatch also helps pro- The Sentinel Initiative is a national strategy for moni-
vide timely information about safety alerts, recalls, mar- toring drug and medical product safety, with a primary
ket withdrawals, and drug labeling changes. Voluntary goal of increasing active surveillance for safety problems
reporting by health professionals is conducted on a sin- instead of relying only on passive surveillance through
gle, one-page reporting form (Form FDA 3500) and by spontaneous adverse event reporting. Government and
consumers on Form FDA 3500B. Voluntary reports commercial databases (e.g., managed care organiza-
may also be submitted online on the MedWatch Website. tions, prescription benefit management companies) are
Another form (FDA 3500A) is provided for use by used in the Sentinel Initiative to conduct population sur-
mandatory reporters (FDA, 2016c). veillance and identify safety issues in groups of patients
The FDA began to computerize the storage of adverse rather than relying on isolated individual case reports.
event reports in 1967, and the data were entered into the In this way, a systematic approach using data from
Spontaneous Reporting System (SRS). The SRS was several sources can be used to monitor the effects of
replaced in 1997 by a computerized database (AERSd drugs in populations, identify safety problems and the
Adverse Event Reporting System, now known as need for drug use modifications or restrictions while
FAERSdFDA Adverse Event Reporting System) to sup- facilitating an evidence-based approach to adverse
port its postmarketing safety surveillance programs for drug event monitoring (FDA, 2016e).
all approved human drug and therapeutic biologic Once investigation and confirmation of a safety signal
products. Adverse events in FAERS are coded to terms occurs, the FDA may initiate various regulatory actions,
in the Medical Dictionary for Regulatory Activities depending upon the seriousness of the adverse event,
(MedDRA, 2016). FAERS is a useful tool for FDA for ac- and taking into consideration the availability and
tivities such as looking for new safety concerns that acceptability of alternative therapies. Regulatory inter-
might be related to a marketed product, evaluating a ventions may include changes in labeling approved for
manufacturer’s compliance to reporting regulations practitioners, patient/consumer-directed information
and responding to outside requests for information. (e.g., Medication Guides), issuance of “Dear Doctor” let-
The reports in FAERS are evaluated by clinical reviewers ters, drug name or packaging changes, restricted use or
in the CDER and the CBER to monitor the safety of prod- distribution of a drug (see discussion of RiskMAPs and
ucts after they are approved by the FDA. In a primary REMS below), or even withdrawal of a medical product
triage process, the FAERS program screens incoming from the market. Applicants may be asked by the FDA

to distribute a “Dear Doctor” (or “Dear Health Care assessed at specified intervals. One of the most common
Practitioner”) letter to disseminate information concern- reasons for REMS is when the drug is a teratogen. The
ing a significant hazard to health, to announce important FDA has issued guidance for industry about the format
changes in drug package labeling, or to correct prescrip- and content of REMS and their assessments (FDA,
tion drug advertising or labeling. Applicants may 2009c). A list of currently approved REMS is available
distribute these letters for a variety of other reasons as on the FDA’s Website (FDA, 2016f). The FDA also posts
well. a quarterly report on the FAERS Website describing any
Historically, the information from ADE reports, along new safety information or potential signal of a serious
with data from formal clinical studies and from the med- risk identified within the past quarter (FDA, 2016g).
ical and scientific literature, has made up the primary For many years, the FDA has provided information
data source upon which the FDA’s postmarketing safety on drug risks and benefits to healthcare professionals
surveillance depends. A report issued by the Institute of and patients when that information has generated a spe-
Medicine (IOM) in 2006 to the US Congress made cific concern or prompted a regulatory action, such as a
several recommendations about how the FDA could revision to the drug product’s labeling. The FDA now
improve its drug safety program (Curfman et al., takes a more comprehensive approach to making infor-
2006). The IOM recommended several actions to address mation on potential drug risks available to the public
certain problems and provided the impetus for the FDA earlier, in some cases while the Agency is still evaluating
to enhance postmarketing surveillance. The FDA and whether any regulatory action is warranted. The Drug
the Agency for Healthcare Research and Quality Safety Oversight Board (DSB), created in 2005 and
(AHRQ) conducted a workshop in 2007 about the imple- mandated by law in the FDA Amendments Act of
mentation of risk minimization action plans to support 2007, advises the CDER Center Director on the handling
quality use of pharmaceuticals. The goal of the work- and communicating of important and often emerging
shop was to obtain input from stakeholders about useful drug safety issues. The DSB meets monthly and pro-
mechanisms application holders can take to minimize vides a forum for discussion and input about how to
the risks of medications with unusual safety and patient address potential drug safety issues. The DSB is
monitoring concerns. The FDA’s authority to require composed of representatives from two FDA Centers
holders of applications for human drugs to implement and eight other federal government agencies, the
risk minimization plans was established in the Food AHRQ, Centers for Disease Control and Prevention
and Drug Administration Amendments Act (FDAAA) (CDC), Centers for Medicare and Medicaid Services,
of 2007. Before the FDAAA was enacted, the FDA Department of Defense (DOD), Health Resources and
approved a small number of drug and biological prod- Services Administration, Indian Health Service, Na-
ucts with risk minimization action plans (RiskMAPs). tional Institutes of Health (NIH), and Department of Vet-
A RiskMAP is a strategic safety program designed to erans Affairs. An important role of the DSB is to help the
meet specific goals and objectives in minimizing known FDA assess the impact of their safety decisions on the
risks of a product while preserving its benefits. Risk- healthcare systems of its Federal Partners. The Board,
MAPs were developed for products that had risks that with its broad representation from federal healthcare or-
required additional risk management strategies beyond ganizations, can provide valuable input and allows the
describing the risks and benefits of the product in label- FDA to hear other perspectives on drug safety issues
ing and performing required safety reporting. Since (FDA, 2016h).
FDAAA has been enacted, FDA has the authority to Often, there is a period of uncertainty while the FDA
require Risk Evaluation Mitigation Strategies (REMS) evaluates the new safety information to determine
when necessary to ensure that the benefits of a drug whether there is an important drug safety issue related
outweigh the risks. The simplest REMS involve to a specific drug or drug class and whether regulatory
enhanced patient and healthcare provider education action is appropriate. As CDER evaluates an emerging
and risk communication strategies. Other components drug safety issue to determine whether regulatory ac-
of REMS may include informed consent forms, limiting tion is warranted, information may be communicated
prescribing to practitioners with special training or cer- to the public at appropriate points in the decision-
tification, limiting use of the drug to hospitals or other making process. The FDA considers many factors in
healthcare settings, limiting dispensing of drugs to pa- the course of evaluating an emerging drug safety
tients with documentation of particular laboratory re- concern and deciding when information should be
sults, and enrollment of patients into registries and made available to the public. These factors include, but
other special monitoring programs (FDA, 2007a). The are not limited to, reliability of the data, magnitude of
need for REMS may be determined by the FDA at the the risk, seriousness of the event relative to the disease
time of drug approval, or after approval as safety issues being treated, plausibility of a causal relationship be-
emerge in the postmarketing period. REMS must be tween the use of the drug and the adverse events, extent

of patient exposure and disproportionate impact on about differences in codeine metabolism and potential
vulnerable populations (e.g., children, elderly), and concerns with breast-feeding (FDA, 2007b). The FDA
availability of alternative therapies (FDA, 2012c). may also issue Drug Alerts and Statements
A Drug Safety Communication (DSC) is a specific tool in situations involving recalls of products or when there
used by the FDA to communicate to the public impor- is a need to inform the public of certain risks associated
tant information about safety issues, including emerging with products. For example, the FDA issued an alert for
safety information, about marketed drugs. DSCs are a medicinal clay product sold over the counter, which
standardized electronic communications posted on the had elevated levels of lead in an FDA laboratory analysis
FDA Website. Written as clearly as possible, DSCs are (FDA, 2016k).
targeted to both healthcare professionals and patients. FDA-approved drug product labeling is the primary
DSCs generally communicate the following information: source of information for healthcare providers and con-
a summary of the safety issue and the nature of the risk sumers about a drug’s safety and effectiveness, and it
being communicated, the established benefit or benefits summarizes the essential information needed for the
of the drug being discussed, recommended actions for safe and effective use of the drug. Labeling for prescrip-
healthcare professionals and patients, when appro- tion drug products is directed to healthcare profes-
priate, and a summary of the data reviewed or being sionals, but may include sections that are intended for
reviewed by the FDA. The DSC is FDA’s primary safety patients and that also must be FDA approved. For
communication tool for important postmarket drug some prescription drugs, such as oral contraceptives
safety issues. In the past, safety communications were and estrogens, the FDA long ago determined that the
issued by the FDA in a variety of formats. They were safe and effective use of the drug required additional la-
issued under different titles and targeted to different beling in nontechnical language to be distributed
audiences (e.g., Early Communications about Ongoing directly to patients by their healthcare provider or phar-
Safety Reviews, Public Health Advisories, Patient Infor- macist (21 CFR 310.501 and 310.515). These patient pack-
mation Sheets, Healthcare Professional Sheets, and age inserts also may be provided voluntarily by
Alerts on Patient Information and Healthcare Profes- manufacturers for other drugs and are regulated by
sional Sheets), and as these titles suggest, targeted the FDA as product labeling.
different audiences. To improve the clarity of communi- In some cases, the FDA has required patient labeling
cations, the FDA began using the DSC as the single in nontechnical language in the form of Medication
communication vehicle in early 2010 (FDA, 2012c). Guides (MedGuides). These have been required for
Examples of reproductive system or developmental- certain prescription drugs that pose a serious and signif-
related DSCs include an FDA review of possible risks icant public health concern and for which FDA-
of pain medicines used during pregnancy (FDA, approved patient information is necessary for a patient’s
2016i), and an FDA recommendation not to use certain safe and effective use of the product. MedGuides are
lidocaine formulations to treat teething pain in infants required if the FDA determines that one or more of the
and children due to the potential for seizures, brain following circumstances exists: patient labeling could
injury, and cardiac problems if the product was acciden- help prevent serious adverse effects; a drug product
tally swallowed (FDA, 2016j). DSCs issued since 2010 are has serious risk(s) of which patients should be made
posted on the FDA’s Website. An example of a previous aware because information concerning the risk(s) could
Public Health Advisory (PHA) was that released by the affect a patient’s decision to use, or to continue to use,
FDA in 2007 after it had received new information about the product; or patient adherence to directions for use
a rare but serious side effect in nursing infants whose is crucial to the drug’s effectiveness (21 CFR 208.1).
mothers take codeine. Reports of morphine overdoses Drugs that are prescribed with Medication Guides are
in nursing infants were published in the scientific litera- listed on the FDA’s Website (FDA, 2016l). OTC drugs
ture and it was found that some women are ultrarapid bear a “Drug Facts” label that conveys information in
metabolizers of codeine, which is metabolized to a clear, standardized format to enable patient self-
morphine (Koren et al., 2006). Nursing mothers taking selection of an appropriate drug and enhance the safe
codeine may have higher than normal levels of and effective use of the drug by consumers.
morphine in breast milk, which is subsequently ingested The premarket approval process for new drugs is a
by their infant and may result in life-threatening complex process, which is described in depth on the
morphine overdose in the infant. The FDA issued a FDA’s Website and in various guidance documents.
PHA to inform nursing mothers and prescribing health- The FDA has published guidance for reviewers specific
care professionals about the dangers of potential to human reproduction including “Reviewer Guidance
morphine overdose in nursing infants, and the FDA e Evaluating the Risks of Drug Exposure in Human
requested that manufacturers of prescription codeine- Pregnancies” (FDA, 2005). This guidance is intended to
containing products include information in labeling help FDA staff evaluate human fetal outcome data

generated after medical product exposures during preg- labeling for human prescription drug and biological
nancy. The goal of such evaluations is to assist in the products. The final rule requires the removal of the preg-
development of product labeling that is useful to medi- nancy categories A, B, C, D, and X from all human pre-
cal care providers when caring for patients who are scription drug and biological product labeling. Through
pregnant or planning pregnancy. Whether a drug causes experience and stakeholder feedback, the FDA learned
abnormal development or not depends not only on the that the pregnancy categories were confusing and did
physical and chemical nature of the drug, but also on not accurately and consistently communicate differ-
the dose, duration, frequency, route of exposure, and ences in degrees of fetal risk. In addition, the FDA
gestational timing involved. Pregnant women are rarely learned that the pregnancy categories were heavily
included in clinical trials of new drug products. There relied upon by clinicians but were often misinterpreted
may be inadvertent pregnancy exposures during clinical and misused in that prescribing decisions were being
trials, but available data are usually not sufficient to made based on the pregnancy category, rather than an
permit adequate statistical analysis of outcomes. The understanding of the underlying information that
only data on fetal effects initially available in drug label- informed the assignment of the pregnancy category.
ing usually comes from animal reproductive toxicology For these reasons, FDA determined that a narrative
studies, the results of which may or may not be relevant structure for pregnancy labeling, rather than a category
to safety in humans. system, would best capture and convey the potential
Often little is known before marketing about a drug’s risks of drug exposure based on animal or human
teratogenic potential, so postmarketing surveillance of data, or both. For human prescription drug and biolog-
drug use in pregnancy is critical to the detection of ical products subject to the Agency’s 2006 Physician La-
drug-induced fetal effects. Some drugs may induce tera- beling Rule, the final rule requires that the labeling
togenic effects that are not clinically evident until many include a summary of the risks of using a drug during
years after birth, such as the reproductive tract abnor- pregnancy and lactation, a discussion of the data sup-
malities associated with diethylstilbestrol exposure in porting that summary, and relevant information to
utero. When making a determination about whether help healthcare providers make prescribing decisions
and how human pregnancy data should be included in and counsel women about the use of drugs during preg-
drug labeling, the FDA considers effects such as back- nancy and lactation. The final rule eliminates the “Labor
ground prevalence of adverse pregnancy outcomes, and delivery” subsection because information about la-
timing and intensity of exposure, variability of re- bor and delivery is included in the “Pregnancy” subsec-
sponses, and class effects, among others. Information tion. If there is a scientifically acceptable pregnancy
on human gestational drug exposures will emerge dur- exposure registry for the drug, the “Pregnancy” subsec-
ing the postmarketing phase for most drug products. tion must contain a specific statement about the exis-
In addition, postmarketing pregnancy registries are tence of the registry, followed by contact information
used proactively to monitor for major fetal effects. Spon- needed to enroll or to obtain information about the reg-
sors of new drug applications may develop pregnancy istry. The final rule requires that the labeling include
exposure registries, either on their own initiative or relevant information about pregnancy testing, contra-
when requested by the FDA as a postmarketing commit- ception, and infertility for healthcare providers prescrib-
ment. In 2002, the FDA published industry guidance on ing for females and males of reproductive potential. The
establishing pregnancy exposure registries to encourage final rule creates a consistent format for providing infor-
the development of epidemiologically sound, written mation about the risks and benefits of prescription drug
study protocols (FDA, 2002). A list of current pregnancy and/or biological product use during pregnancy and
exposure registries enrolling women is available on the lactation and by females and males of reproductive po-
FDA’s Website (FDA, 2016m). If there is an increased tential. These revisions will facilitate prescriber coun-
risk associated with the use of the drug during preg- seling for these populations (FDA, 2016n).
nancy, the labeling should describe the specific abnor- In Dec. 2009, the FDA announced the formation of a
mality, the incidence, seriousness, reversibility of the research program called the Medication Exposure in
abnormality, and the effect of dose, duration of expo- Pregnancy Risk Evaluation Program (MEPREP), which
sure, and timing of gestational exposure on the likeli- funds research to study the effects of prescription med-
hood of risk. The labeling should also include and be ications used during pregnancy. The program is a collab-
routinely updated with data from ongoing studies, oration among researchers at the FDA and the Health
such as from pregnancy exposure registries. Maintenance Organization (HMO) Research Network
Effective Jun. 2015, the FDA amended its regulations Center for Education and Research in Therapeutics, Kai-
governing the content and format of the “Pregnancy,” ser Permanente’s multiple research centers, and Vander-
“Labor and delivery,” and “Nursing mothers” subsec- bilt University (FDA, 2009d). About two-thirds of
tions of the “Use in Specific Populations” section of the women who deliver a baby have taken at least one

prescription medication during pregnancy according to biological products, both investigational and licensed,
a journal article published in the American Journal of including allergenics (patch tests and extracts used to di-
Obstetrics and Gynecology (Andrade et al., 2004). There agnose and treat allergic conditions); blood and blood
are very few clinical trials that test the safety of medica- components used for transfusion, clotting factors, and
tions in pregnancy due to concerns about the health of immunoglobulins; human tissues for transplantation
the mother and child. To overcome the challenges pre- and cellular products such as human stem cells; gene
sented by the lack of clinical trial data about the use of therapy products; vaccines; certain medical devices
medications during pregnancy, the research program used to safeguard blood and blood components from in-
links healthcare information for mothers and their ba- fectious agents, blood-typing reagents, and equipment
bies in each of the participating research sites. Collec- used to collect blood and blood components; as well as
tively, the 11 participating sites have healthcare xenotransplantation products. This section will focus
information for about 1 million births over a 7-year on vaccines intended for use in humans.
time period (2001e2007). Many of the mothers associ- Biological products are licensed under Section 351 of
ated with these births likely used medication during the Public Health Service Act. CBER evaluates scientific
their pregnancies and now the FDA and participating and clinical data, as well as a full description of the
researchers have a systematic and timely way of manufacturing methods and other information submit-
retrieving information from this network. A Steering ted by manufacturers to determine if a product meets
Committee composed of representatives from each the conditions of approval specified in the regulations.
participating site and the FDA oversees MEPREP activ- The Biologics License Application is a request for
ities and provides scientific leadership for the program. permission to introduce, or deliver for introduction, a
The investigators participating in the program have biological product into interstate commerce. Biological
collaborated on studies related to medication use during products are regulated by the FDA under 21 CFR
pregnancy and birth outcomes, as well as studies on the 600e680. Because many biological products also meet
effects of antidepressant medications, antibiotics, and the definition of “drugs” under the FFDCA, they are
cardiovascular medications on birth defects and peri- also subject to regulation under 21 CFR Parts 210e211.
natal outcomes. Results of these studies will provide CBER works to ensure that manufacturers follow cur-
valuable information for patients and physicians when rent Good Manufacturing Practices, monitors promotion
making important decisions about medication use dur- and advertising, and collects and analyzes safety data
ing pregnancy. In addition to ongoing descriptive and about biological products that are already on the market.
validation studies of the data, a major focus of Adverse events related to biological products other than
MEPREP’s research agenda includes studies of the asso- vaccines are reported to FAERS as described for drugs.
ciation between in utero exposure to specific medica- Vaccine-related adverse events are reported to the Vac-
tions and congenital anomalies or other birth outcomes cine Adverse Event Reporting System (VAERS). Biolog-
(e.g., preterm birth). Specific medication classes of inter- ical products intended for veterinary use are regulated
est to program researchers more recently include opi- under a separate law, the Virus, Serum and Toxin Act,
oids, antiinfectives (including antivirals), asthma which is administered by the USDA. Blood and most
medications, antidiabetics, antipsychotics, and antiepi- blood products intended for animal use are regulated
leptics (Andrade et al., 2012). as drugs by the FDA; however, there is no premarket
approval or biologics licensing requirement for them.
VACCINES INTENDED FOR USE IN After assessment of premarket data and consider-
HUMANS ation of all of the other conditions for licensure, as
described in 21 CFR 601.20, CBER makes a decision
The CBER protects and enhances public health about approval of a biological product. CBER’s author-
through the regulation of biological and related prod- ity resides in the Public Health Service Act and in spe-
ucts including blood, vaccines, allergenics, tissues, and cific sections of the FFDCA. The Public Health Service
cellular and gene therapies. Biological products, in Act also provides authority to suspend licenses
contrast to drugs, many of which are chemically synthe- in situations where there exists a danger to public
sized, are derived from living sources (such as humans, health. In addition, this statute allows for the prepara-
animals, and microorganisms), may not be easily identi- tion or procurement of products in the event of short-
fied or characterized, and many are manufactured using ages and critical public health needs, and authorizes
biotechnology. These products often represent cutting- the creation and enforcement of regulations to prevent
edge biomedical research and may offer very effective the introduction or spread of communicable diseases
means to treat a variety of medical illnesses and condi- in the United States.
tions that presently have few or no other treatment op- CBER continues to monitor the safety of biological
tions. CBER regulates an array of diverse and complex products after they have been approved. A safe biological

VACCINES INTENDED FOR USE IN HUMANS 155
product does not mean zero risk; rather, it is one that has detection of signals that can then be more rigorously
reasonable risks, given the patient’s condition, the magni- investigated.
tude of the benefit expected, and the alternatives available. The CDC and the FDA use VAERS data to respond to
Manufacturers holding an approved biologics license public inquiries regarding vaccine safety, and both orga-
application are required to report adverse experiences to nizations have published and presented vaccine safety
the FDA under 21 CFR 600.80. Adverse experiences that studies based on VAERS data. VAERS data are also
are both serious and unexpected, whether foreign or do- used by the CDC’s Advisory Committee on Immuniza-
mestic, must be reported as soon as possible but not later tion Practices and the Vaccine and Related Biological
than 15 calendar days of initial receipt of the information. Products Advisory Committee to evaluate possible
The manufacturer must promptly investigate all adverse adverse events after vaccinations and to develop recom-
experiences that are the subject of these postmarketing mendations for precautions and contraindications to
15-day reports and must submit follow-up reports within vaccinations. Through continued reporting of adverse
15 calendar days of receipt of new information, or as events after vaccination by healthcare providers, public
requested by the FDA. Periodic adverse experience re- health professionals and the public, the system will
ports are submitted by the manufacturer at quarterly inter- continue to be able to detect rare but potentially serious
vals for the first 3 years of licensure, then annually. consequences of vaccination. The report of an adverse
Adverse experiences are also reported from postmarket- event to VAERS is not proof that a vaccine caused the
ing studies. event. More than 10 million vaccinations per year are
Vaccines undergo a rigorous review of laboratory and given to children less than 1 year old, usually between
clinical data to ensure the safety, efficacy, purity, and po- 2 months and 6 months of age (FDA, 2009e). At this
tency of these products. Many of these are childhood stage of development, infants are at risk for a variety
vaccines that have contributed to a significant reduction of medical events and serious childhood illnesses. These
of preventable diseases. The prevention of infectious naturally occurring events include fevers, seizures, sud-
diseases through effective immunization programs is den infant death syndrome, cancer, congenital heart dis-
dependent on ensuring the safety of vaccines, as well ease, asthma, and other conditions. Some infants
as successful communication of their risks and benefits. coincidentally experience an adverse event shortly after
Clinical trials conducted prior to vaccine licensure usu- a vaccination. In such situations an infection, congenital
ally reveal that most adverse events are minor. Rare, abnormality, injury, or some other provocation may have
serious adverse events are less likely to be detected dur- caused the event. Because of such coincidences, it is usu-
ing the prelicensure process, even in large clinical trials. ally not possible from VAERS data alone to determine
If a serious adverse event is found to be causally related whether a particular adverse event resulted from a con-
to a vaccine, the balance of benefits and risks of vaccina- current condition or from a vaccination, even when the
tion may shift, possibly leading to changes in recom- event occurs soon after vaccination.
mendations for vaccination (Griffin et al., 2009). If VAERS data suggest a possible link between an
The National Childhood Vaccine Injury Act of 1986 adverse event and vaccination, the relationship may be
mandated reporting of certain adverse events and led further studied in a controlled fashion. Analyzing
to the establishment of VAERS, which is a national vac- VAERS reports is a complex task. Children are often
cine safety surveillance program cosponsored since 1990 administered more than one vaccine at a time, making
by the FDA and the CDC (CDC, 2015). The information it difficult to know which vaccine, if any, may have
collected into the VAERS database comes from a wide contributed to any subsequent adverse events. Although
array of sources, including patients and parents, state about 85% of adverse events reported to VAERS are mi-
health agencies, pharmacies, healthcare providers, and nor (such as mild fevers or redness and swelling at the
vaccine manufacturers. The primary purpose for main- injection site), the remaining 15% describe more serious
taining the database is to serve as an early warning or events. The more serious events include hospitaliza-
signaling system for adverse events not detected during tions, life-threatening events, and deaths. As part of
premarket testing of vaccines. VAERS data can be used the VAERS program, the FDA reviews the deaths and
to aid in the detection of new, unusual, or rare vaccine other serious reports weekly, and conducts follow-up.
adverse events, to monitor increases in known adverse In some cases, certain vaccines and potentially associ-
events, to determine patient risk factors for particular ated symptoms will receive more intense follow-up
types of adverse events, and to identify vaccine lots (FDA, 2009e).
with increased numbers or types of reported adverse In addition to analyzing individual VAERS reports, the
events. Although VAERS data can rarely provide defin- FDA also analyzes patterns of reporting associated with
itive evidence of causal associations between vaccines vaccine lots. Many complex factors must be considered
and particular risks, its unique role as a national sponta- in comparing reports between different vaccine lots.
neous reporting system for vaccines enables the early More reports may be received for a large lot than for a

small one simply because more doses of vaccine from the system, appropriate epidemiologic studies should be
large lot will be given to more individuals. Some lots conducted to confirm or refute the association.
contain as many as 700,000 doses, whereas others as VAERS is subject to the limitations inherent in any
few as 20,000 doses. Similarly, more reports will be passive surveillance system. These limitations include
received for a lot that has been in use for a long time underreporting; differential reporting (increased report-
than for a lot that has been in use for a short time. Even ing in the first few years after vaccine licensure, or
among lots of similar size and time in use, some lots increased reporting of events occurring soon after vacci-
will receive more reports than others, simply due to nation); stimulated reporting (increased reporting after a
chance. The FDA looks for lots that have received more known or alleged type of adverse event); reporting of
death reports than would be expected on the basis of coincidental events; poor data quality; and a lack of de-
such factors as time in use and chance variation as well nominator data (number of doses of vaccines actually
as any unusual patterns in other serious reports within administered), so calculation of adverse event incidence
a lot. If such a lot is detected, further review is conducted rates is not usually possible. Despite these limitations of
to determine if the lot is safe for continued use or if addi- VAERS data, the data collected are valuable in alerting
tional FDA actions are needed. The FDA has the author- the FDA and others to potential vaccine safety signals
ity to recall a vaccine from use in the United States if it that need further investigation. An example of a success-
represents a risk to the American public. ful vaccine safety alert provided by VAERS is that of
The process of identifying a new vaccine safety signal rotavirus vaccination and the risk of intussusception in
requires a combination of clinical insight and epidemio- children. Intussusception had been reported among in-
logic knowledge. Several factors may make identification fant recipients of a rotavirus vaccine, RotaShield,
of true signals difficult, for example, many vaccines are licensed in Aug. 1998. Fifteen VAERS intussusception re-
administered early in life, at a time when “baseline” ports received between Sep. 1, 1998, and Jul. 7, 1999,
risk is continually evolving. The evaluation of safety pro- were initially analyzed, leading to further investigation
files of vaccines may involve comparing the proportions involving caseecontrol and retrospective cohort studies.
of particular symptoms out of the total number of events These studies demonstrated a substantially increased
for a given vaccine to that observed among reports for frequency of intussusception in the first 1e2 weeks after
another vaccine. This is an example of a proportional vaccination with RotaShield, compared with infants
reporting rate ratio method and is a widely used measure who did not receive the vaccine. Multiple studies
in vaccine adverse event reporting systems for prospec- confirmed the association, and the manufacturer volun-
tive and retrospective signal generation (Strom and tarily recalled the vaccine (Zhou et al., 2003). Another
Kimmel, 2006). Signals generated by adverse event example of how VAERS data may be used to assess
reporting systems may need to be confirmed in epidemi- safety of certain vaccines is that of the human papillo-
ologic studies. These studies can have several limitations, mavirus (HPV) virus vaccine, Gardasil. The FDA
including exposure misclassification if there is poor docu- approved Gardasil on Jun. 8, 2006. It was approved for
mentation of vaccinations, difficulty in identifying females 9e26 years of age to protect against cervical,
enough cases for a meaningful study due to rare outcome vulvar, and vaginal cancers caused by HPV types 16
events, difficulty in identifying a comparable control and 18 and genital warts caused by HPV types 6 and
group of unvaccinated people, and potential confound- 11. The CDC’s Advisory Committee on Immunization
ing factors, such as age in children. In 1990, the CDC initi- Practices recommended a routine three-dose vaccination
ated the Vaccine Safety Datalink (VSD) project. This study series for girls 11 and 12 years of age. The vaccine is also
prospectively collects vaccination, medical outcome, and recommended for girls and women aged 13 through
covariate data under a joint protocol with multiple 26 years who have not yet been vaccinated or who
HMOs. Data from the VSD project may be used to explore have not received all three doses. On Aug. 19, 2009,
new vaccine safety hypotheses that may arise from med- the Journal of the American Medical Association published
ical literature, the VAERS database, or introduction of an article coauthored by the FDA and the CDC that
new vaccines (CDC, 2016). The FDA, the CDC, and other reviewed the safety data for Gardasil for select adverse
Federal and private partners conduct active surveillance, events that had been reported to VAERS, from the time
in addition to full epidemiologic studies, to monitor and period starting from product licensure in Jun. 2006
improve vaccine safety. The purpose of active safety sur- through Dec. 31, 2008 (Slade et al., 2009). The article de-
veillance is to rapidly identify signals of potential excess scribes 12,424 reports of adverse events following Gar-
risk of adverse outcomes following introduction of a drug dasil vaccination. Of these, 772 were reports of serious
or vaccine into clinical practice. Electronic data, including events (6.2% of the reports) and the remaining 11,652
but not limited to claims data, are often used for active (93.8%) were classified as nonserious. The Gardasil
surveillance of large medical databases. Once a signal safety review assessed the following adverse events:
of a potential excess risk is detected by the surveillance local injection site reactions, syncope, dizziness and

VACCINES INTENDED FOR USE IN HUMANS 157
nausea, headaches, hypersensitivity reactions, such as births are contacted annually through early childhood
rashes, hives, itching, anaphylaxis, Guillain-Barré (i.e., approximately 5 years of age) to evaluate the over-
syndrome, transverse myelitis, motor neuron disease, all health and developmental progress of their child/
venous thromboembolic events, pancreatitis, autoim- children. Enrollment in the registry began in 2003, and
mune disorders, and deaths. All of these events as of 2015, 517 women were actively followed in the reg-
are included in Gardasil’s approved labeling. Based on istry, representing 522 pregnancies. Approximately 95%
the review of available information by the FDA and of these women received the smallpox vaccine before
the CDC, it was determined that Gardasil’s benefits 8 weeks estimated gestational age. Delivery information
continue to outweigh its risks. As with all licensed vac- was pending on 12 subjects, but 429 of the pregnancies
cines, the FDA continues to closely monitor the safety of had thus far resulted in live births (Conlin et al., 2015).
Gardasil. Since its original approval, Gardasil has also The Smallpox Vaccine in Pregnancy Registry continues
been approved for vaccination in boys and men 9 to actively enroll women and follow infant and early-
through 26 years of age for the prevention of genital childhood health outcomes.
warts caused by HPV types 6 and 11, and for vaccination CBER reviews a broad spectrum of applications for
in people ages 9 through 26 years for the prevention of investigational vaccines intended for the prevention
anal cancer and associated precancerous lesions due to and treatment of infectious diseases and indicated for
HPV types 6, 11, 16, and 18 (FDA, 2014). immunization of adolescents and adults. Thus the target
Registries of people inadvertently exposed to vac- population for vaccines often includes females of child-
cines can contribute to the knowledge base regarding bearing potential who may become pregnant during the
prognosis in these populations, and registries of those vaccination period. A number of vaccines are in clinical
with rare adverse events allow exploration of genetic development specifically for maternal immunization in-
or other predictors of such effects. An example of such dications with the goal of preventing infectious disease
a registry is the National Smallpox Vaccine in Pregnancy in the pregnant mother and/or neonate through passive
Registry, established by the CDC in collaboration with antibody transfer from mother to fetus. Unless the vac-
the FDA and the DOD in 2003. When the United States cine is specifically indicated for maternal immunization,
implemented civilian and military smallpox vaccination studies are typically not conducted prior to product
programs in 2003, the National Smallpox Vaccine in licensure to determine the vaccine’s safety in pregnant
Pregnancy Registry was established to better evaluate women. During clinical development of most vaccines
outcomes after the inadvertent vaccination of pregnant not specifically intended for use during pregnancy,
women. Smallpox vaccine is known to cause fetal pregnant women are generally ineligible to participate
vaccinia, a very rare but serious complication of expo- in clinical trials. If pregnancy occurs during a study,
sure to smallpox vaccine during pregnancy. Fewer treatment is usually discontinued and the woman does
than 50 cases have been reported, three of which not receive additional immunizations. Consequently,
occurred in the United States in 1924, 1959, and 1968. there are few clinical data to address reproductive and
Affected pregnancies have been reported in women developmental toxicity of the vaccine in pregnant
vaccinated in all three trimesters, in primary vaccinees women or females of childbearing potential at the time
and in those being revaccinated, and in nonvaccinated of product licensure. As more women of childbearing
contacts of vaccinees. Because a risk of infection to the potential participate in clinical trials and as more pre-
fetus is possible, smallpox vaccination is not recommen- ventive and therapeutic vaccines are developed for ado-
ded for pregnant women or anyone with close physical lescents and adults, there is increasing concern about the
contact to a pregnant woman. To prevent inadvertent unintentional exposure of an embryo/fetus before infor-
exposure of pregnant women to vaccinia virus, mation is available about the risk versus benefit of the
screening for pregnancy is a component of smallpox vaccine. Also, following approval, vaccines not indi-
vaccination programs. Women are referred to the regis- cated for use during pregnancy may be recommended
try by vaccine administrators, healthcare providers, or by health policy makers for use in pregnant women. In
state health departments, through self-referral or addition, use of licensed vaccines in females of child-
through reports from the DOD, the CDC, the FDA and bearing potential will likely result in inadvertent expo-
VAERS (Ryan and Grabenstein, 2003; CDC, 2003). Regis- sure of the pregnant woman and her fetus to the
try professionals actively follow up with all enrolled vaccine. Considering that more than half of pregnancies
women and collect data on pregnancy, birth, and infant in the United States are unintended, it is unlikely that
health outcomes. Data captured include pregnancy los- vaccine exposure would be avoided in these pregnan-
ses (miscarriage, stillbirth), voluntary interruption of cies prior to their clinical recognition. In these situations,
pregnancy, live birth status (preterm or full term), and in the absence of clinical data, it is difficult for the prac-
infant health outcomes (birth defects diagnosed through titioner to make an informed risk assessment, even
the first year of life, or other outcomes). Women with live in situations where immunization of pregnant women

may be appropriate. In 2006, the FDA published a Guid- Among the CVM’s regulatory activities are reviewing
ance for Industry, with recommendations pertaining to new animal drug applications for innovator and generic
the assessment of the developmental toxicity potential animal pharmaceuticals; enforcement of regulations
of preventive and therapeutic vaccines for infectious governing the manufacture of animal pharmaceutical
diseases indicated for females of childbearing potential products, the promotion and advertising of prescription
and pregnant individuals (FDA, 2006). animal drugs, and drug experience reporting by firms
The CDC provides guidelines for the vaccination of marketing drugs; taking action against animal drugs
pregnant and lactating women. According to the CDC, marketed without approval; and collecting and
risk to a developing fetus from vaccination of the mother analyzing safety data about marketed animal pharma-
during pregnancy is primarily theoretical. No evidence ceuticals. One of CVM’s primary objectives is to ensure
exists of risk to the fetus from vaccinating pregnant that prescription and OTC medications intended for an-
women with inactivated virus or bacterial vaccines or imal use are safe and effective when used as directed.
toxoids. Live vaccines administered to a pregnant All drugs have risks, and veterinary healthcare profes-
woman pose a theoretical risk to the fetus; therefore, sionals and animal owners must balance the risks and
live, attenuated virus and live bacterial vaccines gener- benefits of a drug when making decisions about medical
ally are contraindicated during pregnancy. Benefits of therapy. The FDA monitors and reviews available safety
vaccinating pregnant women usually outweigh poten- and effectiveness information related to marketed ani-
tial risks when the likelihood of disease exposure is mal drugs throughout each product’s life cycle. Similar
high, when infection would pose a risk to the mother to human drugs, when an animal drug is approved,
or fetus and when the vaccine is unlikely to cause the product labeling includes, among other things, avail-
harm. If a live-virus vaccine is inadvertently given to a able information about the benefits and risks of the drug.
pregnant woman, or if a woman becomes pregnant CVM’s additional responsibilities include ensuring
within 4 weeks after vaccination, she should be coun- that food products from treated food-producing animals
seled about the potential effects on the fetus, but vacci- are safe for human consumption. Part of the preapproval
nation is not ordinarily an indication to terminate the process for drugs intended for use in food-producing
pregnancy. Whether live or inactivated vaccines are animals includes the determination of safety of drug res-
used, vaccination of pregnant women should be consid- idues in animal-derived food products. Tolerances for
ered on the basis of risks versus benefits, i.e., the risk of residues of animal drugs in food are codified in 21
the vaccination versus the benefits of protection in a CFR Part 556. In addition, preapproval safety evaluation
particular circumstance. The CDC also currently recom- of certain animal drugs includes a determination of the
mends prenatal screening for rubella and hepatitis B and effects of the animal drug on the environment and on
prenatal assessment for varicella. Regarding breast- human health in some cases. In support of the drug re-
feeding and vaccination, the CDC has reported that view function, the CVM’s Office of Research conducts
neither inactivated nor live-virus vaccines administered studies in animal drug safety and efficacy, antimicrobial
to a lactating woman affect the safety of breast-feeding resistance mechanisms, metabolism, standardization of
for women or their infants. Although live viruses in vac- test methods, and pharmacokinetics/pharmacody-
cines can replicate in vaccine recipients (i.e., the mother), namics. The Office of Research supports compliance
the majority of live viruses in vaccines have been programs of the Center through the development of
demonstrated not to be excreted in human milk. Howev- analytical methods and evaluation of screening tests
er, breast-feeding is a contraindication for smallpox for detection of drug residues in imported and domestic
vaccination of the mother because of the theoretical food products. It also conducts research to understand
risk for contact transmission from mother to infant, the microbiology of animal feeds and the dissemination
and yellow fever vaccine should be avoided in breast- of resistant bacteria via livestock feeds, and develops
feeding women unless they cannot avoid or postpone methods to detect material prohibited by the BSE
travel to areas endemic for yellow fever in which risk (bovine spongiform encephalopathy) feed regulation
for acquisition is high (CDC, 2014). that could compromise animal feed safety (FDA, 2016o).
After drug approval, the FDA may learn of new, or
more frequent, serious ADEs from postapproval clinical
DRUGS INTENDED FOR USE IN ANIMALS studies or from clinical use in animals. For example,
additional ADEs may be identified as a drug is more
The CVM is responsible for approving drugs for ani- widely used and under more diverse conditions. Regu-
mals, including drugs used in medicated feeds, and for lations at 21 CFR 514.80 describe the spontaneous
monitoring drugs and feeds intended for use in animals. reporting obligations for holders of approved new ani-
There are currently no requirements for FDA premarket mal drug applications and other firms marketing these
approval of medical devices intended for animal use. products. Definitions in 21 CFR 514.3 for “adverse

DRUGS INTENDED FOR USE IN ANIMALS 159
drug experience,” “serious adverse drug experience,” Medicinal Drug Use Clarification Act of 1994
and “unexpected adverse drug experience” are similar (AMDUCA) allows veterinarians to prescribe extralabel
to the human definitions found in 21 CFR 314.80, with uses of certain approved animal drugs and approved
a few exceptions. “Adverse drug experience” as defined human drugs for animals under certain conditions.
in 21 CFR 514.3 is any adverse event associated with the Extralabel use refers to the use of an approved drug in
use of a new animal drug, whether or not considered to a manner that is not in accordance with the approved la-
be drug related, and whether or not the new animal bel directions. The key constraints of the AMDUCA are
drug was used in accordance with the approved labeling that any extralabel use must be by or on the order of a
(i.e., used according to label directions or used in an veterinarian within the context of a veterinariane
extralabel manner, including but not limited to different clientepatient relationship, must not result in violative
route of administration, different species, different indi- residues in food-producing animals, and the use must
cations, or other than labeled dosage). ADE includes, but be in conformance with the implementing regulations
is not limited to, an adverse event occurring in animals published at 21 CFR Part 530.
in the course of the use of an animal drug product by Spontaneous reports of ADEs, medication errors, and
a veterinarian or by a livestock producer or other animal product defects comprise the primary data source upon
owner or caretaker; failure of a new animal drug to pro- which CVM’s postapproval surveillance and pharmacovi-
duce its expected pharmacological or clinical effect (lack gilance efforts depend. Also, data from postapproval clin-
of expected effectiveness); or an adverse event occurring ical studies and from the scientific literature may
in humans from exposure during manufacture, testing, contribute to surveillance. Limitations of utilizing sponta-
handling, or use of a new animal drug. “Serious adverse neous ADE reporting databases for pharmacovigilance ac-
drug experience” as defined by 21 CFR 514.3 is an tivities include the significant underreporting of ADEs,
adverse event that is fatal, or life threatening, or requires limited detail in submitted reports, and reporting bias.
professional intervention, or causes an abortion, or still- As with other pharmacovigilance databases, for any given
birth, or infertility, or congenital anomaly, or prolonged ADE report, there is no certainty that the reported drug
or permanent disability, or disfigurement. “Unexpected caused the adverse event. The adverse event may have
adverse drug experience” has the same definition as been related to an underlying disease, using other drugs
found in 21 CFR 314.80. at the same time, or other nondrug related causes. In addi-
Reporting of ADEs by veterinarians and animal owners tion, the accuracy of information regarding an ADE de-
is voluntary and mandatory for animal drug application pends on the quality of information received from the
holders and, in the case of serious and unexpected adverse reporter. Despite these limitations, the monitoring and
events, manufacturers or distributors named on the label. evaluation of ADE reports is very important in the identi-
Application holders send ADE reports directly to the fication of previously unrecognized adverse events, iden-
CVM, manufacturers and distributors to CVM or the tification of subgroups of animals at particular risk of
application holder. The CVM also accepts electronic sub- adverse events, and to generally ensure that the risk and
mission of adverse event information for veterinary drugs. benefits of a particular drug remain acceptable. Addition-
Electronic submission of adverse event information is ally, it allows for communication of essential drug safety
possible through the Electronic Submissions System and information to veterinarians and others involved in the
the Rational Questionnaire in the Safety Reporting Portal treatment of animals. Similar to other FDA Centers,
(SRP), a joint FDAeNIH initiative. The SRP was launched CVM is utilizing data mining and automated signal detec-
on May 24, 2010, and provides a mechanism for the report- tion methods to augment its ability to monitor the safety of
ing of certain pre- and postmarket safety data to the Fed- animal drugs.
eral government. Currently the SRP can be used by Just as for human drugs, FDA-approved animal drug
manufacturers to report safety issues involving marketed product labeling is the primary source of information
human drug and therapeutic biologics, human or animal about a drug’s safety and effectiveness, and it summarizes
reportable foods, animal drugs, animal food, tobacco the essential scientific information needed for the safe and
products, dietary supplements, and NIH safety issues effective use of the drug. Labeling for prescription animal
involving gene-transfer research. Consumers can also drug products is directed to healthcare professionals, but
use the site to report problems with pet foods and pet may include sections that are intended for animal owners
treats (FDA, 2016p). and that also must be FDA approved. Similar to Medica-
The primary objectives of CVM’s pharmacovigilance tion Guides for humans, which are commonly distributed
program are to provide for early recognition of signals with human pharmacy prescriptions, Client Information
about potentially serious and previously unknown Sheets may be required by the FDA as part of the approved
safety problems associated with marketed animal drugs, labeling for animal drugs. These are written in “consumer-
and to monitor the performance of drugs used both on friendly” language and provide information in easily un-
and off label (extralabel) in animals. The Animal derstood terms about the benefits and side effects

associated with the use of certain drugs. Examples of Suppression of estrus may be used to facilitate sched-
drugs that include Client Information Sheets as part of uled breeding during the physiological breeding season.
the labeling are the nonsteroidal antiinflammatory drugs The drug label for this product contains specific human
intended for use in companion animals. The CVM utilizes warnings regarding the potential effects of exposure to
its Website to disseminate information about ADEs and the drug on human reproduction: “Human Warning:
important announcements regarding animal drug prod- Skin contact must be avoided as Regu-MateÒ (altreno-
uct safety. One section of the Website, “CVM Updates,” gest) Solution 0.22% is readily absorbed through unbro-
contains brief press releases issued by the CVM on devel- ken skin. Protective gloves must be worn by all persons
opments of interest to stakeholders and the public. CVM handling this product. Pregnant women or women who
Updates may relate to any topic, but are often used to suspect they are pregnant should not handle Regu-
convey information about drug safety issues. The CVM MateÒ (altrenogest) Solution 0.22%. Women of child-
also publishes a cumulative summary of ADE reports, bearing age should exercise extreme caution when
which contains a listing of clinical signs in the reports handling this product. Accidental absorption could
that the CVM has received from 1987 to Apr. 2013. This lead to a disruption of the menstrual cycle or prolonga-
web report is currently in the process of development tion of pregnancy. Direct contact with the skin should
for continued posting of information. In Jul. 2010, the therefore be avoided. Accidental spillage on the skin
FDA published a Consumer Updates article, warning con- should be washed off immediately with soap and wa-
sumers of the dangers of inadvertent exposure of children ter.” There has been no approved human use of this spe-
and pets to a topical estradiol spray used to treat the symp- cific product. The information contained in the labeling
toms of menopause in women. The CVM had received of this product is extrapolated from data available on
several reports of pets exhibiting mammary enlargement other products of the same pharmacological class that
and vulvar swelling in female dogs. Reports had also have been used in humans. Effects anticipated are due
been received for children, describing premature puberty to the progestational activity of altrenogest. Acute effects
and breast enlargement in boys and girls. The CVM after a single exposure are possible; however, continued
worked together with CDER to develop this safety daily exposure has the potential for more untoward ef-
communication (FDA, 2010c). fects such as disruption of the menstrual cycle, uterine
Certain animal drug labels are required to bear spe- or abdominal cramping, increased or decreased uterine
cific warnings or precautions as related to potential ani- bleeding, prolongation of pregnancy, and headaches.
mal or human reproductive toxicity issues. For example, Presently, animal drug labeling is not required by
as the safety of most corticosteroid drugs for use during regulation to contain specific “Pregnancy” or “Lacta-
all stages of pregnancy has not been adequately estab- tion” subsections. Drug manufacturers generally will
lished in animals, 21 CFR 510.410 requires corticoste- provide any known information, or a statement indi-
roids for oral, injectable, and ophthalmic use in cating that use in pregnant or lactating animals has not
animals to contain the following statement: “Warning: been evaluated. Drugs reported to be contraindicated
Clinical and experimental data have demonstrated that during pregnancy in animals include fluoroquinolones,
corticosteroids administered orally or by injection to an- tetracyclines, griseofulvin, pentobarbital, misoprostol,
imals may induce the first stage of parturition if used warfarin, diethylstilbestrol, estracypionate, mitotane,
during the last trimester of pregnancy and may precipi- stanozolol, and testosterone (Evans, 2012).
tate premature parturition followed by dystocia, fetal The CVM does not regulate animal vaccines or any
death, retained placenta, and metritis. Additionally, cor- other biological products that achieve their primary
ticosteroids administered to dogs, rabbits, and rodents intended purposes by enhancing or stimulating the ani-
during pregnancy have resulted in cleft palate in mal’s immune system, such as bacterins, antisera, and
offspring. Corticosteroids administered to dogs during some diagnostic kits. These products are regulated by
pregnancy have also resulted in other congenital anom- the USDA under the Virus-Serum-Toxin Act through
alies, including deformed forelegs, phocomelia, and its Center for Veterinary Biologics (CVB). The CVB is
anasarca.” Certain animal drugs may be required to charged with ensuring that the veterinary biologics
bear warnings or precautions as related to human expo- available for the diagnosis, prevention, and treatment
sure to the product. For example, Regu-Mate (altreno- of animal diseases are pure, safe, potent, and effective.
gest) Solution 0.22% is indicated to suppress estrus in The Veterinary Biologics Pharmacovigilance Program
mares. Suppression of estrus allows for a predictable is for the ongoing surveillance of adverse events associ-
occurrence of estrus following drug withdrawal. This fa- ated with animal vaccines and other biologics, in coop-
cilitates the attainment of regular cyclicity during the eration with the veterinary profession and the
transition from winter anestrus to the physiological veterinary biologics industry. Information about report-
breeding season. Suppression of estrus will also facili- ing adverse events related to animal vaccines may be
tate management of prolonged estrus conditions. found on the USDA’s Website (USDA, 2016).

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C H A P T E R

Introduction 145 Vaccines Intended for Use in Humans 154

Reproductive and Developmental Toxicology

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

II. TOXICITY TESTING MODELS AND SAFETY EVALUATION

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