CDER
Report to the Nation: 2005
Table
of Contents
Print version
Slides of charts for presentations
2 Drug Safety and Quality
Index
Highlights
The practical size of
premarketing clinical trials means that we cannot learn
everything about the safety of a medicine before we approve
it. Therefore, a degree of uncertainty always exists about
the risks of a medicine, not only when we approve it but
also after we approve it. This uncertainty requires our
continued vigilance, along with that of the industry, to
collect and assess safety data for medicines on the market.
As Americans are increasingly receiving the benefits of
important new drugs before they are available to citizens of
other countries, we must be especially vigilant in our
surveillance.
We also monitor the quality of
marketed drugs and their promotional materials through product
testing and surveillance. In addition, we develop policies, guidance
and standards for drug labeling, current good manufacturing
practices, clinical and good laboratory practices and industry
practices to demonstrate the safety and effectiveness of drugs.
Highlights of medication safety
and quality activities in 2005 include:
n
Improving the electronic infrastructure to
support real-time availability of the most up-to-date drug
information for health-care providers and consumers.
n
Establishing and operating the
Drug Safety
Oversight Board.
n
Processing and evaluating more than 460,000
reports of adverse drug events, including more than 25,000 submitted
directly from individuals.
n
Issuing 60 letters on violations in drug
promotion and more than 600 letters to help ensure manufacturers
comply with regulations concerning drug promotion. Included in the
total were more than 200 letters concerning direct-to-consumer
advertising.
n
Issuing warning and other regulatory letters to firms selling drugs
that were unapproved, poorly poor manufactured or labeled
incorrectly. We also supported successful federal lawsuits against a
firm importing unapproved drugs and a firm distributing unapproved
and poorly manufactured prescription and over-the-counter drugs.
n
Evaluating more than 2,800 reports concerning
problems that occur in the manufacturing, processing, packing,
labeling, storing or distributing drugs.
n
Issuing 16 Public Health Advisories regarding
drug safety issues.
n
Approving Medication Guides for prescription
non-steroidal anti-inflammatory drugs with any of 18 active
ingredients and for five additional prescription drugs.
Back
to Index
Safety System for Medicines
Our current system for evaluating drug
safety provides:
n
Extensive premarket testing with rigorous
review, including evaluation of remaining uncertainties.
Premarket testing cannot, however, detect very rare, serious
adverse events (see below).
n
Risk management strategies before
and after approval.
n
Voluntary adverse event reporting systems with
additional population-based information.
n
User-friendly communication through
an improved drug label compatible with e-prescribing and
electronic decision support.
Capacities of current postmarketing safety system
n
Profile of common adverse events in populations studied
during development.
n
Understanding of medication metabolism and common
metabolism-based drug-drug interactions.
n
Management and evaluation of certain anticipated
postmarketing risks.
n
Identification of rare serious adverse events that occur
after marketing.
Knowledge gaps in postmarketing safety system
n
Differences in the frequency of events between those taking
and not taking a drug.
n
Detection of events after long-term exposure.
n
Adverse events that occur more frequently in populations not
normally studied in trials such as those who are very sick
or on multiple drugs.
n
Adverse events that occur more frequently with off-label
use.
n
A tendency for medical errors or abuse.
Approaches to resolving knowledge gaps
n
Use emerging electronic medical record systems for
surveillance.
n
Randomized trials or registries conducted in practice
settings after marketing.
n
More surveillance systems in specialized settings such as
emergency rooms or nursing homes.
Click on image for accessible text.
Types of risks from medicines
Product quality defects. These are controlled through
good manufacturing practices, monitoring and surveillance.
Known side effects. Predictable adverse events are
identified in the drug's labeling. These cause the majority
of injuries and deaths from using medicines. Some are
avoidable, and others are unavoidable.
n
Avoidable. Drug therapy
requires an individualized treatment plan and careful
monitoring. Other avoidable side effects are caused by known drug-drug
interactions.
n
Unavoidable. Some known side effects
occur with the best medical practice even when the drug is
used appropriately. Examples include nausea from antibiotics
or bone marrow suppression from chemotherapy.
Medication errors. For example,
the drug is administered incorrectly or the wrong drug or
dose is administered.
Remaining uncertainties. In addition to rare
events occurring in about 1 in 10,000 persons,these include
long-term effects and unstudied uses and populations.
Back
to Index
Drug Safety
Surveillance
We evaluate the safety of drugs available to
American consumers using a variety of tools and disciplines. We
maintain a system of postmarketing surveillance and risk assessment
programs to identify adverse events that did not appear during the
drug development process. We monitor adverse events such as adverse
reactions, drug-drug interactions and medication errors.
We have access to commercial databases that
contain non-patient-identifiable information on the actual use of
marketed prescription drugs in adults and children. This
dramatically augments our ability to determine the public health
significance of adverse event reports we receive.
As we discover new knowledge about a drug’s
safety profile, we make risk assessments and decisions about the
most appropriate way to manage any new risk or new perspective on a
previously known risk. Risk management methods may include new
labeling, drug names, packaging, “Dear Health Care Practitioner”
letters, education or special risk communications, restricted
distribution programs or product marketing termination.
Adverse Event Reporting System
A powerful drug safety tool is the Adverse Event
Reporting System, known as AERS. This computerized system
combines the voluntary adverse drug reaction reports from
MedWatch and the required reports from manufacturers. These
reports often form the basis of “signals” that there may be
a potential for serious, unrecognized, drug-associated
events. When a signal is detected, further testing of the
hypothesis is undertaken using various epidemiological and
analytic databases, studies and other instruments and
resources. AERS features both paper and electronic submission
options, international compatibility and pharmacovigilance
screening.
Adverse event reporting
In 2005, we received 464,068
reports of suspected drug-related adverse events:
n
25,325 MedWatch reports directly from individuals.
n
213,537 manufacturer 15-day (expedited) reports.
n
84,770 serious manufacturer periodic reports.
n
140,436 nonserious manufacturer periodic reports.
Click image for larger chart,
click here for accessible
text.
Adverse event reporting compliance
We monitor the pharmaceutical
industry’s submission of adverse event reports. A firm’s
procedures for collection, evaluation and submission may
affect the transfer and quality of safety data that we have
for analysis. Our surveillance of industry is based upon the
risks associated with specific drug products and specific
data processing procedures.
Risk-based inspections
We inspect drug firms' adverse event
reporting based upon risk criteria associated with specific
drug products and corporate performance. These include:
n
Newly marketed drugs.
n
Emerging safety signals.
n
Previous violations.
n
Corporate transitions.
Inspection outcome
In fiscal year 2005, our field investigators inspected
106 domestic and six foreign firms to assess compliance with
our regulations for adverse event reporting. We sent three
firms official notification that they had significant
uncorrected deficiencies. We were able to work with about 40
firms to obtain voluntary correction of deficiencies
identified by our monitoring.
Outreach and education
In addition to our inspectional
program for adverse event compliance, we improve safety
reporting through educational presentations to industry.
These provide industry with a direct opportunity to expand
their understanding of reporting requirements and best
practices in drug safety and to alert them to pending
regulatory changes. These meetings also serve to expand our
own knowledge of industry’s worldwide pharmacovigilance
activities. Our educational activities include formal
presentations at global industry meetings and training for
FDA field investigators.
Adverse event electronic submissions
Electronic submission of adverse
event reports permits more timely receipt and evaluation at
considerable cost savings for us and industry. Our
initiative to encourage electronic reports continues to make
progress and remains a high priority. We provide useful
information on electronic adverse event reports at
http://www.fda.gov/cder/aerssub/default.htm.
AERS on Internet
You can learn more about the
Adverse Event Reporting System at
http://www.fda.gov/cder/aers/default.htm.
Data mining
We concluded work under our two-year data mining cooperative
research and development agreement with a commercial firm to develop
advanced software tools for quantitative analysis of drug safety
data. The resulting software, WebVDME, is now in full production use
by safety evaluators and epidemiologists. Data mining for simple
drug-event signal generation is one potential contribution data
mining and related quantitative methods can make to increase our
awareness and understanding of trends and patterns in adverse drug
reactions.
Population-based drug safety evaluation
New contracts will help us evaluate the safety of newly marketed
drugs faster and more effectively. We awarded four contracts that
give us access to databases that include more than 20 million
patients in different geographic areas and include special
populations. The contracts, which give us more flexibility and
access to a wider range of data resources than we previously had,
can be used to:
n
Conduct safety analyses.
n
Respond in a timely manner to urgent
public safety concerns.
n
Provide a mechanism for collaborative
research designed to test hypotheses, particularly those arising
from suspected adverse reactions reported to us.
n
Enable our rapid access to U.S.
population-based data sources to ensure public safety when
necessary.
Back
to Index
MedWatch Outreach and Reporting
We administer the MedWatch program that
helps promote the safe use of drugs by:
n
Rapidly disseminating new safety information
on the Internet and by providing e-mail notification to
health professionals, institutions, the public and our
MedWatch partners consisting of professional societies,
health agencies and patient and consumer groups.
n
Providing a mechanism for health professionals
and the public to voluntarily report serious adverse events,
product quality problems and product use errors for all
FDA-regulated medical products. Reports can be filed by
mail, fax, telephone or the Internet.
n
Educating health professionals and consumers
about the importance of recognizing and reporting serious
adverse events and product problems, including medication
errors. Our education program includes Internet outreach,
speeches, articles and exhibits.
Individual health-care professionals and consumers can
subscribe to our e-mail notification service, which now has
56,000 members. We also have 160 MedWatch Partner
organizations. In 2005, these individuals and groups
received:
n
109 safety alerts for drugs and therapeutic
biologics.
n
25 to 70 safety-related labeling changes for
drugs each month.
MedWatch Internet resources
n
You can find the latest medical product safety information
at
http://www.fda.gov/medwatch/.
n
You can sign up for immediate e-mail notification of
MedWatch safety information at
http://www.fda.gov/medwatch/elist.htm.
Back
to Index
Public Health
Advisories in 2005
We issued 16 advisories
to alert health-care providers and consumers to:
n
Increased liver toxicity associated
with the anti-HIV drug nevirapine.
n
Concerns about the risk of sudden death in patients treated with
Adderall XR,
a drug product containing amphetamines, and a Canadian action on the
product.
n
Our warning to avoid using the
epilepsy drug tiagabine in patients without epilepsy
because of seizures.
n
The suspended marketing of
natalizumab, a treatment for multiple sclerosis, which was
remarketed in 2006 with a risk management plan.
n
Our advice that the eczema therapies
pimecrolimus and tacrolimus only be used as
directed—that is for short term use and not at all in children
younger than 2 years of age—and only after other treatments have
failed to work because of a potential cancer risk.
n
An increased risk for serious muscle
toxicity associated with the cholesterol-lowering drug
rosuvastatin, especially at the highest approved dose.
n
The increased risk of heart attack and
stroke associated with the long-term use of non-steroidal
anti-inflammatory drugs.
n
Increased deaths when
atypical antipsychotic drugs are used to treat behavioral
disorders in elderly patients.
n
Suicidality in adults being treated
with antidepressants.
n
The suspended marketing of
Palladone, an extended-release formulation of an opioid pain
medication.
n
Our highlighting the importance of the
safety information in the labeling when using fentanyl
transdermal skin patches for pain control because of reports of
death and other serious side effects.
n
Four cases of fatal infection in women
following medical abortion with mifepristone.
n
Suicidal thinking in children and
adolescents associated with atomoxetine, a drug
approved to treat attention deficit hyperactivity disorder.
n
Possible increased risk of worsening
wheezing and death in some people treated with several long-lasting
bronchodilator medicines.
n
Increased risk for congenital
malformations when the antidepressant paroxetine is
used in the first trimester of pregnancy.
n
The marketing suspension of a
diagnostic imaging agent.
Internet resources
Links to our Public Health Advisories and
associated information are at
http://www.fda.gov/cder/news/pubpress.htm.
Medication Guides
We may require specific
written patient information for selected prescription drugs
that pose a serious and significant public health concern.
This information is called a Medication Guide. We require
Medication Guides when the information is necessary for
patients to use the product safely and effectively.
In 2005, we approved Medication Guides for
prescription pain relievers with any of 18 nonsteroidal
anti‑inflammatory ingredients (below) and these five other drugs:
n
Atomoxetine hydrochloride (Strattera).
n
Lenalidomide (Revlimid).
n
Pramlintide acetate (Symlin).
n
Tamoxifen citrate (Soltamox).
These Medication Guides must be provided to
patients with each prescription dispensed.
NSAID MedGuide active ingredients
n
Celecoxib
n
Diclofenac
n
Diflunisal
n
Etodolac
n
Fenoprofen
n
Flurbiprofen
n
Ibuprofen
n
Indomethacin
n
Ketoprofen
n
Ketorolac
n
Mefanamic acid
n
Meloxicam
n
Nabumetone
n
Naproxen
n
Oxaprozin
n
Piroxicam
n
Sulindac
n
Tolmetin
User fees support risk
assessment, minimization
In recent years, about half of all new
medicines marketed worldwide have been launched in the United States,
and American patients have had access to about
three-quarters of the world’s new medicines within the first
year of their introduction.
The law authorizing us to
collect user
fees allows us to
spend some of those funds to increase our assessment and
minimization of risks of medicines both before they are
approved and after approval:
n
Preapproval. Sponsors are invited to
submit proposed risk management plans before they submit an
application for a new drug or biologic. Our drug safety
experts carefully review the proposals and begin discussions
with sponsors at this early stage that continue through
application review and after approval.
n
Postapproval. User fees also fund
surveillance of the safety of medicines during their first
two years on the market or three years for potentially
dangerous medications. It is during this initial period,
when new medicines enter into wide use, that we are most
likely to identify and counter adverse side effects that did
not appear during the clinical trials.
Risk management guidances
published
We published three risk management
draft guidances for industry in 2005:
n
Premarketing Risk Assessment focuses on
measures companies might consider throughout all stages of a
medicine’s clinical development.
n
Development and Use of Risk Minimization
Action Plans describes how to address specific
risk-related goals and objectives and also suggests various
tools to minimize the risks of drug and biological products.
n
Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment identifies recommended
reporting and analytical practices to monitor the safety
concerns and risks of medicines in general use.
The three guidances fulfill our commitment to the risk
management performance goals that are part of the 2002
reauthorization of the Prescription Drug User Fee Act.
Medication Error
Prevention
Avoiding name, label, labeling and packaging confusion
We work hard to ensure the safe use of
drugs we approve by weeding out brand names that look or
sound like the names of existing products. We identify and
avoid brand names, labels, labeling and packaging that might
contribute to problems or confusion in prescribing,
dispensing or administering drug products.
We review about 300 post-marketing
reports of medication errors each month. About half are due
to error-prone labeling such as similar looking labels and
labeling, poor package design, confusing instructions for
use and confusing names. We investigate the causes and
contributing factors of these errors and recommend
revisions to the label, labeling and/or packaging of these
products to avert further error.
Our comprehensive Web site on
medication errors is at
http://www.fda.gov/cder/drug/MedErrors/default.htm.
Bar codes required on medicines
Our regulation that calls for medicines
to have a bar code became final in February 2004. It covers
most prescription medicines and certain over-the-counter
medicines commonly used in hospitals. The bar code rule aims
to protect patients from preventable medication errors by
helping ensure that health professionals give the right
patient the right drug, at the appropriate dosages, at the
right time. The rule will support and encourage widespread
adoption of advanced information systems that, in some
hospitals, have reduced medication error rates by as much as
85 percent.
We estimate that the rule will help
prevent nearly 500,000 adverse events and transfusion errors
while saving $93 billion in health costs over 20 years.
Back
to Index
Drug Shortages
We work to help prevent or alleviate
shortages of medically necessary drug products. Drug
shortages occur for a variety of reasons including
manufacturing difficulties, bulk supplier problems and
corporate decisions to discontinue drugs. Because drug shortages can have
significant public health consequences, we work with all
parties involved to make sure all medically necessary
products are available within the United States.
Drug shortage program aids counterterrorism effort
Utilizing data obtained from
manufacturers and distributors, our drug shortage program
provides supply and production information in response to
federal government requests in relation to counterterrorism
efforts.
Drug shortages on the Internet
We have a Web site that lists
current drug shortages, describes efforts to resolve them
and explains how to report them.
n
The site is at
http://www.fda.gov/cder/drug/shortages.
n
We have an e-mail address to provide the public a
communication tool for drug shortage information at
DrugShortages@fda.hhs.gov.
Back
to Index
Back
to Contents
Next
Page
Back to Top
Back to
About CDER
PDF requires the free Adobe
Acrobat Reader
Date created: August 18, 2006 |