CDER
Report to the Nation: 2005
Table
of Contents
Print version
Slides of charts for presentations
2 Drug Safety and Quality
(continued)
Index
Drug Recalls
In some cases, a drug product must be
recalled due to a problem occurring in the manufacture or
distribution of the product that may present a significant
risk to public health. These problems usually, but not
always, occur in one or a small number of batches of the
drug. The most common reasons for drug recalls include those
listed in the column at the left. In other cases, a drug is
determined to be unsafe for continued marketing and must be
withdrawn completely.
Manufacturers or distributors usually
implement voluntary recalls in order to carry out their
responsibilities to protect the public health when they need
to remove a marketed drug product that presents a risk of
injury to consumers or to correct a defective drug product.
A voluntary recall of a drug product is more efficient and
effective in assuring timely consumer protection than an
FDA-initiated court action or seizure of the product.
How we coordinate drug recalls
We coordinate drug recall information,
assist manufacturers or distributors in developing recall
plans and prepare health hazard evaluations to determine the
risk posed to the public by products being recalled.
We classify recall actions in
accordance to the level of risk. We participate in
determining recall strategies based upon the health hazard
posed by the product and other factors including the extent
of distribution of the product to be recalled. We determine the need for public
warnings and assist the recalling firm with public
notification about the recall.
Spike in 2005 recalls
One firm had more than 100 recalls in 2005, which caused
a spike in the recall figures.
Drug recalls in fiscal year 2005
n
401 prescription drugs
n
101 over-the-counter drugs
Click image for larger chart,
click here for accessible
text.
Top 10 reasons for drug recalls in fiscal year 2005
n
Miscellaneous cGMP
deviations (other than below)
n
Failed USP dissolution test
requirements
n
Microbial contamination of
non-sterile products
n
Lack of efficacy
n
Impurities/degradation
products
n
Lack of assurance of
sterility
n
Lack of product stability
n
Labeling: Label error on
declared strength
n
Misbranded: Promotional
literature with unapproved therapeutic claims
n
Labeling: Correctly labeled
product in incorrect carton or package
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Safety-based Drug Withdrawals
In some cases, there is an intrinsic property of a drug
that makes it necessary to withdraw the drug from the market
for safety reasons. The rates of safety-based withdrawals of
new molecular entities are similar for an earlier period
before we collected user fees and for the period, beginning
Oct. 1, 1992, when we collected user fees (click
here). Our time periods are based on when we
received an application rather than when we approved it.
Beginning Oct. 1, 2003, approvals include new therapeutic
biologics. Applications exempt from user fees are also
counted.
Click image for larger chart,
click here for accessible
text.
Four safety withdrawals of NMEs or new BLAs in 2005
n
Valdecoxib,
a COX-2 selective non-steroidal anti-inflammatory pain
reliever, was withdrawn because it carried an increased risk
of serious skin reactions in addition to the risk of heart
disease associated with prescription NSAIDs.
n
Pemoline,
a central nervous system stimulant treatment
for attention deficit hyperactivity disorder, was withdrawn
because of its overall risk of liver toxicity and
association with life-threatening liver failure.
n
Natalizumab,
a treatment for multiple sclerosis, was withdrawn because
three patients developed a serious viral infection of the
brain. It was reintroduced in 2006 with a special restricted
distribution program.
n
Technetium (99m Tc)
fanolesomab, a radiological
imaging agent for unclear signs and symptoms of
appendicitis, was withdrawn for fatal and life-threatening
cardiopulmonary arrest occurring shortly after
administration.
One non-NME safety withdrawal in 2005
n
Palladone,
a brand of hydromorphone hydrochloride extended-release
capsules, was withdrawn because serious and potentially
fatal adverse reactions could occur if the drug was taken
with alcohol, which harmed the extended-release mechanism
and could lead to dose-dumping.
Recent safety-based NME withdrawals
Drug name
(FY received [bold=PDFUA]/CY approved/CY
withdrawn)
approved use/reason withdrawn
n
Azaribine
(1970/1975/1976)
psoriasis treatment/serious blood clots
n
Ticrynafen
(1978/1979/1980)
blood pressure reduction/liver toxicity
n
Benoxaprofen
(1980/1982/1982)
pain relief/liver toxicity
n
Zomepirac
(1979/1980/1983)
pain relief/fatal allergic reaction
n
Nomifensine
(1979/1984/1986)
antidepressant/hemolytic anemia
n
Suprofen
(1979/1985/1987)
pain relief/acute kidney failure
n
Encainide
(1984/1986/1991)
irregular heartbeat/fatal arrhythmia
n
Temafloxacin
(1990/1992/1992)
antibiotic/kidney failure
n
Flosequinan
(1991/1992/1993)
congestive heart failure/increased deaths
n
Fenfluramine
(1967/1973/1997)
appetite suppression/heart valve disease
n
Terfenadine
(1983/1985/1998)
antihistamine/fatal arrhythmia
n
Bromfenac
(1995/1997/1998)
pain relief/liver toxicity
n
Mibefradil
(1996/1997/1998)
blood pressure reduction/serious drug-drug interactions
leading to muscle damage and fatal arrhythmia
n
Grepafloxacin
(1997/1997/1999)
antibiotic/fatal arrhythmia
n
Astemizole
(1985/1988/1999)
antihistamine/fatal arrhythmia
n
Cisapride
(1991/1993/2000)
heartburn/fatal arrhythmia
n
Troglitazone
(1996/1997/2000)
diabetes/liver toxicity
n
Alosetron
[Remarketed in 2002 with
restricted distribution]
(1999/2000/2000)
irritable bowel syndrome/ischemic colitis, severe
constipation
n
Cerivastatin
(1996/1997/2001)
cholesterol reduction/muscle damage leading to kidney
failure
n
Rapacuronium
(1998/1999/2001)
anesthetic/severe breathing difficulty
n
Etretinate
(1985/1986/1999)
psoriasis/birth defects
n
Levomethadyl
(1993/1993/2003)
opiate dependence/fatal arrhythmia
n
Rofecoxib
(1999/1999/2004)
pain relief/heart attack, stroke
n
Valdecoxib
(2001/2001/2005)
pain relief/skin disease
n
Natalizumab
[Remarketed in 2006 with restricted distribution]
(2004/2004/2005)
multiple sclerosis/brain infection
n
Technetium (99m Tc) fanolesomab
(2000/2004/2005)
diagnostic aid/cardiopulmonary arrest
n
Pemoline
(1969/1975/2005)
ADHD/liver failure
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Drug Promotion Review
The information about a
drug available to physicians and consumers is critically
important to its safe use. We promote and
protect the health of Americans by ensuring that drug
advertisements and other promotional materials are truthful
and balanced. We operate a comprehensive program of
education, surveillance and enforcement about drug
advertising and promotion.
Surveillance of drug promotion activities
Drug advertising and
promotion must be truthful, fair, balanced and not
misleading. We issue letters to ensure compliance with our
regulations when asked or as a result of our own
surveillance.
Regulatory letters citing violations
We issued 60 regulatory action letters to
companies for prescription drug promotions determined to be
false, misleading, lacking in fair balance of risks and
benefits or that promoted a product or indication before
approval. These were either “untitled” letters for
violations or “warning” letters for more serious or repeat
violations. Examples of violative promotions include exhibit
hall displays, oral representations, Internet sites, plus
traditional materials such as journal advertisements, sales
brochures and TV ads.
Click image for larger chart,
click here for accessible text.
Click image for larger chart,
click here for accessible text.
Launch campaign advisory letters
When requested, we review advertisements
and other promotional materials before drug companies launch
marketing campaigns that introduce either new drugs or new
indications or dosages for approved drugs. In 2005,
we issued 158 advisory letters to companies regarding their
promotional materials for launch campaigns.
Other advisory letters
We issued 348 other advisory letters to
the industry regarding proposed promotional pieces, both
professional- and consumer-directed. We also issued 122
other types of correspondence to the pharmaceutical
industry, such as letters of inquiry, closure letters or
acknowledgement letters.
Direct-to-consumer
promotion
We are reviewing and developing methods
to increase our effectiveness in the oversight of
direct-to-consumer advertising. Evidence from our own
studies as well as those conducted by consumer groups and
other entities consistently shows that direct-to-consumer
ads encourage some patients to seek care for undertreated
conditions. This often results in prescription of a
treatment that
is not the one advertised but a treatment that is more appropriate for the patient. But physicians and others are concerned that consumers
may not always get a balanced view of the benefits and risks
of a product and may sometimes be given drugs they do not
need or are not the best choice.
Public meeting addresses DTC promotion
issues
In November 2005, we took part in a two-day FDA public
hearing on direct-to-consumer promotion of regulated medical
products, including prescription drugs for humans. We heard
more than 30 presentations representing the viewpoints of
consumers, patients, caretakers, health professionals,
managed care organizations, insurers and the regulated
industry. Topics included:
n
Various ways of presenting
risk and benefit information to consumers, including what
and how it should be presented in consumer friendly
language.
n
The impact of DTC promotion on
the diagnosis and treatment of disease.
n
How DTC promotion might impact
under-treated and under-diagnosed medical conditions.
n
Data from research conducted
related to DTC promotion.
n
The use of celebrities in DTC
promotion.
n
The use of disease awareness
campaigns.
n
The impact of images and
graphics on promotions and reminder advertisements.
We are reviewing the comments from the
meeting and an additional 1,200 written comments submitted
to us.
DTC promotion letters
In 2005, 203 or 30 percent of the letters we issued
concerned direct-to-consumer promotion.
We issued guidance on direct-to-consumer
broadcast advertisements in 1997. Since then, the number of
letters addressing direct-to-consumer promotion and their
percentage of the total letters addressing promotion have
been:
n
2005: 203 (30%)
n
2004: 217 (27%)
n
2003: 254 (34%)
n
2002: 188 (27%)
n
2001: 190 (22%)
n
2000: 215 (24%)
n
1999: 247 (19%)
n
1998: 282 (44%)
n
1997: 240 (31%)
DTC promotion research
We are conducting three studies to help
find the best way or ways to present information in the
“brief summary”—the page of risk information in a print ad:
n
Purpose.
The first study will concern the purpose of
the brief summary—how do people use it and what topics do
they find most useful. We hope to have data collected for
this study by the end of summer 2006.
n
Content.
The second study will address content issues
in the brief summary, including the amount of common side
effect information and the inclusion of numerical context.
n
Format.
The third study will examine format issues,
such as graphics, layout and font.
Back
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Compliance Oversight
We provide comprehensive regulatory
coverage of the production and distribution of drug
products. We manage inspection programs designed to minimize
consumer exposure to defective drug products. We have three
basic strategies to meet this goal:
n
Evaluate the findings of
inspections that examine the conditions and practices in
plants where drugs are manufactured, packed, tested and
stored.
n
Monitor the quality of
finished drug products in distribution, through sampling and
analysis.
n
Monitor drug products to
ensure that they comply with applicable approval and
labeling requirements.
We identify, evaluate and analyze inspection findings for
trends in deficiencies. We publish guidances to assist drug
manufacturers in gaining a better understanding of our
regulations. We communicate the expectations of compliance
through outreach programs. We review and evaluate for
regulatory action all reports of FDA inspections of foreign
drug manufacturing facilities. We determine which foreign
manufacturers are acceptable to supply active pharmaceutical
ingredients or finished drug products to the U.S. market.
Risk-based surveillance sampling of
drugs
We monitor the quality of the nation’s
drug supply through surveillance and sampling of foreign and
domestic finished dosage forms and bulk shipments of active
ingredients.
The drug products surveyed are selected
according to a risk-based strategy that targets products
with the greatest potential to harm the public health. FDA
district offices conduct follow-up inspections to
determine the cause of sample failures and
to assure corrective action by the firms.
Criteria for risk-based sampling
n
Microbial/endotoxin concerns
n
Stability concerns
n
Sterility issues
n
Dissolution issues
n
Impurities/contaminants
n
Product quality history
n
Counterfeit drugs
n
History of violations.
Compounded drugs
We generally defer to state authorities
regarding the regulation of traditional pharmacy
compounding—on-site compounding of reasonable quantities of
drugs by a pharmacist in response to a practitioner’s
prescription for an individual patient to accommodate the
specialized medical needs of that particular patient.
Manufacturing disguised as compounding
Some pharmacies manufacture and
distribute compounded drugs in a way that goes beyond
traditional pharmacy practice. Many of these pharmacies make
large quantities of unapproved drugs in advance of receiving
valid prescriptions. They also copy commercially available
drugs when there is no medical need to do so. We hold
pharmacies that manufacture drug products under the guise of
pharmacy compounding to the same federal legal requirements
as drug manufacturers.
Furthermore, some pharmacies have
compounded drugs that are contaminated, dangerously
subpotent (weak) or superpotent (strong). In these
situations, we take steps to protect the public from these
products. These steps include issuing enforcement letters,
referring complaints to state authorities, providing support
when states ask, and pursuing enforcement actions, such as
seizure of violative products.
Misbranded drugs, unsubstantiated
claims
Mislabeled, fraudulent, hazardous
products. We often encounter mislabeled and fraudulent
products that make unsubstantiated claims. Consumers may use
these products inappropriately. They may use a fraudulent
product for treating a serious disease in place of an
approved, effective treatment, or they may delay the use of
a proper treatment in favor of a fraudulent remedy.
Fraudulent products may also contain toxic compounds or
other hazardous substances that have the potential to cause
serious illness, injury or even death. For these reasons,
products that are mislabeled, fraudulent or make unproven
claims may pose a significant health risk.
Protecting consumers from misbranded or
fraudulent drugs
We protect consumers from mislabeled,
fraudulent or hazardous products. We locate and identify
these products on the Internet and other outlets, and we
take steps to prevent their sale and to remove them from the
market. These steps include issuing enforcement letters and
pursuing enforcement actions, such as seizures of violative
products and injunctions against firms and individuals. We
also work with other federal agencies to coordinate
enforcement action against firms and individuals who violate
federal law.
We may also take steps to warn the public
about misbranded and fraudulent products. These steps
include issuing press releases and MedWatch alerts to warn
consumers about the potential health risks associated with
these products.
Drugs sold without required applications
We identify drugs that are marketed
without an approved new or generic drug application. The
marketing of products that lack required FDA approval may
present safety risks and threatens to undermine the U.S.
drug development and approval process, as well as the
over-the-counter drug review process.
We estimate that there are several
thousand illegally marketed drug products in the United
States, comprised of several hundred unique molecules. We
issued a draft guidance in 2003 that describes how we intend
to:
n
Encourage companies to sponsor
unapproved drugs through the approval process.
n
Avoid unnecessarily
restricting patient access to useful medicines.
n
Use risk-based criteria for
enforcement action.
Regulation of over-the-counter drugs
The formulation of OTC drugs and the
information that accompanies them or is displayed with them
is critical to their safe use.
Approved drug applications
and OTC drug monographs
(click here)
define acceptable formulations and the consumer
labeling and promotional statements for drugs sold
over-the-counter.
We monitor the statements that accompany
these products along with their formulations to make sure
they comply with the appropriate application or final
monograph.
We also monitor the formulations,
labeling and promotional materials associated with
over-the-counter drugs marketed without an approved
application or final monograph, including fraudulent drugs,
and take enforcement actions against these products where
necessary.
Council for Pharmaceutical Quality
FDA formed a Council for Pharmaceutical
Quality in 2005 to oversee policy development and
implementation, including the ongoing implementation of
internal quality management systems relating to drug quality
regulations.
Through our active participation in this program, we have
provided the Pharmaceutical Inspectorate advanced training
on risk-based approaches to inspections, modern quality
systems and the legal and scientific application of good
manufacturing practice regulations to manufacturing
operations. We certified the first class of these highly
trained investigators and are preparing for the next class.Back
to Index
Manufacturing Plant Inspections
FDA field offices conduct inspections of
domestic and foreign plants that manufacture, test, package
and label drugs. Before a drug is approved, FDA
investigators must determine if data submitted in the firm’s
application are authentic and if the plant is in compliance
with good manufacturing practices. After a drug is approved,
FDA conducts periodic inspections to make sure a firm can
consistently manufacture the product with the required
quality. We develop compliance programs to guide the
investigators in conducting these inspections, and we
identify facilities that are high priority for inspection
based on their identified risk potential.
Prioritizing sites for inspection
Our 2004 white paper,
Risk-Based Method for Prioritizing CGMP Inspections of
Pharmaceutical Manufacturing Sites—A Pilot Risk Ranking
Model, creates a formal risk ranking of manufacturing
plants by using an analytical process to:
n
Pose a risk question.
n
Identify potential hazards and
risks.
n
Characterize factors that can
be used as variables for quantifying risk.
n
Mathematically combine the variables to yield
an overall risk score.
This program continues to be refined and
improved by better evaluation of the risk factors available
to us. For example, we added adverse experience reports data
to the model in addition to the many data sources already
being used. This allows us to maximize our limited resources
by focusing our field force on those sites that most affect
product quality and safety.
Good manufacturing practice enforcement
We have acted under our regulatory
enforcement program to address products not manufactured
under current good manufacturing practice regulations. We
provide expert technical support that employs science and
risk-based principles in applying these regulations. As a
result, many corrections are achieved voluntarily or through
administrative means. Some corrections, though, require the
involvement of the judiciary system. One case of note
resulted in a court-ordered injunction against a firm
violating cGMPs and selling unapproved drugs. The judge in
this case stated that he was “simply unwilling as a court of
equity to place the health, safety and welfare of the
general public at risk in order to accommodate the economic
well-being of defendants.”
Domestic drug plant inspections
In fiscal year 2005, FDA field office
inspections included:
n
188 preapproval inspections
in support of:
o
105 new drug applications
o
98 generic drug applications
n
1,437 current good
manufacturing practice inspections
For these, we approved 22 field
recommendations for regulatory action, including:
o
15 warning letters
o
6 injunctions
o
1 seizure
n
152 medical gas inspections
We reviewed 152 medical gas inspections
and approved two warning letters.
Biologics license inspections
Our experts conduct the preapproval inspections in
support of biologics license applications and supplements to
them. In fiscal year 2005, there were:
n
9 domestic inspections
n
3 foreign inspections
In other work to ensure the quality of
biologics, we reviewed:
n
4 supplements for which we
waived the inspection
n
35 supplements that did not
require an inspection
n
63 annual reports
We held 38 meetings with industry and
answered 38 inquiries about good manufacturing practices.
Foreign drug inspections
There were 213 foreign
current good manufacturing practice inspections and 234
foreign preapproval inspections in 2005
(click here).
Correction
In previous editions of
this report, the data labeled “preapproval inspections” were
for “establishment evaluation requests.” All requests are
evaluated, but only some trigger an in-plant inspection.
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Drug Quality
Surveillance Systems
Our reporting tools help us rapidly
identify significant health hazards and quality problems
associated with the manufacturing and packaging of
medicines. Problems that may affect a medicine’s safety,
purity or potency may occur during manufacturing, processing, packing, labeling, storage or distribution.
We evaluate reports and FDA field
inspections to identify specific firms with manufacturing
quality problems with the most potential impact on public
health. We target these candidates for inspection and
further product sampling and laboratory analysis. We
recommend appropriate corrective actions based upon our
analysis of the findings. We may take enforcement action in
some cases.
Drug quality reports
n
325 field alerts
n
2,864 MedWatch reports
Click image for larger chart,
click here for accessible text.
Click image for larger chart,
click here for accessible text.
Types of reports
n
Drug Quality Reporting System. Through MedWatch
(click
here), we receive
reports from consumers and health care professionals of
observed and suspected product quality defects. Our central
reporting system assists us in evaluating and prioritizing
these data to identify potential manufacturing quality
problems and industry trends.
n
Field Alert Reports. Firms are required to promptly
notify FDA district offices about possible quality and
labeling problems that may represent a safety hazard.
Experts in FDA district offices evaluate the reports and
conduct further investigations when needed.
n
Biological Product Deviation Reports. Manufacturers are
required to report any event associated with the
manufacturing of a therapeutic biological that may affect
its safety, purity or potency.
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Product
Quality Science
The Pharmaceutical
cGMPs for the 21st Century Initiative
(click here)
stresses the need to apply more scientific and
engineering knowledge to regulatory decision making and to
the evaluation of manufacturing processes. The goal is to
improve upon the overall efficiency and effectiveness of
manufacturing processes and to enhance product quality. We
have looked closely at manufacturing science to develop
recommendations for improvements.
One of the areas that
we focused on was the Process Analytical Technologies
Initiative. The capability to use process analytical
technologies encourages manufacturers to be innovative and
to apply state-of-the-art quality assurance methodologies to
their manufacturing processes. Process analytical
technologies incorporate assessment of a product’s
characteristics in real-time and feed that information back
into process control systems that maintain the desired state
of product quality throughout manufacturing.
2005 progress highlights
We moved into the
implementation phase after the release of our final PAT
guidance in 2004. We note the following highlights:
n
PAT review and inspections.
PAT applications and
implementations have been approved or passed inspection for
brand-name products, generics, over-the-counter drugs and
active pharmaceutical ingredients.
n
Training.
There have been a number of training sessions for PAT,
including training of the Pharmaceutical Inspectorate. We
have developed plans for extensive internal training on PAT
concepts to prepare our reviewers to routinely incorporate
PAT evaluation into standard reviews.
n
Industry interactions.
We continue to facilitate the
adoption of PAT. Dialogue continues with all segments of the
industry.
n
Academics.
We note the development of several academic programs
dedicated to PAT both domestically and in Europe and Asia.
We continue to evaluate
those scientific and engineering tools that support a better
understanding of product and process and that will help:
n
Reduce production time and
delays in product release.
n
Prevent rejections, scrap
and reprocessing.
n
Improve operator safety and
reduce human error.
n
Use small-scale equipment to
eliminate certain scale-up issues and dedicated
manufacturing facilities.
n
Improve energy and material
use and increase capacity.
PAT Web site
More information on
process analytical technologies can be found at
http://www.fda.gov/cder/OPS/PAT.htm
Laboratory support
We assessed several analytical
technologies for characterizing active pharmaceutical
ingredients and guarding against counterfeit product
marketing. We applied near infrared, Raman, Isotope ratio
mass spectrometry to the problem of distinguishing between
production sources of active pharmaceutical ingredients and
finished dosage forms.
We developed methodology to better
characterize nasal spray products. We evaluated a new
aerodynamic particle size analyzer.
We evaluated instrumentation for the
determination of particle size and particle size
distribution for cyclosporin drug products.
We are developing physicochemical
methods to assess quality changes in liposomal drug
products.
Microbiology
We assess product
sterility, maintenance of product safety and the
microbiological controls used by firms for drug development
and manufacturing.
Our microbiology review
assures the safety of sterile and non-sterile products
through scientific evaluation and communication with the
industry and assures consistency through guidance documents.
We promote the
development of uniform and practical test methods and
criteria for our own use and through the U.S. Pharmacopoeia
and the International Conference on Harmonization
(click here).
We have a new program
to advance rapid microbiology test methods.
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Date created: August 14, 2006 |