CDER
Report to the Nation: 2004
Table
of Contents
Print version
Slides of charts for presentations
Drug Review
(continued)
Index
Pediatric Drug Development
2004 pediatric drug statistics
n
19 written requests issued
n 25 pediatric exclusivity labeling changes granted
n 17 exclusivity determinations made
The Best Pharmaceuticals for Children
Act of 2002 renewed our authority to grant six months of
additional marketing exclusivity to manufacturers who
conduct and submit pediatric studies in response to our
written requests. In calendar year 2004, we approved 25
pediatric labeling changes as a result of the exclusivity
provision.
n
NME approval. We provided a priority review and
orphan status to one new molecular entity—clofarabine
(Clolar)—for use in children
(click here).
n
Exclusivity. As of April 30, 2005, we had received
374 proposed pediatric study requests from manufacturers,
issued 300 written requests, made 121 exclusivity
determinations, granted exclusivity to 111 drugs and added
new pediatric information to 90 labels.
n
Improved safety, dosing information. About one-fourth
of the new pediatric labels have safety or dosing information. We are discovering important differences
between adults and children in the clearance and metabolism
of drugs. Underdosing leads to ineffective treatment, and
overdosing poses a greater risk of adverse reactions.
Pediatric safety signals identified in these studies include
effects on growth, school behavior, suppression of the
adrenal gland and suicidal ideation. As a result of this
pediatric testing we now have 10 drugs with new pediatric
formulations and six drugs with recipes in their labels to
provide directions for the pharmacist to compound an
age-appropriate formulation. The failure to produce drugs in
dosage forms that can be taken by young children—such as
liquids or chewable tablets—can also deny them access to
important medications.
n
Off-patent drugs. The law also established a publicly
funded contracting process to study drugs that lack patent
protection or market exclusivity, referred to as
“off-patent.” In consultation with FDA and other pediatric
experts, the National Institutes of Health has published
four lists of off-patent drugs for which additional
pediatric studies are needed. We have issued and forwarded
11 written requests—four in 2004—for these off-patent drugs.
We also forwarded five written requests for on-patent drugs,
for which sponsors declined pediatric studies.
n
Public disclosure. We publish a summary of the
medical and clinical pharmacology reviews of the pediatric
studies conducted under the law. We have posted 49
summaries, regardless of the regulatory action, at
http://www.fda.gov/cder/pediatric/Summaryreview.htm.
n
Adverse events reported. The act mandates review of
all adult and pediatric adverse event reports for a one-year
period after pediatric exclusivity is granted and
presentation of these reports to a pediatric advisory
committee. As of February 2005, reports for 34 drugs have
been presented. Significant pediatric safety signals have
been found, including neonatal withdrawal with
antidepressant use during pregnancy and serious adverse
events, including deaths, due to fentanyl transdermal use.
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Notable 2004 pediatric new or
expanded uses
The Best Pharmaceuticals for Children
Act requires us to provide priority reviews to pediatric
supplements for drugs submitted under the law. Reviews of
these supplements resulted in new or expanded medication
opportunities for children [number of approvals]:
n
Ciprofloxacin (Cipro) can be used to
treat complicated urinary tract infections and
pyelonephritis for pediatric patients 1 to 17 years of age.
[4]
n
Fenoldopam mesylate (Corlopam) can be
used for in-hospital, short-term (up to 4 hours) reduction
in blood pressure in pediatric patients. [1]
n
Lansoprazole (Prevacid) can be used to
treat symptomatic gastroesophageal reflux disease,
nonerosive esophagitis and erosive esophagitis in pediatric
patients between 12 and 17 years of age. [1]
n
Methylphenidate (Concerta)
extended-release tablets (previously approved for pediatric
patients 6 to 12 years of age) can be used in adolescents
with attention deficit hyperactivity disorder. Labeling has
been expanded to include a 72 mg dose. [1]
n
Nelfinavir mesylate (Viracept) in
combination with other antiretroviral agents can be used to
treat HIV-1 infection in pediatric patients from 2 to 13
years of age. [3]
n
Paricalcitol (Zemplar) can be used in
pediatric patients with end-stage kidney disease. [1]
n
Sodium ferric gluconate complex in sucrose
(Ferrlecit) can be used to treat iron deficiency
anemia in pediatric patients age 6 years and older who are
undergoing chronic hemodialysis and receiving supplemental
erythropoietin therapy. [1]
2004 priority pediatric labeling changes
An efficacy supplement may change
labeling to reflect new information about pediatric use,
even if there are no new or expanded uses. Consistent with
the Best Pharmaceuticals for Children Act, we gave priority
reviews to these pediatric supplements [number of approvals]:
n
Anagrelide hydrochloride [1]
n Benazepril hydrochloride
[1]
n Dorzolamide hydrochloride ophthalmic solution
[1]
n Glyburide and metformin hydrochloride
[1]
n Irinotecan hydrochloride
[1]
n Lansoprazole
[2]
n Tolterodine [1]
n Venlafaxine hydrochloride
[1]
n
Zolmitriptan [1]
Pediatric study information in labeling
We work with sponsors to put more
information on pediatric studies into their labels even when
the studies did not show efficacy for the indication
studied.
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Some conditions with approved
pediatric labeling
n Abnormal heart rhythms
n Allergies
n Anesthesia and
sedation
n Asthma
n Attention deficit
hyperactivity disorder
n Diabetes mellitus
(Type 1 and Type 2)
n Gastroesophageal
reflux
n High blood pressure
n High cholesterol
n High eye pressure
n HIV infection
n Infectious diseases
n Juvenile rheumatoid
arthritis
n Low levels of calcium
in severe kidney disease
n Malaria
n Nerve agent poisoning
n Obesity
n Obsessive compulsive
disorder
n Pain
n Seizures
n Severe recalcitrant
nodular acne
Internet resources
Our Web site for up-to-date
pediatric labeling changes is at
http://www.fda.gov/cder/pediatric/index.htm.
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to Index
Pregnancy and Lactation
Labeling
To improve our knowledge of the use of
drugs during pregnancy and lactation, we sponsor research
and provide scientific guidance to industry and our
reviewers.
Women who are pregnant often need to
use prescription medicines. In many cases, a disease or
condition left untreated may be more harmful to a woman and
her fetus or nursing baby than a drug treatment. In other
cases, a different drug treatment than she is already on may
be safer.
We have reviewed the current system of
labeling drugs for use by pregnant and lactating women and
are developing an improved, more comprehensive and
clinically meaningful approach. We consult with government
agencies, medical experts, consumer groups and the
pharmaceutical industry to develop this new labeling format.
We work with our reviewers and pharmaceutical companies to
update product labels with available human data regarding
exposure to drugs during pregnancy and lactation.
Scientific guidance
n
Risks of drug exposure in human
pregnancies. In 2005, we issued our final guidance for
our reviewers on how to evaluate human data on the effects
of in utero drug exposure on the developing fetus.
n
Lactation studies in women. In 2005, we
published a draft guidance for industry that provides the
basic framework for designing, conducting and analyzing
clinical lactation studies.
n
Determining the appropriate dose of a drug
for pregnant women. In 2004, we published a draft
guidance for industry that provides the basic framework for
designing, conducting and analyzing pharmacokinetic and
pharmacodynamic studies in pregnant women.
n
Pregnancy exposure registries. In 2002,
we published a final guidance for industry that provides
advice on how to establish registries that prospectively
monitor the outcomes of pregnancies in women exposed to a
specific drug. These registries can provide clinically
relevant human data for treating or counseling patients who
are pregnant or anticipating pregnancy.
Scientific research in pregnancy and lactation
We funded several studies to
evaluate either fetal safety from drug exposure or whether
the dose of a drug should be adjusted during pregnancy or
lactation:
n
Counter-terrorism. These studies look at specific
anti-infective drug products that would be used for
treatment following exposure to specific bioterrorism
agents. They focus on use in special patient populations,
such as women who are pregnant or lactating and the elderly.
They evaluate either the need for dose adjustments in these
special patient populations or fetal safety following in
utero drug exposure.
n
Liver enzymes. These studies look at the effects of
pregnancy on specific drug-metabolizing enzymes in the
liver.
Research on drugs for high blood pressure, depression
FDA’s Office of Women’s Health funded
studies to look at specific drugs used to treat high blood
pressure and depression and determine if the doses of these
drugs should be adjusted during pregnancy.
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Over the Counter Drug
Review
Over-the-counter drug statistics
n
5 approvals for first-time OTC sale
n 3 new uses
Over-the-Counter Drug Review
We approved five drugs for first-time
over-the-counter sale:
n
Guaifenesin 600 mg/pseudoephedrine
hydrochloride 60 mg tablets and guaifenesin
1200 mg/pseudoephedrine 120 mg tablets (Mucinex-D Extended
Release) for use as an expectorant and nasal
decongestant in adults and children 12 years and older.
n
Guaifenesin 600 mg/dextromethorphan 30 mg
tablets and guaifenesin 1200 mg/dextromethorphan 60
mg tablets (Mucinex-DM) for use as an expectorant and
cough suppressant in adults and children 12 years and older.
n
Ibuprofen 100 mg/pseudoephedrine
hydrochloride 15 mg/chlorpheniramine maleate 1 mg per 5 mL
(Children’s Advil Allergy & Sinus Elixir) for the relief
of symptoms of allergic rhinitis and the common cold in
children 6 years and older.
n
Ibuprofen 100 mg per 5 mL oral suspension
(Children’s Elixsure IB) for the relief of minor aches
and pains and fever in children 2 years of age and older.
n
Ranitidine hydrochloride 150 mg (Zantac 150
Tablets) for prevention and relief of heartburn in
adults.
We also approved three new uses for
existing OTC products, all of which can be used in children
12 years and older:
n
Loratadine 5 mg/pseudoephedrine
hydrochloride 120 mg (Claritin-D 12 Hr. Extended Release
Tablets) and loratadine 10 mg/pseudoephedrine
hydrochloride 240 mg (Claritin-D 24 Hr. Extended Release
Tablets) for the nasal congestion due to the common cold
in adults and adolescents 12 years and older.
n
Miconazole nitrate (Monistat 1 Combination
Pack) for anytime use in the treatment of vaginal yeast
infections in adults and adolescents 12 years and older.
Improved labels for OTC medicines
American consumers are benefiting
from easy-to-understand labels on drugs they buy without a
prescription. A mandatory changeover to the new labels,
titled “Drug Facts,” began in 2002 and is now complete for
all products, with a few exceptions, as of May 2005.
Education campaign on safe use of OTCs
We developed a national education
campaign to provide advice on the safe use of
over-the-counter pain and fever reducers
(http://www.fda.gov/cder/drug/analgesics/).
Because many OTC medicines for different uses have
the same active ingredients, an unintentional overdose is
possible. We are focusing on OTC drug products that contain
acetaminophen and non-steroidal anti-inflammatory agents,
which include products such as aspirin, ibuprofen, naproxen
sodium and ketoprofen.
How we regulate OTC drugs
We publish monographs that
establish acceptable ingredients, doses, formulations and
consumer labeling for OTC drugs. Products that conform to a
final monograph may be marketed without prior FDA clearance.
Drugs also can be approved for OTC sale through the new drug
review process. More information about the OTC drug review
process is at
http://www.fda.gov/cder/about/smallbiz/OTC.htm.
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Generic Drug Review
Generic drug statistics
n
380 generic drug approvals
n Median approval time: 15.7 months
n 95 tentative approvals
n 635 receipts
We approved 380 generic drug products
in 2004, including a substantial number of products that
represent the first time a generic drug was available for
the brand-name product. The median approval time was 15.7
months.
The median statistic for total approval
time had hovered at about 18 to 19 months for six years. We
made changes that decrease the overall time to approval of
applications by three months. We are improving the efficiency of our generic drug
review process and increasing the number of our chemistry
reviewers by one-third.
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Notable 2004 generic drug
approvals
Examples of first-time approvals for
the brand-name equivalent drugs are:
n
Fluconazole (Diflucan) in several
dosage forms for use as an antifungal agent.
n
Benazepril hydrochloride (Lotensin)
used to treat high blood pressure.
n
Ciprofloxacin (Cipro) for antibiotic
use, particularly as an agent to treat anthrax exposure.
n
Ribavirin (Rebetol) used in combination
with interferon alpha 2-A for several indications, including
the treatment of chronic hepatitis C.
n
Metformin hydrochloride extended release
tablets (Glucophage XR) used to treat Type 2 diabetes
mellitus.
Our approval of generic versions of
these drugs could save American consumers and the federal
government hundreds of millions of dollars each year.
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Tentative vs. full approval
The only difference between a full
approval and a tentative approval is that the final approval
of these applications is delayed due to existing patent or
exclusivity on the innovator drug product. These and other
legal issues continue to be a challenge to the generic drug
review program.
The review of an application that is
tentatively approved requires the same amount of work as a
review that results in a full approval.
While tentative approvals represent a
full workload for us, they are only displayed in our
approvals chart once they are converted to full approvals.
For example, some of 2004’s approvals represent conversions
of tentative approvals granted in 2003 or previous years.
Tentative approvals key to affordable, worldwide AIDS
relief
Tentative approval is a key
regulatory mechanism to support the availability of drugs
for the President’s Emergency
Plan for AIDS Relief (click
here for more information).
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How we approve generic drugs
Generics are not required to
repeat the extensive clinical trials used in the development
of the original, brand-name drug. For many products such as tablets
and capsules, the generics must show bioequivalence
to the brand-name reference listed drug. This means that the
generic version must deliver the same amount of active
ingredient into a patient’s bloodstream and in the same time
as the brand-name reference listed drug. The rate and extent of absorption
is called bioavailability. The bioavailability of the
generic drug is then compared to that of the brand-name.
This comparison is bioequivalence. Brand-name drugs are subject to
the same bioequivalency tests as generics when their
manufacturers reformulate them.
Scientific basis for generic drug review
We continue to articulate the
scientific underpinnings of our review process and to work
to define mechanisms to evaluate equivalence of certain
unique products.
Online education
We are offering a free online
educational tutorial on the generic drug approval process
that offers one hour of continuing education credit for
certain health professionals. The course, available at
http://www.connectlive.com/events/genericdrugs/,
educates health professionals on how our approval assures
that generic drugs are safe, effective and high quality
products.
Improving manufacturing practices
Our strategic initiative, Pharmaceutical cGMPs for the
21st Century, also applies to generic drugs.
Consumer communication
Our efforts to build consumer
confidence in generic drug products are continuing through
our Generic Drug Quality Awareness program. We have partnered with a number of
professional and consumer organizations to launch programs
about the quality and benefits of generic drugs. We have
helped design messages that appear on prescription bags in
chain drug stores. Radio public service announcements with
the generic drug quality message will be appearing in
several geographic areas.
Our generic drug public service
announcements are at
http://www.fda.gov/cder/consumerinfo/generic_info/default.htm.
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Generic drug review
efficiencies
The dramatic increase in receipts of
generic drug applications makes it imperative that we
process generic drug applications more efficiently. With the
overall goal of getting generic drug products to the
consumer as efficiently as possible, we continue to look for
ways to improve our processes and also to provide
communication and guidance to industry.
We are taking steps aimed at improving
the content and completeness of generic drug applications
and assuring that the applications contain the needed
information to be evaluated successfully in one cycle. These
steps include:
n
Enhanced communication with individual
applicants during the review process.
n
Working with the generic drug industry
association to help their members submit applications that
can be reviewed more efficiently.
n
Exploring further enhancements to the review
process.
n
Holding joint meetings and workshops with
industry to enhance knowledge of topics of interest.
n
Efforts to encourage submission of
applications in an electronic format for greater efficiency
(page 32).
Electronic submissions
Through public presentations, we are
encouraging the generic drug industry to submit their
applications electronically.
Increased generic drug review staff
We have constituted a third chemistry
review division for generic drugs. We are augmenting our
clinical review staff to further speed our review of generic
drug applications.
Reducing legal hurdles to generic drug availability
We are working on regulations to decrease time-consuming
legal delays in the approval and marketing of generic
products. These rules, implementing provisions of the
2003 Medicare Prescription Drug, Improvement and
Modernization Act, will:
n
Limit an innovator firm to one 30-month delay for courts to
resolve patents challenged by an generic manufacturer.
n
Prevent a generic manufacturer with 180-day exclusivity from
delaying marketing in order to deny other generic firms
entry into the market.
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Assessing Data
Quality, Research Risks
Inspections for data quality, research risks in 2004
We conducted a total of 730
inspections in 2004:
n
242 U.S. clinical investigators
n 82 foreign clinical investigators
n 178 institutional review boards
n 18 sponsors, monitors or contract research
organizations
n 74 good laboratory practices
n 136 in-vivo bioequivalence
When obtaining data about the safety
and effectiveness of drugs, sponsors rely on high quality
laboratory studies and human volunteers to take part in
clinical studies. Protecting volunteers from research
risks is a critical responsibility for us and all involved
in clinical trials.
We perform on-site inspections to
protect the rights and welfare of volunteers and verify the
quality and integrity of data submitted for our review. We
inspect domestic and foreign clinical trial study sites;
institutional review boards; sponsors, monitors and
organizations conducting research; laboratories that obtain
data; and sites performing bioequivalence studies in humans
(see “How we approve generic drugs”)
and preclinical studies in animals.
Our programs to protect volunteers are
challenged by increases in the number of clinical trials,
the types and complexity of products undergoing testing, and
the increased number of trials performed in countries with
less experience and limited or no standards for conducting
clinical research.
Sponsors and clinical investigators
protect volunteers by ensuring that:
n
Clinical trials are appropriately designed and
conducted according to good clinical practices.
n
Research is reviewed and approved by an
institutional review board.
n
Informed consent is obtained from
participants.
n
Ongoing clinical trials are actively
monitored.
n
Special attention is given to protecting
vulnerable populations, such as children, the mentally
impaired and prisoners.
We require sponsors to disclose
financial interests of clinical investigators who conduct
studies for them. This helps identify potential sources of
bias in the design, conduct, reporting and analysis of
clinical studies.
2004 top 5 deficiencies in inspections of clinical
investigators
n
Failure to follow the protocol
n Failure to keep adequate and accurate records
n Failure to account for the disposition of study
drugs
n Failure to report adverse events
n Problems with the informed consent form
International inspections of clinical research
We have conducted 592 inspections
of clinical research in 55 countries from 1980 to 2004. We participate in international
efforts to strengthen protections for human volunteers
worldwide and encourage clinical investigators to conduct
studies according to the highest ethical principles. This
includes our work with the International
Conference on Harmonization and the Declaration of
Helsinki.
Internet resources
More information on data integrity
and patient safety is at
http://www.fda.gov/cder/offices/dsi/index.htm.
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Electronic Submissions
We cooperated with outside
organizations working to publish standards for submitting
study data. These groups include the Clinical Data
Interchange Standards Consortium and Health Level 7. Some of
these projects are:
n
Clinical trial data. We adopted the
consortium’s Study Data Tabulation Model version 1.0 for
submission of information from clinical trials.
n
Preclinical data. The consortium is
working to extend the model to handle animal toxicity and
microbiology data.
n
Database development. We completed a
database model for storing and accessing both clinical and
animal toxicity data submitted using the Study Data
Tabulation Model. We are collaborating with the National
Cancer Institute and software vendors to implement the
database and develop “smart” tools for accessing the data.
n
Electrocardiogram data. We adopted the
Health Level 7 standard for annotated electrocardiogram
waveform data. We are working with a vendor to develop
software for analyzing the data and a warehouse for storing
it.
n
Structured product labeling. We are
accepting Health Level 7 Structured Product Labeling for
content of labeling submissions. We are developing a
repository for storing the data and software to improve the
processing and reviewing of labeling changes. This is part
of our effort to improve patient safety through access to
the most recent information about medicines
(click
here).
We continue to receive electronic submissions
using the specifications of the electronic Common Technical
Document.
Internet resources
More information on our electronic submissions
program is at
http://www.fda.gov/cder/regulatory/ersr/.
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User Fee Program
Americans deserve timely access to
potentially lifesaving new drugs as soon as possible once
they are proven safe and effective. The Prescription Drug
User Fee Act of 1992 received its second five-year extension
in 2002, known as PDUFA III. This reauthorization is helping
us ensure that we have the expert staff and resources to
review applications promptly and get safe, effective new
drugs into the hands of the people who need them. The
current user fee law maintains our high review performance
goals, includes increased consultations with drug sponsors
and provides for earlier feedback on their submissions.
User fee performance
Under legislation authorizing us to
collect user fees for drug reviews, we agreed to specific
performance goals for the prompt review of submissions.
n
We exceeded all our performance goals for the
fiscal year 2003 receipt cohort.
n
We are on track for exceeding all user-fee
performance goals for the fiscal year 2004 cohort.
Continuous marketing application pilot programs
Under PDUFA III, we are assessing the
value of both early review of parts of marketing
applications and of more extensive feedback to sponsors
during their development programs. Two pilots for
“continuous marketing applications” apply to drugs and
biologics in our fast track program:
n
Pilot 1 allows applicants to submit
predefined portions of their marketing applications called
“reviewable units” before submitting the completed
application. Each reviewable unit has a six-month goal for
issuing a discipline
review letter. In fiscal year 2004, we met our goals
for all 14 reviewable unit submissions for seven different
products.
n
Pilot 2 allows us to enter into
agreements with sponsors for frequent scientific feedback
and interactions during the clinical trial phase of product
development. As of Aug. 1, 2005, there were nine
development projects entered in the Pilot 2 program.
The pilots have limitations and
specific criteria for entry. More information is available
at
http://www.fda.gov/cder/pdufa/CMA.htm.
User fees support risk assessment and minimization
The reauthorization allows user fees to
support some safety activities, both during development and
for newly approved medicines
(click
here for more information).
Internet resources for user fees
Our user fee Web site at
http://www.fda.gov/cder/pdufa/default.htm has
links to PDUFA:
n
Legislation
n Federal Register
documents
n Guidances
n Letters
n Performance reports
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Drug Review Team
We use project teams to perform
reviews. Team members apply their individual special
technical expertise to review applications:
n
Biologists, biochemists and
immunologists evaluate the manufacturing processes for
biological products to ensure the continued purity, potency
and safety of these products. They also provide insights to
the review team regarding the mechanism of action and
potential and observed adverse events associated with
specific products.
n
Chemists focus on how a drug is
manufactured. They make sure the manufacturing controls,
quality control testing and packaging are adequate to
preserve the drug product’s identity, strength, potency,
purity and stability.
n
Clinical pharmacologists and
biopharmaceutists evaluate factors that influence the
relationship between the body’s response and the drug dose
and evaluate the rate and extent to which a drug’s active
ingredient is made available to the body and the way it is
distributed, metabolized and eliminated. They also assess
the clinical significance of changes in the body’s response
to drugs through the use of exposure-response relationships
and check for interactions between drugs.
n
Microbiologists evaluate the effects of
anti-infective drugs on germs. These medicines—antibiotics,
antivirals and antifungals—differ from others because they
are intended to affect the germs instead of patients.
Another group of microbiologists evaluates the manufacturing
processes and tests for sterile products, such as those used
intravenously.
n
Pharmacologists and toxicologists
evaluate the effects of the drug on laboratory animals
in short-term and long-term studies, including the potential
based on animal studies for drugs to induce birth defects or
cancer in humans.
n
Physicians evaluate the results of the
clinical trials, including the drug’s adverse and
therapeutic effects, and determine if the product’s benefits
outweigh its known risks at the doses proposed.
n
Project managers orchestrate and
coordinate the drug review team’s interactions, efforts and
reviews. They also serve as the regulatory expert for the
review team and as the primary contact for the drug
industry.
n
Statisticians evaluate the designs and
results for each important clinical study.
Scientific training for reviewers
Our systematic, internal training
program is based on core competencies, learning pathways and
individual development plans. In 2004:
n
We presented 51 scientific seminars and scientific rounds.
n
We offered a strong and innovative curriculum of 28
scientific courses.
n
We brought in 45 visiting professors to talk directly to
individual review divisions about critical, new drug-related
research and techniques.
n
We offered additional courses in job skills, research tools,
leadership and management.
Advanced scientific education
A committee of our scientists
oversees a program of scientific training, seminars, case
study rounds and guest lectures. This multidisciplinary program
helps keep our scientists up-to-date on the latest
developments in their fields and current industry practices.
Academics to CDER
Each spring, we collaborate with
five local universities to present an up-to-date course on a
compelling scientific topic. Recent topics were:
n
2005: Critical path science
n 2004: Exposure-response concepts
n 2003: Drug safety
n 2002: Pharmacogenetics
n 2001: QT prolongation
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Date created: Aug. 22, 2005