CDER
Report to the Nation: 2004
Center for Drug Evaluation and
Research
Food and Drug Administration
U.S. Department of Health and Human Services
CDER 2004 Report to the Nation:
Improving Public Health Through Human Drugs
Print version
Slides of charts for presentations
Director's Message
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Introduction
Who we are
The Center for Drug Evaluation and Research is America’s
consumer watchdog for medicine. We are part of one of the
nation’s oldest consumer protection agencies-the Food and
Drug Administration. The FDA is an agency of the federal
government’s Department of Health and Human Services. We
are the largest of FDA’s five centers, with about 1,800
employees. Approximately half of us are physicians or other
kinds of scientists. Many of us have experience and
education in such fields as computer science, legal affairs
and regulatory matters.
What we do
Our best-known job is to evaluate new drugs for safety
and effectiveness before they can be sold. Our evaluation,
called a review, makes sure that the drugs we approve meet
our tough standards for safety, effectiveness and quality.
We also make sure that you and your doctor will have the
information you need to use medicines wisely. Once drugs are
on the market, we monitor them for problems.
Reviewing drugs before marketing. A drug company
seeking to sell a drug in the United States must first test
it. We monitor clinical research to ensure that people who
volunteer for studies are protected and that the quality and
integrity of scientific data are maintained. The company
then sends us the evidence from these tests to prove the
drug is safe and effective for its intended use. We assemble
a team of physicians, statisticians, chemists,
pharmacologists and other scientists to review the company’s
data and proposed use for the drug. If the drug is effective
and we are convinced its health benefits outweigh its risks,
we approve it for sale. We don’t actually test the drug when
we review the company’s data. By setting clear standards for
the evidence we need to approve a drug, we help medical
researchers bring safe and effective new drugs to American consumers more
rapidly. We also review drugs that you can buy over the
counter without a prescription and generic versions of
over-the-counter and prescription drugs.
Watching for drug problems. Once a drug is approved
for sale in the United States, our consumer protection
mission continues. We monitor the use of marketed drugs for
unexpected health risks. If new, unanticipated risks are
detected after approval, we take steps to inform the public
and change how a drug is used or even remove it from the
market. We monitor changes in manufacturing to make sure
they won’t adversely affect safety or efficacy. We evaluate
reports about suspected problems from manufacturers, health
care professionals and consumers. We try to make sure an
adequate supply of needed drugs is always available to
patients who depend on them
Monitoring drug information and advertising.
Accurate and complete information is vital to the safe use
of drugs. We regulate information that accompanies or is
displayed with an over-the-counter drug. In the past, drug
companies promoted their products almost entirely to
physicians. More frequently now, they are advertising
directly to consumers. We oversee advertising of
prescription drugs, whether to physicians or consumers. We
pay particular attention to broadcast ads that can be seen
by a great many consumers. We oversee advertising of
prescription drugs, whether to physicians or consumers. The
Federal Trade Commission regulates advertising of
over-the-counter drugs. Advertisements for a drug must
contain a truthful summary of information about its
effectiveness, side effects and circumstances when its use
should be avoided.
Protecting drug quality. In addition to setting
standards for safety and effectiveness testing, we also set
standards for drug quality and manufacturing processes. We
work closely with manufacturers to see where streamlining
can cut red tape without compromising drug quality. As the
pharmaceutical industry has become increasingly global, we
are involved in international negotiations with other
nations to harmonize standards for drug quality and the data
needed to approve a new drug. This harmonization will go a
long way toward reducing the number of redundant tests
manufacturers do and help ensure drug quality for consumers
at home and abroad. We also protect drug quality with
rigorous manufacturing inspections to ensure compliance with
current Good Manufacturing Practice requirements.
Why we do it
Our present and future mission remains constant: to
ensure that drug products available to the public are safe
and effective. Our yardstick for success will always be
protecting and promoting the health of Americans.
Getting consumer input. Protecting consumers means
listening to them. We consult with the American public when
making difficult decisions about the drugs that they use. We
hold public meetings about once a week to get expert,
patient and consumer input into our decisions. We also
announce most of our policy and technical proposals in
advance. This gives members of the public, academic experts,
industry, trade associations, consumer groups and
professional societies the opportunity to comment before we
make a final decision. In addition, we take part in
FDA-sponsored public meetings with consumer and patient
groups, professional societies and pharmaceutical trade
associations. These help us obtain enhanced public input
into our planning and priority-setting practices.
What is a drug?
We regulate drugs used to treat, prevent or diagnose
illnesses. However, drugs include more than just medicines.
For example, fluoride toothpaste, antiperspirants, dandruff
shampoos and sunscreens are all considered
"drugs." You can buy some drugs in a store without
a prescription, while others require a doctor's
prescription. Some are available in less-expensive generic
versions.
Prescription drugs
Prescription medicines must be administered under a
doctor’s supervision or require a doctor’s authorization
for purchase. There are several reasons for requiring a
medicine be sold by prescription:
n
The disease or condition may be serious and require a
doctor’s management.
n
The medicine itself may cause side effects that a doctor
needs to monitor.
n
The same symptoms may be caused by different diseases that
only a doctor can diagnose.
n
The different causes may require different medicines.
n
Some medicines can be dangerous when used to treat the wrong
disease.
Over-the-counter drugs
You can buy OTC drugs without a doctor’s prescription.
You can successfully diagnose many common ailments and treat
them yourself with readily available OTC products. These
range from acne products to cold medications. As with
prescription drugs, we closely regulate OTC drugs to ensure
that they are safe, effective and properly labeled.
Generic drugs
A generic drug is a chemical copy of a brand-name drug.
There are generic versions of both prescription and
over-the-counter drugs. Generic drugs approved by the FDA
have the same therapeutic effects as their brand-name
counterparts.
Scientific research
We conduct and collaborate on focused laboratory research
and testing. This maintains and strengthens the scientific
base of our regulatory policy-making and decision-making. We
focus on:
n
Drug quality, safety and performance.
n
Improved technologies.
n
New approaches to drug development and review.
n
Regulatory standards and consistency.
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Mission
The Center for Drug Evaluation and Research promotes and
protects public health by assuring that safe and effective
drugs are available to Americans. The Food and Drug
Administration Modernization Act of 1997 affirmed the
center's public health protection role, clarified the FDA's
mission and called for the FDA to:
- Promote the public health by promptly and efficiently
reviewing clinical research and taking appropriate
action on the marketing
of human drugs in a timely manner.
- Protect the public health by ensuring that human drugs
are safe
and effective.
- Participate through appropriate processes with
representatives
of other countries to reduce the burden of regulation,
harmonize regulatory requirements and achieve
appropriate reciprocal arrangements.
- Carry out its mission in consultation with experts in
science, medicine and public health and in cooperation
with consumers, users, manufacturers, importers,
packers, distributors and retailers of human drugs.
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Highlights and Initiatives
We are pleased to present our ninth
performance report. Our work in 2004 offered many Americans
new or improved choices for protecting and maintaining their
health or new ways to use existing products more safely. We
worked hard at our mission of ensuring that Americans have
safe and effective drugs and also developed these
initiatives to bring the latest science and technology to
bear on our mission:
n Reforming our drug safety oversight.
n Identifying steps to improve the science of
drug development.
n Improving manufacturing practices.
n Protecting the homeland with improved medical
countermeasures to be used in event of a terrorist attack or
disaster.
n Conducting targeted scientific research to
improve our regulatory practices.
We accomplished our work on these
initiatives while maintaining our performance on our reviews
of safety and efficacy and our oversight and surveillance of
the safety of products sold to Americans.
n Reviews.
We approved 119 new medicines, including 36 truly new
medicines that had not been marketed in any form before in
this country. We approved 147 new or expanded uses for
already approved medicines. We approved 380 generic versions
of existing drugs.
n User
fee performance. We exceeded our goals for review
performance.
n Drug
safety surveillance. We processed and evaluated more
than 400,000 reports of adverse drug events, including more
than 20,000 submitted directly from individuals.
n Drug
promotion and advertising. We issued more than 800
letters to help ensure manufacturers comply with regulations
concerning drug promotion.
n Bar
codes on medicines. We promulgated a regulation that
calls for bar codes on over-the-counter medicines commonly
used in hospitals and most prescription medicines.
n Public health advisories. We issued
warnings on non-steroidal anti-inflammatory pain medicines
and on antidepressant use in children, adolescents and
adults.
n Manufacturing. We implemented our
initiative that encourages adoption of state-of-the-art
manufacturing processes.
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Drug Safety
Initiative
Americans are rightly concerned about
the safety of their drugs. Too many suffer from unexpected
and unpreventable adverse events from the medicines they need. This results in
human suffering and avoidable medical costs. Some have
worried about “dangerous” drugs, while others have worried
that an “overemphasis” on safety will delay developing new
therapies.
The most important concern for many
Americans, however, has been the gap between the time a
safety issue emerges and the time we know enough to make a
regulatory decision. Our reforms of our drug safety efforts
will:
n Give patients, healthcare professionals and
consumers quick and easy access to the most up-to-date and
accurate information on medicines.
n Make our drug review, approval and monitoring
programs as transparent as possible.
Drug safety has been and will continue
to be a top priority for us. A recent internal audit showed
that our professional staff spends about one-half its time
addressing safety issues. Drug safety involves more than
watching for problems once we approve a drug. Other
important areas where the evaluation of drug safety takes
place include:
n
Oversight of clinical trials.
n
Evaluation of safety and efficacy of new
therapies and new or expanded uses for existing therapies.
Because all drugs have risks, our evaluation must balance
those risks against expected benefits.
n
Regulation of manufacturing, distribution and
promotional activities.
n
Prevention of medication errors by evaluating
proposed proprietary names, labeling and packaging.
n
Development of proactive risk management
strategies both before and after approval.
Oversight board
The new, independent Drug Safety
Oversight Board will oversee the management of drug safety
issues and will provide emerging information to doctors and
patients about the risks and benefits of medicines. It will:
n
Recommend information and updates for
placement on the proposed Drug Watch Web page.
n
Resolve disagreements over approaches to drug
safety issues.
n
Assess the need for MedGuides.
n
Oversee development and implementation of
Centerwide drug safety policies.
Oversight Board members don’t directly supervise
approvals
The board consists of FDA supervisors,
members and medical experts from other medical agencies in
the Department of Health and Human Services and other
government departments such as the Department of Veterans
Affairs. The board will consult with outside medical experts
and representatives of patient and consumer groups. To avoid
conflicts of interest, the board members have no direct
supervision of approval decisions. Because board members are
government employees, they will be able to freely discuss
confidential and proprietary information.
New communications channels
We will share drug safety information
sooner, more broadly and more conveniently through tailored
drug safety information sheets for healthcare professionals
and patients.
We expect these new and direct
communication channels will enhance knowledge and
understanding of safety issues. Emerging or potential safety
problems can be discussed even before we have reached
conclusions that would prompt a regulatory action.
The new communication channels include:
n
Drug Safety Web
site. Consumers will find a variety of new
information on specific drug products, including information
sheets for patients and healthcare professionals (described
below), the product’s regulatory history and its prescribing
information. The site is
http://www.fda.gov/cder/drugsafety.htm.
n
Proposed Drug
Watch Web site. The Drug Safety Oversight Board will
place “emerging” drug safety information on this site, such
as possible serious side effects of particular drugs, before
we have fully determined that the drug was responsible. This
information will also include risks that might alter the
benefit and risk analysis of a drug, affect patient
selection, change monitoring decisions or could otherwise be
avoided.
n
Healthcare
professional information sheets. These will be
one-page information sheets for all drugs on FDA’s Drug
Watch and all drugs with Medication Guides. They will
contain the most important new information for safe and
effective product use, such as known and potential safety
issues based on reports of adverse events, new information
that may affect prescribing of the drug and the approved
indications and benefits of the drug.
n
Patient
information sheets. These one-page information sheets
in a consumer friendly format will contain new safety
information as well as basic information about how to use
the drug for all products on Drug Watch. Ultimately, such
sheets will be made available for every new drug that is
approved.
Institute of Medicine Study
We have contracted with the IOM to
study the effectiveness of the nation’s drug safety system.
The study will have an emphasis on the post-market phase and
assess what additional steps could be taken to learn more
about the side effects of drugs as they are actually used.
The IOM is the nation’s foremost body for science-based
advice on matters of biomedical science, medicine and
health.
Differences of professional opinion
In most cases, free and open
discussion of scientific issues among review teams and with
supervisors, managers and external advisors, leads to an
agreed course of action. Sometimes, however, consensus
cannot be reached. We normally document these differences
and their resolution in the official file of an action.
An employee may sometimes feel
that the normal process was inadequate and the decision made
will have a significant negative impact on the public
health. We have implemented a pilot process, coordinated by
our ombudsman (click here),
to provide for expeditious review and resolution of these
differences by qualified staff not directly involved in the
decisions.
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Critical path
Critical Path Initiative
FDA’s March 2004 report, Innovation
or Stagnation?—Challenge and Opportunity on the Critical
Path to New Medical Products, provides our analysis of
the “pipeline problem.”
There has been a slowdown—instead of the
expected acceleration—in innovative medical therapies
reaching patients. The medical product development path is
becoming increasingly challenging, inefficient and costly.
As a consequence, our mission to ensure the availability of
safe and effective medical treatments for Americans that
take advantage of the latest science is becoming
compromised.
In our view, the applied sciences for
product development have failed to keep pace with the
tremendous advances in the basic sciences. New science is
not being used to guide the development process in the same
way that it is accelerating the discovery process.
To focus the attention of the public,
academic researchers, funding agencies and industry, our
report identifies:
n
The critical path for product development from
design and discovery to commercial marketing.
n
The scientific and technical dimensions of the
critical path.
n
The three types of research that support the
critical path.
Personalized medicine
The Critical Path recognizes the
importance of “pharmacogenomics” and encourages its use in
drug development.
n
Pharmacogenomics allows health
care providers to identify differences in people’s drug
response profiles and predict the best possible treatment
options for them.
Instead of a hit-or-miss approach to
treating patients where it can take multiple attempts to
find the right drug and the right dose, pharmacogenomics
holds the promise that doctors will be able to analyze a
patient’s genetic profile and prescribe the best available
drug therapy and dose from the start.
The field has experienced significant
growth over the last few years. The sequencing of the human
genome and the advent of new tools and technologies have
already opened new possibilities in drug discovery and
development.
Personalized medicine for cancer
Genomic tests are helping to identify
cancers that have a good chance of responding to a
particular medication or regimen. This has enabled the
development of targeted therapies like trastuzumab for
metastatic breast cancer, imatinib mesylate for chronic
myeloid leukemia and cetuximab for metastatic colorectal
cancer.
Critical path dimensions
From the earliest phases of
preclinical work to commercialization, developers must
manage successfully in these three dimensions:
n
Assessing safety. Showing that a product is adequately
safe for each stage of development.
n
Demonstrating medical utility. Showing a new product
will actually benefit people.
n
Industrialization. Turning a laboratory concept into a
consistent and well-characterized medical product that can
be mass produced.
Research needed to improve development tools
Together with academia, patient
groups, industry and other government agencies, we need to
embark on an aggressive, collaborative research effort to
create a new generation of performance standards and
predictive tools. We need tools that will provide better
answers about the safety and effectiveness of
investigational products, faster and with more certainty.
We at FDA are uniquely suited to
play a major role in this effort because of:
n
Our experience overseeing medical product development,
assessment and manufacturing/marketing.
n
Our vast clinical and animal databases.
n
Our close interactions with all the major players in the
critical path process.
Public support for Critical Path
We have heard from patient groups,
the drug and biotech industry, and industry groups. They
concur with the scientific infrastructure problem and the
focus on research, science-based standards and
collaboration. Areas of major concern are:
Clinical trials
n
Statistical tools to support innovative trial design.
n
Disease modeling and trial simulation.
n
Standardization of trial administration.
n
Development of consistent electronic data collection,
monitoring and reporting.
Biomarkers and endpoints
n
Clarification of the process for validating surrogate
endpoints.
n
Evidence needed to use biomarkers for other purposes, such
as patient selection.
n
Standards for imaging as a biomarker.
The way forward
This initiative is not a fundamental
departure for us, but rather builds on our proven best
practices for developing industry guidance and expediting
the availability of promising medical technologies.
The next steps in this initiative
include a series of workshops and meetings, to start
development of a National Critical Path Opportunities list
and to identify the key priorities.
The full Critical Path report is
available at
http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html.
You can view public comments to our
proposal at
http://www.fda.gov/ohrms/dockets/dockets/04n0181/04n0181.htm.
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Improving Manufacturing Practices
Our overhaul of our regulatory and
quality control systems for pharmaceutical products
encourages manufacturers to modernize their methods,
equipment and facilities. Our goal is to help eliminate both
production inefficiencies and undue risks for consumers. Our
initiative implements improved policies that are making
better use of our limited resources through more targeted
and effective inspections.
Collectively, our policies are known as
“current good manufacturing practices” or cGMPs, and our
last comprehensive revisions to them took place nearly a
quarter of a century ago.
Pharmaceutical cGMPs for the 21st
Century is the umbrella name for this strategic
initiative, and more information is available at
http://www.fda.gov/cder/gmp/.
Pharmaceutical cGMP initiative final report issued
In 2004, we transitioned into an
implementation phase and issued a final report on:
n
Our assessment of our regulations, current
manufacturing practices as well the new tools in
manufacturing science that will enable a progression to
controls based on quality systems and risk management.
n
Specific steps we have taken and will take to
develop and implement quality systems management and a
risk-based product quality regulatory system.
The report is available at
http://www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm#_Toc84065734.
Process analytical technologies initiative
A key element of the cGMP initiative is
our effort to encourage adoption of state-of-the-art quality
control systems in manufacturing. This work is based on the
premise that quality cannot be tested into products; it
should be built into products by design.
Process analytical technology is a
system for design, analysis and control of manufacturing
with the goal of ensuring final product quality. It does
this through timely measurements—during processing—of
critical quality and performance attributes of raw and
in-process materials and processes.
Effective use of the most current
pharmaceutical science and engineering principles and
knowledge—throughout the life cycle of a product—can improve
the efficiencies of both the manufacturing and regulatory
processes.
Click here for more information.
Emerging technologies in process validation recognized
We revised a long-standing policy
document regarding the validation of pharmaceutical
manufacturing processes. New to this version is the
recognition of the role of emerging advanced engineering
principles and control technologies in ensuring batch
quality.
For drugs produced using these new
principles and technologies, we provide for possible
exceptions to the need for manufacturing multiple
conformance batches prior to initial marketing.
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Counterterrorism
The first therapy for those exposed to
a terrorism agent is often a drug. We have been taking an
aggressive and proactive approach to our role in helping
prepare the nation for terrorist events. These steps
include:
n
Assuring the availability of medicines to
treat victims of terrorist attacks.
n
Leveraging resources with other federal
agencies to answer scientific questions concerning therapies
to treat conditions caused chemical, biological or
radioactive agents.
n
Preparing ourselves to continue operations
during a crisis.
n
Protecting the nation’s drug supply from
attack or deliberate contamination.
Medical countermeasure approvals
n
The infant atropine autoinjector (Pediatric
AtroPen) provides an automatic injection of a
potentially life-saving nerve agent antidote to children as
young as 6 months. Doses and dosage forms of the AtroPen for
adults and older children had been approved previously.
n
Pentetate calcium trisodium injection
(Calcium DTPA) and pentetate zinc trisodium injection
(Zinc DTPA) treat people who have become internally
contaminated with certain radioactive isotopes (plutonium,
americium or curium). The label includes information on
pediatric dosing. These new molecular entities received
priority approval and have orphan drug status. A second
manufacturer received tentative approvals for these two
drugs.
n
A second
manufacturer of insoluble Prussian blue (Manoplex),
to treat people internally contaminated with radioactive
cesium-137 or thallium, received tentative approval in 2004.
The first approval for insoluble Prussian blue was in 2003,
and the product received orphan exclusivity.
n
We updated the ciprofloxacin (Cipro)
label to include human information based on its use to
prevent inhalational anthrax during the attacks in 2001. The
label previously referenced only animal efficacy data for
this indication.
n
Levofloxacin (Levaquin) is now approved
to treat inhalational anthrax (post exposure prophylaxis) in
adults. Levaquin is similar to ciprofloxacin, except it can
be dosed once daily.
n
Fifteen new generic ciprofloxacin drug
products were approved. Each will be indicated for
prevention of inhalational anthrax post-exposure.
n
Penicillin G procaine injectable suspension
(Wycillin) was approved to prevent the occurrence or
progression of anthrax disease following exposure to
Bacillus anthracis (including inhalational anthrax).
Emergency use authorization
Under the 2004 Project BioShield
Act, we worked with the Centers for Disease Control and
Prevention to identify potential medical countermeasures in
the Strategic National Stockpile that we could authorize for
emergency use for an unapproved indication.
We also outlined the internal
processes and procedures we need to handle an emergency use
authorization.
Emergency preparedness
We participated in four emergency
response exercises. Threat agents were smallpox, anthrax,
radiological contamination from a dirty bomb and cyanide. We
also engaged in continuity of operations exercises,
including an “at home” test to assure maintenance of vital
operations and services in an emergency.
Strategic National Stockpile regulatory, policy issues
working group
We participated in this internal FDA working group to
address issues such as:
n
Compounding medical countermeasures during a mass casualty
situation.
n
Labeling and dispensing medical countermeasures during a
mass casualty.
n
FDA-shelf-life extension program and re-labeling.
n
Cities Readiness Initiative (mass prophylaxis dispensing).
n
Availability and vulnerability of products in the stockpile.
n
Risk assessment and enforcement discretion.
n
Proactive facilities inspections.
n
Patient access to life-saving therapies through
investigational applications for countermeasures.
Facilitating medical countermeasure development
n
Plague. The Centers for Disease Control
and Prevention began enrolling patients in an FDA-funded
clinical trial to assess the efficacy of the antibiotic
gentamicin for endemic plague in two African countries where
antimicrobial options for plague are extremely limited. We
contributed to protocol design and the formation of a data
safety monitoring board to oversee study safety concerns. We
are continuing our collaboration with the Center for Devices
and Radiological Health to evaluate the performance of a
novel, rapid bedside plague diagnostic test kit under study
conditions.
n
Pneumonic plague. We also continued our
collaboration with the National Institute of Allergy and
Infectious Diseases and the U.S. Army Medical Research
Institute of Infectious Diseases to evaluate the safety and
efficacy of five antibiotics (gentamicin, ciprofloxacin,
levofloxacin, doxycycline and ceftriaxone) to treat
pneumonic plague in a non-human primate model. Natural
history studies, pharmacokinetic and toxicology studies to
support efficacy studies and efficacy studies with high-dose
and a humanized (lower) dose of gentamicin have been
completed and analyzed.
n
Radiological and nuclear threats. We
began another collaboration with the National Institute of
Allergy and Infectious Diseases to identify promising new
products for use against radiological and nuclear threats.
We discuss scientific and regulatory issues with
manufacturers of such products and inform them about
possible funding sources, both for early development and for
procurement by the federal government.
Interagency collaborations
n
Post-event surveillance planning. Along
with the FDA’s other medical centers and the CDC, we
developed a plan to identify processes for collecting
adverse event and outcome data on medical products
distributed in response to an emergency.
n
Project BioShield prioritization. We
participated in many interagency working groups engaged in
counter-terrorism efforts. These groups have contributed to
gap analyses in medical countermeasures and have authored
many of the requirements documents that will be used to
prioritize products for development and eventual procurement
under BioShield.
Counterterrorism guidances published in 2004
n
Guidance for Federal Agencies and State and
Local Governments: Potassium Iodide Tablets Shelf Life
Extension.
n
Draft Guidance for Industry: Vaccinia
Virus—Developing Drugs to Mitigate Complications from
Smallpox Vaccination.
Counterterrorism biotechnology research
We have used congressionally
mandated special funding to initiate research in several
areas relevant to counterterrorism. Our scientists are
studying:
n
Microarray technologies, which could assist in identifying
infectious biowarfare agents.
n
Non-specific immune boosters, which could provide transient
protection against such agents.
n
Monoclonal antibodies as neutralizers of biological toxins.
n
Various strategies to defend against anthrax.
By establishing a core of
scientists experienced in several areas of bioterrorism,
these projects anticipate high-priority regulatory
submissions likely to require rapid science-based
evaluation.
Internet resources
We provide links at
http://www.fda.gov/cder/drugprepare/default.htm
to the most current information on:
n
Drugs to prevent or treat disease caused by terrorism agents
including drugs for use against anthrax, plague, radiation
emergencies and chemical agents.
n
Drug development of counterterrorism products.
n
Vaccines.
n
Pediatric counterterrorism measures.
n
Prescribing and buying countermeasures.
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Scientific Research
We advance the scientific basis of
regulatory practice by developing, evaluating or applying
the best, most appropriate and contemporary scientific
methods to regulatory testing paradigms. We provide
scientific support for reviewer training, regulatory
decision making and the development of regulatory policy.
We focus on creating a tighter
scientific linkage between non-clinical and clinical
studies, enhancing methodology for assuring product quality,
building databases for improved drug development and review
and providing regulatory support through laboratory testing.
Linking nonclinical and clinical studies
n
Biomarkers for organ damage. We are
identifying, evaluating and establishing relevant protein
biomarkers in blood in both animal models and in humans.
These will help detect the very earliest damage that can be
caused by certain drugs to the heart, kidney, immune system
and liver.
n
Biomarkers for inflammation. To enhance
safety within broad segments of patient populations and
enable safe development of new drug classes, we are working
on the identification and elucidation of associated serum
biomarkers and mechanisms responsible for the development of
vascular inflammation in specific organ systems.
n
Evaluation of microarrays. We conduct
targeted research on microarrays, a new technology that can
identify thousands of genes or proteins rapidly and at the
same time. We are evaluating how this technology could
improve the interface between drug development and
regulatory practice.
n
Medicinal plants, herbs. We established
scientific research capabilities in the analyses of
medicinal plant and herbal products.
n
Imaging drug targets. We continue to
explore noninvasive imaging technology to extend our
long-standing interest in the application of accurate
dose-concentration-response principles by viewing drugs and
their actions directly at the level of the drug target,
rather than indirectly via plasma concentrations.
n
Better use of exposure-response data.
We are developing a standardized approach for using
exposure-response information to help evaluate the risks and
benefits of drug therapies and recommending dose adjustments
in special populations.
n
Pediatric pharmacokinetics. We are
developing a pediatric population pharmacokinetics study
design template to facilitate implementation of sparse
sample strategies in pediatric drug development.
Biotechnology research
Our new Office of Biotechnology
Products was officially transferred to our center in 2003 from the Center
for Biologics Evaluation and Research. The office consists
of about 80 scientists and other staff who are responsible for evaluating
therapeutic biotechnology product submissions as well as
carrying out scientific research related to biologics
regulatory issues.
n
Immune responses. We review many
submissions aimed at inhibiting unwanted immune responses,
such as autoimmune diseases or rejection of transplanted
organs, or aimed at enhancing desired immune responses, such
as those against infections or cancer. To facilitate review
of such immunology-related submissions, we study the
mechanisms by which immune cells are activated, suppressed
or channeled from one kind of active response to another.
n
Metabolic pathways. We study the
mechanisms by which various regulated products induce their
intended effects, as well as unintended adverse effects. Our
investigations also examine various normal and pathogenic
pathways that are targeted by regulated agents.
Our research enhances the ability of
our scientist/regulators to evaluate risks and benefits of
biotech products, to advise industry on difficult regulatory
problems, such as potency assays, and to develop hands-on
expertise in the modern technologies used by sponsors of
biotech products.
Informatics and computational safety analysis
n
Cancer toxicity predictive software.
Our cooperative research and development agreements with
several commercial software developers have resulted in the
development and marketing of new computer software to
predict the cancer-causing potential of chemicals based on
their molecular structure. The software makes use of our
extensive rodent carcinogenicity database without
compromising proprietary information.
n
Safe starting dose models. We have
successfully developed computer models to estimate the safe
starting dose for clinical trials of drugs based on their
molecular structure. The current method for estimating the
starting dose is highly inexact and requires the use of
multiple safety factors because it is based exclusively on
an extrapolation from animal toxicity studies. We have begun
studies to validate the new method.
Scientific research in pregnancy and lactation
Click here
for studies to evaluate fetal safety from drug
exposure or whether the dose of a drug should be adjusted
during pregnancy or lactation.
Laboratory support
Our efforts included:
n
Development of methods to evaluate quality attributes of
drug products and raw materials by chemical imaging. These
properties include polymorphic form, hydration state,
stability and purity.
n
Rapid identification of counterfeit products using
near-infrared spectroscopy and chemical imaging to
discriminate drug products and raw materials.
n
Development of a methodology for the determining glove
permeability to lindane shampoo and lotion, treatments for
lice whose active ingredient is highly toxic.
Pharmaceutical analysis
We collaborate with other
organizations to ensure the availability of high quality
standards and calibration materials.
We collaborated with state
pharmacy boards to evaluate Internet pharmaceuticals.
We evaluated the quality of a
select group of the most-often-ordered pharmaceutical
products from foreign Internet suppliers.
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Date created: Aug. 22, 2005