CDER 2003 Report to the Nation

CDER Report to the Nation: 2003

Center for Drug Evaluation and Research
Food and Drug Administration
U.S. Department of Health and Human Services

CDER 2003 Report to the Nation:
Improving Public Health Through Human Drugs

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2003 Highlights

Summary
Critical Path
Pharmaceutical cGMPs
Counterterrorism
Scientific Research

1 Drug Review

New Drug Review Statistics

Notable 2002 new drug approvals

New or Expanded Use Review

Director's Message

Last year, we at the Center for Drug Evaluation and Research worked hard to meet the challenge of promoting and protecting the public health. We were pleased to welcome our new colleagues involved in the review of therapeutic biologics. The dedication, creativity and expertise of all our professional staff have enabled us to meet our everyday deadlines and embark on new initiatives under the framework of FDA’s strategic plan. The strategic plan is very familiar to us because it builds on what we have been doing. The plan outlines a very ambitious effort to achieve five broad priority goals.

Efficient, science-based risk management

We have long led the world in applying the principles of risk management-assessing public health risks, analyzing methods for reducing them and taking appropriate action. With the expanding complexity of our medical challenges and the need to reduce the health risks facing the public at the lowest cost to society, efficient risk management is more important than ever.

Our approach to efficient risk management requires the use of the most current biomedical, statistical, managerial and economic science. We aim to achieve quicker access to safe and effective new products and reduce public health risks without unnecessary costs by:

Identifying scientific research gaps along the critical path to drug approval.
Employing principles and technologies that can reduce avoidable delays and costs in product approvals.
Overhauling and updating the way medical products are manufactured.
Implementing an enforcement strategy that combines clear communications to industry backed up by effective civil and criminal enforcement.

Patient and consumer safety

Too many Americans suffer from preventable adverse events related to pharmaceutical products resulting in human suffering and avoidable medical costs. Consequently, we are enhancing our post-market monitoring, communication and regulatory activities.

In addition, one of the most promising new ways we can improve the system for reporting safety problems is to have direct and secure access to relevant modern electronic health information. By supplementing the current passive reporting systems and partnering with healthcare providers and other government agencies, we will develop more innovative and effective information on the risks associated with regulated products.

We will help speed the implementation of safer systems for medical care through steps such as:

Bar coding medications in hospitals.
Implementing 21st-century methods for communicating with health professionals to reduce adverse events.
Improving our current system for colleting and acting on adverse events related to the products we regulate.

Better informed consumers

Informed consumers represent our nation’s greatest public health asset, because the choices Americans make every day can have a great impact on their own health and the health of the nation.

We are undertaking major new efforts to ensure consumers have the most up-to-date, truthful information on the benefits and risks of regulated products. In this arena, we meet two complementary objectives:

Ensure the information that sponsors provide about prescription drug products is accurate and allows for their safe use.
Communicate directly with the public concerning benefits and risks of the products we regulate.

Our goal is a well-informed public, empowered to make better choices to improve their health.

Counterterrorism

We are working harder and more creatively than ever to speed the availability of the next generation of safer, more effective countermeasures to protect Americans from biological, chemical, nuclear and radiological agents of terrorism. We have two complementary-but necessarily separate-roles in this effort:

We will help get products developed.

We will then review marketing approval data on the same products.

A strong FDA

Our continued ability to carry out our mission of protecting and advancing America’s health rests squarely on our most important resource: a talented and dedicated staff. More than ever, we rely on a solid cadre of experienced physicians, toxicologists, chemists, statisticians, mathematicians, project managers and other highly qualified and dedicated professionals. The expertise of our professional staff is essential for making our regulatory decisions balanced and fair. A committee of our scientists oversees an extensive program of training, seminars, case study rounds and guest lectures that helps keep our scientists up-to-date on the latest developments in their disciplines and current industry practices.

As we look to the challenges ahead, we remain steadfast in our commitment to facilitate the availability of safe and effective drugs, keep unsafe or ineffective drugs off the market, improve the health of Americans and provide clear and easily understandable drug information to health professionals, patients and consumers.

Janet Woodcock, M.D.
Director, January-September 2003
Center for Drug Evaluation and Research
Acting Deputy Commissioner for Operations
Food and Drug Administration

Steven Galson, M.D., MPH
Acting Director
Center for Drug Evaluation and Research

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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 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 a drug from the market. We also monitor manufacturing changes to make sure they won’t adversely affect the safety or efficacy of the medicine. We evaluate reports about suspected problems from manufacturers, health care professionals and consumers. Sometimes, manufacturers run into production problems that might endanger the health of patients who depend on a drug. We try to make sure that an adequate supply of drugs is always available.

Monitoring drug information and advertising. Accurate and complete information is vital to the safe use of drugs. Drug companies have historically promoted their products directly to physicians. More and more frequently now, they are advertising directly to consumers. While it is primarily the Federal Trade Commission that regulates advertising of over-the-counter drugs, we regulate unapproved products that may be marketed OTC, including their associated promotional materials, to ensure that they meet applicable approval requirements and are not fraudulent. Advertisements for a drug must contain a truthful summary of information about its effectiveness, side effects and circumstances when its use should be avoided. We are monitoring the industry’s voluntary program to provide consumers useful information about prescription drugs when they pick up their prescriptions. We are watching this program closely to see that it meets its goals for quantity and quality of information.

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:

The disease or condition may be serious and require a doctor’s management.
The medicine itself may cause side effects that a doctor needs to monitor.
The same symptoms may be caused by different diseases that only a doctor can diagnose.
The different causes may require different medicines.
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:

Drug quality, safety and performance
Improved technologies
New approaches to drug development and review
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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2003 Highlights

We are pleased to present our eighth performance report. Our work last year offered many Americans new or improved choices for protecting and maintaining their health or new ways to use existing products more safely.

Drug review

Children and adults with cancer, heart disease and other serious conditions have benefited from our approvals in 2003. We saw improved results from the previous year on overall approvals and decreases in the time it took us to review and approve most applications.

A highlight was the approval of 21 new molecular entities with active ingredients never before marketed in the United States. This number increased from the 2002 total of 17. Priority approvals for products of special medical importance increased from 2002 as well. There were 14 priority NDAs and nine priority NMEs, compared to 11 and seven in 2002, respectively..

We met all of our obligations to Congress for prompt and thorough review of drug applications supported by user fees.

We increased choices for self-care by approving three medicines for over-the-counter marketing. This included the first switch of a previously prescription-only treatment for frequent heartburn.

Our reviews of generic drugs have been prompt and predictable. We approved 263 generic equivalents for prescription or over-the-counter drugs. These included first-time generic approvals of treatments for depression, seizures and high blood pressure.

Drug safety and quality

All medicines have risks. With modern, state-of-the-art tools and techniques, we are able to detect rare and unexpected risks rapidly and take corrective action quickly.

We processed and evaluated more than 370,000 adverse drug events and 3,000 reports of medication errors. We proposed a regulation that called for over-the-counter medicines commonly used in hospitals and all prescription medicines to have a bar code. The rule became final in 2004.

We continued to focus on managing risks of marketed medicines, including having a public workshop to gather consumer and scientific input on our proposals for risk management strategies during drug development and after a drug is marketed.

We held several public meetings to discuss our effort to promote modernization of pharmaceutical manufacturing.

Communications

We met almost weekly with outside experts on difficult scientific and public health issues.

Each month, our Internet information site averaged 750,000 visitors and 13.5 million hits.

We developed public education campaigns in areas such as antibiotic resistance and buying drugs from outside the United States. Our education program on generic drug quality, specially funded by Congress, has been enormously successful, with many organizations reproducing our materials at no cost to the government.

International activities

We continued our close work with our colleagues in Japan and the European Union on finding ways to make the drug development process more efficient and uniform.

We entered new information-sharing agreements with Canada, Switzerland and the European Union.

Quality systems

We are starting down a long road toward making major improvements to our quality systems to improve the way we do our work. We already have some quality systems and subsystems in place, so we will build on those and add new ones.

The basic concepts underlying quality systems are quite simple:

Say what you do.
Do what you say.
Prove it.
Improve it.

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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 is a slowdown-instead of an 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:

The critical path for product development from design and discovery to commercial marketing.
The scientific and technical dimensions of the critical path.
The three types of research that support the critical path.

Critical Path diagram

Critical path

An idealized “critical path” encompasses the medical product development process. The critical path begins after basic research provides candidate products for development. These products then face successively more rigorous evaluation steps along the path, including:

Drug discovery
Preclinical development
Clinical development
Scale-up for mass production
FDA filing/approval and launch preparation

A striking feature of this path is the difficulty, at any point, of predicting ultimate success with a novel candidate. Recent biomedical research breakthroughs have not improved our ability to identify successful candidates.

Critical path dimensions

From the earliest phases of preclinical work to commercialization, developers must manage successfully in these three dimensions:

Assessing safety--showing that a product is adequately safe for each stage of development.

Demonstrating medical utility--showing a new product will actually benefit people.

Industrialization--turning a laboratory concept into a consistent and well-characterized medical product that can be mass produced.

The traditional tools used to assess product safety-animal toxicology and outcomes from human studies-have changed little over many decades and have largely not benefited from recent gains in scientific knowledge.

Better tools are needed to identify products that will prove clinically useful and eliminate impending failures more efficiently and earlier in the development process.

The current drug discovery process, based on in-vitro screening techniques and animal models of often poorly understood clinical relevance, is fundamentally unable to identify candidates with a high probability of effectiveness. Reaching a more systemic and dynamic understanding of human disease will require major additional scientific efforts as well as significant advances in bioinformatics.

The challenges involved in successful industrialization are complex, though highly underrated in the scientific community. Problems in physical design, characterization, manufacturing scale-up and quality control routinely derail or delay development programs and keep needed treatments from patients.

Critical path research

These different types of research support medical product development:

Basic research is directed toward a fundamental understanding of biology and disease processes. It provides the foundation for product development.

Translational research is concerned with moving basic discoveries from concept into clinical evaluation and is often product or disease specific.

Critical path research is directed toward improving the medical product development process itself by establishing new evaluation tools.

Research needed to improve development tools

While the biomedical research community has widened its efforts to include translational research, in our report, we call for a new focus on critical path research.

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 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 take a major role in this effort because of our experience overseeing medical product development, assessment and manufacturing/marketing; our vast clinical and animal databases; and our close interactions with all the major players in the critical path process.

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 report is available at http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html.

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Pharmaceutical cGMP Initiative

Our regulatory and quality control systems for pharmaceutical products, known as current good manufacturing practices, have become a gold standard for the world; however, the last comprehensive revisions to these regulations took place nearly a quarter of a century ago.

Pharmaceutical cGMPs for the 21st Century is a multi-year Agency effort begun in 2002 to enhance the regulation of pharmaceutical manufacturing and product quality.

We evaluated our internal operations under this initiative last year:

We are developing a quantitative, risk-based site-selection model for use in choosing sites for inspection. This will encourage implementation of risk-based approaches that focus on critical areas. It will ensure a risk-management approach is applied to allocating FDA inspection resources.
We revised our Preapproval Inspection Compliance Program to give field inspectors more opportunity to use a risk-based approach, allowing greater flexibility in determining whether a preapproval inspection is warranted. The number of categories of drug products that require mandatory inspection have been reduced.

cGMP initiative goals

Public health protection is strengthened by implementing risk-based approaches that focus both industry and our attention on critical areas for improving product safety and quality:

The regulatory review program and the inspection program operate in a coordinated and synergistic manner
Regulation and manufacturing standards are applied consistently using state-of-the-art pharmaceutical science
Innovation in the pharmaceutical manufacturing sector is encouraged
Our resources are used most effectively and efficiently to address the most significant health risks.

More information is at http://www.fda.gov/cder/gmp/index.htm.

Guidances to encourage manufacturing improvements

We issued one final and four draft guidances to encourage rapid adoption by industry of modern manufacturing practices. These were:

A final guidance on the use of electronic records and signatures. which explains the goals of this initiative and removes barriers to scientific and technological advances and encourages the use of risk-based approaches. The guidance clarifies the scope and application of Part 11 of the Code of Federal Regulations and provides for our enforcement discretion in certain areas while we undertake rulemaking to revise Part.
A draft guidance on the aseptic processes used in the manufacture of sterile drugs, emphasizing current science and risk-based approaches. This provides recommendations on how to build quality into products using science-based facilities, equipment and systems design. Sterile drug products are generally of high therapeutic significance, and our proactive efforts to enhance cGMP understanding in this area are intended to promote compliance and ensure a steady supply of these medically necessary products to U.S. consumers.
A draft guidance on a process for resolving disputes arising over scientific and technical issues related to pharmaceutical current good manufacturing practices.
A draft guidance on preparation and use of a comparability protocol for assessing chemistry, manufacturing and control changes to protein drug products and biological products.
A draft guidance for process analytical technology, a framework for allowing regulatory processes to adopt more readily state-of-the-art technological advances in drug development, production and quality assurance (page 44).

cGMP collaborations

A collaboration with two universities to identify the factors that predict manufacturing performance to further refine our pharmaceutical manufacturing risk-based assessment.
A collaboration with the National Science Foundation’s Center for Pharmaceutical Processing Research allowing us to expand our scientific foundation in the area of innovative pharmaceutical manufacturing technology.
A cooperative research and development agreement with a major pharmaceutical manufacturer to research chemical imaging applications in pharmaceutical manufacturing and quality assurance.
A memorandum of understanding between us and FDA’s field force to set up the Pharmaceutical Inspectorate who will devote most of their time to conducting human drug manufacturing quality inspections.

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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 terrorism attacks. These steps include:

Assuring the availability of medicines to treat victims of terrorism attacks.
Leveraging resources with other federal agencies to answer scientific questions concerning therapies to treat conditions against terrorism agents.
Protecting the nation’s drug supply from attack or deliberate contamination.
Preparing ourselves to continue operations during a crisis.

We continue to facilitate development of new drugs and new uses for already approved drugs that could be used as medical countermeasures. We work with other agencies to implement a shelf-life extension program for stockpiled drugs for military use. We gather information on drugs that might be used in response to an attack, including data on manufacturers, bulk suppliers, inventories and lead times for production. We participate in preparedness and response activities to test and establish appropriate communications procedures for emergency situations. We are collaborating with the Centers for Disease Control and Prevention on plans for obtaining post-event outcome data on the use of medical countermeasures.

Counterterrorism notable 2003 achievements

Approved pyridostigmine bromide tablets as a pretreatment to increase survival after exposure to Soman “nerve gas” poisoning. The product is approved for combat use by U.S. armed forces. This is the first drug approved under the animal efficacy rule.

Approved lower doses of the atropine autoinjector (AtroPen) for use in children and adolescents exposed to certain nerve agents and insecticides. The atropine autoinjector was approved for adult use in 1973.
Approved insoluble Prussian blue (Radiogardase) capsules to treat people exposed to radiation contamination from harmful levels of cesium-137 or thallium poisoning. The application for this drug was sent in response to the publication of our findings that Prussian blue would be safe and effective for this indication when produced under conditions specified in approved marketing applications. More information is at http://www.fda.gov/cder/drug/infopage/prussian_blue/.

Published our findings on intravenous chelators for treating exposure to radioisotopes. We determined that pentetate calcium trisodium (Ca-DTPA) and pentetate zinc trisodium (Zn-DTPA) are safe and effective, when produced under conditions specified in approved marketing applications, for treatment of contamination with radioactive isotopes of the elements plutonium, americium and curium. We are encouraging manufacturers to use these findings to submit new drug applications.
Published information on the World Wide Web on how to dissolve and mix doxycycline tablets with food or drinks. Following an exposure to inhalational anthrax, parents may receive stockpiled tablets for their children if suspensions are not available. We published these instructions for making palatable doses of the antibiotic to give small children who may not be able to swallow tablets.
Participated in emergency response activities, including the international Global Mercury smallpox exercise and the U.S. government’s Scarlet Cloud anthrax exercise. We also began testing components of our continuity of operations plan to assure that we can maintain vital operations and service.
Began discussions with CDC on mechanisms to collect and assess outcome information following the use of medical countermeasures in a terrorist event.
Drafted a guidance for industry that we published in March 2004, Vaccinia Virus: Developing Drugs to Mitigate Complications from Smallpox Vaccination.

Animal efficacy rule

Certain human drugs and biologics intended to reduce or prevent serious or life-threatening conditions may be approved based on animal evidence of effectiveness when human efficacy studies are not ethical or feasible. The regulation, also known as Subpart I for drugs (21 CFR Part 314) or Subpart H for biologics (21 CFR Part 601) applies when:

The pathophysiology of the disease and the mechanisms of action of the drug are reasonably well-understood.
The efficacy endpoints in the animal trials are clearly related to human benefit.
The drug effect is demonstrated in more than one well-characterized animal species expected to react with a response predictive for humans; and
Data allow selection of an effective human dose.

Counterterrorism scientific research

Some medical countermeasures are stockpiled in tablet form that may be difficult to swallow for infants, small children and others. Two examples are doxycycline, for post-exposure prophylaxis for anthrax, and potassium iodide, for use in emergencies involving radioactive iodine. We used the “electronic tongue” instrument to extend our studies of the stability and palatability of these drugs when crushed and mixed with different foods or drinks. We compared the results to those of human taste panels. We developed an exposure-response model for pyridostigmine, an anti-nerve gas agent, to extrapolate animal efficacy data to a human dose regimen.

Counterterrorism biotechnology research

We have used congressionally mandated special funding to initiate research in several areas relevant to counterterrorism. Our scientists are studying:

Microarray technologies, which could assist in identifying infectious biowarfare agents
Non-specific immune boosters, which could provide transient protection against such agents
Monoclonal antibodies as neutralizers of biological toxins
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.

Collaborative research on pneumonic plague

We are collaborating with the National Institute of Allergy and Infectious Diseases and the U.S. Army Medical Research Institute of Infectious Diseases to investigate the use of the antibiotic gentamicin and other antimicrobials for the treatment of pneumonic plague. Natural history, pharmacokinetic and toxicology studies were performed to support planned efficacy studies using a non-human primate model of pneumonic plague.

Shelf-life extension for drug stockpiles

Our laboratories perform shelf-life extension testing for drug products stockpiled by the U.S. military and the Strategic National Stockpile. We published the Guidance for Federal Agencies and State and Local Governments: Potassium Iodide Tablets Shelf Life Extension as a draft, and it became final in March 2004.

Counterterrorism Internet resources

We provides links to the most current information on:

Drugs to prevent or treat disease caused by terrorism agents including drugs for use against anthrax, plague, radiation emergencies and chemical agents.
Drug development of counterterrorism products.
Vaccines.
Pediatric counterterrorism measures.
Prescribing and buying countermeasures.

You can find these links at http://www.fda.gov/cder/drugprepare/default.htm.

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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

We are identifying, evaluating and establishing relvant 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.
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.
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.
We established scientific research capabilities in the analyses of medicinal plant and herbal products.
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.
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.
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 in 2003 from the Center for Biologics Evaluation and Research. The office consists of about 80 scientists who are responsible for evaluating therapeutic biotechnology product submissions as well as carrying out scientific research related to biologics regulatory issues.

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.
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

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 propriety information.
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.

Clinical pharmacology

We are exploring the utility and value of quantitative drug-disease state models and clinical trial simulation in drug development and regulatory review.
We issued the final guidance on Exposure-Response Relationships: Study Design, Data Analysis, and Regulatory Applications.

We cosponsored an open workshop pharmacogenomics in drug development and regulatory Decision-making.
We published a draft guidance for industry, Pharmacogenomic Data Submissions, to provide a better understanding on the current use of pharmacogenomics in drug development and gain experience in handling and evaluating genotype and gene expression data.
We are working on a draft guidance for industry on the regulatory pathway for pharmacogenomic drug-device combinations.

Pharmaceutical analysis

We assure that analytical methods being developed by pharmaceutical companies are suitable for quality assurance and regulatory purposes. We assessed analytical methods for six new drugs and one generic drug.
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.

Laboratory support

Last year our efforts included:

Assessment of the safety (cyanide release) and the efficacy (cesium binding) of Prussian blue in support of its approval as a medical countermeasure.
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.
Rapid identification of counterfeit products using near-infrared spectroscopy and chemical imaging to discriminate drug products and raw materials.
Development of a methodology for the determining glove permeability to lindane shampoo and lotion, treatments for lice whose active ingredient is highly toxic.

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Date created: May 24, 2004