U.S. Food and Drug Administration Center for Drug Evaluation and Research
About CDER - Report
Center for Drug Evaluation and Research
CDER 2002 Report to the Nation:
Last year, we at the Center for Drug Evaluation and Research worked hard to meet the challenge of promoting and protecting the public health. The dedication, creativity and expertise of our professional staff, coupled with new authorities and resources, enable us to continue to meet this challenge.
Our new Commissioner has established five strategic areas for the Agency:
In 2002, we took significant steps in each of these areas.
Strong and sound science means our scientists stay on the cutting edge of new technologies. Our mission depends more than ever 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.
Quality of work life is important in retaining our professional staff, who rated CDER very high in the Secretary's 2002 survey on organizational environment.
Last year, Congress reauthorized our collection of user fees for drug reviews. The reauthorization maintains our rigorous review and drug development goals, places the program on a sound financial footing and increases our resources for surveillance of newly marketed drugs. The review function for therapeutic biological products will be transferred to our center in 2003. Consolidation will strengthen our science base, and we look forward to working with, and extend a warm welcome to, our colleagues from the Center for Biologics Evaluation and Research.
Efficient risk management
Last year, our hard work enabled us to meet nearly all of the demanding application review goals of the Prescription Drug User Fee Act. We evaluated many new drugs that offered important treatment options for Americans. For example, we approved the first non-sedating antihistamine for over-the-counter sale and the first non-stimulating treatment for attention deficit/hyperactivity disorder in children.
However, we are concerned that the approval of truly new drugs is at the lowest level in a decade. We have launched an important initiative to remove barriers to innovation in drug development.
We are leading an important FDA initiative to facilitate the modernization of American drug manufacturing. Use of cutting-edge technology will allow manufacturers to produce high-quality drug products with greater efficiency and lower cost.
Patient and consumer safety
We continued to enhance our drug safety program to help make sure that drugs are used safely once they're approved. Legislation has given us new authority and resources to conduct more rigorous safety monitoring of newly approved drugs in the first few years on the market. Last year, we evaluated more than 300,000 adverse event reports. We alerted the public to the dangers of importing or buying over the Internet 10 drugs that are marketed in this country with special safety restrictions.
Balanced and fair information is critical to the safe use of medicines. We completed surveys of physicians and consumers about direct-to-consumer advertising. About 40 percent of patients and about 45 percent of physicians feel DTC advertising encourages information seeking about potentially serious medical conditions. We are working on new guidance for direct-to-consumer advertising.
Better consumer information
We are collaborating with a broad spectrum of groups to improve information for prescribers and consumers. Last year, we implemented a mandatory changeover to new, easy-to-understand labels for medicines sold over the counter. Industry and consumers are increasingly turning to our Internet site for important and up-to-date information on our regulatory programs and on the drugs they take to improve their health. We have 10 public education programs to promote the safe use of medicines. The program to bolster consumer confidence in generic drugs has met with particularly outstanding success and acceptance.
We continue to facilitate development of new drugs and new uses for already approved drugs that could be used as medical countermeasures. We amended our regulations so that 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 way forward
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.
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.
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 the Federal Trade Commission regulates advertising of over-the-counter drugs, we oversee the advertising of prescription 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. 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.
Conducting applied research. We conduct and collaborate on focused laboratory research and testing. Research 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; and regulatory standards and consistency.
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 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 proposals in advance. This gives members of the public, academic experts, industry, trade associations, consumer groups and professional societies the opportunity to comment and make suggestions before we make a final decision. In addition, we take part in a series of FDA-sponsored public meetings with consumer and patient groups, professional societies and pharmaceutical trade associations. These stakeholder meetings 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 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:
You can buy OTC drugs without a doctor's prescription. You can successfully diagnose many common aliments 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.
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. The biggest difference between a generic drug and its brand name counterpart is usually price. A generic drug may be priced anywhere between 20 percent and 75 percent of the cost of the brand-name version.
We are pleased to present our seventh 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.
New, reauthorized legislation
Our programs will benefit from additional authorities and resources.
Children and people with cancer, heart disease and other serious conditions have benefited from our approvals in 2002. Our workload remained very high; however, our experience last year included some concerning trends in drug development. The number of filings and approvals of new molecular entities, significant new drugs never before approved for marketing in the United States, continued to decline to their lowest point in a decade. Our statistics for priority drug reviews have also been affected by this trend.
Last year saw a steep rise in median total approval times for priority new drugs and priority new molecular entities. This resulted from the approval of drug applications received in previous years coupled with the decrease in recent priority submissions. With a smaller pool of recent priority applications with short approval times, the submissions from previous years dominated the median approval time statistics.
We met or exceeded most of our obligations to Congress for prompt and thorough review of drug applications supported by user fees.
We approved 78 new drugs, including 17 new molecular entities. We also approved 152 new or expanded uses of already approved drugs, an increase of 67 percent from the previous year.
We increased choices for self-care by approving 13 medicines for over-the-counter marketing. This included the first switch of a non-sedating antihistamine from prescription only to over-the-counter sale. A mandatory changeover to new, easy-to-understand labels for OTCs began last year.
Our reviews of generic drugs have been prompt and predictable. We approved 321 generic equivalents for prescription or over-the-counter drugs. Our generic drug education program, specially funded by Congress, has been enormously successful, with many organizations reproducing our materials at no cost to the government.
Our effort to protect our citizens and soldiers against chemical, biological and nuclear weapons was bolstered last year. We amended our regulations to permit us to approve certain countermeasures based on animal studies when human efficacy studies are infeasible or unethical.
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 improved our risk-assessment ability by gaining access to actual use data.
Last year, we processed and evaluated more than 320,000 adverse drug events. We issued nearly 700 letters to help ensure that the promotion of drug products presents a fair balance of risks and benefits and isn't false or misleading.
We met almost weekly with outside experts on difficult scientific and public health issues. We received valuable input from a public hearing on risk management tools.
Each month, our Internet information site averaged 750,000 visitors and 13.5 million hits.
We responded to more than 70,000 individual requests for information.
We developed public education campaigns in areas such as new OTC drug labels, generic drug quality, proper drug dosing for children and pregnancy and drug use.
We worked closely with our colleagues in Japan and the European Union on finding ways to make the drug development process more efficient and uniform.
We finalized the electronic version of the Common Technical Document format. The CTD can be used for seeking approval to market new drugs in the United States, the European Union and Japan.
Last year, we adjusted our organizational structure to enhance how we use risk management principles in our operations:
With additional resources, our post-market drug safety experts have begun to contribute their insights to the premarket review of risk management plans for new drugs.
Our compliance operations have relocated and reorganized.
Our current organizational charts are at http://www.fda.gov/cder/cderorg.htm.
Pharmaceutical reviews to be consolidated
The review of some new biologic products will be transferred to our center in 2003. This will enhance the efficiency and consistency of reviewing clinically similar products.
Consolidation will strengthen our science base, increase timeliness of reviews and contribute to greater uniformity of regulations, policies and practices involving all therapeutics.
Planned for transfer are cytokines, growth factors, enzymes and interferons-including recombinant versions-plus proteins for therapeutic use that are extracted from animals or microorganisms and other therapeutic immunotherapies.
We believe we can help speed potentially important new drugs to the market by reducing regulatory uncertainty and increasing the predictability of product development. We are playing a key role in a broad FDA initiative called Improving Innovation in Medical Technology: Beyond 2002. The initiative is aimed at:
We are looking to achieve these goals through new actions in three major areas:
Our proposals are outlined in a detailed report at http://www.fda.gov/bbs/topics/NEWS/2003/beyond2002/report.html. The executive summary is at http://www.fda.gov/bbs/topics/NEWS/2003/beyond2002/execsumm.html.
Our regulatory and quality control systems for pharmaceutical products have become a gold standard for the world; however, the last comprehensive revisions to these regulations are nearly a quarter of a century old. Last year, we announced a significant new initiative, called Pharmaceutical cGMPs for the 21st Century, to enhance the regulation of pharmaceutical manufacturing and product quality and to bring a 21st century focus to this FDA responsibility.
The major goals of the initiative are to make sure that:
More information on the program, including the concept paper, progress reports and announcements of public meetings, is on our Web site at http://www.fda.gov/cder/gmp/index.htm.
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:
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.
Increased counterterrorism resources
We hired additional experts in medicine, science and regulatory affairs dedicated to our counterterrorism mission.
We have improved coordination and communication with other federal agencies and manufacturers.
We provide guidance and direction for the research and development of new and existing medical countermeasures.
Counterterrorism notable 2002 achievements
Animal efficacy rule. We amended our regulations so that 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 rule-also known as the Animal Efficacy Rule or Subpart I-applies when: the pathophysiology of the disease and the mechanisms of action of the drug are well understood; the efficacy endpoints in the animal trials are clearly related to human benefit; the drug effect is demonstrated in at least one well-characterized animal species expected to react with a response predictive for humans; and data allow selection of an effective human dose. We reviewed and, in February 2003, approved pyridostigmine bromide to increase survival after exposure to Soman nerve gas poisoning-the first use of the rule.
New drug approval-ATNAA. We approved ATNAA (Antidote Treatment-Nerve Agent, Autoinjector) sponsored by the U.S. Army, for use as an antidote to nerve agent exposure. Atropine and pralidoxime, the two nerve agent antidotes in this combination product, were already approved separately. Approval of the combination provided for a single injection containing both drugs, thereby allowing for more efficient and convenient administration on the battlefield.
Generic drug approval-potassium iodide. ThyroSafe Tablets, 65 mg, an over-the-counter generic drug application, was approved in September 2002 under expedited review. This thyroid blocking agent for use in radiation emergencies is half the concentration of the other approved potassium iodide tablets, making it particularly important for use in pediatric populations.
New drug review-Prussian Blue. We completed the review of the data for using Prussian Blue to treat exposure to radioactive cesium and thallium. We published our findings of safety and efficacy in February 2003 to encourage sponsors to submit applications for this indication.
New drug review-Chelators. We also reviewed all U.S. cases of radiation exposure treated with intravenous chelators. Results of this review are pending.
Grants announcement, interagency agreement. We announced the availability of grants to support clinical trials on the safety and efficacy of drug products for the treatment of human plague. We are supporting an interagency agreement with the Centers for Disease Control and Prevention to fund such studies.
Contracts. Through FDA's Office of Women's Health, we contracted for studies on therapies that may be used to treat conditions caused by terrorism agents. These studies will enroll special populations such as lactating and pregnant women and the elderly.
Shelf-life extension for drug stockpiles
Our laboratories perform shelf-life extension testing for drug products stockpiled by the U.S. military.
We issued a draft guidance on developing drugs to treat inhalational anthrax.
Public health guidance
With the results from the research on doxycycline and potassium iodide (see below), we provided medical professionals and the public information on:
Counterterrorism Internet resources
Our Internet site 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 counter-terrorism products; vaccines; pediatric counter-terrorism measures; and prescribing and buying countermeasures.
You can find these links at http://www.fda.gov/cder/drugprepare/default.htm.
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.
In collaboration with the National Institute of Allergy and Infectious Diseases and the Department of Defense, we developed a monkey model for pneumonic plague to be used to study a number of potential therapies. We are also collaborating with them on a monkey model for studies of smallpox therapies.
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 studied the stability and palatability of these drugs when crushed and mixed with different foods or drinks.
We developed an exposure-response model for pyridostigmine, an anti-nerve gas agent, to extrapolate animal efficacy data to a human dose regimen.
Linking nonclinical and clinical studies
We are identifying, evaluating and establishing improved protein biomarkers in blood in both animal models and in humans. These will help monitor 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 confirmed reports of brain toxicity findings in neonatal rats with ketamine, an anesthetic widely used in children. Our rapid research resulted in the National Toxicology Program undertaking broad ranging non-human primate studies to assess better human relevance of these rodent findings.
We established scientific research capabilities in the analyses of medicinal plant and herbal products.
We continue to explore noninvasive imaging technology to extend the 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 for evaluating the risk and benefit 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.
We assure that analytical methods being developed by pharmaceutical companies are suitable for quality assurance and regulatory purposes. Last year, we assessed analytical methods for more than 20 new drugs.
We collaborate with other organizations to ensure the availability of high quality standards and calibration materials.
Other analytical methods under development last year included characterization of nasal inhalation products and complex drug substances.
We tested several analytical technologies for characterizing active pharmaceutical ingredients and guarding against counterfeit product marketing. These included isotope ratio mass spectroscopy, ion mobility spectroscopy, near infrared and Raman spectroscopies. We examined Raman imaging's ability to determine particle size distribution of the active ingredient in nasal sprays.
We use project teams to perform drug reviews. Team members apply their individual special technical expertise to review applications:
Chemists focus on how the 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.
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.
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.
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.
Statisticians evaluate the designs and results for each important clinical study.
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.
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.
Scientific training for reviewers
Our systematic, internal training program is based on core competencies, learning pathways and individual development plans.
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.
Quality of work life survey
In a survey conducted last year by the Department of Health and Human Services, we did better than both FDA and the entire department in 13 of 14 general areas important to organizational performance.
About three-fourths of our scientists and other employees reported positively on the effectiveness of our management practices, their feelings about the organization and the effective use of their abilities.
FDA/Center for Drug Evaluation and Research