About CDER - Report

CDER Report to the Nation: 2001

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

CDER 2001 Report to the Nation:
Improving Public Health Through Human Drugs

Adobe Acrobat version of this document

Contents

Director's Message

Introduction

2001 Highlights

• Counterterrorism
• Scientific Research

1 Drug Review

• New Drug Review
• Standard new drugs
• Priority new drugs
• New molecular entities
• Standard NMEs
• Priority NMEs
• Orphan drug approvals
• Notable 2001 new drug approvals
• New or Expanded Use Review
• Pediatric Exclusivity
• Over-the-Counter Drug Review
• Generic Drug Review
• User Fee Program
• Manufacturing Supplement Review
• Antimicrobial Resistance
• Electronic Submissions
• Assessing Data Quality, Research Risks
• Drug Review Team

2 Drug Safety and Quality

• Types of Risks from Medicines
• Drug Safety
• MedWatch Outreach and Reporting
• DrugShortages
• Cyber Letters for Foreign Ciprofloxacin
• Drug Promotion Review
• Drug Recalls and Withdrawals
• Drug Product Quality
• Drug Product Quality Science
• Export Certificates

3 International Activities

• International Conference on Harmonization
• Harmonization Initiative in the Americas
• U.S.-European Union Mutual Recognition Agreement

4 Communications

• Public participation
• Consumer and Industry Outreach
• Where to Find More Information

Director's Message

Last year, we at the Center for Drug Evaluation and Research worked hard to:

• Provide rapid access to new therapies while maintaining rigorous safety and effectiveness standards.
• Listen to the voices of consumers, patients and health care professionals as well as those of regulated industry.
• Match the effort in premarket evaluation with a vigorous postmarket monitoring program.
• Make sure we support the people in CDER as well as serving the outside world.

However, routine operations were not the hallmark of a year that witnessed the terrorist attacks on and after Sept. 11. The brutal assaults challenged us to rise to the defense of the American consumers. In close cooperation with other authorities, we responded with our traditional vigor, initiative and scientific expertise.

We developed strategies to strengthen the protection of drug products against willful contamination and to improve the availability of drugs for the prevention or treatment of injuries caused by biological, chemical or nuclear agents.

For example, we took the initiative to clarify that the antibiotics doxycycline and penicillin G procaine are effective and approved for use in treating all forms of anthrax infections. This notice included explicit dosing based on our review of scientific literature and data from the same rhesus monkey study that had been used to support our August 2000 approval of ciprofloxacin for anthrax. The assurance that the three drugs are effective against all forms of anthrax infection eased public concerns about a potential shortage of medication for the victims of the mailed anthrax powder.

We also stepped up our work on measures to encourage the development of new drugs to counter the toxic effects of chemical, biological, radiological and nuclear weapons.

In addition to doing our part in protecting Americans against terrorism, we evaluated many new drugs that advanced the frontier of modern medicine. For example, we approved a new drug to treat a rare form of life-threatening cancer in two and one-half months. We are continuing to develop science-based data on safety and dosing regimens for drugs to treat children.

Once again, we met all of the demanding application review goals of the Prescription Drug User Fee Act, but we have encountered challenges. Our efforts to meet goals for drug development may have had an unintended impact on approval times for standard applications. These approval times have begun to increase because more applications require multiple review cycles to reach approval. We are watching trends closely.

Our generic drug program is providing a steady supply of more affordable drugs that meet our uniform and stringent standards for safety, effectiveness and quality. We are developing an education program to bolster consumer confidence in generic drugs.

We continued to enhance our drug safety program. In recent years fully 50 percent of all new drugs worldwide have been launched in the United States, and American patients have had access to 78 percent of the world's new drugs within the first year of their introduction. More rigorous safety monitoring of newly approved drugs in the first few years on the market is key to detecting unanticipated problems earlier. We have entered into several agreements that will give us access to data about the actual use of prescription drugs by children and adults. This will augment our ability to determine the significance of adverse events we receive. We will have the benefit of advice about general and product-specific safety issues from a new panel of experts in areas related to risk perception and management, pharmacology and other related disciplines.

We launched an important initiative to build the scientific data needed to modernize American drug manufacturing. While Americans have the highest quality of drugs in the world, the process used to produce them can be expensive and wasteful. We have observed an increasing trend toward manufacturing-related problems, such as recalls, disruptions of manufacturing operations and the loss of availability of essential drugs. Modern technology holds the promise of manufacturing to the same or higher quality standards while reducing the workload for industry and for us and ensuring the highest quality drug products for American consumers.

We are making strenuous efforts to come to grips with the reality of globalization in the marketplace. Cornerstones of our efforts are the International Conference on Harmonization, the Mutual Recognition Agreement with the European Union, and building relationships with the international regulatory community. We have begun work to promote harmonization within the Americas.

An urgent priority for us is improving our communications. Information is a key element in the safe and effective use of drugs. We are collaborating and leveraging with a broad spectrum of groups to improve information for prescribers and consumers. 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.

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 for safe and effective use.

        /s/
Janet Woodcock, M.D.
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 nearly 1,700 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 doesn't stop. 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 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 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.

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. 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.

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2001 Highlights

We are pleased to present our sixth 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. In the wake of the terrorist attacks, our nation was prepared with an antibiotic approved to treat inhalational anthrax. We had worked on this program for several years and reported on the approval in last year's report. We were rapidly able to provide health professionals with additional guidance on using other safe and effective medicines.

Drug review

People with cancer, heart disease, HIV, AIDS, and other serious conditions have benefited from our approvals in 2001. We met our obligations to Congress for prompt and thorough review of drug applications supported by user fees. Our reviews of generic drugs have been prompt and predictable.

We approved 66 new drugs, including 24 new molecular entities. New molecular entities contain an active substance never before approved for marketing in any form in the United States. We also approved 91 new or expanded uses of already approved drugs. We increased choices for self-care by approving six medicines for over-the-counter marketing and one new or expanded use for an existing over-the-counter drug. We approved 234 generic equivalents for prescription or over-the-counter drugs.

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 more rapidly and take corrective action more quickly. We augmented our risk-assessment ability by gaining access to actual use data. We will be able to consult with a new expert panel of advisors.

Last year, we processed and evaluated more than 280,000 adverse drug events. We issued nearly 900 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 mandated that three drug products be dispensed with specific consumer information that will help ensure the products are used safely and effectively. Our review of the safety profile of one approved drug resulted in its voluntary withdrawal, and the manufacturer of another drug withdrew it after reviewing safety reports.

International activities

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 began accepting the first new drug applications in 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.

We are collaborating on prioritizing issues for our harmonization efforts among the countries of North and South America. We are leading the U.S. consultations with the European Union to allow for reciprocal reliance on manufacturing plant inspections. Last year we began exchanging recall information and alerts concerning significant emerging product quality problems with the European Union.

Communications

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

We held two week-long introductory workshops for our stakeholders.

We responded to more than 52,000 individual requests for information.

Each month, our Internet information site averaged nearly 550,000 visitors and 10 million hits.

We developed public education campaigns in areas such as risk management and buying prescription drugs over the Internet.

Realignment

We began the new year with a revised structure aimed at aligning similar functions and creating smaller, more manageable work units.

Our organizational charts are at http://www.fda.gov/cder/cderorg.htm.

Counterterrorism

The terrorist attacks of Sept. 11, 2001, and the subsequent anthrax contamination of the mail underscored our role in:

• Protecting the nation's drug supply from attack or deliberate contamination.
• Assuring the availability of medicines to treat victims of terrorist and bioterrorist attacks.
• Preparing ourselves to continue operations during a crisis.

The first therapy for those exposed to a terrorist attack or a biological warfare agent is often a drug. We have been taking an aggressive and proactive approach to getting antibioterrorism treatment information into the labeling of already approved drugs. We approved the first such drug, ciprofloxacin, in 2000 for treating inhalational anthrax.

The Sept. 11 terrorist attacks and the subsequent anthrax attacks have vaulted this work and other actions to protect public health and safety to our top priority.

On Sept. 11, we continued to communicate with the Centers for Disease Control and Prevention. By that night, the CDC had submitted to us a "streamlined" investigational new drug application that would allow government physicians to prescribe the antibiotic gentamicin for the treatment of pneumonic plague in the event of a bioterrorist attack.

In November, in response to concerns about a potential nuclear event, we finalized our guidance on potassium iodide, or KI, as an agent to protect the thyroid gland in radiation exposure emergencies.

Immediate response to the anthrax crisis

• Published new labeling information for doxycycline and procaine penicillin in post-exposure management to prevent the development of inhalational anthrax.
• Issued a public health advisory on the use of doxycycline for anthrax exposure.
• Coordinated with other agencies to halt the importation of unapproved ciprofloxacin.
• Posted information on antibiotic use for anthrax on the Internet.

Ongoing and long-term counterterrorism work

• Coordinating with the Department of Defense to develop an appropriate animal model to study whether available antibiotics, which aren't labeled for pneumonic plague, are effective in the treatment of this highly contagious lung disease.
• Cooperating with the National Institutes of Health, CDC, DOD and sponsors from industry to facilitate development of both investigational new drug applications and new uses for already approved drugs that could be used as medical countermeasures to a terrorist attack with agents such as smallpox and plague.
• Assisting the CDC to obtain follow-up drug safety and outcome information for patients treated with antibiotics during the anthrax post-exposure prophylaxis campaign.
• Expediting work on a final regulation that would allow us to rely on animal studies and supporting data to approve drugs for bioterrorism agents when clinical studies in humans would be unethical.
• Assisting the CDC in managing the National Pharmaceutical Stockpile.
• Coordinating with FDA's field inspectors and manufacturers to help evaluate and resolve any manufacturing concerns that might arise during emergency production.
• Expediting reviews and inspections for manufacturing supplements that may be required for expanded drug production.
• Working with CDC, DOD and the Department of Veterans Affairs to implement a shelf-life extension program for stockpiled drugs for civilian and military use.
• Gathering and maintaining information on drugs that might be effective in an attack, including data on manufacturers, bulk suppliers, inventories and lead times for production.

The animal efficacy rule

We are preparing a final regulation to implement our 1998 proposal, commonly called "the animal efficacy rule." The rule would permit us to rely on animal evidence when a bioterrorism agent's mechanism of toxicity is well understood in humans; the efficacy endpoints in the animal trials are clearly related to benefit in humans; the drug's effect is demonstrated in a species expected to react similarly to humans; and data allow selection of an effective human dose.

Such approvals could include possible postmarketing studies when feasible and ethical, possible restrictions on distribution and a requirement that information about the basis of approval be provided to patients.

Ciprofloxacin for anthrax

We recognized several years ago that no drugs were specifically labeled for the treatment or post-exposure prevention of inhalational anthrax. We worked on ciprofloxacin first, based on expert assessment that anthrax was the most likely biological agent. We also feared that anthrax might be modified to be resistant to older antibiotics with an anthrax indication.

Ciprofloxacin has an enormous safety database. It has been used for more than 14 years with more than 100 million prescriptions in the United States and 250 million worldwide-more than 4 million of those for children.

We knew we could get similar drug levels in humans to the blood levels in the monkeys that the U.S. Army had exposed to anthrax.

We initiated the identification and collection of the data. The sponsor then submitted a supplemental application, which we approved.

Internet resources

To help prepare our nation for possible bioterrorism attacks, we are working with other federal agencies to make sure adequate supplies of medicines are available to the American public.

Our Internet site provides links to the most current information on drug therapy, including information on special populations such as children and pregnant women, plus advice on purchasing and taking medication. You can find it 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 and evaluating new scientific methods and 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 linkage between nonclinical and clinical studies, enhancing the 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

• 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, blood vessels, kidney, immune system and liver.
• Identifying cellular and tissue biomarkers predictive of safety and efficacy, through DNA microarrays and noninvasive imaging. The use of these novel technologies enables evaluations of their strengths and limitations for practical applications that could improve the interface between drug development and regulatory practice.
• Elucidating the molecular mechanisms operating in transgenic mice to ensure the appropriate use of more rapid and reliable tests that will detect the cancer-causing potential of drugs.
• Developing experimental models for detecting early signals of damage in liver cells. This will facilitate understanding why certain types of drugs cause liver damage.

Clinical Pharmacology

• Results from St. John's Wort interaction studies demonstrated that this herb could reduce the effectiveness of some prescription drugs. The results also provided the scientific basis for our recommendation to FDA's Center for Food Safety and Applied Nutrition and the Federal Trade Commission on the labeling of St. John's Wort products.
• Results from studies on the metabolism of hormone replacement therapy provided critical information for labeling these products and drugs that will be co-administered with them.
• We evaluated the stability and palatability of ground and dissolved antibiotic tablets for use in children in a bioterrorism emergency.
• Noninvasive imaging is an emerging technology increasingly used drug development. We are using this tool to extend our long-standing interest in the application of dose-concentration-response principles for regulatory decision-making by viewing drugs and their actions directly at the level of the drug target, rather than indirectly via plasma concentrations and/or downstream indicators of target modulation.

Studies of drugs that affect metabolic enzymes

We carefully monitor the inhibition of drug metabolism in both our research and review programs.

Clarithromycin is an example of drugs that have mechanism-based effects on metabolic enzymes.

These often cause longer-lasting drug interactions and have resulted in serious adverse events when additional drugs are prescribed.

Data on and an understanding of the effect and the time-course of mechanism-based inhibitors is critical for providing accurate dosing information when new drugs are co-administered with these agents.

Leveraging scientific resources

The Product Quality Research Institute is a unique and innovative collaboration among our scientists and those from academia and industry. PQRI conducts research to establish better testing methods, standards and controls for assessing product quality and manufacturing and management processes.

The institute's research will help us develop consistent and reasonable requirements for product quality information in regulatory submissions.

Leveraging scientific expertise in this way contributes to streamlining the drug development and approval processes for industry and ourselves while ensuring the highest level of product quality for American consumers.

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