About CDER - Report

CDER Report to the Nation: 2000

Table of Contents

Drug Safety and Quality

The practical size of premarketing clinical trials means that we cannot learn everything about the safety of a drug before we approve it. Therefore, a degree of uncertainty always exists about the risks of drugs. This uncertainty requires our continued vigilance, along with that of the industry, to collect and assess data during the post-marketing life of a drug.

We monitor the quality of marketed drugs and their promotional materials through product testing and surveillance. As Americans are increasingly receiving the benefits of important new drugs before they are available to citizens of other countries, we must be especially vigilant in our surveillance. In addition, we develop policies, guidance and standards for drug labeling, current good manufacturing practices, clinical and good laboratory practices and industry practices to demonstrate the safety and effectiveness of drugs.

Highlights of drug safety and quality activities include:

• Processed and evaluated 245,750 reports of adverse drug events, including 15,374 submitted directly from individuals.
• Conducted 74 inspections to ensure adverse event reports submitted by manufacturers are accurate, timely and complete.
• Issued 1,123 letters to help ensure that the promotion of drug products presents a fair balance of risks and benefits and isn't false or misleading.
• Mandated that five drug products be dispensed with specific consumer information to help make sure them the products are used safely and effectively.
• Issued a proposed rule to revise prescription drug labeling to improve its accessibility and enhance safe and effective prescribing and use.
• Conducted reviews of the safety profile of three approved drug products that resulted in their voluntary withdrawal from the market.
• Issued a public health alert about a once widely used decongestant that has been withdrawn from the market by manufacturers.
• Evaluated results of 1,144 preapproval inspections of new drugs, 1,085 preapproval inspections of generic drugs and 1,436 postapproval inspections.
• Issued 4,197 export certificates for U.S. drug products.

Mission

Protect the public health by ensuring that human drugs are safe and effective.

Public meeting on safe drug use

We held a two-day public meeting on the safe use of drug products to inform and obtain feedback from consumer and patient groups.

Types of Risks from Medicines

Product quality defects. These are controlled through good manufacturing practices, monitoring and surveillance.

Known side effects. Predictable adverse events are identified in the drug's labeling. These cause the majority of injuries and deaths from using medicines. Some are avoidable, and others are unavoidable.

• Avoidable. In many cases drug therapy requires an individualized treatment plan and careful monitoring. Other avoidable side effects are known drug-drug interactions.
• Unavoidable. Some known side effects occur with the best medical practice even when the drug is used appropriately. Examples include nausea from antibiotics or bone marrow suppression from chemotherapy.

Medication errors. The drug is administered incorrectly or the wrong drug or dose is administered.

Remaining uncertainties. These include unexpected side effects, long-term effects and unstudied uses and populations. For example, a rare event occurring in fewer than 1 in 10,000 persons won't be identified in normal premarket testing.

U.S. risk management system fails to respond to new information about a drug's risks

We cosponsored a study of contraindicated use of cisapride. Our 1998 regulatory action involving cisapride resulted in a black-boxed warning on the labeling and a "Dear Health Care Professional" letter from the manufacturer.

The study indicated the percentage of patients inappropriately exposed to cisapride was unchanged after the warnings (http://jama.ama-assn.org/issues/v284n23/rfull/joc00932.html).

Medication errors

We help ensure the safe use of drugs we approve by identifying and avoiding brand names that contribute to problems in prescribing, dispensing or administration of the product.

In 2000, we reviewed about 300 proprietary names and developed standard operating procedures on the review process.

We developed a comprehensive Web site on medication errors at http://www.fda.gov/cder/drug/MedErrors/default.htm.

Drug-induced liver injury

Drug-induced liver injury is the most common cause for removing approved drugs from the market, limiting a drug to second-line use or requiring special monitoring or restricted use.

We have been working with manufacturers to address clinical studies in patients with impaired liver function. Data from these studies will provide information on dose adjustment and help prevent drug-induced liver injury.

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Drug Safety

We evaluate the ongoing safety profiles of drugs available to American consumers using a variety of tools and disciplines. We maintain a system of postmarketing surveillance and risk assessment programs to identify adverse events that did not appear during the drug development process. We monitor adverse events such as adverse reactions, drug-drug interactions and poisonings. We use this information to update drug labeling and, on rare occasions, reevaluate the approval or marketing decision.

As we discover new knowledge about a drug's safety profile, we make risk assessments and decisions about the most appropriate way to manage any new risk or new perspective on a previously known risk. Risk management methods include new labeling, "Dear Health Care Practitioner" letters, restricted distribution programs or product marketing termination.

Information technology

A powerful tool for detecting signals is the computerized spontaneous reporting evaluation system. We use a new, state-of-the-art system: the Adverse Event Reporting System. This system combines the voluntary adverse drug reaction reports from MedWatch and the required reports from manufacturers. These reports often form the basis of various "signals" that there may be a potential for serious, unrecognized, drug-associated events. After the signal is generated, further testing of the hypothesis is undertaken using various epidemiological and analytic databases, studies and other instruments and resources. The Adverse Event Reporting System offers paper and electronic submission options, international compatibility and pharmacovigilance screening.

Adverse event reporting

In 2000, we received 245,750 reports of suspected drug-related adverse events:

• 87,160 manufacturer 15-day (expedited) reports.
• 15,254 MedWatch reports directly from individuals.
• 143,336 manufacturer periodic reports and other follow-up reports.

Report types

15-day (expedited) reports. These report serious and unexpected adverse events to us as soon as possible within 15 days of discovering the problem.

Direct reports from MedWatch. An individual, usually a health care practitioner, notifies us directly of a suspected serious adverse event.

Manufacturer periodic reports. These report all other adverse events, such as those that are less than serious or described in the labeling. This type of report is submitted quarterly for the first three years of marketing and annually after that.

AERS on Internet

You can learn more about the Adverse Event Reporting System at http://www.fda.gov/cder/aers/index.htm.

Adverse event reporting enforcement

We enforce regulations on postmarketing adverse event reporting to ensure that reports are accurate, timely and complete. During fiscal year 2000, we accomplished 74 inspections to ensure industry compliance. There were 52 domestic and 22 foreign inspections.

Postmarketing adverse drug event reporting inspections in fiscal year 2000:

• 52 U.S. inspections
• 22 foreign inspections

Drug safety research

We sponsored research that identified the mechanisms for drug interactions between St. John's Wort, an unregulated dietary supplement, and prescription drugs.

MedWatch Outreach and Reporting

We administer the MedWatch program that helps promote the safe use of drugs by:

• Rapidly disseminating new safety information on the Internet and by providing e-mail notification to health professionals, institutions, the public and our MedWatch partners consisting of professional societies, health agencies and patient and consumer groups.
• Providing a mechanism for health professionals and the public to voluntarily report serious adverse events and problems with all FDA-regulated medical products. Reports can be filed by mail, fax, telephone or the Internet.
• Educating health professionals and consumers about the importance of recognizing and reporting serious adverse events and product problems, including medication errors. Our education program includes Internet outreach, speeches, articles and exhibits.

Currently, we have 8,000 subscribers to our e-mail notification service and 190 MedWatch partners.

MedWatch drug safety Internet resources

The latest medical product safety information can be found on the MedWatch Web site at http://www.fda.gov/medwatch/.

You can sign up for immediate e-mail notification of MedWatch safety information at http://www.fda.gov/medwatch/new.htm.

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Drug Promotion Review

The information about a drug available to physicians and consumers is just as important to its safe use as drug quality. We promote and protect the health of Americans by ensuring that drug advertisements and other promotional materials are truthful and balanced. We operate a comprehensive program of education, surveillance and enforcement about drug advertising and promotion.

Launches and advisories

When requested, we review advertisements and other promotional materials before drug companies launch marketing campaigns that introduce new drugs or campaigns that introduce new indications or dosages for approved drugs. In fiscal year 2000, we issued 276 advisory letters to companies regarding their promotional materials for launch campaigns.

We also issued 306 other advisory letters to the industry regarding proposed promotional pieces, both professional and consumer directed. In addition, we issued 209 other types of correspondence to the pharmaceutical industry, such as letters of inquiry, closure letters or acknowledgement letters.

Regulatory actions

We issued 117 regulatory action letters to companies for prescription drug promotions determined to be false, misleading, lacking in fair balance of risks and benefits or that promoted a product or indication before approval. These were either "untitled" letters for violations or "warning" letters for more serious or repeat violations. Examples of specific types of violative promotions include "homemade" promotional pieces (seven letters), Internet Web sites (six letters), promotional exhibit hall displays (three letters), oral representations (two letters), plus traditional materials such as journal advertisements and sales brochures.

Direct-to-consumer promotion

We issued 215 letters regarding direct-to-consumer promotion, including 47 letters for launch campaigns, 147 for non-launch advisories, and 20 regulatory letters. Of the regulatory letters, 13 were for advertisements broadcast on television or radio and 7 were for print advertisements.

We posted on our Web site the results from a national telephone survey of patient attitudes and behaviors associated with direct-to-consumer advertisements and obtained funding for a follow-up survey of patients and a new survey of physicians.

Drug promotion review statistics for FY 2000

We issued a total of 1,123 drug promotion letters last year.

• 117 regulatory action letters

• 276 launch campaigns
• 515 advisory acknowledgement or closure letters
• 215 direct-to-consumer advertising advisory and regulatory action letters

Improved patient information for prescription drugs

We held a two-day public workshop to discuss the findings of an interim study of the degree to which useful written information about prescription drugs was given to patients in eight states. The study examined if the information was consistent with the criteria specified in a 1997 action plan agreed to by the government and the private sector.

The meeting presented the study methodology and results. It provided us feedback before we developed an assessment of the year 2000 goals specified in the action plan. More information is at http://www.fda.gov/cder/calendar/meeting/rx2000.

We obtained funding for the assessment and used feedback from the public meeting and written comments from the public to further develop the assessment methodology.

Medication Guides

We may require specific written patient information for selected prescription drugs that pose a serious and significant public health concern. These are called Medication Guides. They must be distributed to patients with each prescription dispensed. We determine if a drug requires a Medication Guide because information is necessary for patients to use the product safely and effectively or to decide to use or continue to use the product. Last year we issued Medication Guides for five products.

Medication Guides issued in 2000:

• Abacavir (Ziagen)
• Abacavir, lamivudine and zidovudine combination (Trizivir)
• Alosetron (Lotronex)
• Isotretinoin (Accutane)
• Mifepristone (Mifeprex)

Proposed rule to revise prescription drug labeling

We published a proposed rule that would revise the content and format of prescription drug labeling. The main purpose of labeling is to communicate essential information about prescription drugs to health care providers.

The proposal would add a highlights section of critical prescribing information and an index. It would reorganize and reorder labeling to make the information easier for practitioners to find, read and use. We expect the proposed changes to contribute to our risk communication efforts by improving the accessibility of labeling information and consequently enhancing the safe and effective use of prescription drugs.

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Drug Recalls and Withdrawals

We coordinate drug recall information and prepare health hazard evaluations to determine the risk to public health by products being recalled. We classify recall actions in accordance to the level of risk, and we participate in determining recall strategies based upon the hazard and other factors including distribution patterns and market availability. We determine the need for public warnings and assist the recalling firm with public notification.

Voluntary recalls

A voluntary recall is taken by a manufacturer or distributor to carry out their responsibilities to protect the public health when they need to remove or correct a marketed drug product that presents a significant risk to public health. A voluntary recall is more efficient and effective in assuring timely consumer protection than an FDA initiated court action or seizure.

Top 10 reasons for drug recalls in fiscal year 2000:

• Lack of assurance of sterility in production or testing of sterile drug products
• Deviations from current good manufacturing practices
• Subpotency
• Microbial contamination of nonsterile products
• Chemical contamination
• Penicillin cross-contamination of other products
• Failure of or inability to validate manufacturing processes
• Drug product marketed without an approved new or generic application
• Failure of drug to dissolve properly
• Product found to exceed limits set for impurities or degradation

Safety-based withdrawals in 2000

In some cases, drugs are withdrawn from the market. Based on reports that we reviewed in consultation with the manufacturers, these drugs were withdrawn from the U.S. market last year:

• Alosetron (Lotrenox), a treatment for irritable bowel syndrome in women, was voluntarily withdrawn after analysis of adverse event reports (http://www.fda.gov/cder/drug/infopage/lotronex/lotronex.htm).
• Cisapride (Propulsid), a treatment for severe nighttime heartburn, is no longer marketed in the United States. We and the manufacturer determined that many preventable adverse events were occurring in patients who should never have been prescribed cisapride.
• Phenylpropanolamine, a decongestant ingredient used in many prescription and over-the-counter cough and cold medications, was voluntarily removed from the U.S. market by manufacturers after FDA issued a public health advisory that it might cause strokes and announced it was taking steps that might lead to its withdrawal. Phenylpropanolamine was never formally approved for safety and efficacy (http://www.fda.gov/cder/drug/infopage/ppa/default.htm).
• Troglitazone, (Rezulin), a treatment for type 2 diabetes, was voluntarily withdrawn by after review of safety data showed that the drug is more toxic to the liver than two other more recently approved drugs that offer a similar benefit.

During the period 1981 to 2000, we approved 543 new molecular entities. Fourteen of these, or 2.6 percent, were withdrawn for safety reasons after joint FDA-manufacturer review. The record of withdrawal of drugs approved in recent years is similar to previous periods when we were criticized for taking too long to review drug applications. Nonetheless, the increased number of drugs and the large number of patients taking multiple drugs have created the potential for more drug safety problems.

1981-2000 NME withdrawals resulting from joint FDA-manufacturer reanalysis of risks vs. benefits

• 543 NMEs approved
• 14 withdrawn
• 2.6 percent withdrawn

Recent safety-based drug withdrawals

• Fenfluramine (1973/1997)
• Ticrinafen (1979/1980)
• Zomepirac (1980/1983)
• Benoxaprofen (1982/1982)
• Nomifensine (1984/1986)
• Suprofen (1985/1987)
• Terfenadine (1985/1998)
• Encainide (1986/1991)
• Astemizole (1988/1999)
• Flosequinan (1992/1993)
• Temafloxacin (1992/1992)
• Cisapride (1993/2000)
• Dexfenfluramine (1996/1997) (not an NME)
• Bromfenac (1997/1998)
• Grepafloxin (1997/1999)
• Mibefradil (1997/1998)
• Troglitazone (1999/2000)
• Rapacuronium (1999/2001) (manufacturer only decision)
• Alosetron (2000/2000)
• Phenylpro- panolamine (-/2000) (never approved by FDA)

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Drug Product Quality

We provide comprehensive regulatory coverage of the production and distribution of drug products. We manage inspection programs designed to minimize consumer exposure to defective drug products. We have two basic strategies to meet this goal:

• Evaluating the findings of factory inspections of the conditions and practices in plants under which drugs are manufactured, packed, tested and stored.
• Monitoring the quality of finished drug products in distribution through sampling and analysis.

We identify, evaluate and analyze inspection findings for trends in deficiencies. We develop guidances to assist drug manufacturers in gaining a better understanding of our regulations. We communicate the expectations of compliance through outreach programs. We review all international pharmaceutical inspection reports. We determine which foreign manufacturers are acceptable to supply active pharmaceutical ingredients or finished drug products to the U.S. market.

FDA field offices conduct inspections of domestic and foreign plants that manufacture, test, package and label drugs. Before a drug is approved, FDA investigators must determine if data submitted in the firm's application are authentic and if the plant is in compliance with good manufacturing practices. After a drug is approved, FDA conducts an inspection to make sure a firm can consistently manufacture the product. Finally, routine inspections evaluate the firm's entire operations.

• Preapproval inspections. During fiscal year 2000, FDA evaluated 1,144 domestic plants in support of new drug applications. One user fee goal was missed. Also, FDA evaluated 1,085 domestic firms in support of generic drug applications.
• Good manufacturing practice inspections. There were 1,436 good manufacturing practice inspections in fiscal year 2000. Of the warning letters that resulted from these inspections, we reviewed 34 policy consistency. We also reviewed 48 field recommendations for regulatory action and approved 28. These included two injunctions, 14 seizures and seven warning letters. We reviewed 248 foreign establishment inspection reports. These reviews resulted in 11 warning letters and two import alerts. Import alerts prevent violative foreign drug products from entering the United States.

New drug preapproval plant evaluations

• FY 2000: 1,144
• FY 1999:   773

Generic drug preapproval plant evaluations

• FY 2000: 1,085
• FY 1999: 1,775

Good manufacturing practice inspections

• FY 2000: 1,436
• FY 1999: 1,844

Reporting systems for drug quality problems

Two important tools help us rapidly identify significant health hazards associated with the manufacturing and packaging of drugs:

• Field Alert Reports. Firms are required to notify FDA promptly of significant problems they discover that may represent safety hazards for their marketed drug products.
• Drug Quality Reporting System. We analyze voluntary reports on drug product quality problems submitted by health care practitioners through MedWatch and other systems. We maintain these reports in a central database to aid in detecting problem areas and identify trends requiring regulatory action.

Surveillance sampling of drugs

The Drug Quality Surveillance Sampling Program helps determine the quality of imported and domestic drugs distributed in the United States. Samples of drug products are tested for conformance with quality specifications to ensure that the nation's drug supply is safe and effective and to provide rapid identification of emerging problems. We have intensified surveillance of imported drug products because of the increased number of imports.

Sampling criteria

We chose drugs for the sampling program based on the following criteria:

• New molecular entities.
• Drugs with dissolution issues.
• Highly active drugs that have effects in low doses.
• Drugs with a history of quality problems, field alerts or recalls.
• Suspected counterfeit drugs.

Unsubstantiated claims; fraudulent, hazardous products

We encounter many products that are vitamins, minerals, amino acids and herbal preparations with labeled drug claims. These products may be labeled as dietary supplements but make claims that they are safe and effective for the prevention, treatment or cure of such diseases as AIDS or cancer. Because these claims are unsubstantiated, they could present a health hazard when consumers delay or avoid seeking effective medical care.

• We take enforcement action when these products are likely to cause serious injury.
• We identify fraudulent or hazardous drug products and assist in developing enforcement strategies involving counterfeit drugs.

Drug Product Quality Research

We conduct scientific research on drug product quality issues. Last year our efforts included:

• Developing in vitro, or test tube, methods for studying the impact of excipients and diluting agents on the absorption of orally administered drugs. Excipients are commonly known as "inactive ingredients."
• Identifying genetic markers that will authenticate cultivated St. John's Wort and detect contamination by related species.
• Developing and validating numerous methods for testing the quality of pharmaceutical products. For example, near-infrared spectroscopy can detect and quantify different hydrated forms of an active ingredient in commercial drug products.

PQRI 2000 update

The Product Quality Research Institute marked its first year by initiating seven working groups to address:

• Blend uniformity.
• Oral biopharmaceutics.
• Packaging changes.
• Bulk drug post-approval changes.
• Drug substance impurity testing.
• Drug substance particle size analysis.

PQRI is expected to make recommendations in 2001 aimed at ensuring thorough mixing of a drug within the blend and dosage unit.

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Export Certificates

We promote goodwill and cooperation between the United States and foreign governments through the Export Certificate Program. These certificates enable American manufacturers to export their products to foreign customers and foreign governments. The demand for certificates by foreign governments remains high due to expanding world trade, ongoing international harmonization initiatives and international development agreements.

The certificates attest that the drug products are subject to inspection by the FDA and are manufactured in compliance with current good manufacturing practices. Export certificates verify that drug products being exported:

• Were freely marketed in the United States.
• Were in compliance with U.S. laws and regulations.
• Met certain national or international standards, such as quality standards.
• Were free of specific contaminants.

Drug Shortages

We work to help prevent or alleviate shortages of medically necessary drug products. Drug shortages occur for a variety of reasons including manufacturing difficulties, bulk supplier problems and corporate decisions to discontinue drugs.

Because drug shortages can have significant public health consequences, we work with all parties involved to make sure all medically necessary products are available within the United States.

Drug shortages on Internet

We developed a Web site that lists current drug shortages, describes efforts to resolve them and explains how to report them. The site is at http://www.fda.gov/cder/drug/shortages/.