Office of Drug Safety Annual Report 2001

Fiscal Year 2001 was a successful year for OPDRA in terms of achieving organizational, strategic, regulatory and scientific objectives. These accomplishments, which are described in detail later in this report, are summarized below:

� Planned the reorganization of the Office of Drug Safety to incorporate MedWatch and Patient Labeling program functions and to achieve additional strategic objectives.

� Supported Federal patient safety and medication error initiatives.

� Engaged in extensive leveraging activities with other Federal agencies, private organizations, industry and the Centers for Education and Research on Therapeutics (CERTs) to support our mission of ensuring the safety of drugs.

� Continued the development and enhancement of the Adverse Event Reporting System (AERS).

� Completed Step 4 signoff of E2B and continued progress in developing other aspects of the International Conference on Harmonization (ICH) that relate to postmarketing adverse event reporting and drug safety.

� Increased support of the Office of Review Management regulatory actions and risk management program development.

� Acquired mission-critical data resources including longitudinal, inpatient and pediatric inpatient data utilization data.

� Maximized the utilization of managed care databases through the cooperative agreements to evaluate important safety questions in formal epidemiological studies.

� Recompeted the cooperative agreement grant through the competitive RFA process to ensure continued access to these important databases by FDA for the coming years.

� Completed and published important research in quantifying the effect of regulatory actions.

� Codified and expanded collaboration with other regulatory drug bodies.

As the new year begins, there are several new challenges to meet and strategic initiatives to plan.

The first priority for the new Office will be the tactical implementation of the reorganization of the Office of Drug Safety (ODS); including selecting appropriate people to lead the different ODS divisions and establishing internal procedures for existing and newly assigned responsibilities (e.g. MedWatch and patient labeling). We will also have to develop processes to incorporate new data resources into the business of safety evaluation.

A second, but equally important priority, is developing ODS/Office of Review Management (soon to be the Office of New Drug Evaluation) interaction operating principles. It is critical that ODS maintains close communication and synergistic relationships with ORM and the ORM reviewing divisions. Codification of relationships through MaPPs on such issues as tradename reviews, postmarketing safety issues, evaluation of risk management programs and medication guides will be addressed. Furthermore, the shared responsibilities in the review of Periodic Safety Update Reports (PSURs) will be addressed through a MaPP and the initiation of development of a guidance to industry. The appropriate use of the new Drug Safety and Risk Management Advisory Committee will also be codified in a MaPP. In addition to these MaPPs and guidances, it is critically important for ODS to maintain regular participation in ORM activities by attending critical ORM meetings such as ministaff, division director meetings, etc.

The final priority for the new office will focus on the Center initiative relating to Risk Management. The development of the Risk Management White Paper, the identification of a risk management and risk communication research agenda, the successful launch and utilization of the new Drug Safety and Risk Management Advisory Committee, the optimal use of MedWatch and the CERTs for risk communication and outreach, the identification of additional data resources to optimize risk assessment, and, ultimately, the codification of ODS' role in risk management for marketed drugs will represent major opportunities and challenges for the next year.

Introduction

FY 2001 has been a challenging and rewarding time for the Office of Postmarketing Drug Risk Assessment. In addition to the traditional role of postmarketing assessment of adverse event reports for marketed drugs, the Office has engaged in many initiatives focused on developing a comprehensive risk assessment and management program that can support ongoing Center priorities in these areas. We are very proud that CDER management has recognized the contributions that OPDRA has made and is recommending increasing OPDRA's responsibilities in a proposed reorganization. This decision is based on a growing sense of confidence that OPDRA has worked effectively in the past to ensure the safer use of drugs, thereby; better protecting the public health. The purpose of this annual report is to highlight the OPDRA accomplishments over the past year and to outline strategic plans for the upcoming year.

I. Office Vision Building:

The success over the recent past has significantly improved morale and sense of purpose in OPDRA. We have worked with an external consultant to identify critical areas to be addressed by management and staff to further improve communication and working relationships within the office. We believe the following vision is a good foundation on which to continue to build the best possible postmarketing drug safety program for CDER and FDA.

Vision

"OPDRA excels in the assessment, management and communication of drug risks. OPDRA integrates science, research, and the principles of public health to guide appropriate and consistent regulatory decision-making in order to optimize the safe use of marketed drugs. OPDRA is a growing, evolving, and adaptable unit based on outstanding individual and team efforts and we recognize the value and contributions of all members of our organization."

II. Current OPDRA Structure and Function:

OPDRA, as originally established in 1998, consists of an Immediate Office with two Divisions of Drug Risk Evaluation (DDREs) and various staff units to support medication error initiatives and resource management. Peter Honig, M.D., and Martin Himmel, M.D. are the OPDRA Director and Deputy Director, respectively.

The Divisions of Drug Risk Evaluation led by Drs. Julie Beitz (Director) and Anne Trontell (Deputy Director) collaborate with CDER's new drug review offices to ensure that a careful safety evaluation of marketed drugs is provided. In this role, OPDRA's safety evaluators and epidemiologists critically review adverse experience reports that are submitted by manufacturers, health care professionals and consumers. The DDREs are proactively engaged in important FDA functions and participate in advisory committee preparation, risk management program development and pre-approval safety conferences. OPDRA increasingly interacts with our regulatory counterparts in Australia, Canada and the European Union to share information about Adverse Drug Reaction (ADR) reports and drug safety issues.

OPDRA's Medication Error Staff of eight safety evaluators assesses risk factors that could lead to medication errors resulting from nomenclature, labeling and packaging of drug products. This staff, led by Captain Jerry Phillips reviews proposed proprietary names for unapproved drug products and is responsible for assessing not only actual medication errors that have led to patient injury or death, but also those errors that have the potential to cause patient harm.

OPDRA's Information Technology Staff led by Jerry Phillips assume a wide array of responsibilities including desktop support, AERS special searches, database development and support, and website maintenance.

The Extramural Program Staff, led by Jerry Phillips, is critical in maintaining existing grants and contracts as well as identifying and procuring new grants and data resources.

III. Office of Drug Safety: Rationale for Reorganization

OPDRA has worked hard to build strong relationships with CDER staff and other OPDRA customers by creating trust and demonstrating value. CDER management has proposed a significant reorganization of the CDER structure that includes increasing OPDRA's responsibilities and retitling it the Office of Drug Safety. This is a tremendous honor that has been accompanied with an increase in resources and reflects the value that OPDRA has contributed to CDER. ODS will incorporate the MedWatch and patient labeling responsibilities that are currently in other parts of the Center. In order to meet this challenge, the Office of Drug Safety will be reorganized to meet these challenges. The guiding principles behind the reorganization include:

� Provide staff development opportunities

� Harness economies of scale and configure to maximize efficiency

� Allow synergy of the new responsibilities and existing functions and provide avenues of communication for these interactions

� Create a scalable structure that could allow assumption of new responsibilities in the future

� Allow for localized decision-making

� Strongly support the scientific base for risk assessment, management and communication

The reorganization will merge the existing DDREs into one division that takes advantage of economies of scale and efficiencies. Dr. Julie Beitz will direct this large division which will remain a centerpiece of the Office of Drug Safety. The second division will be titled the Division of Medication Errors and Technical Support (DMETS) and be headed by Jerry Phillips. Finally, a third division will be created and led by Dr. Anne Trontell. This new division will be called the Division of Surveillance, Research and Communication Support (SuRCoS) and assume the leadership of new responsibilities (MedWatch, MedGuides/patient labeling) and identification and management of an increasing array of postmarketing data resources.

IV. Safety Review of Drugs

Overview

DDRE twenty safety evaluators performed hands-on review of adverse drug event reports reviewed by FDA throughout the year. This was carried out through daily review of AERS reports that are triaged to each Safety Evaluator's electronic inbox. These reports include 15-day expedited reports, direct serious reports, and reports of designated medical events. The latter are serious events targeted by OPDRA that are often drug-related (e.g., liver failure, bone marrow failure, Stevens-Johnson syndrome, etc). Individual reports may trigger further evaluation of similar reports in the database and development of a case series. Case series could signal important safety concerns prompting regulatory actions both in the U.S. and abroad.

A total of 634 consults were received and processed in fiscal year 2001 by the Divisions of Drug Risk Evaluation I and II. The origin of these consult requests was as follows:

355 consults (56%) originated from the fifteen ORM Review Divisions;

145 consults (23%) were generated by OPDRA staff;

134 consults (21%) originated from requests from other sources.

Total number of consults in fiscal year 2001

Summary data are presented graphically by requestor (ORM review division, self-generated, other sources) and by review division.

Consults by HFD Division

Other consult requests from within FDA include: Office of the Commissioner, CFSAN, CDRH, CBER, Office of the Center Director, Office of Criminal Investigations, Office of Compliance, Office of General Counsel, Office of Women's Health, Office of Legislative Affairs, Regulatory Policy Staff, Office of Generic Drugs, Office of Pharmaceutical Sciences, Office of Clinical Pharmacology and Biopharmaceutics, Controlled Substances Staff, MedWatch, Pregnancy Working Group, Executive Projects Team, and Office of Training and Communications.

Consult requests from outside of FDA include: Congress, GAO, the Secretary of DHHS, World Health Organization, Federal Bureau of Investigation, Department of Justice, Centers for Disease Control, U.S. Consumer Products Safety Commission, University of Pennsylvania (CERTS Program), VA Medical Center (California), Division of Federal State Relations, and several Foreign Regulatory Agencies.

Drug Risk Assessment: From Signals to Regulatory Actions

OPDRA staff worked closely with review division staff to develop the scientific basis for labeled warnings, postmarketing safety studies, drug withdrawals and compliance activities. The following are selected regulatory actions that were supported in OPDRA:

Boxed Warnings

� Gemtuzumab ozogomicin: new boxed warnings for serious hypersensitivity reactions, adult respiratory distress syndrome, veno-occlusive disease.

� Capecitabine/warfarin interaction: new boxed warning added

� Itraconazole - boxed warning describing the risk of congestive heart failure with itraconazole when used for the treatment of onychomycosis; a Public Health Advisory issued May 2001.

Other Important Labeled Warnings

� Topiramate: warning for glaucoma

� Terbinafine: warning for liver failure; a Public Health Advisory issued May 2001

� Linezolid: OPDRA identified myelosuppression as a safety signal; this resulted in a new labeled warning and a Dear Health Care Professional Letter was issued by the sponsor

Postmarketing Safety Studies

� Perflutren: a postmarketing surveillance study to monitor adverse events in at least 1000 patients exposed to this ultrasound drug product was developed

� Mifepristone: OPDRA was instrumental in crafting Phase 4 commitments in conjunction with the drug's marketing approval, and reviewing the submitted post approval protocols and foreign postmarketing report summaries.

Drug Withdrawals

� Cerivastatin: OPDRA coordinated with the review division and shared scientific developments with our foreign regulatory counterparts regarding rhabdomyolysis associated with cerivastatin. This adverse event was the primary reason for which Bayer withdrew cerivastatin from the global market.

� Alosetron: OPDRA's review of postmarketing adverse event reports supported the review division's concerns regarding ischemic colitis and serious constipation. The sponsor voluntarily stopped marketing Alosetron in November 2000.

Pre-approval Safety Conferences

Pre-approval safety conferences are held with review division staff as per CDER MaPP 6010.1 prior to the marketing approval of a new drug product. These meetings typically involve discussions of safety information in labeling. Specific safety concerns are identified that OPDRA staff will monitor after product launch. Other topics may include the need for postmarketing safety studies, patient registries, or a risk management program to closely monitor safety concerns. Examples of recently approved drugs and safety issues discussed at recent pre-approval safety conferences are:

� Ziprasidone: need for OPDRA to continuously monitor spontaneous reports of QTc prolongation and related events, with quarterly updates to the review division

� Nasiritide: need for a warning for fluid retention in labeling

� Bosentan: need for boxed warnings in labeling for teratogenicity and liver toxicity; need for a medication guide and risk management programs to monitor pregnancy exposures and cases of liver injury after product launch

� Bimatroprost and Travoprost ophthalmic solutions: approved as second line treatments for glaucoma (instead of first line) due to concerns about cardiovascular events and deaths with a related product (latanoprost)

� Verteporfin: need for information on drug-drug interactions in labeling

Waivers of Postmarketing Safety Reporting Requirements

OPDRA has the authority to grant waivers of postmarketing safety reporting requirements (additional information may be found at http://www.fda.gov/cder/mapp/6004-1.pdf). In addition, OPDRA is developing a database for waiver information that will accessible to CDER.

In FY 2001, OPDRA staff extensively briefed CDER staff about the waiver procedures.

OPDRA encourages industry to request a waiver of the requirement to submit FDA form 3500A for each adverse experience that is determined to be both nonserious and labeled. By the end of FY 2001, over 60 firms had been granted this type of waiver for over 2300 applications (NDAs and ANDAs).

OPDRA has granted waivers to firms of requirements to submit postmarketing periodic safety reports in the format described in the regulations (21 CFR 314.80). Instead, firms may use the Periodic Safety Update Report (PSUR) format described in ICH E2C (with modifications to meet U.S. requirements).

When a firm asks to modify the frequency of submission of a report, OPDRA consults with the appropriate review division before acting on the waiver request. By the end of FY 2001, fewer than 10 firms had been granted PSUR waivers (for PSUR format with or without frequency changes) for fewer than 25 applications. However, through OPDRA presentations to industry, firms are becoming aware of this option, and the number of requests for this type of waiver is rising dramatically. By mid-November 2001, OPDRA had received requests from more than 15 firms for more than 275 applications.

Contact Person: Kathleen Bongiovanni, 301-827-3191

V. Risk Assessment

AERS Reports

OPDRA's AERS group oversees activities relating to the adverse event reporting system, including paper and electronic submission of adverse event reports. The group provides the programmatic expertise to the AERS database application, serving to bridge the users with the Office of Information Technology for daily operations, system troubleshooting and long-range improvements. The group also serves as the primary liaison between CDER and foreign regulatory bodies regarding drug safety issues. In addition, the group provides expertise on the Medical Dictionary for Regulatory Activities (MedDRA), an ICH-developed medical terminology used for coding medical information and which is used in AERS.

In FY2001, AERS received 205,101 Individual Safety Reports (ISRs) + 75,989 non-serious periodic ISRs (Total = 281,090)¹ . At the present time, AERS is entering reports for direct², 15-day (expedited)³ and serious periodic⁴ ISRs. AERS captures all of the ISRs for current New Molecular Entities (NMEs). The chart below shows the reporting trend over time. It is anticipated that the total number of reports in CY 2001 will be close to 271,000 ISRs.

CDER Post-Marketing Adverse Events Reports Received (Data in Excel Spreadsheet)

If this trend holds, it will mark the second consecutive year in which the number of reports entered into AERS has slightly decreased. There are several possible explanations for this including the decrease in the number of NMEs approved by the center since the high water mark in 1996 as well as the aggressive OPDRA waiver program relieving the industry from the requirement of submitting non-serious and labeled events.

The table below indicates the top 20 suspect products submitted to FDA and entered in AERS (NME is defined as a drug approved in the past three years and designated by an asterisk *)

Rofecoxib (Vioxx) 6,994*

Etanercept (Enbrel) 6,789*

Isotretinoin (Accutane) 3,605

Alosetron HCl (Lotronex) 3,190*

Celecoxib (Celebrex) 3,087*

Sertraline HCl (Zoloft) 2,834

Atorvastatin Ca (Lipitor) 2,641

Omeprazole (Prilosec) 2,066

Cerivastatin Na (Baycol) 1,992

Rosiglitazone (Avandia) 1,965*

Citalopram HBr (Celexa) 1,947*

Infliximab (Remicade) 1,635*

Sildenafil (Viagra) 1,642*

Orlistat (Xenical) 1,633*

Tolterdine (Detrol) 1,515*

Olanzapine (Zyprexa) 1,480

Pioglitazone HCl (Actos) 1,464*

Azithromycin (Zithromax)1,413

Thalidomide (Thalmid) 1,378*

MedWatch's Central Triage Unit (CTU):

OPDRA staffs the MedWatch Central Triage Unit that supports the identification and appropriate routing of direct reports on all medical products received through MedWatch. Two FTEs are allocated to this important function. In FY01, CTU processed 23,601 MedWatch reports for all of FDA's centers. As can be seen below, 70% of the reports were triaged to CDER and entered into AERS. Direct reports from biologic therapeutics are also entered into AERS.

CTU by Center: CDER: 70%, CBER 5%, CFSAN 3%, DQRS 10%, CDRH 12%

The Central Triage Unit also tracks the reports by the source of the submission and seriousness of the adverse experience. As can be seen from the figure below, the single-leading source of direct reports to FDA are pharmacists. 59% of the reports are serious by outcome and 30% of the reports are being submitted to the MedWatch are via the internet

CTU by occupation: Pharmacist 41%, Doctor 11%, Nurse 11%, Other HP 11%, Unknown 18%, Consumer 8

Electronic Submission of Adverse Experiences Initiative:

This is a high priority for OPDRA and CDER because the successful implementation of electronic submissions will result in considerable cost savings to CDER and FDA. To date, the electronic submissions (e-sub) pilot has been very successful in establishing a mechanism for companies to work with FDA in sending e-sub reports into AERS.

CDER implemented an Electronic Submission Product Test Pilot for AERS in October 2000. This pilot provided a mechanism for companies to test and send electronic submissions of expedited reports via physical media or gateway (without attachments) directly into AERS (Docket 925-0251).

In spring of 2002, AERS will upgrade the Data Transfer Document (DTD) to 2.1 and always maintain the latest two versions of DTD. 11,404 individual case safety reports (ICSR)⁵ were submitted electronically under the pilot program in FY 2001.

The current industry participants in e-sub include: Bristol-Myers Squibb, GlaxoSmithKline, Merck, Roche, Pharmacia, Sanofi-Synthelabo, Pfizer, MedImmune, Dupont Pharmaceuticals, J&J Pharma Group, Eli Lilly, AstraZeneca, Immunex, Celgene, Bayer Vital Pharmaceuticals (Germany).

AERS can accept reports via the gateway or physical media without attachments (Docket 925-0251). In January 2002, AERS will upgrade the Data Transfer Document (DTD) to 2.1 and always maintain the latest two versions of DTD.

AERS information is made publicly available by providing quarterly CD ROMs in ASCll format and SGML (ICH E2B) format for six AERS data tables. The tables include demographics, drugs, reactions, report source, outcomes, and therapy date data. The CD ROMs are provided to the Office of the Commissioner for publications. The National Technical Information Service (NTIS) copies the CDs and offers them for sale to the public. The Data are currently not made publicly available through the FOI or Web because of resource limitations.

AERS DataMart:

One of the major success stories has been the development of the AERS DataMart tool by OIT in conjunction with OPDRA. This has allowed CDER to eliminate the dual flow of expedited (i.e. 15-day) paper reports to OPDRA and the medical officers in the reviewing divisions, a strategy consistent with OPDRA's responsibility for the review and aggregate analysis of these reports while at the same time allowing the reviewing medical officer in ORM to have access to the information contained in these reports and in AERS. Medical officers are notified via email that an expedited report has been received and can be viewed in the DataMart desktop application that also allows for aggregate analyses of such events.

Contact person: Roger Goetsch, Pharm. D., 301-770-9299

VI. Risk Management/Communication

DDRE Accomplishments

OPDRA staff worked closely with review division staff to develop and negotiate the following comprehensive programs designed to manage known risks of drug products.

� Isotretinoin (Accutane): a pregnancy prevention program including development of metrics to assess the program's effectiveness was approved October 31, 2001; development of a Medication Guide (issued January 2001) and revised informed consent to alert patients of the risks of depression and suicide; need for OPDRA to continuously monitor spontaneous reports of suicide and depression

� GHB (Xyrem): a restricted distribution program involving patient and prescriber registries and a central pharmacy to limit illicit use after product launch was discussed at an FDA Advisory Committee

� Bosentan (Tracleer): a restricted distribution program to ensure monitoring for liver toxicity and pregnancy prevention was established at the time of marketing approval on November 20, 2001

Advisory Committee Preparation: OPDRA provides pivotal support to review divisions at FDA Advisory Committee Meetings. OPDRA staff has provided testimony on drug-related safety issues, prepared briefing materials for Committee Members and participated in Committee discussions. Examples of recent Advisory Committee Meetings include:

� Phenylpropanolamine (PPA) and risk of hemorrhagic stroke: OPDRA staff performed a critical review of the Hemorrhagic Stroke Project study and testified before the Non Prescription Drugs Advisory Committee. The Committee recommended that PPA not be marketed OTC. FDA issued a Public Health Advisory which led to a voluntary withdrawal of PPA from the US and Canadian markets.

� Cox-2 inhibitors: cardiovascular and thrombotic events, gastrointestinal hemorrhagic deaths, and renal adverse events were evaluated by OPDRA staff; written briefing materials were prepared. The Advisory Committee recommended labeling cardiovascular risks for rofecoxib.

� OTC Switch of Non-sedating Antihistamines: OPDRA and review division staff prepared a comprehensive review of several safety concerns including ventricular arrhythmias, seizures, and drug-drug interactions for loratadine, fexofenadine, cetirizine. The Committee recommended that all three products were appropriate for OTC use.

� Telithromycin: OPDRA staff testified on the risks of QTc prolongation and torsade de pointes.

� Caspofungin: OPDRA staff testified on the use of historical controls as a comparator group in clinical trials submitted in support of marketing approval. The Committee recommended that use of historical controls for this purpose was inappropriate.

Plans for the Future

FDA is proposing to amend its periodic safety reporting regulations by adding an important new type of postmarketing periodic safety report (PSUR). The proposed content and format for the PSUR are consistent with the ICH E2C guidance (62 FR 27470) and would enable applicants to submit a single core document to regulatory agencies worldwide. The purpose of a PSUR is to provide companies with a format that has been standardized worldwide for reporting postmarketing safety information that can be used to evaluate whether the benefit/risk ratio of a drug or biologic has changed since market authorization.

VII. Medication Errors

During FY 2001, the Medication Error Staff completed 305 consults for CDER. This included recommendations on 281 premarketing proprietary names reviews and 24 postmarketing medication error consults. The program also acquired access to a proprietary name database from Thomson and Thomson, which allows the staff to search for sound-alike and look-alike names to the proposed proprietary names.

Pre-approval Assessments

All proposed proprietary names, labels and labeling in CDER are reviewed by OPDRA in its pre-marketing efforts to minimize medication errors due to similar proprietary names or confusion related to labeling and packaging of drug products.

Post-approval evaluation/signal detection

After the approval of drug products, OPDRA monitors all postmarketing reports of medication errors that are related to naming, labeling and/or packaging. Each report is classified for severity, type and cause of error. If appropriate, OPDRA makes specific recommendations to the appropriate reviewing divisions on changing the labeling, packaging or proprietary name.

Contact Person: Sammie Beam, R.Ph., 301-827-3242

Plans for the Future

OPDRA hopes to move forward in developing computer software to screen proposed proprietary names for sound-alike and look-alike similarities with the existing 15,000 marketed proprietary names in the U.S. This tool would enhance the scientific and analytical ability of the Office to determine the potential risk of approving a particular proprietary name.

OPDRA plans to modify AERS by incorporating a Taxonomy of Medication Errors to enhance its ability to detect medication errors. This taxonomy will allow the staff to perform trend analysis based upon the numerous causes and types of medication errors, which is currently not available through AERS.

VIII. Extramural Resource Development

Cooperative Agreement Program

OPDRA's cooperative agreement program in pharmacoepidemiology provides FDA with access to population-based pharmacoepidemiologic databases and with the ability to study important postmarketing drug safety questions. Last year, five sites received grant support through this program. The sites were Boston Collaborative Drug Surveillance Program providing access to UK General Practice Research Database (GPRD); Harvard-Pilgrim/Health Partners providing access to data from three HMOs; Johns Hopkins School of Medicine providing access to its HIV/AIDS database; UnitedHealth Group providing access to claims data from its multi-state membership; and Vanderbilt University providing access to Tennessee Medicaid.

Cooperative agreement grants are awarded in three-year cycles and the program was recompeted this year. Funding for this program was reduced by $0.4 million (from $1.3 million) to $0.9 million in FY 2002. The following applications will be funded at about $300K per year: Harvard-Pilgrim/Health Partners, United Health Group and Tennessee Medicaid. These databases will become available for CDER use in January, 2002.

The following studies were completed in FY 2001:

� Examined the use of cisapride in patients with contraindicated medical conditions or who concomitantly used contraindicated medications known to increase the risk of QT-prolongation and torsades de pointes. The drug continued to be misused despite a major relabeling effort and issuance of a "Dear Healthcare Professional" letter.

� Measured the effect of four separate labeling changes with accompanying "Dear Healthcare Professional" letters on performance of liver enzyme monitoring with troglitazone. After four letters, monitoring was infrequent and inconsistently performed.

� Measured (in general population of troglitazone users) rate of hospitalized liver injury or acute liver failure. ODPRA found (that of 7,600 patients contributing 4,000 person-years of exposure), 5 cases of hospitalized liver injury including 1 case of acute liver failure.

� Conducted a study to determine the pattern and extent of systemic corticosteroid use in children. A sizable number of children were shown to be exposed to long-term (>90 days) oral corticosteroid therapy, placing them at potential risk for adverse side effects.

� The Johns Hopkins HIV/AIDS clinical database was used to study the question of whether there is an association between avascular necrosis (AVN) and use of various anti-viral agents. A non-statistically significant increasing trend in AVN was found, however, no particular drug, drug class or combination of therapy could be shown to confer increased risk possibly because the study was underpowered.

� The GPRD was used to study the use of atypical anti-psychotics and development of new-onset diabetes. The study found an increased risk of diabetes among treated patients but was unable to determine whether this was due directly to the drugs taken or other factors related to their use.

� Evaluated compliance with labeling and "Dear Healthcare Professional" letters on the use of pemoline as a first-line therapy for attention deficit disorder and on recommended biweekly liver enzyme monitoring. The majority of pemoline use was as first-line therapy, despite its labeled designation as second-line therapy because of risks of acute liver failure. Liver enzyme monitoring was rarely performed.

New Data Initiatives

OPDRA has established a New Data Initiatives working group with responsibility for identifying potential, new or emerging data resources that might improve its capacity to evaluate drug safety questions. The following initiatives are significant:

� In FY 2001, OPDRA established a pilot with Kaiser Northern California, that included accessing a database covering 6 million lives and provides information on some details of clinical care provided to patients within this closed-model HMO. The data quality is considered superior to that available through the cooperative agreements.

� OPDRA and Kaiser planned a one-year pilot project to study COX-2 and NSAID use and risk of myocardial infarction. It is hoped that one or two collaborative in-depth epidemiologic studies will be completed in FY 2002.

� OPDRA has established an interagency agreement with the Veteran's Administration to study avascular necrosis (AVN) of the hip and drugs used to treat HIV/AIDS. The VA database (18,000 patients) includes information about underlying health status, risk factors and medical history. In this collaboration, the VA is providing data management support, analysis dataset support, coordination of AVN case-validation, and expert knowledge of the database and VA healthcare system. OPDRA is supplying epidemiologic and clinical research support, including providing expertise for protocol development and data analysis. OPDRA is also responsible for developing the web-based interface critical to cost-effective case validation.

Drug Use Data Resources

IMS

The FDA is a long-time user of IMS Health products and services and the recompetition of this important contract was a major accomplishment this past fiscal year. FDA was able to provide continued access to this important data resource. The contract provides OPDRA with access to the following databases: National Disease and Therapeutic Index^TM (NDTI), National Prescription Audit Plus^TM (NPA), Provider Perspective^TM (PP), and Retail Perspective^TM (RP). While OPDRA uses IMS data in a variety of ways, the most frequent uses include: quantifying the number of prescriptions dispensed to the population and obtaining demographic information on the population exposed to pharmaceutical products. These data are also used in association with spontaneous case report data to understand the context within which ADRs occur. When IMS data are used in conjunction with supplemental data obtained from population-based claims or record-linked databases, it is possible to estimate patient exposure time for a particular drug product.

Contact person: Joslyn Swann, R.Ph., M.G.A., 301-827-3166

Premier, AdvancePCS, Child Health Corporation of America (CHCA)

Although IMS has been a reliable resource, there were some limitations to the program. To help resolve these limitations, OPDRA in collaboration with FDA's Office of Facilities, Acquisitions and Central Services issued three requests for proposals (RFPs) under the competitive bid process. The RFPs were designed to fill in three major blindspots in CDER's understanding on how drugs are used once they are cleared for marketing.

As a result of these efforts, CDER now has access to three large, commercial databases that contain detailed information on the actual use of marketed prescription drugs in hospitalized and non-hospitalized adults as well as hospitalized children. The information contained in these databases will augment CDER's ability to determine the public health significance of the reports it receives through AERS, published information, and other data sources. The acquisition of these new information resources was made possible by awarding contracts to AdvancePCS, Premier, Inc, and CHCA.

The AdvancePCS database will allow FDA to examine how long non-hospitalized patients stay on prescription medication therapy and to learn drug combinations that may be prescribed to the same patients at the same time. The contract awarded to Premier Inc., a strategic alliance of more than 200 hospitals and healthcare systems nationwide, will provide similar information on hospitalized patients. The CHCA database contains information on the use of medicines in hospitalized children. This information will support the ongoing initiative at FDA to approve more prescription drugs for use in children.

Contact Person: Judy Staffa, Ph.D., R.Ph. 301-827-3178

General Practice Research Database (GPRD) Initiative

The UK's GPRD is the largest pharmacoepidemiologic database in the world with the highest quality data. The database covers about 3 million lives with data going back 10 years. The data are collected from the computerized medical record systems of 5% of all GPs in the UK.

This database resource is superior in many ways to any US-based database known to OPDRA. Having in-house access would permit a wide range of crude, "fast and dirty" safety studies as well as a wider variety of in-depth studies of interest to CDER to be performed. In-house access would remove the constraint of working through grantees and provide a basis for training and retaining epidemiology staff as well as attracting new talent.

Contact person: David J. Graham, M.D., 301-827-3238

IX. International Activities

International Conference on Harmonization (ICH)

Members of OPDRA have played a major role in the ICH process. Among the successes of the past fiscal year include Step 4 signoff of the E2B maintenance document at ICH V in San Diego. This was a necessary step to successful implementation of international electronic transmission of adverse event reports and was a major stumbling block until the issues regarding unique identifier, time stamps and causality matrix were worked out by the ICH E2B expert working group. OPDRA members also have participated in the continuing development and maintenance of the Medical Dictionary for Regulatory Activities (MedDRA). CDER is represented by Dr. Honig on the MedDRA Management Board and Drs. Toni Piazza-Hepp, Sally Singer and Andrea Neal have played a major role in developing coding criteria for adverse event reports using MedDRA. Currently, OPDRA is working to develop MedDRA training for ORM medical officers.

Contact Person: Andrea Feight (Neal), DMD, MPH 301-827-3219

Video-conferences

Two separate series of regular video-conferences are held with counterpart regulators in other countries. One series consists of bimonthly meetings with representatives from the Bureau of Licensed Product Assessment of Health Canada, and the Therapeutic Goods Administration of Australia. The second series consists of 8 video-conferences per year with the European Agency for the Evaluation of Medicinal Product, the EMEA, specifically the Pharmacovigilance Working Party of the Committee for Proprietary and Medicinal Products. The meetings are generally one hour in length and involve a variety of topics including:

� Specific ADR topics and epidemiological investigations

� Compliance issues

� Medication errors

� Consumer reporting

� Pharmacovigilance methodology

� Regulatory policy and procedures

� Good pharmacovigilance initiatives

� Periodic safety update reporting experiences.

The utility of these communications is becoming more broadly recognized. Confidentiality agreements are in place with individual national regulatory authorities, which allow discussion of:

� Open investigations

� Deliberative processes

� Predecisional issues, opinions and recommendations

� FOIA exempt issues

Contact: Andrea Feight (Neal), DMD, MPH, 301-827-3219

International Visitors

OPDRA also hosts international visitors on a regular basis. Since April 2000, OPDRA has hosted regulators from Canada, Australia, New Zealand, Japan, Singapore, Taiwan, Sweden, South Africa and Armenia as well as the World Health Organization. This has resulted in one Foreign Regulator Series presentation (Australia and New Zealand).

The building of these relationships has had benefits as EMEA, Canada and Japan have given us advance notice of impending regulatory actions thus allowing FDA to prepare for industry, press and public inquiries.

Contact: Andrea Feight (Neal), DMD, MPH 301-827-3219

AERS to Canada

There is progress to report on the initiative to share the AERS application with our postmarketing regulatory counterparts at Health Canada. A draft memorandum of understanding has been shared and negotiations on technical requirements are underway. A recent videoconference has paved the way to successful implementation of a shared data resource between the two countries.

Contact: Andrea Feight (Neal), DMD, MPH 301-827-3219

In FY 2002, activities described above will continue. In order to support the ODS reorganization, two processes will be formalized:

� managing the Vigimed listserv information exchange

� finding more efficient ways to collaborate with CDER review division staff to share international postmarketing safety surveillance information.

OPDRA also intends to expand the amount of information available from foreign regulators on its intranet web page. OPDRA also hopes to make resources available to foreign regulators, such as web-based materials or videotaped educational presentations, that would obviate the need for on-site visits.

X. Patient Safety Initiatives

QuIC responses to IOM report

In February 2001, the FDA, with significant input from CDER and OPDRA, released a report entitled "Final Summary of Food and Drug Administration (FDA) Action Items - Doing What Counts for Patient Safety: Federal Actions to Reduce Medical Errors and Their Impact" (http://www.fda.gov/cder/drug/MedErrors/patientsafety.htm). The report specifically outlines the steps that FDA has taken in response to action items in the February 2000 Report to the President from the Quality Interagency Coordination Task Force (QuIC) entitled "Doing What Counts for Patient Safety: Federal Actions to Reduce Medical Errors and Their Impact." OPDRA played a significant role in accomplishing a number of the action items listed in the QuIC report.

The first action item was identified as the need to hold a National Summit on Drug Safety. The concept recognizes that drug safety is a complex issue that requires input from all stakeholders and interested parties. In response, many outreach initiatives in which OPDRA played a major role were conducted on issues such as barcoding, safety reporting, and other aspects of drug safety. For example:

� On October 5 and 6, 2000, FDA participated in a major drug safety think tank sponsored by Wake Forest University in Winston-Salem, North Carolina. This meeting brought together thought leaders from academia, industry and FDA to discuss the challenges in minimizing the occurrence of patient injury due to pharmaceuticals.

� FDA worked with the Centers for Education and Research in Therapeutics (CERTs) to develop a workshop on risk communication which took place on April 30-May 1, 2001. This meeting assembled senior representatives from FDA, the Pharmaceutical Research and Manufacturers of America (PhRMA), and experts in the field of risk communication. This workshop examined the challenges of changing inappropriate prescribing behavior through communication, and set a research agenda that is currently being pursued.

� Another action item is a "Report to the Public on the Safety of Drugs, Devices, and Biologics". FDA has always been committed to providing the public with timely safety information, and to further this effort, OPDRA developed a new Medication Errors web page ( http://www.fda.gov/cder/drug/MedErrors/default.htm). The new web page provides information about medication error monitoring, drug products associated with medication errors, and other resources for finding out about medication errors.

OPDRA significantly helped in responding to additional action items including:

� Initiating programs to develop additional standards for drug names

� Initiating development of packaging standards to prevent dosing and drug mix-ups

� Developing new label standards for drugs to address errors related to medications

� Intensifying efforts to ensure manufacturers comply with standards

� Providing access to databases linked to healthcare systems

� Completing online adverse drug event reporting system

� Strengthening FDA's analytic and investigative capacity

� Strengthening FDA's outreach activities and collaboration with federal agencies

Patient Safety Task Force

As a direct outgrowth of the IOM report "To Err is Human" and the QuIC response discussed above, a multi-agency Patient Safety Task Force was organized. The task force includes AHRQ, CDC, FDA and HCFA. The task force was developed by the Department of Health and Human Services to integrate the collection of data on medical errors and adverse events, to coordinate research and analysis efforts, and to collaborate on reducing the occurrence of injuries that result from medical errors. Drs. Honig, Himmel, and Phillips participate in the Patient Safety Task Force and are working to ensure that these worthwhile initiatives are carried out in a manner, which is compatible to both the FDA and CDER mission.

At present, a major initiative by the task force has been the development of a common reporting portal that can be used by the healthcare community to report adverse events and errors and would streamline the current triage process. An additional long-term goal is the potential for sharing of safety information across the involved Agencies. These initiatives raise numerous complex issues for FDA, such as de-identification of reports, need for adequate information on the nature of the event, access to the data, etc.

In parallel, a patient safety working group was established at FDA by Dr. Janet Woodcock, which has representation from CDER, CBER, CDRH and OC. This working group coordinates FDA's position on safety issues across its Centers to ensure good representation of FDA's concerns and issues at the HHS task force. OPDRA participates on this working group as well.

As noted above, the issues surrounding patient safety are complex, and to encourage involvement on the part of all stakeholders, a national summit on patient safety was held this past spring in Washington DC. The keynote speaker at the event was HHS Secretary Tommy Thompson. The summit was organized around four major themes:

� Participation of Federal, State and local governments in health data collection

� Confidentiality and privacy of health data

� Maximize quality and usefulness of data while minimizing collection burden

� Public health data collection as a local issue

OPDRA played a key role in helping to organize this summit, along with fellow FDA staff and staff from the other three participating agencies. In addition, Dr. Honig co-authored an issue paper entitled "The Importance of Definitions for Patient Safety Information Systems" and Dr. Himmel co-authored a paper on Active vs. Passive Surveillance.

Other Safety Initiatives

In addition to the continuing work with the Patient Safety Task Force, OPDRA has helped support safety initiatives undertaken by the National Patient Safety Foundation, the National Coordinating Council for Medication Errors Reporting and Prevention, which is currently chaired by Jerry Phillips, and the Medication Error Task Force, which is a subcommittee of the QuIC.

Finally, over the past year, Temple University School of Pharmacy, the Institute for Safe Medication Practices, and FDA announced the nation's first certificate program in medication safety as part of Temple's Doctor of Pharmacy program. The Temple Pharmacy 12-credit educational track will include coursework in pharmacoepidemiology, risk management, medication error prevention, safe medical product design, and adverse drug reaction recognition, surveillance and prevention. Members of the OPDRA medication errors staff have been involved in developing this program, as well as lecturing at Temple University.

XI. Risk Management

Introduction

In recent years, the term risk management has been used widely to mean many different things, depending on one's perspective and the types of risk being addressed. From OPDRA's perspective, risk management is the activity that results in minimizing the risks of adverse events and medications errors associated with the use of drugs. This includes, for example, product labeling, development of drug distribution systems, registries, etc. At the present time, the tools that are available to the Agency, based on our regulatory authority include labeling, healthcare provider letters, restricted distribution, subpart H and drug withdrawal. The Center may also issue Public Health Advisories and other communications to the public about specific issues. The ability of some of these tools to affect change is limited. In addition, at present, standardized approaches as to which tools to use, when and in what combination, how their effectiveness is assessed and other similar issues are lacking. OPDRA has recognized the need to address these concerns and be better informed regarding the gamut of issues surrounding risk management and has undertaken a number of initiatives over the past year.

Risk Management Toolbox

The risk management toolbox is an effort to systematize the approach to the risk management of drugs. Such an effort involves an evaluation of all the components of the healthcare delivery system, including physician, pharmacist, patient, drug company and others, to determine where processes can be put into place to appropriately manage certain risks. Clear objectives need to be described, processes must be developed and criteria for invoking such systems must be established. We recognize, however, that to bring clarity and predictability to risk management, a broader approach must be considered. The ultimate goal is to develop "off the shelf" systems used consistently for all drugs that require risk management. Discussions are just beginning between CDER and PhRMA to determine what steps are necessary to advance this effort. It is envisioned that this will be a multi-year initiative involving broad input from experts, stakeholders, advisory committees and other affected groups.

Advisory Committee Support

Drug safety, risk management, risk communications, medication errors and patient safety are all issues which have gained prominence over the past few years. In part, this is due to publication of the Institute of Medicine report "To Err is Human" as well as a greater awareness that medications are not safe in an absolute sense. The safety of medications depends on the manner in which the healthcare community uses them. These issues play a significant role in CDER's overall evaluation of the risk benefit of drugs, and are common topics of discussion at advisory committee meetings.

In general, however, these advisory committee meetings tend to be comprised of disease/medical subspecialty experts, rather than experts in risk related issues. At best, we have been able to supplement some meetings with risk management experts in an ad hoc manner. Such an approach does a disservice to the importance and complexity of the issues. Because of these concerns, as well as OPDRA's need to obtain scientific input on a broad range of issues, a working group in OPDRA has been designing a drug safety advisory and risk management committee. This committee will include experts in the areas of medication errors, risk communication, risk perception, risk management, clinical trial methodology, evidence based medicine, biometrics and pharmacoepidemiology. At present, this committee has been developed as a subcommittee to an already standing advisory committee; the Advisory Committee for Pharmaceutical Science, however, because of the importance of this effort, our long-term plan is to ultimately make this a standing advisory committee. It is anticipated that the committee will be up and running in early 2002.

Contact Persons: Martin Himmel, M.D. - 301-827-3219

Kathleen Bongiovanni - 301-827-3191

Risk Management White Papers

In addition to gaining input from outside experts, it is also important to internally consider the extent of our knowledge base and the future direction of our efforts. Two such initiatives have taken place over the past year. Early this year, a CDER working group, directed by Mary Willy, developed a white paper on active surveillance. This document provides an extensive catalog of active surveillance initiatives throughout the world and describes the advantages and disadvantages of various approaches. The document closes with a discussion of how active surveillance could have impacted on the ultimate removal of a number of drugs over the past decade and suggestions for future pilot projects.

A second effort underway, in collaboration with CDER staff, is the development of a risk management white paper. This white paper will define the problem, describe a viable approach to resolving the problem and develop future objectives. Dr. Peter Honig is the OPDRA co-author for this initiative.

Drug Safety Seminar Series

Earlier this year, during the process of developing our advisory sub-committee and working on a number of drug specific risk management programs, it became apparent that OPDRA staff and all of CDER would benefit from having direct contact and input from others who are also grappling with these issues. We believe that academicians, practitioners, researchers and trade groups may have information that could help us design better programs and that keeping the lines of communication open would be important for the future. To that end, a drug safety seminar series was developed in order to bring in leaders from those areas that could impact on risk management. Some examples of recent seminars include:

The Pharmacist's Role in Risk Management: Susan Winckler RPh, JD - American Pharmaceutical Association

Changing Prescribers' Behavior: Peter Gross, MD - Hackensack University Medical Center

Review of the Dofetilide Risk Management Program: Nancy Allen-LaPointe, Pharm.D. & Judy Kramer, MD - Duke CERT

Privacy and Health Information: Potential Impact on Risk Management Initiatives, James Hodge JD - Project Director, Center for Law and Public Health, Georgetown University

OPDRA welcomes feedback on this series as well as suggestions for future topics and speakers.

Contact Person: Kathleen Bongiovanni - 301-827-3191

Fellowship Program

OPDRA recognizes that maintaining one's education is an important link and is necessary to better protect the public health, particularly as it relates to drug safety. OPDRA strives to ensure that there are adequate educational opportunities for our staff, and those who work in other parts of our healthcare system. OPDRA has taken the lead this year on administering a CDER fellowship program for physicians. Specifically, the Center is sponsoring a one- to two-year fellowship, designed to identify and train qualified candidates interested in a career in epidemiology, especially as it relates to the study of drug safety and risk. During the program, fellows will work part time in CDER, while at the same time, conducting course work at a local university, ultimately leading to a Masters degree in Epidemiology /Preventive Medicine, in Public Health, or a similar degree. The fellow will also be expected to identify and complete a research project at FDA during their time in the program. We anticipate enrolling our first fellow in 2002.

Contact Person: Kathleen Bongiovanni - 301-827-3191

XII. Leveraging and Outreach

OPDRA understands the importance of building strong collaborative relationships in order to improve efficiency and productivity. Since its inception, OPDRA has worked hard to improve working relations within CDER, other Centers, OC, other agencies and outside government. This process sometimes involves careful negotiation and meticulous planning, but often results in collegial and more constructive working relationships among the scientific, regulatory and patient communities and results in safer drug use. The following are accomplishments in the outreach area that proved particularly significant:

Accomplishments

� The Centers for Education and Research on Therapeutics (CERTs) represent an unprecedented opportunity for FDA to advance its role and influence in the use of marketed medical products. The CERTs were established under Section 409 of the Food and Drug Administration Modernization Act. Dr. Peter Honig serves as the FDA representative to the CERTs steering committee and has been successful in fulfilling the goal of having the CERTs serve as a field laboratory for FDA issues. CERTs is an Agency for Healthcare Research and Quality (AHRQ) program whose mission is to conduct research and provide education that will advance the optimal use of therapeutics (drugs, medical devices, and biological products). In particular, the CERTs program seeks to increase awareness of the benefits and risks of new, existing, or combined uses of therapeutics, and thereby improve the effectiveness and safety of their use. Seven centers, a coordinating center, a steering committee, and numerous partnerships with public and private organizations make up the CERTs program. The seven centers each focus on therapies for a particular patient population or therapeutic area.

� Duke University - therapies for disorders of the heart and blood vessels

� HMO Research Network - usefulness of HMOs for studying drug use, safety, and effectiveness

� University of Alabama at Birmingham - therapies for disorders of the joints and bones

� University of Arizona (formerly at Georgetown) - drug interactions, particularly in women

� University of North Carolina at Chapel Hill (UNC) - therapies for children

� University of Pennsylvania - therapies for infection

� Vanderbilt University - prescription drug use in a Medicaid population

The centers have completed several important projects during the past 2 years. For example, the UNC center published a study showing a link between rickets in breast-fed children and a lack of Vitamin D supplementation, especially among black infants. As a result of this study, the North Carolina Department of Health and Human Services made vitamin D available free to breast-feeding women through its Women, Infants, and Children program (WIC). Another example is the Web-based registry developed by the University of Arizona center to collect clinical cases of drug-induced cardiac arrhythmias ( www.qtdrugs.org). The information collected by the registry will be used to develop 1) detailed profiles of people most at risk for drug-induced arrhythmias and 2) a genetic test that can identify them in advance.

The Coordinating Center helps support the work of the centers by enhancing synergy across the centers and disseminating information developed by the centers. Serving as counsel to the seven centers and the Coordinating Center is a Steering Committee, whose members include representatives from each center, the government, the private sector, and consumer groups.

A core value of the CERTs program is the belief that collaboration among groups with different perspectives and resources is critical if the results are to be applicable in the "real world." All of the centers work with public and private collaborators on projects, which allows the centers to expand the number of projects they work on and their impact.

At the program level, the CERTs collaborate with other organizations interested in advancing the best use of therapeutics. One example is the Partners to Advance Therapeutics (PATHs) program. In March 2001, the CERTs held the first annual PATHs meeting to provide a forum for organizations to explore potential collaborations in improving the use of therapeutics. A second meeting is planned for March 2002.

Another collaborative project is an expert series of workshops focusing on the risks of therapeutics. CERTs is hosting the workshops in collaboration with AHRQ, the U.S. Food and Drug Administration (FDA), and the Pharmaceutical Research and Manufacturers of America (PhRMA). The goal of the Risk Series is to develop a research agenda to improve the assessment, communication, and management of therapeutic risk.

Other projects include:

� In an effort to properly gauge interest among selected hospital pharmacists regarding their interest in participating in a medical product surveillance system, OPDRA is conducting focus group testing using the services of a CDRH contractor. The current system, MedSuN, currently is a reporting mechanism that collects and submits information to CDRH on device problems. The OPDRA focus group test will be conducted in November, 2001 and the final report will be completed by January, 2002. These data will be used in planning the design of the drug component of MedSuN.

� Min Chen, Pharm. D. is the designated OPDRA liaison to CFSAN. She and others evaluated adverse events reported with the use of ephedra and St. John's Wort, and assisted in responding to a GAO audit on the "Risk of Harm from Questionable Health Products and Services to the Elderly".

� OPDRA staff is collaborating with HCFA's Center for Medicare and Medicaid Services to pilot the concept of "safety signal amplification". In this project, FDA is seeking adverse drug event cases to supplement its own AERS reports of rare and well-defined adverse events related to cases of liver failure associated with Parkinson's disease treatments (Tasmar or Comtan). The amplification is among a population of approximately 37 million elderly patients covered by Medicare. Using a specially-developed algorithm, the Virginia Healthcare Quality Center has identified approximately 19 cases of hospitalized liver failure among elderly Parkinson's patients and will be making these hospital records available to FDA to assess the potential association with either Tasmar or Comtan. FDA will take corresponding regulatory risk management actions based on their findings and completion of this project is anticipated by January 2002. As a result of this collaboration, the Center for Medicare and Medicaid Services is making $250,000 available annually for its contractors to assist FDA in addressing priority drug safety issues among the elderly by signal amplification.

� By working with the Consumer Products Safety Commission, OPDRA's epidemiology staff evaluated the utility of the National Electronic Injury Surveillance System (NEISS) data to detect patients presenting to emergency departments with specific adverse events due to drugs. It was determined that although this system does detect some patients with known, labeled reactions, it does not currently provide enough detail to be of use to FDA for surveillance purposes.

� The medication errors staff with help from CDER's Office of Training and Communications established an Internet site on CDER's homepage. This website provides information to the public on current medication error issues.

� The medication errors staff is writing quarterly articles for Drug Topics that reach out to a large pharmacy audience.

In addition FDA has collaborated in:

� a program to increase the appropriate use of beta blockers in patients with congestive heart failure, and

� a program to evaluate the effectiveness of physician education in the launch of a new drug to treat atrial fibrillation.

American Association for the Study of Liver Diseases/FDA/PhRMA Hepatotoxicity Workshop

A multidisciplinary conference was held in February 2001 to discuss drug-induced liver injury. Topics included preclinical mechanistic studies and models for human hepatotoxicity, early clinical signals in controlled trials, and strategies to improve postmarketing surveillance of marketed drug products that may be potential hepatotoxins. As a result of this conference, the Division of Over the Counter Drugs and OPDRA evaluated the problem of acetaminophen-related hepatotoxicity in preparation for a future public meeting. For more information, see http://www.fda.gov/cder/livertox/.

Contact: John Senior, M.D., 301-827-7280

XIII. Regulatory Research

OPDRA has engaged in research that has served to inform CDER on policy development and appropriate regulatory action. Specifically, we have engaged in research activities that have attempted to characterize the use, consistency of application, and effectiveness of CDER risk management and communication efforts.

Some selected research activities include:

� In conjunction with the Georgetown CERT, a survey of undergraduate and graduate medical program directors was conducted attempting to characterize and quantify the amount of instruction on adverse event identification and reporting. The results of this survey were published, in part, in the Journal of the American Medical Association. It was apparent that these topics were generally not part of the curriculum in the undergraduate medical or residency training programs. In response to these findings, CDER and the Georgetown CERT developed a teaching module on the principles of clinical pharmacology and adverse reactions to drugs. This module was presented to representatives of the American Association of Medical Colleges (AAMC) and will be made available for incorporation into the medical training curricula through the CERTs.

� Epidemiologists in OPDRA have been active in developing new methodologies for assessing the benefit and risk of drugs by applying traditional epidemiological techniques and newer modeling methods to the analysis of clinical trial safety databases. This promising approach will be advanced through a CDER RSR grant application in the upcoming year.

� Zili Li and David Graham have worked closely with the Gastrointestinal Drugs Division Staff to assess time trends of adverse events in premarketing clinical trials submitted in the alostron clinical trial safety database NDA.

XIV. Regulations, Guidances and MaPPS

OPDRA has been involved in supporting several critical regulations and guidances that address postmarketing reporting and patient safety. These include:

� Notification to accept e-sub ISRs without attachments posted on May 18, 2001.

� Proposed Suspected Adverse Reaction Rule (SADR); cleared by FDA; now in HHS.

� Draft Guidance for Industry: Providing Regulatory Submissions in Electronic Format-Expedited Adverse Drug Experience Reports (under development)

� Draft Guidance for Industry: Providing Regulatory Submissions in Electronic Format-Postmarketing Periodic Adverse Drug Experience Reports (under development)

� Draft Guidance for Industry on Periodic Safety Update Reports (under development)

� Proposed Regulation on Electronic Expedited Adverse Event Reporting (under development)

� Draft Guidance entitled, "Postmarketing Safety Reporting for Human Drug and Biologic Products Including Vaccines", published in 3/01, generated approximately 600 public comments; comments under review

� Bar coding proposed regulation (under development)

� Draft guidance to industry on proposed tradenames and packaging (under development)

� Guidance for Industry: Submitting Proprietary Names for Evaluation (under development)

� MaPP: Minimizing Medication Errors associated with confusing drug names, labels, or packaging (under development)

� Guidance for Industry: Minimizing Medication Errors - Names, Labeling and Packaging (under development)

Conclusion

This has been an intensely busy year for OPDRA. OPDRA's increased workload and new responsibilities that will be assessed through the upcoming reorganization may be attributed to our strong belief in the importance of nurturing trust within the Center and demonstrating value in an effort to ensure that drugs are used as safely as possible. We look forward to maturing as an Office and moving forward with several strategic planning initiatives.

The first priority for the new Office will be the tactical implementation of the reorganization; including selecting appropriate people to lead the different ODS divisions and establishing internal procedures for already existing and newly assigned responsibilities (e.g. MedWatch and patient labeling). We will also have to develop processes to incorporate new data resources into the business of safety evaluation.

A second, but equally important priority, for the new Office will be the development of ODS/ORM operating principles. It is critical that ODS maintains close communication and synergistic relationships with ORM and the ORM reviewing divisions. Codification of relationships through MaPPs on such issues as tradename reviews, postmarketing safety issues, evaluation of risk management programs and medication guides will be addressed. Furthermore, the shared responsibilities in the review of Periodic Safety Update Reports (PSURs) will be addressed through a MaPP and a guidance to industry is also necessary. The appropriate use of the new Drug Safety and Risk Management Advisory Committee will also be codified through a MaPP. However, it will be very important for ODS to maintain regular participation in ORM activities by attending the critical ORM meetings such as ministaff, division director meetings, etc.

The final priority for the new office will focus on the CDER initiative relating to Risk Management. The development of the Risk Management White Paper, the identification of a risk management and risk communication research agenda, the successful launch and utilization of the new Drug Safety and Risk Management Advisory Committee, the optimal use of MedWatch and the CERTs for risk communication and outreach, the identification of additional data resources to optimize risk assessment, and ultimately, the codification of ODS' role in risk management for marketed drugs will represent major opportunities and challenges for the next year.

Appendix 1 - OPDRA Organizational Chart

Current OPDRA Units

OPDRA-Honig, DDRE I-Beitz, DDRE II-Beitz (A), ITS Group-Phillips (A), Extramural Programs-Phillips (A), Medication Errors-Phillips

Appendix 2 - OPDRA Meeting Presentations

Beam S. "Update of Proposed Proprietary Name Reviews" DIA Annual Meeting, July 2001.

Bharati M, Drinkard C, Shatin D, Graham D. "The Risk of Esophageal Obstruction Associated with an Anti-Allergy Medication (Claritin-D� 24 Hour)" United Health Group, Minnetonka, MN; Food and Drug Administration, Rockville, MD. Abstract presentation at the Academy for Health Services Research and Health Policy annual meeting, June 2001.

Bharati M, Drinkard C, Shatin D (presenter), Willy M, Graham D. "Cylert� Labeling Compliance: Second Line Therapy Use and Liver Function Monitoring" Abstract presentation at the International Society of Pharmacoepidemiology, August 2001.

Bongiovanni K. "CDER 101 - Overview of CDER's Postmarketing Safety Evaluation", Presentation to Pharmaceutical Industry, May, 2001.

Diwa D, Fan J, Kim H. Mahmud A. "Medications and the FDA" National Boards of Pharmacy, October 2001.

Diwa D, Fan J, Kim H, Mahmud A. "Reporting Medication Errors: A Public Health Responsibility" Annual Commissioned Officers Association Meeting, May 2001.

Graham D. "CDER 101 - Epidmiology Approaches to Postmarketing Drug Safety at CDER", Presentation to Pharmaceutical Industry, May 2001.

Graham DJ. "Postmarketing resources and their utilization within the Center for Drug Evaluation and Research." Seminar presented at course in Clinical Trials, Center for Devices and Radiologic Health, Rockville, MD, June 1, 2000.

Graham DJ. Collaboration between academia and government agencies for study of drug safety issues. 16^th International Workshop on Postmarketing Surveillance, Saint-Paul de Vence, France, June 27, 2000.

Graham DJ. Modeling cumulative risks and hazard rates using postmarketing data. FDA/Industry Workshop on Statistically Sound Decision-Making, Bethesda, MD, September 15, 2000.

Graham DJ. Data resources at FDA for postmarketing safety evaluation and applications of their use. Center Scientific Rounds, December 13, 2000.

Graham DJ. "Interactive problem solving: how would you have epidemiologically studied the problem of liver failure with troglitazone?" Presented at a course in Pharmacoepidemiology, Yale University School of Medicine, New Haven, CT, April 10, 2001.

Graham DJ. "Epidemiologic approaches to drug safety at FDA," presented at course sponsored by the Drug Information Association, Washington DC, October 25, 2001.

Graham DJ. "Principles of pharmacovigilance and methods of practice at FDA," presented to the Nutritional Supplements Subcommittee, Institute of Medicine, Washington, DC, November 29, 2001.

Graham DJ. "Models of excellence in pharmacovigilance." 17^th International Conference on Pharmacoepidemiology, Toronto, Canada, August 25, 2001.

Manda B, Drinkard C, Willy E, Graham DJ, Shatin D. Compliance with labeling for Cylert: use as second-line therapy and liver function monitoring. 17^th International Conference on Pharmacoepidemiology, Toronto, Canada, August 24, 2001.

Himmel, M. Johns Hopkins Graduate Training Program in Drug Development - Panel discussant of student drug development programs, 12/2000.

Himmel, M. PERI - "PSURs: An FDA Perspective" - 3/2001.

Himmel, M. PERI - "Postmarketing Drug Risk Assessment Initiatives at CDER" - 3/2001.

Himmel, M. PERI - "PSURs: An FDA Perspective" - 11/2001.

Himmel, M. Johns Hopkins Graduate Training Program in Drug Development - Seminar on Postmarketing Drug Risk Assessment at FDA - 12/2001.

Holquist C. "CDER 101 - Medication Errors and FDA Perspective", Presentation to Pharmaceutical Industry, May, 2001.

Holquist C. "CDER 101 - Medication Errors and FDA Perspective", Presentation to Pharmaceutical Industry, October, 2001.

Honig P. Regulatory Affairs Professional Society (RAPS) Annual Meeting "Risk Management: Impact on the Consumer" Washington, DC October 2000.

Honig P. Wake Forest Drug Safety Symposium" The Adverse Event Reporting System for Drugs in the United States" Winston-Salem, NC October 2000.

Honig P. Pharmaceutical Education & Research Institute (PERI): Adverse Events: A Review of Regulations and Challenging Exercises in Pharmacovigilance.

Honig P. "Postmarketing Drug Risk Assessment and Initiatives at CDER" Arlington, VA October 2000.

Honig P. European DIA Meeting, "Periodic Safety Update Reports: US Regulatory Perspectives, London, UK December 2000.

Honig P. FDA-PhRMA-AASLD Hepatotoxicity Workshop "Postmarketing Perspectives: State of the Art and Future Initiatives Chantilly, VA February 2001.

Honig P. American Society of Clinical Pharmacology and Therapeutics "FDA Perspectives on Drug Labeling as a Risk Management Strategy" Orlando, Fl March 2001.

Honig P. American Society of Clinical Pharmacology and Therapeutics Chair, Public Policy Session on "Translating Research Into Practice" Orlando, FL March 2001.

Honig P. American Society of Clinical Pharmacology and Therapeutics Government Affairs Committee.

Honig P. "Proposed Changes to the Professional Labeling Regulations" Orlando, FL March 2001.

Honig P. Temple University FDA/Industry Conference, "FDA's Drug Risk Management Initiatives" Philadelphia, PA April 2001

Honig P. DIA Pharmaceutical Outcomes Meeting, "FDA Patient Safety Initiatives" Savannah, GA April 2001

Honig P. FDA Office of Women's Health Dialog Session, "Dialog on Federal Patient Safety Initiatives" Washington DC April 2001.

Honig P. Annenberg 3: Let's Talk: Communicating Risk and Safety in Health Care, "FDA and the Risk Management of Medical Products: Impact on the Patient", St Paul, MN, May 2001.

Honig P. PERI: Clinical Trials Course "Regulatory Perspectives on Metabolism-Based Drug-Drug Interactions", Washington DC, May 2001.

Honig P. International Conference on Harmonization (ICH), Postmarketing Surveillance Workshop on Postmarketing Surveillance, "FDA Perspectives on PSUR (E2C) Implementation", Tokyo, May 2001.

Honig P. Infectious Disease Society of America Symposium: Effective Strategies for Improving Patient Safety and Preventing Medical Errors in Infectious Diseases, "FDA Actions to Reduce Medical Errors and Their Impact", Chicago, IL July 2001.

Honig P. Regulatory Affairs Professional Society (RAPS) Meeting "Future Perspectives on Risk Management", Washington, DC August 2001.

Honig P. Regulatory Affairs Professional Society (RAPS) Annual Meeting, "CDER Risk Management Tools and their Utility" Baltimore, MD, November 2001.

Honig P. First Annual DIA Workshop in Japan on Global Pharmacovigilance ,"Postmarketing Safety Surveillance and Risk Management of Marketed Drugs", Tokyo, November 2001.

Honig P. First Annual DIA Workshop in Japan on Global Pharmacovigilance "Postmarketing Safety Studies: US Regulatory Perspective" Tokyo, November 2001.

Kweder S, Holmboe E, Shaffer D, and Sacks L. "Managing drug risks: from policy to bedside". The Society of General Internal Medicine 24^th Annual Meeting - Workshop. San Diego, CA, May 3, 2001.

Manda B, Drinkard C, Willy M, Graham D, Shatin D. "Compliance with labeling for pemoline (Cylert): use as second-line therapy and liver function monitoring". International Conference on Pharmacoepidemiology, Toronto, Canada, August, 2001.

Neal A. Global Challenge in Pharmacovigilance, "Exchange of Safety Information between the FDA and other Regulators". Drug Information Association Annual Meeting, Denver, CO, July, 2001.

Neal A. "FDA on MedDra Implementation". MedDRA MSSO User's Group Meeting, Denver, CO, July 2001.

Neal A. "MedDRA Implementation at the FDA: an Update". Pharmaceutical Education and Research Institute, Arlington, VA, May 2001.

Neal A. "Lessons Learned in Implementing MedDRA at the FDA", Pharmaceutical Education and Research Institute, Adverse Events: A Review of Regulations and Challenging Exercises in Pharmacovigilance, Arlington, VA, March 2001.

Neal A. "MedDRA Implementation at the FDA: an Update", DIA Drug Safety Surveillance and Epidemiology Training Course, Washington, D.C., April 2001.

Neal A. "Lessons Learned in Implementing MedDRA at the FDA", DIA Drug Safety Surveillance and Epidemiology Training Course, Washington, D.C., October 2000.

Neal A. "MedDRA Implementation and the FDA: an Update". Pharmaceutical Education and Research Institute, MedDRA: An Update, Philadelphia, PA, December 2000.

Neal A. "MedDRA Implementation for Regulatory Reporting". MedDRA MSSO User's Group Meeting, San Diego, CA, November 2000.

Nourjah P. "The Value of NEISS Data as a Resource for Postmarketing Surveillance of Drug Products", Interagency Meeting, Bethesda, Maryland, August 14, 2001.

Piazza-Hepp, T. Postmarketing Safety Evaluation, "CDER 101" Course, cosponsored by DIA/CDER Staff College, Washington, D.C., May 2001.

Piazza-Hepp, T. Overview of AERS and Postmarketing Safety, to Vitali Pool, M.D., CDC Epidemiologist, VAERS Project, June 2001.

Piazza-Hepp, T. MedDRA: Current Issues, to Clinical Safety Committee of PhRMA, Washington, D.C., September 2001.

Senior J. "Surveillance for Hepatotoxicity", National Institutes of Health workshop on Mechanisms and Test Systems of Drug-Induced Liver Injury, Lister Hill Center, Bethesda MD, October 2000.

Senior J. "Drug Development and review at the FDA", Science for Physicians Lecture Series, University of Texas Southwestern, Dallas TX, February 2001.

Senior J. "Overview of the problem of drug-induced liver injury, at session on Drug-Induced Liver Injury: A Global Problem", 27th Annual Summer Meeting of the Toxicology Forum, Given Institute, Aspen, CO, July 2001.

Senior J. "Data sources and descriptors of hepatotoxicity, at special session on "Biomarkers of Toxicity", Toxicology Discussion Group, 7th Annual Meeting of the Society for Biomolecular Screening, Baltimore Convention Center, September 2001.

Shaffer D. "QT Prolongation and torsade de pointes: From idiosyncrasy to postmarketing analyses". International Symposium on Mechanisms, Models, and Predictions of Idiosyncratic Drug Toxicity. Atlantic City, NJ, June 11-13, 2001.

Shaffer D, Singer S, Korvick J. "Macrolide and fluoroquinolone associated torsade de pointes: review of the FDA Adverse Event Reporting System". The 41^st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, September 22-25, 2001. (Rescheduled to December 16-19 2001.)

Toyer D. "Sildenafil and hemorrhagic events", COA Public Health Professional Conference, Alexandria, A, May 2001.

Trontell, Anne. "Evaluating the Impact of Risk Management Programs - OPDRA Capabilities & Experience", CDER CASE Seminar November 2000.

Trontell Anne. "CDER Initiatives in PostMarketing Drug Risk Assessment", DIA Conference on Pharmacovigilance in the New Millennium, January 2001.

Trontell Anne. "CDER's Postmarketing Safety Program", 2 presentations at DIA Drug Safety and Surveillance Course, April and October 2001.

Trontell Anne. "Adverse Drug Events/Reactions: FDA Definitions and Databases", NIH Conference on Pediatric Adverse Drug Reactions, April 2001.

Trontell Anne. "Developing Risk Management Programs Post-Approval: Options, Experience, and Lessons Learned", DIA Annual Meeting, Plenary Session, July 2001.

Trontell Anne. "Update of OPDRA Postmarketing Activities, DIA Annual Meeting", OPDRA Update Session, July 2001.

Trontell Anne. "Risk Communication: FDA Perspectives and Initiatives International Society for Pharmacoepidemiology", Plenary Session on Risk Communication, August 2001.

Trontell Anne. "CDER's Postmarketing Safety Program" (2 presentations at DIA Drug Safety and Surveillance Course, April and October 2001).

Trontell Anne. "DDRE1 Safety Surveillance and Risk Management" (2 presentations, to the Divisions of Oncologic Drug Products and the Office of Clinical Pharmacology and Biotherapeutics) .

Trontell Anne. "CDER's Postmarketing Safety Program" , New Reviewer's Workshop, April 2001.

Uhl K. An FDA perspective. Gordon Research Conference on Medicinal Chemistry; "Drug Safety in the 21^st Century", August 2001.

Uhl K. "CDER safety surveillance and risk management: OPDRA capabilities and experience" American Association of Pharmaceutical Scientists Indianapolis/Cincinnati Discussion Group (I/CDG), 1^st Annual Symposium on Current Topics in Drug Development, May 2001.

Wilson J. "Electronic Submission of Postmarketing ADR Reports", Presentation to Pharmaceutical Industry, May 2001.

Appendix 3 - OPDRA Publications

Ahmad SR, Singer S, Leissa BG. Congestive heart failure associated with itraconazole. Lancet 2001; 357:1766-7.

Beitz J. Trial endpoints for drug approval in oncology: Chemoprevention. Urology 2001: 57(4A)213-215.

Brinker AD, Bonnel RA, Feight AG, Nourjah P. Celecoxib and rofecoxib. JADA 2001;132:1497-1498.

Bross PF, Beitz J, Chen G., Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R. Approval summary: Gemtuzumab ozogomicin in relapsed acute myeloid leukemia. Clin Cancer Res 2001;7:1490-1496.

Chiao J, Beitz J, DeLap RJ. Antimetabolic agents in Current Cancer Therapeutics, 4^th Edition, JM Kirkwood, MT Lotze, JM Yasko eds., Philadelphia 2001.

Drinkard C. MPH, PhD, Shatin D. PhD, Clouse J. RPh, MS. "Postmarketing Surveillance of Medications and Pregnancy Outcomes: Clarithromycin and Birth Malformations" Pharmacoepidemiology and Drug Safety 2000:9:549-556 Authors acknowledged contribution of David Graham MD, MPH at the Food and Drug Administration.

Fanning MM, Wassel R, Piazza-Hepp T. Pyrogenic reactions to gentamicin therapy. N Engl J Med 2000; 343:1658-9.

Galson S, Kweder S, Houn F, Raczkowski V, Honig P. The FDA and the Lancet: an exchange. Lancet 2001; 358:415.

Gardner J, Blough D, Drinkard C, Shatin D, Anderson G, Graham D, Alderfer R. "Tramadol and Seizures: A Surveillance Study in a Managed Care Population" Pharmacotherapy 2000;20(12):1423-1432.

Graham D, Drinkard, C, Shatin D, Tsong Y, Burgess M. "Liver Enzyme Monitoring in Patients Treated with Troglitazone" JAMA 2001; 286:831-833.

Rodriguez EM, Staffa JA, Graham DJ. The role of databases in drug postmarketing surveillance. Pharmacoepidemiol Drug Safety 2001; 10:407-10.

Graham DJ, Waller PC, Kurz X. A view from regulatory agencies. In: Strom BL, ed. Pharmacoepidemiology (3^rd edition). John Wiley & Sons, Ltd., New York, 2000:109-124.

Holquist C., Phillips J. "FDA Advise-Err: Dispensing Errors Associated with Zantac and Zyrtec" ISMP Medication Safety Alert, November 1, 2000.

Holquist C., Phillips J. "FDA Advise-err: Medication Errors Associated with Confusion between Flomax and Volmax" ISMP Medication Safety Alert, November 15, 2000.

Holquist C., Phillips J., "Safety Briefs: Antibacterial Gel or Risperdal Oral Solution?" ISMP Medication Safety Alert, June 27, 2001.

Holquist C., Phillips J., "FDA Safety Page: Curbing Med Errors Involving Anzemet, Bentyl" Drug Topics, July 2, 2001.

Honig PK, Phillips J, Woodcock J. How many deaths are due to medical errors? JAMA 2000; 284:2187-8.

Honig PK Commentary: On-demand use of B2-agonists led to better asthma control than did regular use in moderate-to-severe asthma. ACP Journal Club 2001;134:17.

Honig PK Commentary: On-demand use of B2-agonists led to better asthma control than did regular use in moderate-to-severe asthma. Evidence Based Medicine 2001;6:15.

Honig PK. Commentary: Herbal preparations may improve FEV1 and symptoms in asthma. ACP Journal Club 2001;134:96.

Huang S-M, Honig P, Lesko LJ, Temple R, Williams RL. An Integrated Approach to Drug-Drug Interactions- A Regulatory Perspective, Chapter 18 in Drug-Drug Interactions: From Basic Pharmacokinetic Concepts to Marketing Issues, Ed. A.D. Rodrigues, Marcel Dekker, New York 2001.

Kleiner DE, Lee WH, Senior JR, Balistreri WF. The burden of hepatotoxicity, in Bissell DM, Gregory JG, Laskin DL, Hoofnagle JH, eds., Drug-induced liver injury: mechanisms and test systems. [meeting report] Hepatology 2001 (April); 33:1009-13.

LeGrenade L, Myocarditis and cardiomyopathy associated with clozapine use in the United States. NEJM, Vol 345, No 3, July 19, 2001.

La Grenade L, Graham D, Trontell A., Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Engl J Med 2001; 345(3): 224.

Levy D, Stergachis A, McFarland L, Van Vorst K, Graham D, Johnson E, Park B, Shatin D, Clouse J, Elmer G. "Antibiotics and Clostridium difficile Diarrhea in the Ambulatory Setting" Clinical Therapeutics 2000:22(1):91-102.

Malozowski S, Green L. Reply to the Editor. Reports of premature thelarche in girls. J. Pediatr 2001; 138(3):449.

Park B, Clouse J, Shatin D, Stergachis A. "Incidence of Adverse Oesophageal and Gastric Events in Alendronate Users" Pharmacoepidemiology and Drug Safety 9 371-376 (2000) Authors acknowledged the assistance of Diane Wysowski PhD, OPDRA for initiating the study and reviewing and commenting on the results.

Phillips J, Beam S, Brinker A, Holquist C, Honig P, Lee LY, Pamer C. Retrospective analysis of mortalities associated with medication errors. Am J Health-Syst Pharm, October 2001; 58:1835-41.

Ray W, Meredith S, Thapa P, Meador K, Hall K, Murray K "Antipsychotics and the Risk of Sudden Cardiac Death" Arch Gen Psychiat In Press.

Rosebraugh CJ, Honig PK, Yasuda et al. Formal education about medication errors in internal medicine clerkships. JAMA 2001;286:1019.

Smalley W, Shatin D, Wysowski DK, Gurwitz J, Andrade SE, Goodman M, Chan KA, Platt R, Schech SC, Ray W. Contraindicated use of cisapride: impact of Food and Drug Administration regulatory action. JAMA 2000;284:3036-3039.

Senior J. Drug-induced liver injury: A national and global problem, internet publication of 3 "white papers" on preclinical, clinical, and postmarketing considerations, and 11 invited presentations at www.fda.gov/cder/livertox, posted April 2001.

Singer SJ, Tiernan R, Sullivan EU. Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients [letter]. N Engl J Med 2000;343:1815-6.

Smalley W, Shatin D, Wysowski D, Gurwitz J, Andrade S, Goodman M, Chan K.A, Schech S, Ray W. "Contraindicated Use of Cisapride: Impact of Food and Drug Administration Regulatory Action" JAMA 2000(April); 20(7):410-416.

Thomas M., Holquist C., Phillips J., "Med Error Reports to the Food and Drug Administration Show a Mixed Bag , Drug Topics, October 2001.

Trontell AE, Honig PK. Clopidogrel and Thrombotic Thrombocytopenia Purpura. New England Journal of Medicine 2000;343:1191-92.

Trontell, A., How the US Food and Drug Administration defines and detects adverse drug events, Current Therap. Res. 62(9):641-649, 2001.

Uhl K, Honig PK. Risk Management of Marketed Drugs: FDA and the interface with the practice of medicine, Pharmacoepidemiology and Drug Safety 2001;10:1-4.

Weller PF, Plaut M, Taggart V, Trontell A., The relationship of asthma therapy and Churg-Strauss syndrome: NIH workshop summary report. J Allergy Clin Immunol, 108 (2): 175-183.

Wysowski DK, Corken A, Gallo-Torres H, Talarico L, Rodriguez EM. Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisapride and Food and Drug Administration regulatory actions. Am J Gastroenterol 2001;96:1698-1703.

Wysowski DK, Pitts M, Beitz J. Depression and suicide in patients treated with isotretinoin. New Engl J Med 2001;344:460.

Wysowski DK, Beitz J. Methodological limitations of the study "Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide," Arch Dermatol 2001;137:1102.

Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001;45:515-519.

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Appendix 4 - Posters

Ahmad SR, Nourjah P, Trontell A. Drug use in pregnancy. Poster presentation at ISPE, Toronto, Canada, August 2001. Published in Pharmacoepidemiology and Drug Safety 2001; 10:S83-S84.

Ahmad SR, Trontell A, Pitts M, Karwoski C, Beitz J. Risk of liver failure in association with antifungal drugs for onychomycosis. Poster presentation at ISPE, Toronto, Canada, August 2001. Published in Pharmacoepidemiology and Drug Safety 2001; 10:S68.

Brinker A, Beitz J. Analysis of spontaneous reports data for possible beneficial hypotheses. American College of Clinical Pharmacology and Therapeutics Annual Meeting, March 2001.

Bonnel RA, Villalba ML, Midthun K, Karwoski C. Deaths associated with inappropriate intravenous colchicine administration. American College of Rheumatology Annual Meeting, San Francisco, November 12-15, 2001.

Boxwell D, Toerner J. Fatal hepatotoxicity associated with combination hydroxyurea and nucleoside reverse transcriptase inhibitors (NRTIs): Cases from the FDA Adverse Event Reporting System (AERS). 8^th Annual Conference on Retroviruses and Opportunistic Infections, Chicago, Illinois, February 4-8, 2001.

Brown SL, Kedas A, Bascanyi JT, Purvis-Wynn SL, Fatal and serious complications associated with cosmetic suction lipectomy. 17th International Conference on Pharmacoepidemiology, Toronto, Canada, August 2001.

Green L, Zawadzki J. Thiazoline-associated hepatoxicity: Comparison of spontaneously reported postmarketing cases in association with troglitazone, rosiglitazone, and pioglitazone. Annual Endocrine Society Meeting, Denver, CO, June 2001.

La Grenade L, Graham D, Trontell A, Beitz J, Sherman R, Nourjah P. Postmarketing drug risk assessment: the phenylpropanolamine experience. 2001 FDA Science Forum, Washington DC, February 15-16.

La Grenade L, Estimating public health impact of adverse drug events in pharmacoepidemiology: phenylpropanolamine and hemorrhagic stroke. ISPE, 17th Annual International Conference on PharmacoepidemiologyToronto, Canada, August 2001.

La Grenade L, Myocarditis and cardiomyopathy associated with clozapine use: the US experience. ISPE, 17th Annual International Conference on PharmacoepidemiologyToronto, Canada, August 2001.

McCloskey CA, Staffa JA. Pediatric inpatient use of eleven selected drugs: Results of two pilot studies. 2001 FDA Science Forum, Washington DC, February 15-16.

McCloskey CA, Staffa JA. Pediatric inpatient drug exposures: Results of two pilot studies of eleven selected drugs. International Society of Pharmacoepidemiology Annual Meeting, Toronto, Canada, August 2001.

Nourjah P, Trontell A., Song Y., La Grenade L., Graham D., Beitz J. Sparse-data bias in pharmacoepidemiology: the Hemorrhagic Stroke Project (HSP) case-control study on PPA and risk of hemorrhagic stroke (HS). ISPE Meeting, Toronto, Canada, August 2001.

Willy ME, Li Z. A study of product labeling - retrospective analysis of the content of the product labeling of prescription drugs with the risk of hepatic failure. International Conference on Pharmacoepidemiology Toronto, Canada, August 2001.

1 Data collected as of September 24, 2001

2 An individual, usually a health care practitioner, notifies us directly of a suspected serious adverse event.

3 These report serious and unexpected adverse events to us as soon as possible within 15 days of discovering the problem.

4 These report all other adverse events, such as those that are less than serious or described in the labeling.

5 An ICSR is an individual case safety report, also known as one adverse event report. When an ICSR is loaded into AERS, it is known as an ISR.

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Office of Drug Safety Annual Report Center for Drug Evaluation and Research Food and Drug Administration Annual Report FY 2001

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