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Office of Drug Safety Annual Report 2004

Table of Contents

I. Introduction


III. Cooperative Agreement Program

IV. Risk Management Program Activity 

V. Healthy People 2010

VI. International Activity 



IX. DMETS Activities 

X. DSRCS Activities 

XI. Other ODS Activities 

XIII. Conclusion

 I. Introduction

In FY 2004, the Office of Drug Safety (ODS) was led by Dr. Paul Seligman, who is also the permanent Director of the Office of Pharmacoepidemiology and Statistical Science. Dr. Anne Trontell continued in her position as Deputy Director of the Office. ODS staff is comprised of a broad spectrum of health professionals from a variety of disciplines, including physicians, epidemiologists, pharmacists, nurses, project managers, social scientists, contract specialists, and technical information specialists, as well as administrative and support staff. ODS staff routinely evaluates drug safety profiles of marketed products, communicates drug risk information to health care professionals and patients and reduces medication errors through improving drug packaging and labeling and evaluating proprietary drug names. ODS is composed of an Immediate Office staff and three Divisions, the Division of Drug Risk Evaluation, the Division of Medication Errors and Technical Support and the Division of Surveillance, Research and Communication Support.

Significant FY 2004 accomplishments include:

  • Collaborating with the Office of New Drugs in publishing three draft guidance documents on: Premarketing Risk Assessment, Development and Use of Risk Minimization Action Plans and Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment

  • Utilizing managed care databases to evaluate important drug safety questions by employing formal epidemiological studies with cooperative agreement partners

  • Working in partnerships with the international community to improve public health, the timely sharing of drug safety information, and maintaining consistent global standards

  • Developing software to aid in pre-market identification of drug and/or biologic names that are phonetically and orthographically similar to proposed proprietary drug names

  • Continuing to review consumer-oriented materials to ensure information is communicated clearly to patients, especially those with limited literacy

  • Increasing the proportion of electronically submitted adverse event reports from 10 to 16 percent for all reports and 19 to 29 percent for expedited reports

  • Developing the final rule on Barcode Requirements for Human Drug Products and Blood

  • Taking a leadership role in several important advisory committee meetings that influenced risk management and patient safety activities

  • Developing an intranet office webpage containing an orientation program that is used as a guide and reference tool for new ODS staff


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II. Adverse Event Reporting System (AERS)

In FY 2004, a total of 426,109 adverse event reports were received by ODS. Of these, 263,352 Individual Safety Reports (ISRs) were entered into AERS. At the present time, AERS is entering reports for all direct, 15-day (expedited), and all serious periodic reports. AERS also enters nonserious periodic reports for new molecular entities approved for three years or less. Nonserious periodic reports for drugs approved for more than three years are not entered into AERS. The chart below shows the reporting trend over time.

CDER Post-Marketing Adverse Event Reports Received FY 99 FY 04

CDER Post-Marketing Adverse Event Reports Received FY 99 FY 04

Electronic Submission of Adverse Event Reports Initiative:

The electronic submission initiative continued to progress successfully during FY04, and remains a high priority for the Center. Electronic submission of reports by sponsors allow more timely receipt and evaluation of adverse event reports at considerable cost savings to both FDA and those submitting the reports. CDER provides useful information for manufacturers on its Electronic Regulatory Submissions and Review (ERSR) web page.

In FY 2004, 69,111 individual case safety reports were submitted electronically (44,922 expedited and 24,189 periodic) in a standard generalized markup language (SGML) format using ICH E2B(M) standards (see graph below). The proportion of reports submitted electronically increased between FY03 and FY04: from 10 to 16 percent for all reports and 19 to 29 percent for expedited reports.

Electronic Submissions

Fifteen manufacturers were submitting electronic adverse event reports to the FDA by the end of FY 2004.

Public Access to AERS Data

The National Technical Information Service (NTIS) receives extracts of the AERS data on a quarterly basis. These data are available for sale to the general public through the NTIS (http://www.ntis.gov; search term "FDA AERS"). As of January 2005, quarterly AERS data extracts from 2004 are available for downloading at the website See Section IX, DMETS, for additional information.


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III. Cooperative Agreement Program

Cooperative Agreements

ODS' cooperative agreement program in pharmacoepidemiology provides CDER with access to population-based databases for the purpose of studying important postmarketing drug safety questions. In FY 2004, the following sites received grant support through this program:

  • Harvard Pilgrim Health Plan/Fallon Clinic/Health Partners

  • Vanderbilt University

  • UnitedHealth Group

CDER works collaboratively with the cooperative agreement partners to identify research areas, to design and conduct studies to investigate suspected associations between specific drug exposures and specific adverse events, and to estimate risk.

During FY 2004, a decision was made to shift the program's funding mechanism from a cooperative agreement (grant) to a multiple award task-order contract to facilitate greater flexibility and responsiveness to FDA questions. This new program should become operational during 2005.

Feasibility studies performed during FY 2004:

1. Drugs for the treatment of attention deficit and hyperactivity disorder and cardiovascular outcomes

2. Yasmin use and thromboembolic outcomes

3. Ortho Evra use and thromboembolic outcomes

4. Vadecoxib use and serious skin reactions

5. Tegaserod use and ischemic colitis

In-depth studies performed during FY 2004:

1. Statin and fibrate use and risk of rhabdomyolysis

2. Drug exposure and new-onset thrombotic thrombocytopenic purpura

3. Adverse drug reaction signal detection using automated claims data, in collaboration with the HMO Network, Center for Education and Research on Therapeutics (CERTs).

Publications of study results from the Cooperative Agreements during FY 2004:

1. Manda B, Drinkard CR, Shatin D, Graham DJ. The risk of esophageal obstruction associated with an anti-allergy
    medication (Claritin-D® 24-Houroriginal formulation). Pharmacoepidemiol Drug Saf 2004; 13: 29-34.

2. Griffin MR, Stein M, Graham DJ, Daugherty JR, Arbogast PG Ray WA. High frequency of use of rofecoxib at greater than recommended doses: cause for concern. Pharmacoepidemiol Drug Saf 2004; 13: 339-43.

3. Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, et al. Incidence of hospitalized
     rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004; 292: 2585-90.


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IV. ODS Risk Management Program Activities

Under the Prescription Drug Users Fee Act (PDUFA III) that became effective on October 1, 2002, the Office of Drug Safety assumed an important new role in the review and evaluation of risk management plans and the need for post-approval observational studies. The goals letter for PDUFA III calls for ODS participation in pre-NDA meetings and pre-BLA meetings to discuss preliminary risk management plans and proposed observational studies, and in the period 2-3 years after approval to evaluate risk management plans after implementation. In FY 2004, ODS participated in the review of 23 Risk Management Plans (including 5 NMEs and one BLA) of which 11 were related to NDAs submitted after PDUFA III took effect. FDA also participated in 20 pre-NDA/BLA review meetings, 3 pre-approval safety conferences, 3 peri-approval RMP reviews and the evaluation/validation of 4 active RMPs.

ODS staff also played an important leadership role in the development of three draft guidances that were published on May 5, 2004. For the most recent publicly available information on CDER's views on RiskMAPs, please refer to the Draft Guidance for Industry Development and Use of Risk Minimization Action Plans and the Draft Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, which can be located electronically at http://www.fda.gov/cder/guidance/5766dft.pdf and http://www.fda.gov/OHRMS/DOCKETS/98fr/04d-0189-gdl0001-5767dft.doc .

In FY 2004, the following examples of drugs were identified as needing a new or modified risk management program:

  • Ezicom Tablets (abacavir sulfate and lamivudine) was approved on August 2, 2004 for the treatment of HIV- 1 infection. The primary toxicity of abacavir is a serious and sometimes fatal hypersensitivity reaction (HSR). Risk management measures for all abacavir-containing products include: a Boxed Warning, a Medication Guide, and a Warning Card for Ezicom™, and other education tools. Additionally, the manufacturer will evaluate the practical aspects of the Medication Guide and Warning Card in order to obtain information on the utility of these sources of information for patients.

  • Palladone  (extended-release hydromorphone) was approved on September 24, 2004 for the management of persistent, moderate to severe pain in opiate-tolerant patients requiring continuous, around-the-clock analgesia with a high potency opioid for an extended period of time. The risk posed by abuse or diversion of Palladone Capsules include instances of improper dose, indication or patient selection, exposure to opioid-naïve persons, exposure to pediatric patients, and the risk posed by opening, chewing, crushing, or dissolving Palladone Capsules. The Sponsor has initiated risk management measures which include a boxed warning in the package insert, a Medication Guide, Healthcare Professional and Patient/Caregiver Education, an enhanced surveillance program which includes initiation of specific interventions when monitoring reveals a safety issue and evaluation of the effectiveness of those interventions. The program also includes a limited marketing program as well as a plan to evaluate components of the Risk Minimization Action Plan (RiskMAP).


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V. Healthy People 2010

FDA/ODS/DSRCS led the Healthy People 2010 Focus Area, Medical Product Safety initiative. The goal of Healthy People 2010's Medical Product Safety focus area is to ensure the safe and effective use of medical products. Objectives for this goal are:

  • Improved monitoring of adverse events,

  • Improved linked, automated information systems,

  • More efficient provider oversight of medications taken by patients,

  • Patient receipt of useful information about prescriptions from pharmacies,

  • Patient receipt of oral counseling about medications from prescribers and dispensers, and

  • Increase in blood donations, and at the same time, ensuring that the blood supply remains safe.

In FY 04, FDA/ODS coordinated the Healthy People 2010 Medical Product Safety Progress Review, chaired by Acting Assistant Secretary for Health, Cristina Beato with participants from Agencies within the U.S. Department of Health and Human Services. Mark McClellan, then Commissioner of Food and Drugs, provided the context for FDA's actions to achieve the targets of the objectives for Medical Product Safety.


VI . International Activities

ODS staff are major contributors to many important activities that impact on international public health activities including the following:

  • International Conference on Harmonization (ICH)

The ICH launched a new topic during FY 2004 which involved ODS staff participation. M5 (Data Elements and Standards for Drug Dictionaries) was established to develop a new guideline that defines the Data Elements and Standards for Drug Dictionaries supporting all aspects of pre- and post-approval pharmacovigilance activities as well as communication of regulatory information.

  • E2B Implementation

The ICH E2B Implementation Working Group continued their work to establish and promote uniform standards for reporting of adverse events electronically in the three ICH regions by development of the Guidance for Industry, E2B(M): Data Elements for Transmission of Individual Case Safety Reports, Questions and Answers. In June 2004, the ICH E2B Expert Working Group was established to modify existing elements, add new elements and update the Guidance for Industry.

  • E2E Pharmacovigilance Planning

The ICH E2E Working Group completed and published the draft guidance on Pharmacovigilance Planning that specifies a framework for the organization and analysis of pre-clinical and clinical safety data obtained during trials in preparation and planning for post-marketing adverse event surveillance and observational studies.

  • MedDRA

ODS remains actively involved in the continued management and maintenance of the Medical Dictionary for Regulatory Activities (MedDRA). ODS staff are included on the MedDRA Management Board and have played a major role in developing and maintaining coding criteria for the entry of reports into the FDA AERS database using MedDRA. ODS staff have also been active members of the ICH working group that produces a continuously updated version of a helpful document entitled MedDRA Term Selection: Points to Consider, which is accessible at: http://www.fda.gov/medwatch/report/ptc_3.2_final.pdf. The working group initiated a new Points to Consider, which addresses the use of MedDRA for data retrieval and presentation.

  • CIOMS Working Groups

ODS is represented on various "Council for International Organizations of Medical Sciences" (CIOMS) working groups including CIOMS VI on surveillance and assessment of drug safety data from clinical trials and the standardized MedDRA Queries (SMQ) development group.


    World Health Organization (WHO)

ODS staff respond to requests for copies of case reports from AERS from medical reviewers at WHO-Uppsala Monitoring Centre (UMC). Such reports are redacted of personal identifiers and forwarded on to WHO-UMC for assessment in a larger dataset and possible discussion in the WHO publication "SIGNAL." A majority of the WHO-UMC's 70 participating national centers participate in a listserve (Vigimed) that provides a mechanism for the rapid exchange of pharmacovigilance information to regulatory agencies worldwide. ODS staff monitor this listserve and prepare responses to selected queries that appear in the Vigimed forum. In addition, ODS provides an AERS data extract on a quarterly basis to the WHO-UMC, which enters a large proportion of these reports into their adverse reactions database (Vigibase) to be made available to participating member countries for review and analysis.

  • Pharmacovigilance Videoconferences

Two separate series of regular video-conferences are held with counterpart regulators in other countries. One series consists of bi-monthly meetings with representatives from the Health Protection and Food Branch of Health Canada, the Therapeutic Goods Administration of Australia, and Medsafe of New Zealand. The second series of eight scheduled video-conferences during the year is with the European Medicines Agency (EMEA) and involves topics including specific safety concerns, medication errors, epidemiological investigations, international initiatives, and regulatory practices.

  • Consult Requests to and from Various Regulatory Authorities

ODS staff responds to international regulatory authorities seeking drug product safety information from the FDA. Confidentiality agreements are in place with several individual national regulatory authorities, which allow discussion of issues such as open investigations, deliberative processes, and pre-decisional issues, opinions and recommendations.


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VII. Drug Safety and Risk Management Advisory Committee

Several important advisory committee meetings were held this year including:

  • December 4, 2003 A one-day DSaRM meeting to discuss current screening methods to assess sound alike and look alike proprietary drug names, in order to reduce the incidence of medication errors resulting from look alike and sound alike names. This advisory committee meeting was in follow-up to the FDA, Institute for Safe Medication Practices, and the Pharmaceutical Research and Manufacturers of America public meeting on the same subject, held on June 26, 2003. See DMETS Section IX (other medication error initiatives) for additional information.

  • February 26 and 27, 2004 A two-day joint DSaRM and Dermatologic and Ophthalmic Drugs Meeting to discuss the effectives of the risk management plan for isotretinoin.

  • May 5, 2004: A one-day DSaRM meeting to discuss medication errors that were traced to the illegibility of the label on low density polyethylene vials. During this meeting, committee members also received an update on activities surrounding the alosetron risk management program. Per this discussion, the members stated that the alosetron RiskMAP appeared to manage risk and appropriate patient use; they agreed that the program should be continued with only minor changes. See DMETS Section IX (other medication error initiatives) for additional information.

  • July 12, 2004: A joint Dermatologic and DSaRM advisory committee meeting to discuss the new drug application (NDA) 21-701, proposed tradename Tazoral (oral tazarotene 1.5 mg and 4.5 mg) capsules proposed for the treatment of moderate to severe psoriasis, including risk management options to prevent fetal exposure.

  • May 10, 2004: Some DSaRM members were also asked to participate in an Anti Infective advisory committee meeting to debate the safe use of Gatifloxacin in children with otitis media who are otherwise healthy.

ODS staff also participated in the evaluation and planning of two Psychopharmacologic Drugs Advisory committee meetings where there was discussion of the potential link of suicidality in pediatric patients prescribed antidepressant drugs. In addition, ODS participated in the Gastrointestinal Drug Product advisory committee meeting to discuss the potential expansion in the approved indication for Zelnorm, a drug approved to treat irritable bowel syndrome.


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VIII. Division of Drug Risk Evaluation (DDRE)

DDRE Activities

Dr. Mark Avigan is the Director of DDRE. DDRE staff includes safety evaluators and epidemiologists to monitor drug safety by critically reviewing adverse experience reports that are submitted by manufacturers, health care professionals and consumers. The staff works closely with review division staff to develop the scientific basis for the assessment of safety signals and labeled warnings of serious adverse events, postmarketing safety studies, compliance and other regulatory activities. DDRE staff members also participate in advisory committee meeting preparation and presentation, risk management program evaluation, pre-approval safety conferences, and many pre-NDA submission related meetings mandated under PDUFA III. Internationally, DDRE continues to interact with regulatory counterparts in Australia, Canada, New Zealand and the European Union to share and discuss information about drug safety issues. The following are selected risk assessment and other consultative activities that were performed in 2004 fiscal year:


Safety Review of Drugs

A total of 609 consults were completed by DDRE staff. Summary data are presented graphically by review division and by requester as follows:

DDRE Consults

Long Description: Pie graph by review division- HFD-110 8%, HFD-120 11%, HFD-150 6%, HFD-510 11%, HFD-570 2%, HFD-580 9%, HFD-160 4%, HFD-170 8%, HFD-180 7%, HFD-520 2%, HFD-530 2%, HFD-590 5%, HFD-550 4%, HFD-560 2%, ODE VI 13%

DDRE Consults to OND:
Distribution by Review Division

DDRE Consults to OND

Long Description: Pie graph by review requester - 434 OND= 71%, 44 DDRE= 7%, 131 Other= 17%

DDRE Consults: Distribution by Source of Initiation

In FY 2004, there was a significant increase in the number of therapeutic products monitored by DDRE after marketing, as well as mandated initiatives with assigned responsibility to provide safety reviews and risk assessment requiring the expertise of safety evaluators and epidemiologists. These added responsibilities entailed two broad categories:

  • As a consequence of the CDER/CBER reorganization initiative implemented by FDA in 2003, the regulation of biologics products assigned to CBER's Therapeutic Biological Oncology and Internal Medicine products review divisions became a CDER responsibility. In conjunction with the creation of a new OND office to review BLA applications, DDRE plays an essential role in the evaluation of post-marketing safety and risk management issues surrounding these new product categories. In addition, DDRE participates in pre-approval safety conferences and monitor and evaluate post-marketing safety profiles of these products.

In 2002 Congress passed the Best Pharmaceuticals for Children Act (BPCA) that mandates review of AE reports one-year after pediatric exclusivity is granted. BPCA also refers the Pediatric Advisory Subcommittee for review of these AE reports. In 2004, Safety Evaluators conducted 17 drug product reviews and participated in four Pediatric Advisory Subcommittee meetings to discuss the safety of these drugs in children. Issues that were reviewed included pediatric and adolescent suicidality and neonatal withdrawal syndromes associated with the SSRIs, and overdose adverse events related to variations in fentanyl patch product quality.

Preapproval Safety Conferences

Preapproval safety conferences are held with OND prior to marketing approval of a new drug. During these meetings, specific safety concerns are identified that ODS will then monitor after product launch. Other topics may include the need for postmarketing safety studies, patient registries or risk management programs. One example of approved drugs and safety issues discussed at 3 pre-approval safety conferences in 2004 is summarized as follows:

  • Ventavis (iloprost, an inhaler) indicated for pulmonary hypertension. Dosing and labeling suggestions including Precautions, Warnings, and Patient Package Information to address nebulizer use have been incorporated into the labeling.

Safety Issues Leading to Boxed Warnings

There have been many safety issues that DDRE reviewers initiated or collaborated on with the review divisions that resulted in major labeling changes or initiation of risk management plans or RiskMAP. Labeling changes included addition of boxed warnings of serious risks in the labeling of many products that warranted FDA Public Health Advisory, manufacturers' Letters to Healthcare Professionals, or Medication Guides issued for communicating these risks. Examples are:

Antidepressants - Increased risk of suicidality in children and adolescents.

Antipsychotics - Increased risk of hyperglycemia and diabetes.

Crestor (rosuvastatin) - Serious muscle toxicity (myopathy and rhabdomyolysis).

Mifeprex (mifepristone) - Serious and sometimes fatal infections and bleeding following the use of mifeprex.

Effexor (venlafaxine) - Neonatal exposure to Effexor and other serotonin and norepinephrine reuptake inhibitors, late in the third trimester of pregnancy have developed withdrawal syndrome requiring prolonged hospitalization, respiratory support and tube feeding.

Levoxyl (levothyroxine) - Choking, gagging, tablets stuck in throat and dysphagia occurred when tablets were not taken with water.

Rituxan (rituximab) - Hepatitix B virus (HBV) reactivation with fulminant hepatitis, cases of hepatic failure and death in some patients with hematologic malignancies.

Serzone (nefazodone) - Risk of liver failure.

Zelnorm (tegaserod) - Serious consequences of diarrhea and reports of ischemic colitis.

Zometa (zoledronic acid) - Osteonecrosis of the jaw in cancer patients.

Other New and Ongoing DDRE initiatives

  • FDA-PhRMA-AASLD (American Association of Severe Liver Disease) Hepatotoxicity Steering Committee

  • DDRE has regularly attended and made presentation to these Steering Committee meetings to improve strategies for the identification and characterization of idiosyncratic drug-induced liver injury. The Steering Committee has members from the Acute Liver Failure Study Group and NIH's Drug Induced Liver Injury Network (DILIN). DDRE has contributed to an initiative by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in the planning of studies to identify and characterize drug induced liver injury. Cases of liver injuries will be identified in 5 clinical centers in the country covering approximately 12.8 million persons.

  • Case Definition Working Group

  • This group creates a set of evidence-based and consensus-generated guides to assist safety evaluators in the development of a case series for selected drug-induced adverse events, and to develop search strategies to assist with the retrieval of possible cases from AERS or other data sources. The document contains clinical information of the disease, such as etiology, differential diagnosis, clinical manifestations and treatment of the disease. Examples of recently completed working case definitions include: interstitial lung disease, myocardial infarction and pancreatitis.


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IX. Division of Medication Errors and Technical Support (DMETS)

This year brought some personnel changes to the leadership of the Division. The Director of DMETS, VIII. DMETS Activities Captain Jerry Phillips, retired from Government service in April 2004. The former Deputy Director, Commander Carol Holquist, RPh, was appointed permanent Division Director effective May 1, 2004. Former team leader, Captain Denise Toyer, Pharm D, was permanently appointed Deputy Director effective June 27, 2004.

Information Management Initiatives

The DMETS Information Management Team provides support to ODS by routinely performing the quarterly extracts from AERS, maintaining the ODS web pages, serving as the focal point for technical issues within the office and providing specialized searches in AERS and Drug Quality Reporting System (DQRS) when requested. Additionally, the team processes and provides microfiche images of adverse event reports, and reviews and approves computer generated FDA Form 3500A for manufacturers. FY 04 requests for these data are as follows:

Medwatch Review form changes (n=9)*

RxStudy data entry (n=76)

Microfilm requests (n=2601)

- 2552 from DDRE

- 49 from DMETS

AERS Data Extracts


Since 1997, DMETS has shared drug adverse event information with the World Health Organization (WHO). Additionally DMETS made data available to the public via a paid subscription through the U.S. Department of Commerce National Technical Information Service (NTIS); http://www.ntis.gov .

Veteran's Administration (VA) Project

DMETS developed an Access 2000 in support of an FDA/Veterans Affairs collaboration to examine Case Verification Information. Transactions were developed to capture the Case Verification Information from the different local VA hospital sites for the FDA/VA project on Avascular Necrosis (AVN) in HIV-afflicted patients receiving highly active anti-retroviral therapy.

AERS Change Control Requests (CCR)

DMETS performs acceptance testing to ensure completeness and validity on all change control requests proposed for AERS prior to release. For example, the latest production release implemented features such as the ability to conduct fuzzy searches on lot numbers, migrate country codes from older records, clean-up of country codes, add multiple active ingredients to CBER dictionary tables, obtain proper retrieval of ISRs when searching patient age ranges, and clean-up of products incorrectly coded as Combination Products.

DMETS performs acceptance testing on all CCRs that are included in AERS releases before the release goes into production in order to ensure completeness and validity. The latest release implemented features described in 10 CCRs dealing with the ability to conduct fuzzy searches on lot numbers, migrate country codes from older records, clean-up of country codes, add multiple active ingredients to CBER dictionary tables, obtain proper retrieval of ISRs when searching patient age ranges, and clean-up of products incorrectly coded as Combination Products.

Advanced Searches

Many offices and divisions request advanced searches in AERS, DQRS and COMIS databases from DMETS. FY04 requests are as follows:

AERS Searches (n=175)
DQRS Searches (n=110)

DMETS - 12

DMETS -100

DDRE - 110

DDRE - 4


OC- 4

OC - 4


FOI - 6


CBER - 3


OPaSS - 3


Congressional - 2




COMIS (n=65)








OC - 2


Medication Errors

The medication error component of DMETS is comprised of safety evaluators (e.g., clinical pharmacists and nurses) who monitor medication error safety issues by reviewing adverse experience reports that are submitted by manufacturers, health care professionals and consumers through the MedWatch and the Institute for Safe Medication Practices (ISMP)/United States Pharmacopeia (USP) Medication Error Reporting and Prevention (MERP) reporting program. A root cause analysis is conducted on each report to determine the contributing factors involved in any medication error event. The staff works closely with review division staff in the Office of New Drugs and Office of Generic Drugs to develop and implement recommendations for revision of error prone product labels, labeling, packaging and nomenclature.

Additionally, DMETS safety evaluators review proposed proprietary drug names for their orthographic (look-alike) and phonetic (sound-alike) similarity to currently marketed drug products. In conjunction with the review of the proprietary drug name, an analysis of the proposed container label, carton and insert labeling, and packaging is conducted in order to identify an error-prone aspects of these drug products that might contribute to user error.

Medication Error Postmarketing Reviews

The Division conducts routine post-marketing surveillance of medication errors submitted to FDA's MedWatch, ISMP and USP's medication error reporting program and from sponsors. Additionally, review divisions request safety reviews of labels, labeling, and packaging involving supplemental NDAs and ANDAs. DMETS completed 80 reviews involving medication error postmarketing issues or label and labeling postmarketing safety reviews for the following review divisions, offices, and centers:

DMETS Returns

Long Description: Pie graph - DMETS completed 80 reviews involving medication error postmarketing issues or label and labeling postmarketing safety reviews for the following review divisions, offices, and centers: HFD-007 1%, HFD-020 1%,HFD-110 6%, HFD-120 10%, HFD-150 4%, HFD-160 1%, HFD-170 10%, HFD-180 8%, HFD-510 19%, HFD-520 4%, HFD-530 3%, HFD-540 3%, HFD-550 1%, HFD-560 1%, HFD-570 4%, HFD-580 4%, HFD-590 3%, HFD-600 4%, HFD-600 4%, CBER 4%, CDRH 3%, CDER LNC 1%, HFM-500 5%, Compliance 3%

DMETS worked closely with review divisions to negotiate several label and labeling revisions designed to prevent medication errors or to manage known risks associated with the use of certain drug products. Factors that contribute to medication errors include the similar appearance of labels/labeling, packaging, drug name confusion, drug name modifier confusion, and lack of total drug content information on intravenous container labels.

Medication Error Pre-Marketing Reviews

In total, DMETS received and processed 383 premarketing consults in Fiscal Year 2004, 338 of which were proprietary name reviews. The remaining premarketing consults involved reviews of labels/labeling, PPIs and proprietary name rebuttals. The proprietary name reviews were requested by the following review divisions:

Medication Error Pre-Marketing Reviews

Long Description: Pie graph - The proprietary name reviews were requested by the following review divisions: HFD-110 3%, HFD-120 10%, HFD-150 6%, HFD-160 3%, HFD-170 7%, HFD-180 8%, HFD-520 2%, HFD-530 3%, HFD-640 5%, HFD-660 8%, HFD-560 5%, HFD-570 6%,HFD-580 11%, HFD-590 5%, HFD-600 19%, HFM-500 3%

In total, DMETS recommended against the approval of one hundred and twenty-three (36%) proprietary names reviewed. In conjunction with the proprietary name review, the Division provided numerous label, labeling, and packaging recommendations in an effort to minimize potential user error. Since the inception of the two medication error review teams, DMETS has had an average review time of 83 days for all NDAs, INDs, and ANDAs.

Other Medication Error Initiatives

In FY 2004, DMETS continued to develop enhancements for the Phonetic and Orthographic Computer Analysis (POCA) software. The POCA software was designed to help identify drug and/or biologic names and medical terminology that are phonetically and orthographically similar to one another; it is one tool that will be used in the proprietary name review process. The pilot system was released in June of 2003. Other enhancements include the development of an office-wide tracking system, Rx studies, and Spanish version of POCA. These enhancements remain in the development phase.

This fiscal year, DMETS held two DSaRM advisory committee meetings on medication error issues. The first meeting entitled "Screening Methods to Assess Sound-Alike and Look-Alike Proprietary Drug Names" was held on December 4, 2003, focused on the current methods used for screening proprietary drug names both internally and externally. The committee was asked to consider the advantages and disadvantages of taking a risk-based approach to testing proprietary drug names; identify critical design elements of each method to be included in good naming practices; describe circumstances when a field test should be required and to indicate whether any one method could stand alone; and to describe circumstances, if any, when it would be appropriate to approve a proprietary drug name contingent on a risk management program. The committee concluded that it would not be appropriate to approve a proprietary drug name contingent on a risk management program. It was also apparent that the current screening processes are subjective and a combination of all methods would be an optimal approach to screening proprietary names for potential look and sound-alike confusion.

The second advisory committee entitled "Medication Errors Relating to the Labeling and Packaging of Various Drug Products in Low Density Polyethylene Plastic Vials (LDPE) meeting was held on April 5, 2004. This meeting discussed the safe use of drug products packaged in low density polyethylene (LDPE) containers. The current techniques used to label the product (e.g. embossing and debossing) in order to preserve drug product purity, diminish the legibility of the product name and strength. The difficult-to-read labels and similar looking containers have contributed to numerous medication errors. The FDA was interested in hearing a discussion about whether there were other solutions or alternative packaging designs that could improve legibility in the labels, prevent the ingress of chemical contaminants, but in the process, avoid additional medication errors.


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X. Division of Surveillance, Research and Communication Support (DSRCS)

DSRCS provides critical safety data and risk communication resources to ODS and CDER. Dr. Toni Piazza-Hepp was the Acting Director of DSRCS from April through November 2003. Dr. Gerald Dal Pan became the permanent Division Director in December 2003. DSRCS maximizes the Center's ability to:

  • utilize and interpret safety and epidemiological data resources;

  • effectively communicate risk information to health care professionals, patients and international regulators;

  • evaluate risk management programs; and

  • enhance the Center's science base through research.

Important Division activities and initiatives are described below.

Drug Use Specialist and Epidemiologic Data Resources and Contracts Teams

The DSRCS Drug Use Specialist team and Epidemiologic Data Resources and Contracts team are involved with acquisition, analysis, and interpretation of data from several proprietary databases. These data are used to describe and analyze the manner in which drug products are used throughout the U.S.

Drug Utilization Data Resources

During FY2004, FDA had contracts with four outside companies to provide drug utilization data across various care settings:

  • IMS Health

  • National Sales Perspectives (sales data)


  • National Prescription Audit (dispensed prescriptions)


  • National Disease and Therapeutic Index (physician office visits)


  • Integrated Promotional Services (pharmaceutical promotion activities)

  • Premier

  • RxMarket Advisor (inpatient drug use)


  • Caremark (formerly known as AdvancePCS)

  • DimensionRX (longitudinal drug use)


  • CHCA

  • Pediatric Health Information System (inpatient drug use from freestanding children's hospitals)


In addition, DSRCS continues to search for other data sources to address unmet needs of the Agency. For example, in FY 2004, a data agreement was initiated for a pilot study with the Slone Epidemiology Unit of Boston University to examine their household survey data on the use of over-the-counter products, specifically in the analgesic class. Work also continues on a second pilot project with Premier to examine hospital outpatient clinic data collected by a subset of hospitals to determine its representativeness and utility for informing drug safety issues relating to the types of products used in that setting.

Drug Utilization Data Consultations

Drug Utilization Data Consultations



Figure 1. Total Drug Use Data Queries by Quarter for FY 2004 (n=587)


Count of Data Runs





The Drug Utilization and Epidemiology teams completed 189 drug use consult requests for drug use data, analysis and interpretation. In FY 2004, the division performed 587 data queries in response to these 189 consult requests (Figure 1).

One data query represents a search of one drug utilization data source; these are listed above under the four outside companies. Consults addressing the extent and/or patterns of drug use often require queries of more than one drug utilization data source. While the majority of drug use data queries were performed in response to consult requests from CDER, queries were performed for other organizations within and outside of FDA (Table 1).


Table 1:Drug Use Data Queries by Requestor



Center for Drugs (CDER)



Center for Biologics (CBER)



Center for Devices (CDRH)



Center for Foods (CFSAN)



Office of the Commissioner



Organizations outside FDA²



Grand Total



² Includes government agencies outside FDA and academic institutions working with FDA under data sharing agreeements.

 Pediatric Consultations

Pediatric Consultations


Figure 2. BPCA Drug Use Consults by Fiscal Year

Fiscal Year

BPCA Reports




The Office of Counterterrorism and Pediatric Drug Development (OCTAP) in CDER is a frequent user of drug utilization data, given their mandate through the Better Pharmaceuticals for Children Act (BPCA) to better understand the safety and use of drug products by children. In FY 2004, DSRCS drug utilization specialists and epidemiologists completed 17 consults (Figure 2) describing the use of specific products in the pediatric population across care settings. These consults are provided to advisory committee members and used extensively during public discussions to better understand the safety of use of drug products in children. DSRCS projects that 22 of these consults will be completed in FY 2005.

Third Party Agreements

A Third Party Agreement is a data-sharing provision in ODS' drug utilization contracts. These agreements allow FDA to collaborate with either a non-Federal party or Federal party on a drug safety issue of mutual interest, provided the study is initiated by FDA and approved by the Contractor. During FY2004, four collaborative efforts with outside organizations were undertaken. The first was a continuation of an agreement between FDA, IMS Health and the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) to examine the use of buprenorphine for the treatment of drug addiction. This information was included in a report to the U.S. Congress in December 2003. DSRCS also continued work on an existing agreement with IMS Health and Duke University in a collaborative effort to examine the use of dofetilide and other antiarrhythmics in the outpatient setting. An agreement was also initiated between Premier and Duke University to examine the use of antiarrhythmics in inpatient settings. Finally, an agreement was initiated between FDA, IMS Health and the National Center for Health Statistics to evaluate trends in the prescribing and utilization of fertility drugs at a national level. It is anticipated that these data will provide a necessary component in the evaluation of postmarketing safety issues associated with fertility products.

Two student projects were completed in FY2004 that involved analysis of Caremark data to examine drug use patterns relating to drug safety issues. In collaboration with a student from Johns Hopkins University, the prevalence of and risk factors for prescribing pemoline as first vs. second line therapy was examined. The frequency of dispensing of statins with potentially interacting drugs was explored in collaboration with a student from George Washington University. The results of both of these projects were presented at national scientific meetings.

Drug use Contracts

1. IMS Health

This contract provides ODS with access to the following databases: National Disease and Therapeutic Index? (NDTI), National Prescription Audit Plus? (NPA), and National Sales Perspective? Retail and Non-Retail. In addition, the Division of Drug Marketing, Advertising, and Communications subscribes to the Integrated Promotional Services, Message Insight (MI) and JARScan for analyzing information on detailing to physicians as well as accessing an electronic library of professional journal advertisements related to pharmaceuticals. DSRCS staff collaborated with the Office of Biostatistics to provide the annual DEA reports on Schedule II narcotic use for quota development, using data from the National Sales Perspective. The most frequent uses of IMS data 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 adverse drug events occur.

Analyses based on IMS Health data were used in support of nine Advisory Committee meetings in FY2004. Topics discussed were the following : effectiveness of the isotretinoin and alosetron risk management programs; the safety of antidepressants in children; prescription to nonprescription consideration of levonorgestrel; the regulation of anti-obesity drugs; and various safety issues involving the drugs tegaserod, droperidol, tazarotene and ximelagatran.

The data were also used in presentations at five scientific meetings and multiple submissions for publication. They also contributed to the base of evidence for several regulatory actions and meetings with other government agencies such as the Environmental Protection Agency, the Department of Defense and the Centers for Disease Control. Sales data were used by the Office of the Commissioner to compare the cost of pharmaceuticals in the U.S. with that in other countries.

2. Premier's Rx Market Advisor™

ODS renewed its contract with Premier to access information on the use of drugs by hospitalized patients in acute short-stay facilities. The database has been queried to examine the use of multiple classes of drug products, including intravenous antibiotics, anticoagulants, drugs used during surgical procedures, and agents used during diagnostic procedures. These data provide an important context for understanding adverse event reports related to the use of drug products in hospitals. For example, Premier data on the use of troponin kits provided important evidence for a regulatory action to withdraw specific products.

Work continued on a project in which ODS is evaluating Premier's methodology to make national projections based on its sample of hospitals by examining pharmaceutical purchasing patterns by Premier and other group purchasing organizations (GPOs). This work is expected to be completed in early 2005.

3. Caremark's Dimension Rx™

The Caremark (formerly known as AdvancePCS) database allows FDA to examine how long non-hospitalized patients stay on prescription medication therapy and to learn about drug combinations that may be prescribed to the same patients at the same time. Caremark data are complementary to IMS Health data and the Agency frequently uses both resources to increase understanding of outpatient drug use. Caremark data have been used primarily in this third year of the contract to address needs relating to age-specific use of drug products, particularly among children, concomitant use of multiple products and duration of therapy. Over 100 queries were run in Caremark in FY2004 and many analytical datasets were obtained for duration of therapy analyses on specific drugs and/or drug classes.

Innovative analyses are also underway to describe the detailed scenarios of concomitant drug use for combinations with potential risk, e.g., understanding the prescribers, timing and patient characteristics of concomitancy. This information is crucial to support ODS' assessment of the effectiveness of risk management programs designed to minimize potentially dangerous concomitant product use.

4. Child Health Corporation of America's (CHCA) Pediatric Health Information System (PHIS)

CHCA's PHIS database contains information on the use of medicines by children during their stay in 35 freestanding children's hospitals. This information continued to support the ongoing initiative at FDA to improve the safety and efficacy of pharmaceuticals for children. Access to the CHCA database was supported jointly by the Office of Counterterrorism and Pediatric Drug Development (OCTAP) and ODS, and it was a valuable resource for understanding the extent to which drugs are used to treat seriously ill children. The data were used extensively by OCTAP staff to support their responsibilities associated with BPCA. Epidemiologists from OCTAP and ODS continued to examine the feasibility of developing methods for using the PHIS database to make national projections of drug use in children's hospitals. That project will be completed in mid 2005.


Active Surveillance

FDA provides support for the National Electronic Injury Surveillance System (NEISS) to collect information on adverse events relating to medication use that present to emergency departments. This is accomplished through an inter-agency agreement with the Center for Disease Control and Prevention (CDC). During FY2004, it was determined that these reports should be coded using MedDRA terminology, to be consistent with coding of adverse event reports in the AERS database. DSRCS staff added this function to the current AERS data entry contract, so that NEISS cases are now coded using the same language, process and contractor as the AERS data. DSRCS epidemiologists have also continued to collaborate with CDC investigators to examine and triage the reports captured through this system.

Patient Information and Research Team

The DSRCS Patient Information and Research Team reviews consumer-oriented materials to ensure that product information is communicated clearly and effectively to patients, especially those with lower literacy. The team reviews Medication Guides, patient package inserts and other patient-oriented materials for content, format, and patient-friendly language. The team is also involved with research aimed at enhancing the understanding, usefulness, and acceptability of these and other forms of patient communication. DSRCS also provides social science expertise to CDER in designing research and in evaluating studies involving patient comprehension or behavioral issues. In FY 2004, the team reviewed and completed 17 Medication Guide, 83 patient package inserts, 22 Consumer Information Sheets, and 9 label comprehension study or other social science-related consults.

The team also contributed greatly to the Department's Healthy People 2010 initiative related to the Chapter 17 Medical Product Safety objectives (see section IV on Healthy People 2010). One of these objectives addresses receipt of useful written information about prescriptions from pharmacies. The team is actively working with the National Council on Patient Information and Education (NCPIE) who have convened interested stakeholders in an effort to improve consumer medication information (CMI) and meet 2006 goals for usefulness as described in Public Law 104-180.

MedWatch Program

The Safety Information and Adverse Event Reporting Program (MedWatch) is led by Dr. Norman Marks. MedWatch reports can be submitted online at www.fda.gov/medwatch, by submitting the MedWatch 3500 form by mail or fax, or by telephone. The MedWatch 3500 and 3500A forms were made available for both voluntary and mandatory reporters in a new fillable PDF format, which replaced more outdated technology. The MedWatch homepage was regularly in the top 20 most frequently visited FDA sites in FY04.

An important focus of the MedWatch program is to provide important and timely clinical information on safety issues involving medical products, including prescription and over-the-counter drugs, biologics, medical and radiation-emitting devices, and special nutritional products (e.g., medical foods, dietary supplements and infant formulas). Medical product safety alerts, recalls, withdrawals, and important labeling changes that may affect the health of all Americans are disseminated to the medical community and the general public via the MedWatch web site www.fda.gov/medwatch and the MedWatch E-list. The E-list consists of over 46,000 individual and approximately 170 professional organization subscribers.

  1. MedWatch's Central Triage Unit (CTU):

DSRCS oversees the MedWatch Central Triage Unit that supports the identification and appropriate routing of direct reports on all medical products received through MedWatch. In FY04, CTU processed 25,553 MedWatch reports for medical products regulated by four centers of the FDA. As shown in the figures below, 73% of the adverse event reports were triaged to CDER (72%) and CBER (1%) and entered into AERS. Transfer of therapeutic products from CBER to CDER occurred during the first quarter of FY04 which explains the increased proportion of direct reports routed to CDER compared to FY03 (69% and 4% to CDER and CBER, respectively). The Drug Quality Reporting System (DQRS) is located in CDER's Office of Compliance and evaluates product-oriented problem reports; these reports may or may not contain patient adverse events. Forty (40) percent of the reports are being submitted to MedWatch via the Internet. Pharmacists continue to be the leading source of direct-to-FDA reports, based on current data.

Direct Reports By Center

Long Description: Pie graph - Direct Reporting by Center - CBER 1%, CDER-DQRS 11%, CVM < 1%, CFSAN 3%, CDRH 13%, CDER 72%, (N=25553)


Method of Reporting

Long Description: Pie graph - Method of Reporting FY04 - Phone 1%, Fax 31%, Internet 40%, Mail 28%

Source of Reporting

Long Description: Pie graph - Source of Reporting FY04 - Unknown 23%, Physician 12%, Pharmacist 37%, Nurse 11%, Dentist <1%, Consumer 17%


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XI. Other ODS Initiatives


a. Waivers of Postmarketing Safety Reporting Requirements

ODS has the authority to respond to requests for waivers of postmarketing safety reporting requirements (see MaPP 6004.1, Granting Waivers Under 21 CFR 314.90 for Postmarketing Safety Reporting Requirements Under 21 CFR 314.80 at http://www.fda.gov/cder/mapp/6004-1.pdf). ODS responds to all types of requests for waivers of postmarketing safety reporting requirements, with the majority covering these two types of requests:

CDER 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. As of September 2004, over 75 firms had been granted this type of waiver for over 3350 applications (NDAs, ANDAs, and BLAs).

ODS also responds to requests for waivers 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 decrease the frequency of submission of a report, ODS consults with the appropriate review division before acting on the waiver request. As of September 2004, more than 25 firms had been granted PSUR waivers (for PSUR format with or without frequency changes) for over 540 applications (NDAs, ANDAs, and BLAs).

b. Data-Mining as a Tool for Post-Marketing Safety Signal Detection

ODS/DMETS with the Office of Information Technology is performing the system Certification and Accreditation for the Office of Pharmacoepidemiology and Statistical Science (OPaSS) AERS data mining tool WebVDME. OPASS has a CRADA partnership with Lincoln Technologies, Inc. in the development of data mining software. DDRE Safety Evaluators and Epidemiologists are working with Lincoln Technologies to develop a desktop data-mining application intended for FDA use under a CRADA. This application uses the AERS database to explore possible utilities to enhance postmarketing pharmacovigilance in safety signal detection.


c. Drug Safety Seminars

In an effort to promote an atmosphere of collegiality with risk management experts from other federal agencies and outside of government, ODS, in cooperation with CDER's Office of Training and Communication's Visiting Professor Lecture Series, presents the drug safety seminar series. Examples of FY 2004 seminars include:

"Randomized Epidemiology to Improve the Evidence Base for Drug Safety", Professor T.M. MacDonald, University of Dundee, Scotland

"Introducing RADAR: A New Approach to Identifying Medication Adverse Effects", Charles Bennett, MD, Northwestern University

"Using Stated Preference Methods to Evaluate Risks and Benefits in Real Life Situations", Elizabeth Andrews, PhD, Reed Andrews, PhD, RTI Solutions

 XII. Conclusion

The Office of Drug Safety plays an important role in protecting the safety of the American people by:

  • monitoring adverse experiences associated with marketed drug products

  • working closely with the Office of New Drugs in developing and evaluating risk management programs designed to encourage the safe use of drug products

  • minimizing the incidence of medication errors through the review of labeling, packaging and drug names

  • answering important drug safety questions through the use of clinical databases, and

  • tracking how drugs are used by patients and prescribed by physicians.

We also seek to ensure that risk information is effectively communicated to patients, particularly those with low levels of literacy. We have an external outreach program that includes: working with the international community to help maintain consistent global standards relating to drug safety and pharmacovigilance; managing public meetings on important drug safety and risk management issues; reaching out to the medical community and the general public through our MedWatch program; and working with the Drug Safety and Risk Management Advisory Committee to tackle scientifically complex issues associated with drug safety. In ODS, we believe the work we do to ensure the safe use of marketed drugs is critical. We thoughtfully consider how we can improve our data resources as well as our collaborative efforts with our colleagues in the Office of New Drugs, others within CDER, FDA and DHHS, and other government agencies in order to improve communication and result in more efficient teamwork. We strive to increase transparency and efficiency within the Office and partner effectively with external constituencies. FY 2004 was a year of change and opportunity for the Office of Drug Safety. Since our beginning as the Office of Drug Safety in January 2002, ODS staff has gained a wealth of experience with a new structure, new management, and new responsibilities. We hope this Annual Report has given you some insight into our challenges and accomplishments. We are looking forward to maturing as an Office, clarifying our roles and responsibilities and improving the value of our work products.