Part 2: Performance Plan and Report--Human Drugs

U.S. Food and Drug Administration
Performance Plan
2002

2.2 HUMAN DRUGS

2.2.1 Program Description, Context, and Summary of Performance

Total Program Resources:

	FY 02 Budget Estimate	FY 01 Current Estimate	FY 00 Actual	FY 99 Actual
Total ($000)	347,829	317,066	311,234	278,299

The Human Drugs Program assures that all drug products used for the prevention, diagnosis, and treatment of disease are safe and effective. Premarket review is accomplished through prompt and efficient review of clinical research and by taking appropriate and timely action to review new drugs and their generic equivalents, over-the-counter (OTC) drugs and labeling, and through quality assurance/quality control. Once drugs have been approved, they may be marketed and distributed for use. At that time, postmarket surveillance assures the quality of drugs on the market and the minimization of adverse events associated with the use of prescription and OTC medications. To meet these goals, FDA frequently consults with experts in science, medicine and public health and coordinates with consumers, product users and industry.

The challenge of assuring drug quality, safety and effectiveness is an ongoing one. While continual growth in the technological complexity of new products promises great health benefits for a growing number of U.S. consumers, FDA must be vigilant in safeguarding their interests. This challenge frames the Agency's strategic goals:

Reduce human suffering and enhance public health by providing quicker access to important, lifesaving drugs and assuring availability of safe and effective drugs.
Prevent unnecessary injury and death to the American public caused by adverse drug reactions, injuries, medication errors and product problems.

This performance plan illustrates the Agency's ongoing efforts and continuing progress in achieving it's mission, which will result in maximizing the pharmaceutical industry's ability to provide the safe and effective medications that will continue to improve the public health. Premarket performance goals include those in the areas of: testing investigational new drugs (INDs), evaluating new drug applications (NDAs); reviewing and taking action on efficacy supplements, manufacturing supplements and generic drug application review; reviewing and labeling for OTC drugs; and reviewing requests from industry for manufacturers who conduct pediatric studies. Postmarket surveillance performance goals include: assessing risk to identify adverse events; and expanding scientific capabilities to respond and contribute to major breakthroughs in pharmaceutical research and technology via research, continuing professional development and training, and continued collaborations with stakeholders.

FY 2000 Performance Highlights

Drug Approvals

New Drugs-- FDA continues to exceed the rigorous performance goals agreed to for each consecutive year under the PDUFA. FocalSeal-L Surgical Sealant was approved as a surgical sealant for use in lungs to seal air leaks following removal of cancerous lung tumors. Betaxon was approved for lowering intraocular pressure in patients with chronic open-angle glaucoma or ocular hypertension. Also approved is the drug Kaletra, which is one of a class of AIDS drugs called protease inhibitors for use by adults and by HIV infected infants and children who are older than six months.
Generic Drug Review--In 2000, FDA approved Taxol, a drug that is used for the firstline treatment of advanced carcinoma of the ovary and non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy. Taxol is indicated in combination with cisplatin.

Postmarket Surveillance--In calendar year 2000, 261,000 individual safety reports (ISRs) were received for entry into the Adverse Event Reporting System (AERS). FDA uses these reports as part of the postmarket surveillance to identify any unexpected, rare or serious events.

Outreach-- FDA is committed to providing the public quicker access to drug information. It has developed several new web sites, such as the Consumer Drug Information web site and the FDA Oncology Tools web site. The Agency has also completed a campaign designed to increase consumer awareness about the problems related to online drug purchases by developing a brochure and newspaper article describing the potential dangers of buying medical products on the Internet. In addition, the Agency has completed the first phase of a new Over-the-Counter Medicine Label Campaign by placing 245 newspaper articles in 45 states reaching more than 17 million people and by reaching an additional 137 million with radio PSA.

Leveraging/Communication--The Agency continues to conduct expeditious drug reviews and provide information by collaborating and cooperating with industry, health care organizations and academia. A web site called ACTIS (www.actis.org) was developed as a resource to provide current information on federally and privately funded clinical trials for AIDS patients. This service is provided collaboratively by the National Institute of Allergy and Infectious Diseases, Food and Drug Administration, National Library of Medicine and the Center for Disease Control.

Reinvention--The Agency is dedicated to developing new standards and guidances that will establish explicit training requirements for staff reviewers such as the Good Review Practice (GRP) guidance. FDA is also in the process of creating a clinical review documentto assess whether an application meets established standards for the clinical portion of a submission.

Through the successful pursuit of these goals, FDA is providing health protection and promotion for the American public, from the inception of new drug concepts, through research, product development, manufacturing, marketing and consumption. The Agency's approach to achieving the strategic goals outlined above, as well as the key performance goals that will move the Program in these directions, are outlined in the next sections.

2.2.2 Strategic Goals

Strategic Goal 1:

Reduce human suffering and enhance public health by providing quicker access to important, lifesaving drugs, and assuring availability of safe and effective drugs.

A. Strategic Goal Explanation

Improving the efficiency and quality of the application review process will assure that safe and effective drugs are available to the American people. Third party outsourcing of application parts, stronger quality assurance and quality control monitoring, more timely inspections, and greater utilization of external expertise such as industry, academia and professional associations will result in significant payoffs. Payoffs to the American people include reduced drug development time, increased and quicker access to new drug products, and an increased number of therapeutic options for health professionals to choose from. Improving product review will also advance the safe and appropriate use of medicines in children. FDA is authorized to grant six months of marketing exclusivity to manufacturers who conduct and file pediatric studies in new or approved drugs. Since 1998 FDA has reviewed over 210 Proposed Pediatric Study Requests (PPSR), issued over 185 Written Requests (WR) asking for over 407 studies to be conducted in the pediatric population and has granted exclusivity to 27 products. Fourteen of the 27 products granted exclusivity now have approved labeling that incorporates information from the pediatric studies. Important information regarding dose and adverse events in pediatric patients has been obtained. Developing a hospital-based pediatric drug use and adverse event reporting system, hiring additional pediatric reviewers, and increased interaction and leveraging with the scientific and academic communities and researchers will facilitate the advancement of pediatric medicine. Goals 12026 and 12001 will support efforts to achieve this strategic goal.

B. Summary of Performance Goals

Performance Goals	Targets	Actual Performance	Reference
1. Review and act on 90% of standard original NDA submissions within 10 months of receipt and 90% of priority original NDA submissions within 6 months. (12001)	Standard NDAs within 10 months: FY 02: 90% FY 01: 70% FY 00: 50% FY 99: 30%	FY 02: FY 01: 01/03 FY 00: 01/02 FY 99: 66%	1999 Update
	Standard NDAs within 12 months: FY 02: NA FY 01: 90% FY 00: 90% FY 99: 90%	FY 02: FY 01: 01/03 FY 00: 01/02 FY 99: 100% FY 98: 100%
	Priority NDAs within 6 months: FY 02: 90% FY 01: 90% FY 00: 90% FY 99: 90%	FY 02: FY 01: 7/02 FY 00 7/01 FY 99: 100% FY 98: 100%
2. Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule. (12026)	FY 02: Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule.	FY 02:
	FY 01: Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule.	FY 01: (1st 4 months) Exclusivity: - 19 PPSR's reviewed - 28 WR's issued - 14 Amended WRs issued - 4 Exclusivity determinations - 2 Exclusivities granted - 3 Labels changed Ped Rule: - PediatricAssessments Deferred = 3
	FY 00: Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule.	FY 00: Exclusivity: - 39 PPSR's reviewed - 62 WR's issued - 59 Amended WR's issued - 19 Exclusivity determinations - 16 Exclusivities granted - 7 Labels changed Ped Rule: - Pediatric Assessments Deferred = 76 - Pediatric Assessments Waived = 91
	FY 99: Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule.	FY 99: Exclusivity: - 155 PPSR's reviewed - 95 WR's issued - 15 Amended WR's issued - 9 Exclusivity determinations - 9 Exclusivities granted - 4 Labels changed
3. Review and act upon fileable original generic drug applications within 6 months after submission date. (12003)	FY 02: 55%	FY 02: Final data avail. 4/03	1999 Update
	FY 01: 50%	FY 01:Final data avail. 4/02
	FY 00: 45%	FY 00: 42% as of 2/01. Expect final data 4/01
	FY 99: 60%	FY 99: 28%
4. Review and act on 90% of resubmitted NDA applications within 6 months of receipt. (12002)	FY 02: NA	FY 02: NA	1999 Update
	FY 01: NA	FY 01: NA
	FY 00: NA	FY 00: NA
	FY 99: 90%	FY 99: 100%
5. Review and act on 90% of standard efficacy supplements within 12 months (30% within 10 months of receipt) and priority efficacy supplements filed within 6 months of receipt. (12004)	FY 02: NA	FY 02: NA	1999 Update
	FY 01: NA	FY 01: NA
	FY 00: NA	FY 00: NA
	FY 99: 90% within 12 mos 30% within 10 mos priority within 6 mos	FY 99: 87% (priority efficacy supplements) 99% (standard efficacy supplements)
6. Review and act upon 90% of manufacturing supplements within 6 months and act on 30% of manufacturing supplements requiring prior approval within 4 months. (12005)	FY 02: NA	FY 02: NA	1999 Update
	FY 01: NA	FY 01: NA
	FY 00: NA	FY 00: NA
	FY 99: 90% within 6 mos. 30% within 4 mos.	FY 99: 99% within 6 mos. 73% of supplements requiring prior approval within 4 mos.
7. Protect human research subjects participation in drug studies and assess the quality of data from these studies by conducting approximately 780 onsite inspections and data audits annually. (12032)	FY 02: 780	FY 02: 1/31/03
	FY 01: NA	FY 01:
	FY 00: NA	FY 00: 697 inspections completed FY 99: 683 inspections completed
	FY 99: NA Note: The number of inspections completed each year is dependent on the number of applications received, has averaged approximately 100-120 per year.
TOTAL FUNDING: ($000)	FY02: 260,872
	FY01: 254,593
	FY00: 233,425
	FY99: 208,724

C. Goal-by-Goal Presentation of Performance

1. Review and act on 90% of standard original NDA submissions within 10 months of receipt and 90% of priority original NDA submissions within 6 months. (12001)

Context of Goal: A major objective of the human drugs program is to reduce the time required for FDA's review of all drugs. Emphasis is put on the review of new drugs that are intended to treat serious or life-threatening diseases, such as AIDS, AIDS-related diseases, and cancer; and those products that demonstrate the potential to address unmet medical needs.
Data Sources and Issues: Center-wide Oracle Management Information System (COMIS); New Drug Evaluation/Management Information System (NDE/MIS): FDA has a quality control process in place to ensure the reliability of the performance data in COMIS. This process provides information on how document room contractors and the Records Management Team quality control this data. See 2.2.3 Verification and Validation Section for a description of this process.
Performance: Children and adults with HIV-1 infection, people with cancer, meningitis and antibiotic-resistant infections all benefited from timely reviews of significant new drugs approved in FY 99. For open cohorts during FY 99, FDA took 185 actions on NDAs, 77 of which were approvals. Final on-time performance information for the FY 2000 submission cohort is not yet available.

Fiscal Year 1999 Cohort as of 12/31/00

Submission Type	Number of Submissions Filed with CDER	Goal (months)	Number of Reviews "On Time"	Percent of Reviews "On Time"
Priority New Drug Application	31	90% in 6 months	31	100%
Standard New Drug Application	95	30% in 10 months	63	66%
Standard New Drug Application	95	90% in 12 months	95	100%

2. Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule; conduct research initiatives and activities to define the quality of the clinical studies, usefulness of data generated from these trials, changes in drug product labeling and resultant public health benefits for children. (12026)

Context of Goal: FDAMA enables FDA to Issue Written Requests (1) for pediatric studies prior to approval of an NDA if FDA has determined that information related to the use of the drug in the pediatric population may produce health benefits and (2) to holders of approved applications for pediatric studies if it has determined that information related to the use of the drug in the pediatric population may produce health benefits. FDAMA also requires FDA to develop, prioritize, and publish a list of approved drugs for which additional pediatric information may produce health benefits in the pediatric populations and update it annually.
FDA issued a regulation (effective April 1, 1999) requiring pediatric studies of certain new and marketed drug and biological products. Most drugs and biologics have not been adequately tested in the pediatric subpopulation. As a result, product labeling frequently fails to provide directions for safe and effective use in pediatric patients. This rule partially addresses the lack of pediatric-use information by requiring that manufacturers of certain products provide sufficient data and information to support directions for pediatric-use for the claimed indications.
Data Sources and Issues: Pediatric Exclusivity Database and the Pediatric Page database. (Database enhancements required to meet goal):
The Pediatric Exclusivity Database tracks all data regarding pediatric exclusivity as mandated by FDAMA. Specifically, this database tracks the number of Written Requests issued and the number of products for which pediatric studies have been submitted and for which exclusivity determinations have been made.
Performance: FDA took several actions to implement portions of FDAMA that make it more likely that children will receive improved treatment. The Agency issued guidance to assist drug companies planning to conduct pharmacokinetic studies in pediatric populations so that drug products can be labeled for pediatric use. Since 1998 FDA has reviewed over 210 Proposed Pediatric Study Requests (PPSR), issued over 185 Written Requests (WR) asking for over 407 studies to be conducted in the pediatric population and has granted exclusivity to 27 products. Fourteen of the 27 products granted exclusivity now have approved labeling that incorporates information from the pediatric studies. Important information regarding dose and adverse events in pediatric patients has been obtained.
The fourth Pediatric Advisory Subcommittee is being planned for April 2001 to discuss issues in pediatric drug development. The Report to Congress mandated by FDAMA was prepared during 2000 and sent to Congress on January 9, 2001. FDA developed an interactive pediatric web page to provide detailed information to the public regarding FDA's pediatric initiatives.

In October 2000, the Children's Health Act was signed into law. As required, the Agency has drafted an interim final rule incorporating Subpart D of the DHHS regulations into FDA regulations. The document is currently with OMB for clearance.

FDA completed 2 pilot studies to evaluate inpatient databases to assist in our assessment of needed pediatric trials. Using information garnered from these pilots FDA has defined the criteria necessary for development of a pediatric inpatient database.

3. Review and act upon 55% of fileable original generic drug applications within 6 months after submission date. (12003)

Context of Goal: An important part of FDA's mission is to assure that safe and effective generic drugs are available to the American people. FDA has approved several thousand generic drugs that have been used successfully by millions of patients. The use of these products has resulted in substantial savings to consumers and the Federal government (Medicare and Medicaid).
Data Sources and Issues: COMIS; NDE/MIS: FDA has a quality control process in place to ensure the reliability of the performance data in COMIS. This process provides information on how document room contractors and the Records Management Team quality control this data. See 2.2.3 Verification and Validation Section for a description of this process.
Performance: Preliminary data indicate CDER may meet its goal for FY 2000. In the six months from November 1999 to April 2000, CDER's Office of Generic Drugs (OGD) acted on 47 percent of original applications. This is an increase from the 31 percent acted on during the previous six months.
During FY 2000, OGD approved 232 ANDAs. This is an increase over the 198 approved last fiscal year. Of these, several represent the first time a generic has been approved for a product.

Significant strides were made toward a paperless review environment. With $1.5 million in funding earmarked for satisfying information technology needs, CDER purchased upgraded hardware and software, and contractual support for the review of electronic submissions. CDER received 101 ANDAs containing at least a portion of the data in electronic format (30 percent of all submissions). This is an increase over the 88 ANDAs with some portion in electronic format submitted last fiscal year. The increase reflects the commitment of OGD to support the Agency's efforts to increase overall efficiency of the review process.

FDA did not meet its expected performance goal (to act upon 60% of original generic drug applications within 6 months) in FY 99. In FY 99, FDA acted on 28% of fileable original applications within 6 months. Beginning in January 1997, FDA implemented a procedure to reduce approval times by allowing reviewers to utilize a facsimile amendment. Facsimile amendments are requests from reviewers to applicants for clarification/resolution of minor deficiencies (e.g., resubmission of illegible pages or typographical errors). These requests did not stop the review of ANDAs and the subsequent amendments/responses were the reviewers' highest priority. This procedure resulted in review times exceeding 6 months, but shortened overall approval times. For example, although FDA did not act on 60% of the original ANDAs in 6 months, the facsimile amendment procedure allowed for approval of 75% of the ANDAs in about 8 months. In June 2000, a slight modification to the facsimile amendment procedure was made that would stop/start the review clock upon issuance of a fax deficiency/amendment. This modification to the procedure will better enable FDA to act upon its target percentage of ANDAs within 6 months.

The inability of FDA to meet the 6-month goal is also a function of the existing backlog of chemistry and microbiology reviews. To address the chemistry backlog, FDA restructured its chemistry review process by adding one additional team (and team leader) to each review division. Additional project managers were hired and assigned to the new chemistry teams. Also, all chemistry vacancies are in the process of being filled. To address the microbiology backlog, FDA assigned a project manager to the microbiology team to monitor the work progress and assign priorities. FDA also named a microbiology team leader and hired two additional reviewers and are in the process of hiring a third. FDA believes that these initiatives will reduce the chemistry and microbiology backlog allowing reviewers to get to the applications sooner and lessen the effect of the facsimile amendments on the 6-month review goal. With these changes in place, the initial performance is expected to decrease due to training of new team leaders and reviewers. As the new personnel become more experienced, the review process is expected to run more efficiently and the backlog is expected to decrease (given a constant number of receipts). FDA expects performance to be 45% by the end of FY 00, 50% by completion of FY 01 and 55% by the end of FY 02.

MEDIAN APPROVAL TIME
Abbreviated Applications

FISCAL YEAR	MONTHS
1997	19.6
1998	18.7
1999	17.3

4. Review and act on 90% of complete NDA applications resubmitted following receipt of a non-approval letter, within 6 months after resubmission date. (12002)

Context of Goal: Resubmissions are responses provided by a pharmaceutical company to questions or deficiencies raised by FDA in an approvable or not approvable letter on an original application.
Data Sources and Issues: COMIS; NDE/MIS: FDA has a quality control process in place to ensure the reliability of the performance data in COMIS. This process provides information on how document room contractors and the Records Management Team quality control this data. See 2.2.3 Verification and Validation Section for a description of this process.
Performance: FDA exceeded this goal in FY99. For the FY 99 submission cohort, 64 resubmissions were submitted for review. This FY 99 goal is included for reporting purposes. For purposes of the Performance Plan, this goal has been dropped for FY 00, FY 01 and FY 02.

Fiscal Year 1999 Cohort as of 5/31/00

Submission Type	Number of Submissions Filed with CDER	Goal (months)	Number of Reviews "On Time"	Percent of Reviews "On Time"
Class 1 Resubmission	17	50% in 2 months	17	100%
Class 1 Resubmission	17	90% in 4 months	17	100%
Class 2 Resubmission	47	90% in 6 months	47	100%

5. Review and act upon 90% of standard efficacy supplements within 12 months (30% within 10 months of receipt) and priority efficacy supplements filed within 6 months of receipt. (12004)

Context of Goal: Efficacy supplements are requests from drug companies to add a new use or a new group of patients to be treated with an already approved drug. They often represent important new treatment options.
Data sources and Issues: COMIS; NDE/MIS: FDA has a quality control process in place to ensure the reliability of the performance data in COMIS. This process provides information on how document room contractors and the Records Management Team quality control this data. See 2.2.3 Verification and Validation Section for a description of this process.
Performance: Adults with HIV infection, people with cancer, diabetes, arthritis and other conditions all benefited from timely reviews of efficacy supplements approved in FY 99. The Standard Efficacy Supplement portion of this goal was met for FY 99. However, of the 15 priority efficacy supplements 13 were reviewed, resulting in only 87% of the 90% goal was met. For the FY 99 submission cohort, 138 efficacy supplements were filed. This FY 99 goal is included for reporting purposes. For purposes of the Performance Plan, this goal has been dropped for FY 00, FY 01 and FY 02.

Fiscal Year 1999 Cohort as of 8/31/00

Submission Type	Number of Submissions Filed with CDER	Goal (months)	Number of Reviews "On Time"	Percent of Reviews "On Time"
Priority Efficacy Supplements	15	90% in 6 months	13	87%
Priority Efficacy Supplements	15	30% in10 months	95	77%
Standard Efficacy Supplements	122	90% in 12 months	121	99%

6. Review and act upon 90% of manufacturing supplements within 6 months and act on 30% of manufacturing supplements requiring prior approval within four months. (12005)

Context of Goal: Manufacturers must notify the Agency in advance of certain manufacturing changes in the form of "manufacturing supplements" to new or generic drug applications. Review of these applications in a timely manner is necessary to assure that any manufacturing changes do not adversely effect strength, identity, quality, purity or potency of the drug product.
Data Sources and Issues: COMIS; NDE/MIS: FDA has a quality control process in place to ensure the reliability of the performance data in COMIS. This process provides information on how document room contractors and the Records Management Team quality control this data. See 2.2.3 Verification and Validation Section for a description of this process.
Performance: For the FY 99 submission cohort, 1,459 manufacturing supplements were filed. This FY 99 goal is included for reporting purposes. The goal does not continue into FY 00, FY 01 and FY 02.

Fiscal Year 1999 Cohort as of 8/31/00

Submission Type	Number of Submissions Filed with CDER	Goal (months)	Number of Reviews "On Time"	Percent of Reviews "On Time"
Manufacturing Supplements	1,459	30% in 4 months	662	73%
Manufacturing Supplements	1,459	90% in 6 months	1,438	99%

7. Protect human research subjects' participation in drug studies and assess the quality of data from these studies and assess the quality of data from these studies by conducting approximately 780 on-site inspections and data audits annually. (12032)

Context of Goal: This is a new goal for FY 02. FDA approves drug products only after the manufacturers/sponsors have provided adequate and reliable information on which FDA can base its decision. Manufacturers/sponsors generate, collect, and report data from both clinical (human subjects) and non-clinical (animal and other) studies in support of their applications. Under FDA's Bioresearch Monitoring (BIMO) Program, FDA inspects sponsors, contract research organizations, monitors, and institutional review boards to ensure that the rights and welfare of human subjects who participate in research are protected, and to verify that data collected by the regulated industry are accurate and reliable. FDA is the only government agency with an active program of on-site inspections, and the necessary expertise, to evaluate the conduct of these studies. The Prescription Drug User Fee act mandates specific deadlines for review of manufacturers'/sponsors' submissions.
Data Source and Issues: COMIS, Field Accomplishments and Compliance Tracking System (FACTS), and ACCESS Databases will be used to track assignments and reviews, and establish baseline-monitoring information.
Performance: DSI completed 627 BIMO inspections in FY 98, 683 in FY 99, and 697 in FY 2000. The number of inspections completed each year is dependent on the number of applications received.

Strategic Goal 2:

Prevent unnecessary injury and death to the American public caused by adverse drug reactions, injuries, medication errors and product problems.

A. Strategic Goal Explanation

FDA cannot learn everything about the safety of a drug before it is approved. FDA must be vigilant to protect Americans from injuries and deaths caused by unsafe, illegal, fraudulent, substandard or improperly used products. FDA assures safe products are marketed by continued surveillance for adverse events and use problems, increased inspectional coverage of both foreign and domestic producers, increased enforcement efforts to prevent fraudulent activities involved with the sale of approved and unapproved prescription drugs over the Internet, and increased educational programs that address the interests of medical professionals, patients and consumers.

A comprehensive safety system for medical products is a critical priority. FDA's current systems are not intended to, and cannot, uncover the incidence of adverse events, their preventability, or the overall health and economic impact on Americans. A DHHS partnership to promote patient safety and prevent medical errors is being developed, with FDA taking the lead on a national critical event reporting system. This program is designed for broader monitoring and prevention of adverse events involving both new and already marketed products and would substantially reduce preventable injuries and death from the use of FDA-regulated products.

FDA uses a number of postmarketing risk assessment approaches to ensure the continued safe use of drug products. The Agency's current adverse event database for drugs and therapeutic biological products, the AERS, contains approximately 2 million adverse event reports from health care professionals (see goal 12007). In calendar year 1999, over 275,000 individual safety reports (ISRs) were received into entry into the AERS of which over 30% represented serious and unexpected events. As of July 20, 2000, 137,000 individual safety reports (ISRs) have been received for entry into the AERS for this calendar year. The first quarter data for calendar year 2000 projects over 300,000 reports for the full year. FDA evaluates spontaneous reporting data from the AERS to identify any serious, rare, or unexpected adverse events or an increased incidence of events. Based on its evaluation, FDA may decide to disseminate risk information, such as Dear Healthcare Professional letters, and may initiate regulatory action. Through a program called MedWatch, the FDA Medical Products Reporting Program, healthcare professionals and consumers are encouraged to report serious adverse events and product problems to FDA, the manufacturer, or both. FDA's Drug Quality Reporting System (DQRS) receives reports from pharmacists of deviations from Good Manufacturing Practices that occur during the manufacturing, shipping, or storage of prescription or OTC drug products. FDA receives medication error reports from pharmacists on marketed human drugs and maintains a central database within the DQRS and the AERS for all reports involving a medication error or potential medication error. The Agency puts substantial effort into reviewing medication error case reports to identify serious or potentially serious outcomes that might be avoided by modifying the labeling or packaging.

B. Summary of Performance Goals

Performance Goals	Targets	Actual Performance	Reference
8. Streamline adverse drug event reporting system. (12007)	FY 02: Issue final rules on ADRs and electronic submissions	FY 02:	1999 Update
	FY 01: Issue Proposed Rule on adverse event reporting requirements. Issue Guidance on electronic submission of adverse event reports. Grant waivers to companies wishing to submit adverse event reports electronically. Continue AERS development (post 2.0 functionality). Roll out of AERS datamart to medical officer in new drug review divisions.	FY 01:
	FY 00: Develop next generation of the AERS to enhance functionality.	FY 00: Development and roll-out of AERS 2.0 was completed. Pilot program to increase participation in electronic expedited reporting is ongoing. Regulation requiring that adverse event reports be precoded using MedRA on target for release for public comment this FY.
	FY 99: Implement AERS for the electronic receipt and review of voluntary and mandatory ADE reports.	FY 99: The AERS was successfully implemented and has been operational for nearly three years.
9. CDER will initiate laboratory research on at least three projects identified and related to the mission of PQRI. (12016)	FY 02: Initiate laboratory research on at least 3 projects	FY 02:
	FY 01: Initiate laboratory research on at least 3 projects	FY01:
	FY 00: 25% Goal metric changed for FY 01 ,02. See Context Section	FY00: Studies were initiated in all the project areas including presentations at a professional meeting. There were two studies for physical attributes, two studies for BACPAC, and seven studies for in vivo bioequivalence.
	FY 99: NA	FY 99: NA
10. Inspect registered human drug manufac-turers, repackers, relabelers and medical gas repackers.1 (12020)	FY 02: 26%	FY 02:
	FY 01: 26%	FY01:
	FY 00: 22%	FY00: 22%
	FY 99: 22%	FY 99: 26%
		FY 98: 24%
		FY 97: 26%
11. Assure that FDA inspections of domestic drug manufacturing and repacking establishments result in a high rate of conformance (at least 90%) with FDA requirements. (12006)	FY 02: at least 90%	FY 02:
	FY 01: at least 90%	FY 01:
	FY 00: at least 90%	FY 00: 93%
	FY 99: at least 90%	FY 99: 95%
		FY 98: 96%
		FY 97: 95%
12. Give consumers and health profes-sionals more easily understandable OTC drug information. (12027)	FY 02: Give consumers and health professionals more easily understandable OTC drug information.	FY 02:
	FY 01: Give consumers and health professionals more easily understandable OTC drug information.	FY 01:
	FY 00: Make new drug approval information increasingly available via the Internet. Develop partnerships with national organizations to disseminate educational information to consumers.	FY 00: OTC label education campaigns were targeted to grassroots consumers and key health professional organizations.
	FY 99: NA	FY 99: NA
TOTAL FUNDING: ($000)	FY02: 86,957
	FY01: 62,473
	FY00: 77,809
	FY99: 69,575
1 Some adjustments in counting inventories and inspectional coverage were necessary due to a few problems resulting from the transition to a new database (FIS to FACTS) in FY 2000.

C. Goal-by-Goal Presentation of Performance

8. Expedite processing and evaluation of adverse drug events through implementation of AERS which allows for electronic periodic data entry and acquisition of fully coded information from drug companies. (12007)

Context of Goal: The Adverse Event Reporting System (AERS) is an Oracle based computerized information system designed to support the Agency's post-marketing safety surveillance program for all approved drug and therapeutic biologic products. The structure of the database is in compliance with the international safety reporting guidance (ICH E2B), including content and format for electronic submission of the reports from the manufacturers. Features include on-screen review of reports, searching tools, and various output reports in support of postmarketing drug surveillance and compliance activities. AERS, contains approximately 2 million individual safety reports (ISRs). FDA evaluates spontaneous reporting data from the AERS to identify any serious, rare, or unexpected adverse events or an increased incidence of events. When a signal of a potential adverse reaction is detected, safety evaluators consult with product reviewers, medical officers, and epidemiologists to review available data and consider further options. FDA may decide to disseminate risk information, such as Dear Healthcare Professional letters, and may initiate regulatory action.
Data Sources and Issues: Adverse Events Reporting System
Performance: The AERS has been operational for nearly three years. In calendar year 99 over 275,000 ISRs were received for entry into the AERS of which over 82,000 (30%) represented serious and unexpected events (30%). In calendar year 2000 261,000 individual safety reports (ISRs) were received for entry into AERS. The processing costs for data entry, coding and database management for this number of reports are substantial and a continuing burden for the CDER.

Currently reports are received either on paper as MedWatch forms or electronically. AERS assigns an individual safety report (ISR) identification number for each report. Paper submissions are scanned and stored in retrieval software. All data elements are entered and undergo data entry quality control to ensure completeness and accuracy. All reported adverse event terms are coded into a standardized international terminology, MedDRA (the Medical Dictionary for Regulatory Activities). This process is also subjected to coding quality control. After data entry, the reports are routed directly to assigned clinical reviewers in the postmarketing office. The reports are assessed individually and in aggregate for safety concerns.

The functions and tools developed in AERS provide the ability to easily customize queries; such queries are performed by multiple users on a daily basis for any drug and/or adverse event of interest. Standardized report outputs from AERS provide useful postmarketing information to many users within and outside FDA. These functions, combined with appropriate management and processes developed by the FDA, make AERS an effective tool for pharmacovigilance. There is an ongoing process in place to further improve the performance and functionalities of AERS.

AERS was designed to allow for electronic submission of individual case safety reports. Electronic submissions provide CDER, FDA, and the public with several tangible benefits. Specifically, automating the receipt and processing of safety reports will allow CDER to be more responsive to public health issues, greatly reduce resources associated with data management, and apply better data and better science to the drug regulatory process. However, there are FDA regulatory and infrastructure changes needed for full-scale implementation of electronic submissions. Accordingly, CDER has proposed a step-level implementation that will allow CDER to identify and resolve several process issues while the regulatory and infrastructure changes are implemented. This step-level implementation includes a pilot program in which manufacturers may submit safety reports electronically. This will be followed by proposed rulemaking to require that manufacturers submit suspected adverse drug reaction reports electronically.

In summary, the AERS database in the FDA assures that postmarketing adverse event reports are completely and accurately data entered, quality controlled and reviewed to monitor product safety and to protect the public health.

9. CDER will initiate laboratory research on at least three projects identified and approved by the PQRI. (12016)

Context of Goal: The Product Quality Research Institute (PQRI) is a first-ever collaboration among CDER, academic, and industry scientists to conduct research in the areas of pharmaceutical chemistry, biopharmaceutics, and science management. The purpose of this research is to establish better testing methods, standards, and controls for assessing product quality and manufacturing and management processes. This knowledge aids the Agency in developing consistent and reasonable requirements for product quality information in regulatory filings. Leveraging scientific expertise in this way contributes to streamlining the drug development and approval processes for industry and the FDA while ensuring the highest level of product quality.
Data Sources and Issues: Office of Testing and Research (OTR) Research Plan; "A proposal - PQRI;" Memorandum of Understanding between FDA and the American Association of Pharmaceutical Scientists; and "Proposed Operating Principles for the PQRI."
The data sources for this goal are the written research plan, the PQRI proposal, a memorandum of agreement, and proposed operating principles. These documents should be examined to verify: that precise definitions have been established to delineate the universe (or listing) of research programs being evaluated; that the definitions of what constitutes a research plan being "initiated" and what "complete 50%" of the projects initiated in FY 99 have been clearly and unambiguously established; and that the percentage of research projects completed are measurable relative to the defined universe of research projects.

A detailed assessment of the reliability of these data sources will be conducted in the coming year to determine whether the data are valid and meaningful to judge successful performance of this goal.
Performance: In FY 2000, PQRI initiated seven working groups to address the following regulatory issues: blend uniformity, manufacturing changes, packaging changes, bulk drug post-approval changes, drug substance impurity testing, drug substance particle size analysis, and topical and aerosol forms.

The Blend Uniformity Working Group is expected to make recommendations to FDA by early next year on science-based changes to regulations for blend uniformity testing. These recommendations will ensure that there is thorough mixing of the drug within the blend and dosage unit. Current regulations advocate the testing of each production batch of a powder-blend drug. However, industry experience suggests that testing every batch is not necessary or meaningful because the current blend sampling technology is flawed and doesn't necessarily provide representative results.

10. Inspect 26% of registered human drug manufacturers, repackers, relabelers and medical gas repackers. (12020)

Context of Goal: This goal measures performance for the statutory inventory of drug establishments for which inspections are required biennially. The total drug inventory is 19,749, of which 33 percent, or 6,509, are statutory. Inspections to accomplish this goal may be done by FDA directly, or through state contracts or partnership agreements. Achievement of this goal relies on the willingness and ability of the states to contract with FDA to inspect a large portion of the medical gas repacker industry. To implement these contracts, FDA's experience predicts that a significant investment in training and time is necessary to ensure quality and uniformity of inspections. In addition, the Human Drugs program has shifted its emphasis away from inspecting medical gas establishments to establishments in other risk categories. Since medical gas inspections represent a large portion of the statutory inspection workload, the statutory inspection coverage will be adversely affected.
Data Sources and Issues: Program-Oriented Data System, Official Establishment Inventory
Performance: The FY 2000 goal of 22% was met. Due to a few problems resulting from the transition to a new database (FIS to FACTS) in FY 2000, some adjustments in counting the inventory and inspectional coverage were necessary. It is expected that any inconsistencies will be corrected when the FY 2001 performance is reported.

11. Assure the FDA inspections of domestic drug manufacturing and repacking establishments, in conjunction with the timely correction of serious deficiencies identified in these inspections, result in a high rate of conformance (at least 90%) with FDA requirements. (12006)

Context of Goal: Conformance rates estimate the post-inspection status of the establishments inspected in the given year. They are based on the number of establishments inspected, the incidence of serious deficiencies detected (Official Action Indicated), and statistical data of deficiency corrections. Since firms inspected are not randomly selected from the entire population, the rates should not be applied across that population. However, as coverage of the inventory of firms is improved the rates will better represent the overall status of the industry sector.
Data Sources and Issues: FDA Field Data Systems
Performance: FY 99: 95%; FY 98: 96%; FY 97: 95%. Conformance rates for FY 97, FY 98 and FY 99 have been adjusted to reflect the observed average correction rate for each year.

12. Make available to consumers and health professionals more easily-understandable information on choosing and taking prescription and OTC drugs to prevent and reduce their misuse, take more of an activist role in how consumers use these drugs, and improve drug risk management, analysis, and communication procedures. (12027) Goal will remain the same for FY 02

Context of Goal: There is increasing public recognition that marketed drugs can lead to harm as well as benefit. Drug-related injuries and deaths can be reduced by creating a more educated public through expanded outreach activities and collaborative efforts with academia, professional societies and health organizations.
Data Sources and Issues: Approval Letter for new and generic drugs and the Labeling Text or Final Printed Label (FPL) for new drugs; Consumer Drug Information Sheets for New Molecular Entities (NMEs); Availability of FDA's reviews of new and generic drugs via the internet; Prescribing Information Sheet for NMEs. Report to the FDA Commissioner - Managing the Risks from Medical Product Uses, An Assessment of FDA's Approval and a Look to the 21st Century.
The program indicated that the following information on the processing procedures for this data is reliable and of sound quality. The information demonstrates that the appropriate quality control practices are in place.

The project manager copies the approval letter and final labeling text to a secured drive. The Freedom of Information (FOI) component completes necessary redaction and transfers them to another secured drive. FOI then notifies the web team that they are ready to post. Posting is verified by FOI. There are time limits for each of these steps as stipulated in a Center policy.

Consumer Drug Information Sheets for NMEs are prepared by Center pharmacists using information from the approved label and other sources and then cleared by the appropriate components. The information is then posted on the internet to a site for "Consumer Drug Information".

It was determined that these data are valid based on the logical assumption that once this information is disseminated, the American public would benefit positively due to reduced drug misuse. A detailed assessment of the quality control process will be conducted in the coming year to ensure that performance data are reliable.
Performance: This goal is a continuation of FY 99 and FY 00 Agency activities regarding providing more easily-understandable and -accessible drug information to interested individuals and organizations. It incorporates the FY 00 goals 12012 and 12025. There is no commitment to a specific FY 99 target and therefore no FY 99 report. In March 1999, the Agency issued a new ruling that sets minimal standards and requirements for the format of OTC drug product labeling which should increase patients knowledge about the medication. In addition, the Agency completed the first phase of a new Over-the-Counter Medicine Label Campaign by placing 245 newspaper articles in 45 states reaching more than 17 million people and by reaching an additional 137 million with radio PSA. Throughout the year 2000, more companies began using the new OTC medicine label. Subsequently, the Agency launched phase two of this educational campaign by producing a new color print public service announcement and a completely revised newspaper article.
In FY 2000 public and advisory committee meetings were held to inform consumers and health care professionals about the Agency's work on making the pregnancy section of labeling more useful.

2.2.3 Verification and Validation

A preliminary assessment for data completeness, accuracy, and consistency and related quality control practices was done for each performance goal. The purpose of the assessment was to determine if the data was of a sufficient quality to document performance and report program results, whether the data was appropriate for the performance measure and if it was considered sound and convincing. The Center obtained from its programs a description of the means that are used to verify and validate measured values for each performance goal. CDER has a number of quality control processes in place to ensure that performance data is reliable. Below are descriptions of several data systems used by CDER.

Adverse Event Reporting System (AERS)

The Adverse Event Reporting System (AERS) is an Oracle based computerized information system designed to support the Agency's post-marketing safety surveillance program for all approved drug and therapeutic biologic products. The structure of the database is in compliance with the international safety reporting guidance (ICH E2B), including content and format for electronic submission of the reports from the manufacturers. Features include on-screen review of reports, searching tools, and various output reports in support of postmarketing drug surveillance and compliance activities. The ultimate goal of AERS is to improve the public health by providing the best available tools for storing and analyzing safety reports.

However, there are FDA regulatory and infrastructure changes needed for full-scale implementation of electronic submissions. Accordingly, CDER has proposed a step-level implementation that will allow CDER to identify and resolve several process issues while the regulatory and infrastructure changes are implemented. This step-level implementation includes a pilot program in which manufacturers may submit safety reports electronically.This will be followed by proposed rulemaking to require that manufacturers submit suspected adverse drug reaction reports electronically.

Pediatric Exclusivity Database and the Pediatric Page database (Database enhancements required to meet goal)

The pediatric databases are complete and accurate and appropriate quality control practices are in place. The data are valid for this goal because they measure the required performance indicators e.g., the number of requested pediatric studies. A detailed assessment of the pediatric Exclusivity Database and the Pediatric Page database quality control process will be conducted in the coming year to ensure that performance data are reliable.

Center-wide Oracle Management Information System COMIS

The Center-wide ORACLE Management Information System (COMIS) is CDER's enterprise-wide system for supporting premarket and postmarket regulatory activities. It consists of multiple applications, or components, that store and retrieve data in a single integrated database. COMIS is the core database upon which most mission-critical applications are dependent. The new drug evaluation (NDE) portion of COMIS contains information about investigational new drug applications (INDs), new drug applications (NDAs), supplements, and amendments, and it tracks their status throughout the review process. The type of information tracked in COMIS includes status, type of document, review assignments, status for all assigned reviewers, and other pertinent comments.

CDER has in place a quality control process for ensuring the reliability of the performance data in COMIS. Document room task leaders conduct one hundred percent daily quality control of all incoming data done by their IND and NDA technicians. Senior task leaders then conduct a random quality control check of the entered data in COMIS.

The task leader then validates that all data entered into COMIS are correct and crosschecks the information with the original document. Once the data are saved in COMIS, the document room staff no longer have the capability to change certain document fields. If a data entry change is necessary, the task leader must request the change in writing. Once the change has been made, the document room is notified and the senior task leader/task leader rechecks the data for accuracy.

The Records Management Team (RMT) conducts weekly quality control checks of the various document rooms. These checks include random quality control of division files, loose files, application jackets, outgoing letters, memoranda, and reviews. Each document room is visited monthly and no advanced notice is given.

Overall, the data in COMIS are complete and accurate, and appropriate quality control practices are in place. The limited number of people with authority to input data into COMIS helps to protect the integrity of the data. Once entered into the system, data are immediately accessible to users. In order to ensure that the system is functioning as needed, a committee consisting of staff from RMT and the Office of Information Technology meet once a month to discuss and ensure that the system reflects changes in policy and legislative requirements. The data obtained from COMIS are valid for this goal because they measure the required performance indicators, e.g., the numbers and types of submissions, receipt dates, and review times.

Preliminary discussions have taken place to alleviate system weaknesses and redesign the system in phases over the next few years to improve efficiency. These weaknesses include a manual, paper-driven quality control process, inflexibility of the system to reflect policy and legislation changes in a timely manner, slow or unavailable network connections impeding a user's ability to acquire requested data, and unrecognizable codes requiring tracking to be done manually.

Previous | Table of Contents | Next