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2.3.1 Program Description, Context, and Summary of Performance

The Human Drugs Program promotes the public health by assuring that all prescription and over-the-counter drugs are safe and effective. The Center for Drug Evaluation and Research (CDER) evaluates all new drugs before they are sold, and serves as a consumer watchdog for the more than 10,000 drugs on the market to be sure they continue to meet the highest standards. CDER routinely monitors TV, radio, and print drug ads to ensure they are truthful and balanced. CDER also plays a critical role in providing health professionals and consumers information to use drugs appropriately and safely. Recent drug approvals represent important advances for children, women, elderly persons, and patients with heart disease and cancer, which are leading causes of death in the United States. To support this mission, the human drugs program focuses on three long-term strategic goals:

1. Protect and promote the health of Americans by providing access to important safe and effective drugs.
2. Enhance organizational performance in response to stakeholder needs with the highest degree of cost effectiveness and efficiency.
3. Prevent injury and death to the American public caused by adverse drug reactions, medication errors and product problems.

In addition to setting standards for safety and effectiveness testing, we also set standards for drug quality and manufacturing processes. We work closely with manufacturers to see where streamlining can cut red tape without compromising drug quality. As the pharmaceutical Industry has become increasingly global, we are involved in international negotiations with other nations to harmonize standards for drug quality and the data needed to approve a new drug. This harmonization will go a long way toward reducing the number of redundant tests manufacturers perform and help ensure drug quality for consumers at home and abroad.

We conduct and collaborate on focused laboratory research and testing. Research maintains and strengthens the scientific base of our regulatory policy-making and decision-making. We focus on drug quality, safety and performance, improved technologies, new approaches to drug development and review, and regulatory standards and consistency.

2.3.2 Strategic Goals

Strategic Goal 1:
Protect and promote the health of Americans by providing access to important safe and effective drugs.

A. Strategic Goal Explanation

A drug company seeking to sell a drug in the United States must first test it. We monitor clinical research to ensure that people who volunteer for studies are protected and that the quality and integrity of scientific data are maintained. The company then sends us the evidence from these tests to prove the drug is safe and effective for its intended use. We assemble a team of physicians, statisticians, chemists, pharmacologists and other scientists to review the company's data and proposed use for the drug. If the drug is effective and we are convinced its health benefits outweigh its risks, we approve it for sale. By setting clear standards for the evidence we need to approve a drug, we help medical researchers bring new drugs to American consumers more rapidly. The average review time for new drugs covered under the Prescription Drug User Fee Act (PDUFA) has been reduced from more than 2.5 years to less than one year and patients with life-threatening illnesses are able to gain access to treatments sooner. We also review drugs that can be bought over-the-counter (OTC) (without a prescription) and generic versions of both over-the-counter and prescription drugs. CDER is also encouraging the development and expediting the review of medications for the prevention or treatment of injuries that could be caused by terrorists using biological, chemical, or nuclear agents.

B.   Summary of Performance Goals

Performance Goals	Targets	Actual Performance	Reference
1. Meet PDUFA III commitments for the review of original NDA submissions. (12001)	Standard NDAs within 10 months: FY 04: 90% FY 03: 90% FY 02: 90% FY 01: 70% FY 00: 50% FY 99: 30% Standard NDAs within 12 months: FY 04: NA FY 03: NA FY 02: NA FY 01: 90% FY 00: 90% FY 99: 90% Priority NDAs within 6 months: FY 04: 90% FY 03: 90% FY 02: 90% FY 01: 90% FY 00: 90% FY 99: 90%	FY 04: FY 03: FY 02: Final data available by 11/03. FY 01: 90% of 86 FY 00: 79% of 92 FY 99: 66% of 95 FY 04: FY 03: FY 02: NA FY 01: 98% of 86 FY 00: 97% of 92 FY 99: 100% of 95 FY 04: FY 03: FY 02: Final data available by 7/03. FY 01: 100% of 10 FY 00: 97% of 29 FY 99: 100% of 31	4
2. Increase the number of drugs that are adequately labeled for children. (12026)	FY 04: BPCA:Complete review and action on 85% of pediatric supplements in response to a Written Request (WR) within 6 months. Work with NIH to update Priority List of Drugs; issue 10-12 WRs for off-patent drugs; work with NIH to issue Requests for Proposals (RFPs) for contracts for the study of drugs (outlined in a WR) and publish 8-10 RFPs. Issue WRs for the study of on-patent drugs in the pediatric populations, make exclusivity determinations once final study reports are submitted, determine final pediatric label changes, and disseminate information. FY 03: BPCA: Complete review and action on 80% of pediatric supplements in response to a WR within 6 months. Work with NIH to publish the initial Priority List of Drugs and work with NIH to update the list. Issue 6-8 WRs for off-patent drugs; work with NIH to issue RFPs for contracts for the study of drugs (outlined in a WR) and publish 5-7 RFPs. Issue WRs for the study of on-patent drugs in the pediatric population, make exclusivity determinations once final study reports are submitted, determine final pediatric label changes, and disseminate information. Pediatric Rule: Track all applications that would have triggered the pediatric rule, to include waivers, deferrals, and completed studies. FY 02: Exclusivity/BPCA:Work with NIH to develop, prioritize, and publish the initial list of off-patent drugs. Work with NIH to develop the Request for Proposal (RFP) process for contracts for study of off-patent drugs. Issue WRs for the study of on-patent drugs in the pediatric population, make exclusivity determinations once final study reports are submitted, determine final pediatric label changes and disseminate information. Pediatric Rule:Track all applications that would have triggered the pediatric rule, to include waivers, deferrals, and completed studies. FY 01: Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule. FY 00: Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule. FY 99: Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule.	FY 04: On-Patent Drugs: Pediatric Proposals Reviewed:Written Requests Issued:Amended WRs Issued:Exclusivity Determinations:Exclusivities Granted:Labels Changed: Off-Patent Drugs: WRs Issued:List Updated: FY 03: On-Patent Drugs: Pediatric Proposals Reviewed:Written Requests Issued:Amended WRs Issued:Exclusivity Determinations:Exclusivities Granted:Labels Changed: Off-Patent Drugs: WRs Issued:Priority List: to be published in January 2003. Peds Rule: FY 02: Exclusivity/BPCA: Pediatric Proposals Reviewed: 42Written Requests Issued: 54Amended WRs Issued: 48Exclusivity Determinations: 23Exclusivities Granted: 22Labels Changed: 18Suppl. Acted on 180 days: NAInfo Disseminated: 2 American Academe of Pediatrics (AAP) News articles published; 2 Pediatric Academic Societies (PAS) abstracts published; I journal article published; 1 Pediatric Advisory Subcommittee meeting held; 21 presentationsBPCA Off-Patent Drugs:WRs sent to NIH: 3WRs assessed and drafted: 4WRs issued to all approved application holders: 41Establishment of off-patent status of drugs: 284Coordination of the development, prioritization, and publishing of the priority list with NIH: 36 Pediatric Rule: Deferrals: 49Waivers: 65Completed Studies: 43 FY 01: Exclusivity:Pediatric Proposals reviewed: 81Written Requests Issued: 49Amended WRs Issued: 46Exclusivity Determinations: 19 Exclusivities Granted: 16Labels Changed: 10Info Disseminated: I Pediatric Advisory Subcommittee meeting heldPediatric Rule:Deferrals: 54Waivers: 78Completed Studies: 29 FY 00: Exclusivity: Pediatric Proposals reviewed: 39Written Requests Issued: 58Amended WRs Issued: 59Exclusivity Determinations: 19 Exclusivities Granted: 16Labels Changed: 7Info Disseminated: 1 Pediatric Advisory Subcommittee meeting held Pediatric Rule: Deferrals: 69Waivers: 79Completed Studies: 30 FY 99: Exclusivity: Pediatric Proposals reviewed: 155Written Requests Issued: 95Amended WRs Issued: 15Exclusivity Determinations: 9 Exclusivities Granted: 9Labels Changed: 4Info Disseminated: Pediatric Rule: Deferrals: 70Waivers: 79Completed Studies: 14	4
3. Complete review and action upon fileable original generic drug applications within 6 months after submission date. (12003)	FY 04: 90% FY 03: 80% FY 02: 65% FY 01: 50% FY 00: 45% FY 99: 60%	FY 04: FY 03: FY 02: 3/03 FY 01: 84% of 298 FY 00: 55.6% of 307 FY 99: 28% of 309	4
4. Increase the number of drugs adequately labeled available for OTC use. (12048)	FY 04: Complete review and action on 100% of Rx-to-OTC Switch applications within 10 months of receipt and make significant progress on completing 6 OTC monographs. FY 03: NA FY 02: NA	FY 04: FY 03: NA FY 02: NA	4
5. Protect human research subjects who participate in drug studies and assess the quality of data from these studies by conducting onsite inspections and data audits annually. (12032)	FY 04: 685 or 90% of the field assignments made by 6/30/2004 FY 03: 685 or 90% of the field assignments made by 6/30/2003 FY 02: 780 FY 01: NA FY 00: NA FY 99: NA Note: The number of inspections completed each year is dependent on the number of New Drug applications received.	FY 04: FY 03: FY 02: 635 inspections completed FY 01: 553 inspections completed FY 00: 697 inspections completed FY 99: 683 inspections completed	4
6. Facilitate development and availability of medical countermeasures to limit the effects of the intentional use of biological, chemical, or radiologic/nuclear agents.(12045)	FY 04: Complete analysis of data from animal studies and incorporate information on pneumonic plague into drug product labeling; review and analyze data from animal studies conducted on inhalational anthrax; publish a revised guidance on potassium iodide for use in special populations. FY 03: Develop guidances for Industry on developing antiviral drugs; identify and begin to address labeling gaps in the therapeutic armamentarium; expedite the review of protocols for investigational new radioprotectant drugs; and facilitate human clinical trials. FY 02: NA	FY 04: FY 03: FY 02: NA	2, 4
7. Publish guidance for Industry on developing antimicrobial drugs for inhalational anthrax (post-exposure). (12033)	FY 04: NA FY 03: NA FY 02: Publish guidance for Industry on developing antimicrobial drugs for inhalational anthrax (post-exposure).	FY 04: FY 03: FY 02: Announced the availability of a draft guidance for industry entitled "Inhalational Anthrax (Post-Exposure) - Developing Antimicrobial Drugs."	2, 4
8. Facilitate the initiation of research in a non-human primate model of pneumonic plague. (12034)	FY 04: NA FY 03: NA FY 02: Facilitate the initiation of research in a non-human primate model of pneumonic plague.	FY 04: FY 03: FY 02: Facilitated the initiation of research through establishment of an Inter-Agency Agreement with NIAID/NIH and USAMRIID entitled "Non-Human Primate Studies of Antibiotic Efficacy for Treatment of Pneumonic Plague by Aerosolized Yersinia Pestis."	2, 4
9. Expedite the review of protocols for investigational new drugs (INDs) to treat organophosphorous nerve agents in the event of chemical attack. Encourage sponsors of these new drug application (NDAs) to update current labeling for Antidote Treatment Nerve Agent, Autoinjectors (ATNAA). (12035)	FY 04: NA FY 03: NA FY 02: Expedite the review of protocols for investigational new drugs (INDs) to treat organophosphorous nerve agents in the event of chemical attack. Encourage sponsors of these new drug applications (NDAs) to update current labling for Antidote Treatment Nerve Agent, Autoinjectors (ATNAA).	FY 04: FY 03: FY 02: Requested information from the American Academy of Pediatrics (AAP) in May 2002 regarding clinical data on atropine and pralidoxime to determine their use as therapies for nerve agent exposure in the pediatric population. On January 17, 2002, FDA approved nerve gas antidote ATNAA (atropine/pralidoxime) for the treatment of poisoning by susceptible organophosphorous nerve agents having anticholinesterase activity.	2, 4
10. Publish a final rule which allows the Agency to approve new drug and biological products for the treatment of chemical, biological, radiological, or nuclear substances based on animal efficacy studies when adequate and well-controlled studies in humans cannot be ethically conducted and field studies are not feasible. (12040)	FY 04: NA FY 03: NA FY 02: Publish a final rule which allows the agency to approve new drug and biological products for the treatment of chemical, biological, radiological, or nuclear substances based on animal efficacy studies when adequate and well-controlled studies in humans cannot be ethically conducted and field studies are not feasible.	FY 04: FY 03: FY 02: The Final Rule on the "New Drug and Biological Drug Products: Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible" was published by FDA in the Federal Register on May 31, 2002.	2, 4
TOTAL FUNDING: ($ 000)	FY 04: 358,080 FY 03: 310,104 FY 02: 273,258 FY 01: 257,984 FY 00: 233,425	Numbers in the Reference column corresponds to the relevant strategic goal in the HHS Strategic Plan

C. Goal-By-Goal Presentation of Performance

1. Meet PDUFA III commitments for the review of original NDA submissions. (12001) Context of Goal:The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 reauthorizes the collection of user fees to enhance the review process of new human drugs and biological products and established fees for applications, establishments, and approved products. The PDUFA amendments of 2002 are effective for a five-year period with certain technical improvements. Specifically, Congress directed FDA to strengthen and improve the review and monitoring of drug safety, consider greater interaction between the Agency and sponsors during the review of drugs and biologics intended to treat serious diseases and life-threatening diseases, and develop principles for improving first-cycle reviews. A major objective of the human drugs program is to reduce the time required for FDA's review of all drugs. The first action is the first regulatory action the CDER takes (approvable, not approvable, or approval letter) at the end of the review of the original NDA submission (the first review cycle). So the first action times refer to the time it takes us to review and take an action on the original submission. This is different from total approval time which is the time it takes from the original receipt of the application until it is approved, which may take more than one review cycle. This includes the time we spend reviewing the application in each of the review cycles plus the time taken by the sponsor to respond to the issues raised in the approvable/not approvable letter(s) and resubmit the application for review. Applications for drugs similar to those already marketed are designated standard, while priority applications represent drugs offering significant advances over existing treatments. (Drugs for AIDS and cancer typically fall into the priority category.) FDA's timely performance of high-quality drug reviews in recent years reflects the importance of managerial reforms and substantial additional resources provided under the Prescription Drug User Fee Act (PDUFA). Under PDUFA, the drug Industry pays user fees for new drug and biologics applications, establishment fees, and product fees. The fee revenues help the Agency hire additional scientists to perform reviews, bringing new drugs to the American consumer more rapidly. PDUFA III revenues will enable FDA to put the program on a sound financial footing, further enhance program efficiency, and improve efficiency for Industry innovators by providing sponsors earlier review, communication, and feedback on products in development. PDUFA III will also provide increased funds for risk management after new product approval.
Performance:CDER met all FY 2000 performance goals (see Table 1 below).

Table 1
Fiscal Year 2000 Cohort (closed out 10/31/01)

In FY 2001, CDER took 186 actions on NDAs, 71 of which were approvals. Of the 71 NDA approvals, 15 were for NMEs. Of the 15 NMEs, five were drugs given a priority review (products offering a significant improvement over currently marketed drugs). CDER approved 18 priority applications (5 NMEs, 5 NDAs that were not NMEs, and 8 efficacy supplements).

CDER has exceeded all FY 2001 performance goals (see Table 2 below).

Table 2
Fiscal Year 2001 Receipt Cohort (closed out 9/30/02)

Several important new drugs were also approved by FDA in FY 2001 (see Table 3 below).

Table 3
Significant NDAs Approved in FY 2001

Drugs approved in FY 2001 under Subpart H (Accelerated Approval) regulations are listed below (see Table 4).

Table 4
NDAs Approved under Accelerated Approval in FY 2001

FDA approved several important new drugs during the first eight months of FY 2002 (see Table 5 below).

Table 5
Significant NDAs Approved in FY 2002

Drugs approved in the first eight months of FY 2002 under Subpart H (Accelerated Approval) regulations are listed below (see Table 6).

Table 6
NDAs Approved under Accelerated Approval in FY 2002

The graph below (Figure 1) illustrates that approval time in months for priority applications has decreased from 15 months in 1994 to 6 months in 2001, and approval time for standard applications has decreased from 22.1 months to 14 months. Approval time represents the total review time at the Agency plus Industry response time to the Agency's requests for additional information.

The following is the preliminary data for the FY 2002 receipt cohort as of November 30, 2002 (see Table 7). Final performance data will be available by November 30, 2003..

Table 7
Fiscal Year 2002 Receipt Cohort (as of 11/30/02)

2. Increase the number of drugs that are adequately labeled for children. (12026)

Context of Goal:In 1997, as part of the Food and Drug Administration Modernization Act (FDAMA), Congress enacted a law to provide marketing incentives to manufacturers who conduct studies in children. This law, which provides six months exclusivity in return for conducting pediatric studies requested by the FDA, is commonly known as the pediatric exclusivity provision. Pediatric provisions of the FDA Modernization Act of 1997 have had a profound impact on the study of drugs in children. Many of the studies reported to date have yielded new dosing and safety information. The recently enacted Best Pharmaceuticals for Children Act (BPCA) is expected to continue providing incentives for the effective development and labeling of information on how to properly use therapies in children. As a result of these initiatives, the number of ongoing pediatric clinical trials in the last 4 years has tripled and many companies have built and continue to build a pediatric research infrastructure that is similar to the one for adults which has been in place for decades.
As mandated by BPCA, pediatric supplements submitted in response to a Written Request (WR) issued by FDA should be reviewed and acted upon within 180 days (i.e., granted a priority review status). The workload associated with the implementation of the Act will be a growing resource challenge as substantial effort will be required in issuing WRs, reviewing the studies, and negotiating labeling changes within the 6-month timeframe. BPCA still allows sponsors of marketed drugs to obtain exclusivity if they conduct and submit pediatric studies that fairly respond to the terms outlined in the WR issued by FDA. WRs may be initiated by FDA or sponsors may submit a proposed pediatric study request (PPSR) to FDA. In response to the PPSR, FDA may issue a WR if they believe there is a public health benefit. In addition, BPCA amended the Public Health Service Act to establish a publicly funded contracting process for the studies of drugs that no longer have exclusivity or patent protection, but for which pediatric information is needed. FDA and NIH are collaborating to transform WRs into Requests for Proposals (RFPs) from NIH when firms do not respond to a WR to conduct clinical trials. All funds for these RFPs are controlled by NIH, along with the contracting process under these NIH-initiated RFPs. FDA's success in meeting this goal is dependent on NIH receiving adequate funding and then proceeding to publish RFPs. Pediatric exclusivity has helped FDA uncover important new dosing and safety information that will help pediatricians and other prescribers use drugs to treat children more confidently. Additionally, we will enhance the surveillance of adverse events in children and coordinate the development of "off-patent" drugs for children with NIH. FDA also plans to negotiate labeling concerns with listed drug holders and further develop the science to address new pediatric issues.
Performance:Since 1998, FDA has reviewed 319 Proposed Pediatric Study Requests (PPSR), issued 259 Written Requests (WR) asking for over 606 studies to be conducted in the pediatric population, and has granted exclusivity to 67 out of the 76 products that have had an exclusivity determination. Forty-seven of the 76 products that have had an exclusivity determination now have approved labeling that incorporates information from the pediatric studies. Accurate dosing and safety information is now available for products labeled for use in allergies, diabetes mellitus, high blood pressure, pain, seizures, obsessive-compulsive disorder, HIV infection, atopic dermatitis, and many other conditions.
In response to the BPCA, the Agency has undertaken numerous collaborative activities with the Institute of Medicine (IOM), NIH and the American Academy of Pediatrics, including working with NICHD on the development of a Priority List of Drugs and a process for transforming WRs into RFPs. Four WRs for off-patent drugs have been assessed. Subsequently, two WRs were then issued to all identified NDA and ANDA holders of approved applications for these drugs. FDA worked with NIH in transforming the WRs into RFPs. In response, two FDA/NIH contract working groups have been established. Two implementation meetings for contracts have been held.
The fifth Pediatric Advisory Subcommittee meeting occurred on June 11, 2002. The Report to Congress mandated by FDAMA was 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 recognition of the need for clear ethical guidance in this pediatric arena and as mandated by the Children's Health Act of 2000, the Agency incorporated Subpart D of the DHHS regulations into FDA regulations (Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products) and published an interim final rule effective on April 30, 2001. The Agency defined and funded an inpatient pediatric database that is being used to accumulate information on the use of drugs in children in the inpatient care setting, e.g., children's hospitals, community hospitals, and chronic care facilities.
Data Sources: Pediatric Exclusivity Database, Pediatric Page database, and CHCA inpatient database. The Pediatric Exclusivity Database tracks all data regarding pediatric exclusivity as mandated by FDAMA and reauthorized by BCPA. Specifically, this database tracks the number of WRs issued and the number of products for which pediatric studies have been submitted and for which exclusivity determinations have been made.

3. Complete review and action on fileable original generic drug applications within 6 months after submission date. (12003)

Context of Goal: Generic drugs are much appreciated for their cost-effectiveness. According to the Congressional Budget Office, they save consumers an estimated $8 billion to $10 billion a year compared with the price of trade-name products. FDA continues to support an active generic drugs program with a focus on expanding the availability of high quality generic drug products to the public. The basic requirements for approval of generic and trade-name drugs are the same as new drug approvals, although the generic drug manufacturer does not need to repeat the safety and efficacy studies conducted by the developer of the original product. The approval time is measured from the date the application is received to the date a major action, either an approval or not approvable, is reached. In approving a generic drug, the FDA relies on its previous finding that the original drug is safe and effective. The generic version must have the same dosage form, safety, strength, route of administration, and conditions of use as the trade-name product. The generic drug's sponsor also must show that its active ingredient is absorbed at a rate and extent similar to the trade-name counterpart. This bioequivalence is critical for drawing the conclusion that both the original and generic drugs will produce similar therapeutic results. With the exception of language protected by patents or exclusivity, the labeling of the generic drug, including directions for use, must be virtually the same as that of the trade-name product. Both generic and trade-name drug companies are required to submit information to ensure that the approved products can be manufactured to FDA's specifications. Following approval, both generic and trade name firms must submit data to the FDA showing that their products continue to meet the Agency's specifications until the established expiration date. The FDA regularly assesses the quality of generic medications on the market and thoroughly researches and evaluates reports about their performance. Once a sponsor submits an abbreviated new drug application (ANDA) to the Agency, we have committed to acting on those submissions, e.g., issuing a complete response letter, within 6 months of the submission date.
Performance: In FY 1999, we set the FY 2001 target of 50 percent based on actual performance of 28 percent. FDA exceeded its goal for FY 2001 acting on 84 percent of original applications within 6 months after the submission date. The Office of Generics Drugs utilized increased funding levels to increase the efficiency of the review process thereby decreasing the average approval time. We have approved approximately 7,000 generic drugs for various treatments, including benign prostatic hyperplasia, various ovarian and breast cancers, and high blood pressure. The Office of Generic Drugs (OGD) continues to refine the review process to increase efficiency with the $1.2 million increase in FY 2001 as well as increases in past fiscal years. It is also evaluating ways to increase resources devoted to information technology. As the backlog of applications is addressed, it is hoped OGD can close the gap between actions so that issuance of a complete response letter is taken within the statutory time frame of six months. There are certain factors outside the control of OGD that may prevent complete adherence to the 180-day time frame. These include the need to adhere to the review queue structure, timeliness of inspections of the manufacturing plants, and legal issues raised late in the review process. In addition to these factors, the Agency continues to examine every aspect of the review process to try to identify problem areas that need to be addressed. We continue to refine the review process to increase efficiency. We are able to accept more electronic submissions to streamline the review process. The number of new staff hired in the last fiscal year is now fully trained and are demonstrating high levels of productivity. We continue to examine every aspect of the review process to try to identify problem areas to be addressed. We also plan to revise the current system for amendment designation (major versus minor) to improve total review times.
CDER targeted a $2.5 million dollar increase in FY 2002 to improve the generic drug review process and educate various audiences in the safe and effective use of generic drugs as a substitute to their brand-name counterparts. Increased staff has provided the Office of Generic Drugs with scientific managers and experts, including a Director of Science, several chemistry reviewers and managers, a Medical Officer, and regulatory management officers. Furthermore, compliance and legal support to the Office of Generic Drugs was expanded. The increased staff were critical in reducing review times for ANDAs/generic drug applications and granting approval as quickly as possible. The percent of original ANDAs acted upon within 180-days exceed the Office's 2002 goal. This represents improvements in nearly every level and scientific discipline supporting the review of generic drug applications, culminating in a record number of approvals of ANDAs. The actual performance data for FY 2002 will not be available till 180 days after the close of FY 2002, approximately March 2003.
With the requested increases for FY 2003 and FY 2004, FDA plans to hire additional reviewers and other staff to accelerate the review and approval of Abbreviated New Drug Applications. In addition, we plan to improve the review of ANDAs without sacrificing product quality to allow the Agency to reach its goal of reviewing 80 percent of ANDAs in FY 2003 and 90 percent in FY 2004 within six months after submission. We also plan to hire additional inspectors to increase inspections of domestic and foreign firms associated with generic drug production, an activity critical to reducing total approval times; and, increase coverage of imported generic drugs to better monitor the quality of finished drug products and bulk drug substances from overseas. Additionally, the increase will also be used to conduct research that will allow us to address specific scientific questions regarding bioequivalence and chemistry of generic products. This research will be directed at evaluating ways to enable approval of generic drugs in areas that currently lack generic alternatives, such as inhalational or topical drug products.

Table 3
Notable First Time Generic Approvals

The FY 2001 18.4-month median approval time compares to 18.9 months in FY 2000 and 17.3 months in FY 1999 (see Figure 2 below). CDER used a $1.2 million dollar increase in FY 2001 to fully annualize the positions added in FY 2000 and add several additional FTEs. Several of these staffers are already on-board, fully trained, and demonstrating high levels of productivity. With this additional increase, all chemistry reviewer vacancies are currently filled. This in itself will hopefully improve performance, as chemistry reviews were a source of delay.

4. Increase the number of drugs adequately labeled available for OTC use. (12048)

Context of Goal: Over-the-counter (OTC) drugs play an increasingly vital role in America's health care system. The trend to self-medication has increased greatly in recent years as health care costs have risen and consumers want to be empowered to treat minor ailments with safe and effective OTC drug products. However, safety, effectiveness, and proper labeling have not always been characteristic of OTC drug products in the United States. The Food and Drug Administration (FDA) has devoted extensive resources to the goal of having safe and effective OTC drug products in the United States, including a number of products formerly marketed by prescription. FDA's goal by 2010 is to complete its existing review of OTC drug products, to have considered a number of key foreign drugs for marketing in the United States, and to have considered a number of key potential "prescription (Rx)-to-OTC" switches that could result in further consumer empowerment in self-medication. FDA would like to be able to become more proactive in recommending Rx-to-OTC switch candidates and in identifying drugs with only foreign marketing experience as candidates for the U.S. OTC market. Accomplishing these goals will benefit both consumers and manufacturers of OTC drug products, as well as help to reduce health care costs. To do so will also require additional resources dedicated to the review of OTC drug products.
The OTC drug monographs are "recipes" for marketing OTC drug products without the need for FDA preclearance. The monographs list the allowed active ingredients and the dosage or concentration, the required labeling, and packaging and testing requirements if applicable. The monographs save manufacturers costs and reduce barriers to competition, as they allow both large and small companies to enter the market place with OTC drug products that have to meet the same, uniform criteria. Final monographs (agency final rules) need to be completed for a number of large product categories (e.g., external analgesics, internal analgesics, antimicrobials, oral health care products, laxatives). The process is very complex and requires extensive resources to fully address multiple issues for each product class. The agency's goal with increased resources is to complete the initial review of OTC monographs for 29 categories of drug products by 2010, thereby eliminating all unsafe and ineffective products from the OTC market. As more monographs are completed, this will reduce manufacturers' costs and increase generic competition of OTC drug products, as manufacturers will know exactly what is needed for a new OTC drug product to enter the market place.
With an estimated increase of $1 million, the agency will increase its staff dedicated to the OTC drug review. In addition, the Division of OTC Drug Products staff needs to devote resources to update the existing monographs as new situations arise, e.g., requests to add ingredients currently marketed OTC under new drug applications to the monographs (e.g., ibuprofen, clotrimazole).
Performance:The OTC drug review, to date, has been an evaluation of OTC drug products marketed only in the United States. Recognizing the importance of OTC drug products marketed in other countries and in response to manufacturers requests, FDA expanded the OTC drug review in 2002 to allow OTC drug products without any U.S. marketing experience to become eligible for the review if they meet certain criteria. The Agency anticipates that a number of products will be submitted for consideration under the new drug application review process, and that eventual inclusion of these products into the OTC drug monographs will help reduce some health care costs, increase competition, and may introduce some new self-medication concepts into the United States. For example, loratadine may have been eligible for consideration under this process as it has been marketed OTC in other countries for some time. If this expansion of the review results in a large number of products being submitted for consideration, the agency will need additional OTC resources to both evaluate these products and complete the original review. Many drugs have been switched from prescription-to-OTC status under the OTC drug review (e.g., antihistamines, nasal decongestants, hydrocortisone for topical use). In recent years, most of the switches have occurred under new drug applications. In FY 2002 four new OTC drug products were approved and seven had approvable actions. FDA acted upon 100% of Rx-to-OTC applications within 10 months of receipt in FY 2002 and made significant progress on 5 OTC monographs (sunscreen, internal analgesic, healthcare antiseptics, laxative, and oral health care). The expansion of the OTC drug review to evaluate foreign OTC drugs is expected to increase switch requests in the near future. The OTC drug industry has stated in the past and continues to state that "Rx-to-OTC" switch has been the impetus for and is the future for growth of the self- medication movement. While CDER is hoping for a 50 percent increase in applications, we do not control the number of applications submitted. For this reason, we do not believe a specific number in this goal is appropriate. FDA recognizes that some of these switch requests involve issues of "OTCness" - determination that the drug is appropriate for OTC use and developing appropriate labeling and other information (such as was done for OTC stop smoking aid products) for safe and effective consumer use of these products without the intervention of a health care professional. Drug products to lower cholesterol are currently being considered, with multiple issues to be resolved. Some of these issues may require FDA research costs via consumer studies.
CDER must be a leader in developing research to better understand consumer behavior. Consumers often make errors in judgement either in selecting to use OTC products or not using OTC products correctly. These errors may lead to increased risk for adverse events for consumers or very little likelihood of benefit. The ability of consumers to appropriately use products marketed OTC is one of the more difficult hurdles for manufacturers to overcome. Many manufacturers are not willing to expend the resources needed to identify possible solutions to errors in consumer use and selection. Research needs to be directed toward understanding the factors that contribute to these consumer behaviors and identify mechanisms for influencing appropriate consumer use of products.
Data Sources and Issues: Review performance monitoring is being done in terms of cohorts, e.g., FY 2003 cohort includes applications received from October 1, 2002, through September 30, 2003. CDER uses the Center-wide Oracle Management Information System (COMIS) and 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. Published monographs that establish acceptable ingredients, doses, formulations, and consumer labeling for OTC drugs.

5. Protect human research subjects who participate in drug studies and assess the quality of data from these studies by conducting onsite inspections and data audits annually. (12032)

Context of Goal:FDA approves drug products only after the sponsors provide adequate and reliable information on which FDA can base its decision. 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, clinical investigators, contract research organizations, monitors, institutional review boards (IRB's), and non-clinical/analytical laboratory facilities 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. Commercial sponsors (e.g., pharmaceutical companies) generally pay for the research studies reported to FDA. Such studies must comply with FDA regulations for informed consent, human subject protection, and the conduct of such studies (21 CFR 50, 56, 312). The Prescription Drug User Fee Act (PDUFA) mandates specific deadlines for review of sponsors' submissions. FDA shares information related to IRB inspections with the Department of Health and Human Services (DHHS) Office of Human Research Protection, which has oversight over federally funded research. DHHS ensures that such studies comply with 45 CFR 46, the "Common Rule."
Performance: PDUFA inspections of clinical investigator study sites are scheduled after a New Drug Application (NDA) has been submitted and, in general, the number of inspections conducted each year has been dependent on the number of NDAs received. The Agency completed 697 BIMO inspections in FY 2000, 553 in FY 2001 and 635 in FY 2002. In FY 2002, there was a reduction in the number of NDAs submitted and this reduced the number of completed inspections. In FY 2001, NDAs submitted to FDA decreased by 40% from the previous year. FDA plans to restore resources to inspections of non-clinical laboratory facilities and IRBs. In addition, FDA plans to conduct more inspections in the earlier stages of the drug development process, and for foreign studies, and those carried out in special populations (e.g., pediatrics, geriatrics). The original target of 780 is being revised to establish a new base line of inspection sites that are a result of decreasing NDA submissions in fiscal years 2001 and 2002. From 1997-2000, FDA received between 120-135 NDAs per year, and FDA diverted resources from inspections of non-clinical laboratory facilities and IRBs to inspections of clinical investigator study sites in order to accommodate this increase.
Data Sources: COMIS, Field Accomplishments and Compliance Tracking System (FACTS), and ACCESS databases are used to track assignments and results of inspections/data audits.

6. Facilitate development and availability of medical countermeasures to limit the effects of the intentional use of biological, chemical, or radiological/nuclear agents. (12045)

Context of Goal:The first therapy for those exposed to a biological, chemical, or radiological/nuclear agent is often a drug. FDA has been taking an aggressive and proactive approach to getting information on medical countermeasures into the labeling of already approved drugs. In the event that the public receives vaccinia immunization as protection against a smallpox threat, it is estimated that some vaccine recipients will experience serious complications due to the vaccine. Drug therapies are needed to mitigate the risks associated with vaccinia immunization. For example, no drug is currently FDA-approved to mitigate the complications associated with vaccinia immunization. Human clinical trial data experience is needed to demonstrate safety and efficacy for specific treatments and to identify new therapeutic drug options.
In the Federal Government's response to various agents of mass destruction, drugs will be mobilized from the CDC's National Pharmaceutical Stockpile (NPS). However, not all drugs in the NPS are FDA-approved for Counterterrorism uses. Identification of these deficits including development of a plan to address these deficits will move the Public Health Service closer to a goal of labeling all drugs that reside in the NPS for Counterterrorism uses.
Performance:We have issued various guidance and regulations to help Industry develop drugs as medical countermeasures for biological, chemical, or radiological/nuclear agents.

• Federal Register Notice - "Prescription Drug Products; Doxycycline and Penicillin G Procaine Administration for Inhalation Anthrax (Post-Exposure) (10/19/01 - on display)
• Final Guidance - "Guidance on Potassium Iodide as a Thyroid Blocking Agent in Radiation Emergencies" (12/10/01 - on display)
• Draft Guidance for Industry - "Inhalation Anthrax (Post-Exposure) Developing Antimicrobial Drugs" (03/15/02 - on display)
• Guidance for Industry - "KI in Radiation Emergencies -- Questions and Answers (04/22/02)
• Federal Register Final Rule - "New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible" (05/31/02 -- published) We are also working with other part of the Agency and government to facilitate development of medical countermeasures.
• In conjunction with CDC, developed a "streamlined IND" for the use of gentamicin to treat pneumonic plague.
• In conjunction with CDC, assessed the databases for the use of gentamicin for the treatment of inhalation plague and reviewed all known cases in this country since the 1950's.
• Worked with the CDC and the Defense Department to implement a shelf-life extension program for stockpiled drugs for civilian and military use.
• Coordinated within FDA and other agencies to halt the importation of unapproved Cipro.
• In an effort to have products in the National Pharmaceutical Stockpile (NPS) adequately labeled, the FDA is worked with CDC to identify products requiring an Investigational New Drug (IND) application. Together the FDA and CDC have developed the concept of a "Streamlined" IND, which meets the Agency regulatory requirements and allows access to the NPS armamentarium in the event of a terrorist event.

Data Sources and Issues: Published case reports of plague by the Center for Disease Control and Prevention, CDC National Pharmaceutical Stockpile (NPS) program, database from Department of Energy/REAC/TS (Oakridge), published guidances for Industry.

7. Publish guidance for Industry on developing antimicrobial drugs for inhalational anthrax (post-exposure). (12033)

8. Facilitate the initiation of research in a non-human primate model of pneumonic plague. (12034)

Context of Goal: This goal has been consolidated into goal #6 above for FY 04 and FY 03. At present, only streptomycin and doxycycline are FDA-approved for the treatment of plague. However, no drug is specifically approved for inhalational pneumonic plague. Animal models are needed to address whether certain drugs are effective (or ineffective) in the treatment of human pneumonic plague.
Performance: The FDA has established an IAG with NIAID/NIH and USAMRIID entitled "Non-Human Primate Studies of Antibiotic Efficacy for Treatment of Pneumonic Plague Induced by Aerosolized Yersinia Pestis.
Data Sources: Published literature, interactions with USAMRIID and NIH as part of the FDA/NIH Antibiotic Working Group Interagency Agreement (IAG) with NIAID/NIH and USAMRIID.

9. Expedite the review of protocols for investigational new drugs (INDs) to treat organophosphorous nerve agents in the event of chemical attack. Encourage sponsors of approved new drug application (NDAs) to update current labeling for Antidote Treatment Nerve Agent, Autoinjectors (ATNAA). (12035)

Context of Goal: This goal has been consolidated into goal #5 above for FY 04 and FY 03. In the event of a nerve agent attack, a vulnerability to the public health exists if limited drugs options are available. Increasing the number of drugs approved for this specific usage improves the Nation's preparedness including the CDC's National Pharmaceutical Stockpile (NPS).
Performance: The FDA has contacted several of its review divisions to identify approved therapies and candidate therapies against nerve agents. A request for information from the American Academy of Pediatrics was made in May 2002 regarding clinical data on atropine and pralidoxime to determine their use as therapies for nerve agent exposure in the pediatric population. On January 17, 2002, FDA approved nerve gas antidote ATNAA (atropine/pralidoxime) for the treatment of poisoning by susceptible organophosphorous nerve agents having anticholinesterase activity. These two products are already approved separately, but this approval provides for one injection rather than two allowing for more efficiency and convenience on the battlefield. This product is a dual-chambered autoinjector intended for intramuscular administration. This product will initially only be used by the military, but there is some talk that it may be shared with first responders in the case of an emergency.
Data Sources: Published literature, data available from poison control centers, and from a survey of the American Academy of Pediatrics, COMIS, DFS.

10. Publish a final rule which allows the Agency to approve new drug and biological products for the treatment of chemical, biological, radiological, or nuclear substances based on animal efficacy studies when adequate and well-controlled studies in humans cannot be ethically conducted and field studies are not feasible. (12040)

Context of Goal:This goal has been consolidated in goal #6 above for FY 04 and FY 03. To date FDA approvals of drugs and biological products require that prior to licensing, safety and efficacy must be substantiated in adequate and well-controlled human clinical trials. Issuance of a final "animal rule" (Evidence Needed to Demonstrate Efficacy of New Drugs When Efficacy Studies in Humans are not Ethical or Feasible) will permit the Agency's determination of substantial evidence for efficacy be based on animal surrogates. This is particularly germane for drugs to prevent, mitigate, or treat the effects of a bioterrorist agent that can't be ethically studied in humans today (e.g., smallpox infection).
Performance:The Final Rule on the "New Drug and Biological Drug Products: Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficiency Studies Are Not Ethical or Feasible" was published by the FDA in the Federal Register on May 31, 2002.
Data Sources: Public comment on the Proposed Rule (October 5, 1999, 64 FR 53960).

Strategic Goal 2:
Enhance organizational performance in response to stakeholder needs with the highest degree of cost effectiveness and efficiency.

A. Strategic Goal Explanation

CDER¥s mission (to assure that safe and effective drugs are available to the American people) is primarily achieved through sound regulatory decision making. However, to ensure that drugs are available in a timely manner, our processes must be efficient. We must continually reevaluate our programs to make sure that they are meeting their goals and keeping pace with advances in technology.

B.   Summary of Performance Goals

C. Goal-By-Goal Presentation of Performance

11. Improve the capability and efficiency of pharmaceutical development and manufacturing. (12016)

Context of Goal: In conjunction with stakeholders from Industry and academia, FDA has started important initiatives to build a foundation of scientific data needed to modernize American drug manufacturing. Although Americans have the highest quality of drugs in the world, the processes used to produce some of them are outdated. An increasing trend of manufacturing-related problems, such as recalls, disruptions of manufacturing operations, and the loss of availability of essential drugs has affirmed CDER's role as a catalyst for this initiative. Implementation of modern technology into the manufacturing process will produce the same or higher quality standards while reducing the workload for Industry and for FDA and ensuring the highest quality drug products for American consumers. More than 40 years ago, Congress required that all drugs must be produced in accordance with current Good Manufacturing Practice (cGMP). This requirement was intended to address significant concerns about substandard drug manufacturing practices by applying quality assurance and control principles to drug manufacturing. As we approach the 25th anniversary of the last major revisions to the drug cGMP regulations, it is time to evaluate the currency of both the cGMP program and the pre-market review of chemistry and manufacturing issues. The initiative seeks to integrate quality systems and risk management approaches into the existing programs and encourages adoption of modern and innovative manufacturing technology. In addition, the initiative will use existing and emerging science and analysis to ensure that limited resources are best targeted to address important quality issues, especially those associated with predicted or identifiable health risks.
Performance: CDER has embarked on two important related activities: the Product Quality Research Institute (PQRI) and the Process Analytical Technology (PAT). PQRI is an effort between the FDA's Center for Drug Evaluation and Research (CDER), the pharmaceutical Industry and academia. PQRI is a foundation established under the auspices of the American Association of Pharmaceutical Scientists (AAPS). The purpose of PQRI is to conduct research on identified projects to establish better testing methods, standards, and controls for assessing product quality and manufacturing and management processes to look at risk/benefit of changing certain policies and requirements. This knowledge aids the Agency in developing consistent and reasonable requirements for product quality information in regulatory filings as a part of our risk management activities. 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. CDER is utilizing the Process Analytical Technology (PAT) Initiative to provide a science based regulatory framework. Industry has been hesitant to implement new technologies because of unknown factors that may arise under the regulatory environment in which it operates. CDER has formed a PAT subcommittee to the Advisory Committee for Pharmaceutical Science. A cadre of PAT specialists from the Office of Regulatory Affairs (ORA) and CDER has been established and trained.
In addition to the improvements of manufacturing development and new technologies, CDER has been very involved in promoting increased usage of electronic submissions. CDER plans to finalize guidance on Electronic Common Technical Document (eCTD), a standardized way of sending a CTD-based electronic submission from Industry to the regulatory authority, including foreign countries. CDER participates in the International Conference on Harmonisation (ICH), a collaboration of representatives from the US, the European Union (EU) and Japan. Implementation of eCTD will eliminate the need to repeat time-consuming and expensive technical tests that have already been performed in other countries participating in the ICH and will enable Industry to submit applications using a standard format.
Data Sources: Guidance documents. Relevant materials may be found on our website.

12. Create state-of-the-art information and knowledge management systems and practices to move to a paperless environment (12051)

Context of Goal: The use of current technology will allow CDER to receive and review regulatory submissions more efficiently. In order to move to a paperless environment in an efficient and cost effective manner, we must develop standards for submission.
Performance: CDER has been increasing its capability and capacity to receive and review electronic regulatory submissions. Currently, 75 percent of original NDAs received in CDER now include sections that conform to the electronic submission guidance. Only 15% of all NDA submissions are provided entirely in electronic format. In FY 2001, CDER received over 1000 electronic submissions, including full NDAs, supplemental NDAs, and amendments. Electronic submissions continue to provide a significant decrease in the average number of volumes per NDA submissions since the start of electronic submissions in 1997. We are in the process of developing the following regulations and guidance documents:

• Updating Providing Regulatory Submissions in Electronic Format - General Considerations with the participation of CBER, CDER, CDRH, CFSAN and CVM
• A joint CDER/CBER guidance, Providing Regulatory Submissions in Electronic Format - Annual Report for Approved NDAs.
• A guidance for electronic submissions of Drug Master Files.
• Providing Regulatory Submissions in Electronic Format - Prescription Drug Advertising and Promotional Labeling , which is being developed with CBER
• A proposed rule for changes to 21 CFR 201.56 and 201.57, Requirements on Submission of Labeling for Human Prescription Drugs and Biologics in Electronic Format
• A proposed rule is being developed to require electronic submissions of drug registration and listing information (DRLS). FDA is building upon the results of the pilot project and is working towards implementing a similar system on a larger scale in the near future. Implementation plans are being developed.

This past year CDER announced a pilot project involving the testing of the Patient Profile Viewer (PPV). The PPV is computer software being developed under a Cooperative Research and Development Agreement which allows a reviewer to display data collected from case report tabulations (CRTs) submitted in electronic format. This program is being developed to improve review efficiency, develop standards for submission of data, and eliminate the need for the submission of separate patient profiles by applicant of NDAs.
CDER together with CBER is working on the development of an electronic Common Technical Document (eCTD) review tool for marketing applications. This tool is intended to utilize submissions in the eCTD format as specified by the technical working group in the International Conference on Harmonisation. This work will be the foundation for efforts on developing an electronic file management system for submission of other applications including the IND. CDER is also involved with the development and implementation of standards through a number of processes.

• CDER is a member of the FDA Data Council which serves as the agency focal point for coordination of standardized data elements and electronic data across all centers.
• CDER is participating in Health Level Seven, an ANSI accredited standards development organization for healthcare issues, for the development and implementation of standards.
• CDER is working on partnerships and leveraging opportunities to develop and implement study data standards to improve communication between organizations involved in regulated research.
• CDER has signed a Memorandum of Understanding with the National Library of Medicine to help with the establishment of medication reference terminology.

Data Sources: The Electronic Document Room

Strategic Goal 3:
Prevent unnecessary injury and death to the American public caused by adverse drug reactions, medication errors, and product problems.

A. Strategic Goal Explanation

The practical size of premarketing clinical trials means that we cannot learn everything about the safety of a drug before we approve it. Therefore, a degree of uncertainty always exists about the risks of drugs. This uncertainty requires our continued vigilance to collect and assess data during the postmarketing life of a drug. Once a drug is approved for sale in the United States, we monitor the use of marketed drugs for unexpected health risks. If new, unanticipated risks are detected after approval, we take steps to inform the public and change how a drug is used or even remove a drug from the market. We also monitor manufacturing changes to make sure they won't adversely effect the safety or efficacy of the medicine. We evaluate reports about suspected problems from manufacturers, health care professionals and consumers. Sometimes, manufacturers run into production problems that might endanger the health of patients who depend on a drug. We try to make sure that an adequate supply of drugs is always available. FDA also must be vigilant to protect Americans from injuries and deaths caused by unsafe, illegal, fraudulent, substandard or improperly used products. We monitor the quality of marketed drugs and their promotional materials through product testing and surveillance. As Americans are increasingly receiving the benefits of important new drugs before they are available to citizens of other countries, we must be especially vigilant in our surveillance to prevent fraudulent activities involved with the sale of approved and unapproved prescription drugs. In addition, we develop policies, guidance and standards for drug labeling, current good manufacturing practices, clinical and good laboratory practices and Industry practices to demonstrate the safety and effectiveness of drugs.

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. FDA has been partnering with others in DHHS to promote patient safety and prevent medical errors. FDA is taking the lead on a national adverse 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.

B. Summary of Performance Goals

C. Goal-By-Goal Presentation of Performance

13. Enhance postmarketing drug safety. (Formerly: Streamline adverse drug event reporting system). (12007)

Context of Goal: CDER uses a number of postmarketing risk assessment approaches to ensure the continued safe use of drug products. Yet, approximately 1.3 million patients each year are injured from medical therapy with up to two thirds of these events due to medical management errors. Costs from these medical errors range from $37 to $50 billion annually. The Institute of Medicine estimates that as many as 100,000 Americans die annually as a result of preventable medical errors and the proliferation of new products may increase this number. In fiscal year 2002, FDA received 291,422 reports of suspected drug-related adverse events for entry into the Adverse Events Reporting System (AERS), of which 43% represented serious or unexpected events. 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. Reports of deviations from Good Manufacturing Practices that occur during the manufacturing, shipping, or storage of prescription or OTC drug products are sent to the FDA's Drug Quality Reporting System (DQRS). FDA receives medication error reports on marketed human drugs and maintains a central database within the DQRS and AERS for all reports involving a medication error or potential medication error. The Agency puts substantial effort into reviewing adverse event and medication error reports to identify serious or potentially serious outcomes that might be avoided by modifying the labeling or packaging or other means. AERS is an important risk assessment database essential for identifying and monitoring the incidence of adverse effects. FDA evaluates spontaneous reporting data from 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. CDER is utilizing a $3 million increase in FY 2004 to support the design and implementation of improvements to the Adverse Events Reporting System (AERS) to enhance medication errors monitoring. Improved efficiencies in AERS will begin to address the challenges inherent in managing the risks and reducing preventable adverse events associated with medical product use by creating a seamless interaction between the FDA and consumers, health care personnel, and the regulated Industry.
CDER will also coordinate with Medical Device contractors to continue Implementation of drug products into Phase III of the Medical Device Surveillance Network (MeDSuN). MeDSuN is designed to train hospital personnel to accurately identify and report injuries and deaths associated with medical products. The MeDSuN model, currently designed to track and analyze adverse events due to medical devices, will be expanded to include drug products. Initial work included a feasibility and acceptability assessment of a small regional group of hospital pharmacists about incorporating MeDSuN into their reporting of adverse drug effects and medication errors. In FY 2003, follow-up activities will include additional focus group assessments and individual site visits. Subsequent research efforts will address the hospital's decision-making process to participate in MeDSuN and to integrate risk manager reporting on devices with the reporting of adverse drug events and medication errors by hospital pharmacists or other personnel. This is also described under the MeDSuN performance goal.
Performance: AERS has been operational for nearly five years. Note the following data:

In February 2001, AERS version 2.1 enhanced the compliance and Freedom of Information portions of AERS by making it more accessible to compliance staff and improving compliance-related search capabilities. In May 2001, AERS version 2.2 enhanced the ability of the system to accept electronic submissions. AERS version 2.3 was implemented in August of 2001. In FY 2002, AERS version 4.0, the Windows/Oracle upgrade, has been implemented. In addition, MedDRA coding version was upgraded to 4.0. AERS versions 3.0 (provides for MedDRA upgrade from v1.9 to v4.0); 3.1 (E2BM and DTD 2.1); and 4.0 (oracle and windows upgrade) were implemented on December 17, 2001; April 1, 2002; and September 23, 2002, respectively.CDER implemented an Electronic Submission Product Test Pilot for AERS in October 2000. This pilot is part of a step-level implementation program to provide a mechanism for companies to test and send electronic submissions of expedited reports via physical media or gateway directly into AERS. The pilot allows FDA to identify and resolve several process issues while regulatory and infrastructure changes are implemented. Automating the receipt and processing of safety reports will allow FDA to be more responsive to public health issues, reduce resources associated with data management, and apply better data and better science to the drug regulatory process. The pilot moved to a production phase in FY 2002. The number of ADR reports submitted electronically has increased each year. (See specific electronic submission data in the first paragraph.) The proposed rule on Adverse Drug Reporting (ADR) and guidance on electronic submissions is in the process of being finalized. In May 2001, a draft guidance for Industry, "Providing Regulatory Submissions in Electronic Format - Postmarketing Expedited Safety Reports" was released. On May 18, 2001, Postmarketing Expedited Safety Reports - 15-Day Alert Reports, was added to public Docket 92S-0251. This allowed for voluntary electronic reporting of 15-day (expedited) safety reports with no paper submissions required. In FY 2001, over 15,000 individual case safety reports were submitted electronically under the pilot program (see Figure 3 below).

In FY 2003, the Agency will conduct additional risk management and risk communication research, including pilot initiatives to minimize preventable adverse drug reactions and medication errors. Guidance document development is a goal included in PDUFA-3. The goal states that by the end of FY 2004, CDER and CBER will jointly develop final guidance documents that address good risk assessment, risk management, and pharmacovigilance practices. A pending proposed rule will include the replacement of periodic drug adverse experience reports (21 CFR 314.80) with Periodic Safety Update Reports (PSURs); currently, CDER encourages Industry to submit a waiver to allow submission of PSURs instead of periodic drug adverse experience reports. PSURs are in the format proposed by the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, Topic E2C. The PSUR summarizes the safety data received by a sponsor for an application from worldwide sources for a specific timeframe. The number of PSURs received is dependent on the number of NDAs/ANDAs marketed.

14. CDER will conduct laboratory research on projects identified as related to the mission of PQRI. (12016)

Context of Goal: This goal has been consolidated into goal #11 above for FY 04 and FY 03. The Product Quality Research Institute (PQRI) is a prototype collaboration among FDA, academic, and Industry scientists to conduct research in the areas of pharmaceutical chemistry, biopharmaceutics. The purpose of this research on the three identified projects is to establish better testing methods, standards, and controls for assessing product quality and manufacturing and management processes to look at risk/benefit of changing certain policies and requirements. This knowledge aids the Agency in developing consistent and reasonable requirements for product quality information in regulatory filings as a part of our risk management activities. Leveraging scientific expertise in this way contributes to streamlining the drug development and approval processes for Industry and FDA while ensuring the highest level of product quality.
Performance: In FY 2001, FDA initiated three laboratory research programs and performed the corresponding research in connection with the mission of PQRI: Oral Biopharmaceutics, Drug Product, and Drug Substance. These programs are expected to contribute to developing/revising bioavailability/equivalence, SUPAC, and drug substance regulations for product quality. In FY 2002, FDA conducted three laboratory research programs and performed the corresponding research in connection with the mission of PQRI: Oral Biopharmaceutics, Drug Product, and Drug Substance. The Oral Biopharmaceutics program added to the Biopharmaceutics Classification System (BCS) database, performed in vitro permeability studies to support the review of BCS biowaiver requests, performed a third food effect clinical studies and continued to develop novel models of using in vitro methods to predict in vivo bioavailability and bioequivalence. The Drug Product program collected Near-IR spectra and then dissolution data of 240 tablets representing the 40 furosemide tablet formulations that were designed and manufactured in FY 2001. Using chemometric analysis, the feasibility of predicting product dissolution using a nondestructive test (Near-IR spectroscopy) was demonstrated. The Drug Product program also investigated regulatory applications of noninvasive imaging by Near-IR and conducted blend uniformity studies in final dosage form. The Drug Substance program initiated the API Test Study as an approach to rapidly detect counterfeit versus authentic drug substances. The study employed three fingerprint techniques: Near-IR, Raman and Ion Mobility. Four test sets (tropicamide, hydrocortisone, quinine, and tryptophan) were evaluated by each technique. The Drug Substance program also evaluated the regulatory acceptability of using Near-IR to monitor drug substances for polymorphism and states of hydration. FDA met its goal for FY 2002. CDER will complete a review of at least one PQRI recommendation and participate in two PQRI work groups to develop additional recommendations. FDA will also cosponsor two scientific workshops to bring together our scientists with external experts. In FY 2004 CDER will continue with significant progress on the three identified project (defined as 50 percent toward completion for each project; completion is considering the recommendations, give them appropriate scientific vetting, and then changing, etc., our policies to incorporate the recommended change(s)).
Data Sources:

15. Inspect 55% of registered high-risk human drug manufacturers. (12020)

Context of Goal: FDA has changed the performance target for manufacturing inspections from 20 percent of all drug establishments to 55 percent of high risk establishments in support of a risk-based approach that focuses scarce inspectional resources on drug establishments where FDA intervention is likely to achieve the greatest public health impact. This approach will encourage more inspections at drug establishments where FDA can intervene to address or prevent manufacturing problems that would have the most significant adverse effect on drug safety and effectiveness. This goal measures performance for the inventory of registered domestic drug establishments which operate under high risk conditions. The categories are defined as follows:

• New registrants - Drug establishments registered over the past year for which no regulatory information about the firm is known. Inventory 100, 100 percent coverage, 100 inspections.
• Manufacturers of sterile drug products - The characteristics of products manufactured in this category are complex, unique and particularly vulnerable to contamination. Inventory 130, 50 percent coverage, 65 inspections
• Prescription drug manufacturers - Drug products that are used to treat, prevent or diagnose illnesses, which are more potent and susceptible to cross contamination and variability concerns. Inventory 400, 50 percent coverage, 200 inspections.

To accomplish this goal, inspections of new registrants may be carried out by FDA directly, or through State contracts or partnership agreements. Achievement of the goal relies on the willingness and ability of the States to contract with FDA to share in the workload. 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. With a working total inventory of 6000 registered/domestic-sited establishments, the 630 high risk establishments represent 11 percent of the total inventory of sites. For FY 2003 we are projecting a total inspection accomplishment of 1,275 inspections, the high risk establishments above plus the balance at other establishments from the inventory, for the assessment of compliance with the GMP requirement. This represents an overall rate of 21 percent against the biennial inspection requirement (50 percent rate).
Performance: There was no planned coverage percentage established in FY 2002. Target coverage percentages for 2003 is 55 percent of an estimated 630 establishments in the high risk inventory categories.
Data Sources: The inventory of high risk drug establishments is based on compliance status reports developed from the Field Information System and is augmented by a list of targeted establishments generated by the CDER, based on their judgement of those establishments that meet the high risk criteria defined above.

16. Give consumers and health professionals more easily understandable, accessible, timely, and accurate prescription and OTC drug information. (12027)

Context of Goal: (Dropped for FY 2002 and 2003) This goal was dropped for FY 2002 and 2003 because more specific and quantifiable milestones needed to be developed. The goal is being reinstated for FY 2004 with new, detailed targets. There is increasing 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. Information and outreach efforts will continue to concentrate on improving the safety of drug use. FDA is the recognized source for having the most up-to-date, accurate information. The Agency strives to conduct timely, relevant campaigns based on existing or emerging needs, issues, and events. Thus, the specific subjects of FY 2004 education campaigns will be determined as issues and events reveal themselves closer to FY 2004. Providing 'user-friendly', accurate information will increase patient safety by potentially reducing medication errors.
Performance: In FY 2001, the FDA met almost weekly with outside experts on difficult scientific and public health issues; responded to more than 52,000 individual requests for information. We also launched twice-yearly, week-long introductory workshops for our stakeholders; and received nearly 6.6 million visitors and about 111 million hits on our Internet information site. We launched a public education campaign on consumer-friendly brochure on how to play an active role to reduce risks and maximize benefits of using medications. We developed an outreach plan to eliminate deaths and injuries occurring when incorrect medical gas tanks are connected to oxygen lines in hospitals and nursing homes. In FY 2001, the Agency responded to more than 31,000 individual inquiries from consumers about their medications and nearly 8,000 similar inquiries from physicians and other health care professionals.
FDA's Web site increasingly focused on consumer information, building introductory pages on drug safety, bioterrorism drugs, and risk management. Examples of Consumer-oriented risk management information were posted on the web site in FY 2001. Public use of the Agency's drug information Internet site averaged more than half a million visitors each month, and each visitor viewed on average 17 pages of information including menus.
FDA has begun focusing on user-focused "sense-making" and content management by designing Web pages that pull information together in a way that will help solve users information problems. All pages are tested for both accessibility compliance and for usability. An initial step in synchronizing the Agency's consumer information campaigns with Web sites included Over-the-Counter labeling and food-drug interactions.
In cooperation with its leveraging partners, FDA continued to develop the Over-the-Counter Medicine Label Campaign in anticipation of full implementation by manufacturers in FY 2002. To address the growing problem of the emergence of drug-resistant bacteria and its effects on drug development and regulation, the Agency is developing approaches to provide education and information on the appropriate use of antibiotics to health care professionals and consumers. Details of these efforts and other resources are available on the Agency's web site.
Data Sources: Approval Letters and the Labeling Text or Final Printed Label (FPL) for new drugs; Consumer Drug Information Sheets for New Molecular Entities (NMEs); 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.

17. Finalize rulemaking to establish a web-based electronic drug registration and listing database to allow for complete and up-to-date data on all regulated drugs products, and follow this finalization with launch of the electronic database. (12042)

Context of Goal: Section 510 of the Federal Food Drug and Cosmetic Act requires all establishments engaged in the handling of pharmaceutical products to register and list their products with the Food and Drug Administration. Recently, Under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, Section 321 - Annual Registration of Foreign Manufacturers, electronic registration is required. CDER has been working to overhaul its legacy Drug Registration and Listing System data and processes, including revisions to the current regulations and mandatory electronic submission of DRLS data by the regulated Industry. This new automated system will provide timely, accurate information about the availability of drugs in an efficient process. Manufacturers of human drugs must register their establishment(s) with the FDA and also submit a listing of every product they market in the US. The Agency uses this information to swiftly communicate with these manufacturers in cases of product emergencies. In the event of a terrorist attack, various drugs may be utilized in response to the attack. Rapid access to accurate and timely information pertaining to the manufacturers and their respective drugs is critical to surge manufacturing production needs and to reduce the risk of drug shortages.
Performance: The current CDER proposal consists of continuing the Drug Listing and Registration paper based system, while concurrently developing the electronic e-DRLS system and moving toward publication of a proposed rule in FY 2003. The rapid development of the system over the next 6 to 12 months would be coordinated with the draft regulations as it works its way to final issuance. The electronic system would be implemented concurrent with the issuance of the final rule. FDA relies on complete and accurate establishment registration and product listing information to accomplish a number of its statutory and regulatory objectives. For example, FDA uses establishment registration and product listing information to: (1) Identify firms that manufacture a specific product or ingredient when that product or ingredient is in short supply or needed for a national emergency, for example, during a bioterrorism threat (for example, the drug listing database was used to identify sources of potassium iodide during the Three Mile Island incident); (2) Identify the locations of all establishment sites engaged in the manufacture, preparation, propagation, compounding, or processing of drugs or biologics; (3) Identify all the establishments involved in the processing of a drug or biologic from the original place of manufacture to the person who makes the final delivery or sale to the ultimate consumer or user; (4) Catalogue human and veterinary drugs and biological products in commercial distribution; (5) Administer FDA's postmarketing surveillance programs for human and veterinary drug products and licensed biological products; (6) Determine which products subject to section 505 of the act (21 U.S.C. 355) are being marketed without approved new drug applications; (7) Schedule and plan inspections of registered establishments as authorized under section 704 of the act (21 U.S.C. 374); and (8) Determine which marketed drug products are identical, related, or similar to drug products reviewed by the Drug Efficacy Study Implementation (DESI). The Agency also relies on registration and listing information to help determine which establishments and products are subject to user fees under the Prescription Drug User Fee Act of 1992 (Public Law 102-571), as amended by the Food and Drug Administration Modernization Act of 1997 (Modernization Act) (Public Law 105-115). In addition, the Agency uses registration and listing information to generate accurate estimates of registered establishments and marketed products that are affected by FDA rulemaking. These estimates help FDA assess the economic impact of its regulations on the regulated Industry, which the agency is required to do under the Regulatory Flexibility Act of 1980 (Public Law 96-354, as amended by Public Law 104-121), the Paperwork Reduction Act of 1995 (Public Law 104-13), and Executive Order 12866 (September 30, 1993). An electronic registration and listing system will enable FDA to use the latest technology to improve its current paper based registration and listing system, which would further its goal of protecting the public health. FDA also believes that the conversion to an electronic system will make the registration and listing process more efficient for Industry and the agency.
Data Sources: Published literature; Drug Registration and Listing System (DRLS).

18. Publish a Notice in the Federal Register on doxycycline and penicillin G procaine dosing recommendations for inhalational anthrax. (12043)

Context of Goal: This goal has been consolidated under goal #6 above for FY 04 and FY 03. At the time of the anthrax attacks, only one drug, ciprofloxacin, was approved for inhalational anthrax post-exposure prophylaxis. Issuance of this notice effectively approves two other drug options for this indication.
Performance: The Notice, Prescription Drug Products; Doxycycline and Penicillin G Procaine Administration for Inhalational Anthrax (Post-Exposure) was published in the Federal Register on November 2, 2001
Data Sources: Published literature.

19. Issue guidance on the use of potassium iodide (KI) as a thyroid blocking agent in radiation emergencies. (12044

Context of Goal: This goal has been consolidated into goal #6 above for FY 04 and FY 03. In the event of an intentional radiation emergency, in addition to evacuation, potassium iodide would be indicated to decrease the risk of thyroid cancer. Issuance of a final KI dosing guidance will provide clear dosing recommendations to the public and facilitate Federal, State, and local preparedness.
Performance: The Guidance: Potassium Iodide as a Thyroid Blocking Agent in Radiation Emergencies was published in November 2001. Additionally, the Guidance for Industry: KI in Radiation Emergencies - Questions and Answers was published in April 2002.
Data Sources: Published literature.

Contact Information:
Planning Staff, Office of Planning, FDA
Phone: 301-827-5210

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