Part 2, human drugs (first part), FY 2003 Annual Performance Plan

U.S. Food and Drug Administration
Performance Plan
2002

2.3 HUMAN DRUGS

2.3.1 Program Description, Context, and Summary of Performance

Total Program Resources:

	FY 03 Current Request	FY 02 Current Estimate	FY 01 Actual	FY 00 Actual	FY 99 Actual
Total ($000)	457,979	366,897	322,480	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 by thoroughly analyzing scientific data submitted to the Agency on prescription and over-the counter (OTC) drug products. Once drugs are approved, they may be marketed and distributed for use. At that time, Agency postmarket surveillance assures the quality of drugs on the market and strives to minimize adverse events associated with their use. To accomplish its premarket and postmarket responsibilities, 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, 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 its 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 associated with the evaluation of investigational new drugs (INDs), new drug applications (NDAs), generic drug applications (abbreviated new drug applications - ANDAs), efficacy supplements, and manufacturing supplements. Review of OTC labeling and pediatric study requests is also an integral part of our premarket review process. Postmarket surveillance performance goals include: assessing risk to identify adverse events; 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.

2.3.2 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. These include reduced drug development time, increased and quicker access to new drug products, and an increased number of therapeutic options for health professionals. 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. The timely performance of high-quality drug reviews in recent years reflects the importance of managerial reforms and additional resources provided under the Prescription Drug User Fee Act (PDUFA). The law, first enacted in 1992, was renewed for an additional five years in the 1997 FDA Modernization Act (FDAMA). Under the law, the drug industry pays user fees for NDAs, efficacy supplements, and some other activities. User fees helped the Agency hire additional scientists to perform reviews.

B. Summary of Performance Goals

Performance Goals	Targets	Actual 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)	Standard NDAs within 10 months: FY 03: 90% FY 02: 90% FY 01: 70% FY 00: 50% FY 99: 30% Standard NDAs within 12 months: FY 03: NA FY 02: NA FY 01: 90% FY 00: 90% FY 99: 90% Priority NDAs within 6 months: FY 03: 90% FY 02: 90% FY 01: 90% FY 00: 90%	FY 03: FY 02: FY 01 Final data available 01/03 FY 00: 79% FY 99: 66% FY 03: FY 02: FY 01: Final data available 01/03 FY 00: 97% FY 99: 100% FY 03: FY 02: FY 01: Final data available 01/03 FY 00: 97%
2. Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule. (12026)	FY 03: Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule FY 02: Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule. FY 01: Implement, evaluate, track and report on the clinical trials FDA is requesting under FDAMA or requiring under the Pediatric Rule.	FY 03: FY 02: FY 01: 43 Written Requests issued;19 Exclusivity Determinations; Over 47,000 children have participated in clinical trials as of October 2001 as a result of the studies FDA requested under the exclusivity provision. Nine drugs were approved and labeled for pediatric use based on studies conducted in response to Written Requests. FY 00: Exclusivity: 39 Proposed Pediatric Study Requests reviewed 62 Written Requests issued 59 Amended Written Requests' issued 19 Exclusivity determinations 16 Exclusivities granted 7 Labels changed Ped Rule: Pediatric Assessments Deferred = 76 Pediatric Assessments Waived = 91
3. Review and act upon fileable original generic drug applications within 6 months after submission date. (12003)	FY 03: 75% FY 02: 65% FY 01: 50% FY 00: 45% FY 99: 60%	FY 03: FY 02: FY 01: Final Data available 4/02 FY 00: 55.6% FY 99: 28%
4. Protect human research subjects who participate in drug studies and assess the quality of data from these studies by conducting approximately 780 onsite inspections and data audits annually. (12032)	FY 03: 780 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 applications received.	FY 03: FY 02: FY 01: 553 inspections completed FY 00: 697 inspections completed FY 99: 683 inspections completed
5. Publish guidance for Industry on developing antimicrobial drugs for inhalational anthrax (post-exposure). (12033)	FY 03: NA FY 02: Publish guidance for Industry on developing antimicrobial drugs for inhalational anthrax (post-exposure). FY 01: NA	FY 03: FY 02: FY 01: NA
6. Facilitate the initiation of research in a non-human primate model of pneumonic plague. (12034)	FY 03: NA FY 02: Facilitate the initiation of research in a non-human primate model of pneumonic plague. FY 01: NA	FY 03: FY 02: FY 01: NA
7. 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 03: NA FY 02: Expeditite 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 labling for Antidote Treatment Nerve Agent, Autoinjectors (ATNAA). FY 01: NA	FY 03: FY 02: FY 01: NA
8. Identify and begin to address labeling gaps in the therapeutic armamentarium for the prevention, mitigation, and treatment of illnesses cases by chemical and biological attacks, including the needs for special populations, such as pregnant women, pediatric, and geriatric populations. (12036)	FY 03: Identify and begin to address labeling gaps in the therapeutic armamentarium for the prevention, mitigation, and treatment of illnesses cases by chemical and biological attacks, including the needs for special populations, such as pregnant women, pediatric, and geriatric populations. FY 02: NA FY 01: NA	FY 03: FY 02: FY 01: NA
9. Develop guidance for Industry on developing antiviral drugs for the mitigation of complications associated with vaccinia immunization. (12037)	FY 03: Develop guidance for Industry on developing antiviral drugs for the mitigation of complications associated with vaccinia immunization. FY 02: NA FY 01: NA	FY 03: FY 02: FY 01: NA
10. Facilitate human clinical trials in pneumonic plague for antimicrobial drugs that are not yet labeled for this treatment indication. (12038)	FY 03: Facilitate human clinical trials in pneumonic plague for antimicrobial drugs that are not yet labeled for this treatment indication. FY 02: NA FY 01: NA	FY 03: FY 02: FY 01: NA
11. Develop guidance for Industry on developing antiviral drugs for the treatment of smallpox. (12039)	FY 03: Develop guidance for Industry on developing antiviral drugs for the treatment of smallpox. FY 02: NA FY 01: NA	FY 03: FY 02: FY 01: NA
12. 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 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 01: NA	FY 03: FY 02: FY 01: NA
13. Expedite the review of protocols for investigational new radioprotectant drugs (including heavy metal chelators) for use in the event of a radiation emergency. (12041)	FY 03: Expedite the review of protocols for investigational new radioprotectant drugs (including heavy metal chelators) for use in the event of a radiation emergency. FY 02: NA FY 01: NA	FY 03: FY 02: FY 01: NA
TOTAL FUNDING: ($000)	FY 03: 343,484 FY 02: 275,173 FY 01: 257,984 FY 00: 233,425 FY 99: 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 given to the review of new drugs 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: CDER met its FY 2000 performance goal (see Table 1 below).

Table 1
Fiscal Year 2000 Cohort (as of 12/31/01)

Submission Type	Number of Submissions Filed	Goal (months)	Number of Reviews "On Time"	Percent of Reviews "On Time"
NDAs -- Priority	29	90% in 6 mo.	28	97%
NDAs -- Standard	92	90% in 12 mo. 50% in 10 mo.	89 73	97% 79%

Submission Type

Number of Submissions Filed

Goal (months)

Number of Reviews "On Time"

Percent of Reviews "On Time"

NDAs -- Priority

90% in 6 mo.

97%

NDAs -- Standard

90% in 12 mo.

50% in 10 mo.

97%

79%

Several important new drugs were also approved by FDA in FY 2001 (see Table 2 below).

Table 2
Significant NDAs Approved in FY 2001

Drug	Purpose
Combination of Xeloda (capectitabine) and Taxotere (docetaxel)	Treatment of metastatic breast cancer that has progressed after treatment with anthracycline cancer therapy (such as Adriamycin and doxorubicin)
Natrecor® (nesiritide) Injection	Treatment of acute congestive heart failure (CHF).
Gleevec (imstinib mesylate, also known as STI-571)	Treatment of chronic myeloid leukemia --a rare life-threatening form of cancer
Cancidas (caspofungin acetate) Intravenous Infusion	New anti-fungal medication for patients who are unresponsive to or cannot tolerate standard therapies for the invasive form of aspergillosis
Femara (letrozole)	First-line treatment for postmenopausal women with hormone receptor positive or hormone receptor unknown, advanced or metastatic breast cancer

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 have 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.

Figure 1

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 for pediatric studies if the Agency determines that information related to the use of a 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 population 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. The April 1, 1999 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.
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 245 Proposed Pediatric Study Requests (PPSR), issued 197 Written Requests (WR) asking for over 421 studies to be conducted in the pediatric population and has granted exclusivity to 32 products. Nineteen of the 32 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.
On January 4, 2002, the President signed into law the "Best Pharmaceuticals Act for Children," which is the final version of the pediatric exclusivity reauthorization legislation. The signing of this important piece of legislation ensures that pediatric studies of drugs will continue to be conducted, providing useful new information in product labeling concerning safety and effectiveness. Pediatric supplements that require clinical data for approval will now be considered Priority supplements under PDUFA and are subject to the performance goals that apply to Priority drugs, which is currently a six-month review. The fourth Pediatric Advisory Subcommittee occurred on April 23 and 24, 2001. Pediatric drug development in two diseases/conditions was discussed: chronic hepatitis C infection in children and drooling in pediatric patients with cerebral palsy and other neurologic disorders. 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.
Ethical issues and concerns have been raised regarding the increase in the enrollment of children in clinical trials. The increase is due to the Pediatric Rule and the pediatric provisions of FDAMA. In October 2000, the Children's Health Act (Pub. L. 106-310) was signed into law. As mandated by the Act, the Agency incorporated Subpart D of the DHHS regulations into FDA regulations. The interim rule, Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products (66 Federal Register 20589), was published on April 24, 2001 and effective on April 30, 2001.
The Agency contracted out development of an inpatient pediatric database that will be 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. The information is critical to the Agency as it determines the potential health benefit for drugs to be issued Written Requests or to comply with the Pediatric Rule.

3. Review and act upon 75% of fileable original generic drug applications within 6 months after submission date. (12003)

Context of Goal: 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. A generic drug product is one that is comparable to the reference listed drug product in dosage form, strength, route of administration, quality, performance characteristics, and intended use. Generic drug applications are termed "abbreviated" in that they generally do not require preclinical (animal) and clinical (human) data to establish safety and effectiveness. These parameters were established upon the approval of the innovator drug product. A Congressional Budget Office report estimates "that the purchase of generic drugs reduced the cost of prescriptions (at retail prices) by roughly $8 to $10 billion in 1994."¹
[¹ Congressional Budget Office, A CBO Study: How Increased Competition from Generic Drugs Has Affected Prices and Returns in the Pharmaceutical Industry (ftp://ftp.cbo.gov/6xx/doc655/pharm.pdf, July 1998), p. 13.]
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 met its goal for FY 2000 acting on 55.6 percent of original applications within 6 months after the submission date. This is an increase of more than 27 percent over FY 1999.
Of these applications, several represent the first time a generic was approved for a product. Examples of important first time approvals are listed in Table 3 below.

Table 3
Notable First Time Generic Approvals

Drug	Purpose
Buspirone Hydrochloride	Management of anxiety disorders or short-term relief of symptoms of anxiety (generic for Buspar by Bristol Myers Squibb)
Famotidine	Prevention and treatment of heartburn (generic for Pepcid AC by Merck)
Fluoxetine	Treatment of depression (generic for Prozac by Lilly)
Butorphanol Tartrate	Management of pain (generic for Stadol NS by Mead Johnson)
Levocarnitine	Treatment of primary systemic carnitine deficiency (generic for Carnitor by Sigma Tau)

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).

Figure 2

CDER used a $1.2 million dollar increase in FY 2001 to fully annualize the positions added in FY 2000 and add several additional FTE. 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.

The Office of Generic Drugs (OGD) continues to refine the review process to increase efficiency with the $1.2 million increase and increases in past 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 the first action is taken within the statutory time frame. 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. OGD also plans to revise the current system for amendment designation, major versus minor, to improve total review times.

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2.3 HUMAN DRUGS

2.3.1 Program Description, Context, and Summary of Performance

2.3.2 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.

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.