EXPLANATION OF PROGRAM

FDA's Human Drugs Program includes oversight of human pharmaceuticals from the time of first entry into people as an investigational product through its obsolescence as a marketed product. This is accomplished through review of investigational new drug applications (INDs); evaluation of marketing applications for new and generic drugs; establishing and monitoring standards for use, labeling and composition of both prescription and over-the-counter (OTC) drugs; monitoring the quality and safety of products manufactured in, or imported into, the United States; regulating the advertising and promotion of prescription drugs; developing and maintaining the management and information systems capability necessary to achieve greater efficiency and effectiveness of operations; and promoting informational and educational programs addressing both medical and consumer interests.

INCREASES:

PUBLIC HEALTH INFRASTRUCTURE - + 14.9 MILLION, + 30 FTE

The FDA has conducted a comprehensive assessment to identify the gap between current performance and what would be required to meet statutory mandates and public expectations of effective product safety systems. Consistent with principles underlying the FDAMA, the Agency listened carefully to its stakeholders to determine priority needs and to develop collaborative, cost effective solutions to public health problems. Based on this assessment, the FDA has developed strategic initiatives to narrow the gap between stakeholder expectations and reality as follows.

Injury Reporting -- ($ 7.3 million, 0 FTE)

An increase of $ 7.3 million is requested for the prevention of medical-related injury. The overall plan for FDA injury reporting envisions Agency databases that are accessible by all programs and that are served by powerful analytical tools. The Adverse Event Reporting System (AERS), is a state-of-the-art information technology system for receiving, storing, and analyzing the 250,000 individual reports of suspected drug-related adverse events received by the Agency annually. AERS will be the first system in the world that actually implements the various information technology and safety reporting agreements reached as part of the International Conference on Harmonization.

AERS contributes to the protection of the public health by providing a science-based integrated approach to safety-related risk assessment including providing wider access by professionals and the public to communicate potential product problems to the FDA; maximizing the safety of approved medical products; providing greater assurance that a potential problem with a marketed medical product will be found and appropriate corrective action expeditiously taken; and providing systematic feedback to the health care community and the public in a more proactive way.

The goal of AERS is to support the strengthening of the Agency's postmarket surveillance program for all regulated products. This goal can be met by providing a consistent, Agency-wide approach to the receipt and processing of adverse events information, and increasing reporting of events by the health care community, and manufacturers. AERS is expected to be a major component in the development of an integrated, science-based Agency-wide approach for collecting, monitoring, evaluating, and reporting adverse events, medication errors, and product defects associated with products regulated by the Agency. Thus, FDA will be able to support the quality of spontaneous reports, improve FDA's infrastructure, and strengthen extramural efforts. Increasing the quality of spontaneous reports involves expanding outreach (communication, education, and training) to health care professionals, industry, and the public, and increasing partnered research. This will enable FDA to better understand the keys to recognition and reporting of adverse events and user error problems and subsequent communication of risk information.

To improve the infrastructure which supports the postmarket surveillance program, it is necessary to develop computer and information systems to handle electronic submission and analysis of adverse event data, including desktop access to outside sources of information, hardware and software upgrades and training, gateways with automated editing templates, and linkages to the premarket review area. It is also necessary to acquire a sufficient cadre of drug evaluators trained to manage and track the flow of reports and conduct evaluations, and to expand capabilities to share information within the Agency and with other government agencies and FDA stakeholders.

FDA intends to move as rapidly as possible to an integrated, fully electronic adverse event reporting system. This will:

• Reduce overall costs (1) by allowing reporters to submit electronically, directly into agency systems which will eliminate or substantially reduce the data entry and record handling costs and (2) through the development and use of uniform coding and nomenclature systems for submission and data handling across Centers.
• Provide wider access by professionals and the public to communicate potential product problems to the FDA and maximize the safety of approved medical products.
• Provide greater assurance that a potential problem with a marketed medical product will be found and appropriate corrective action expeditiously taken and provide systematic feedback to the healthcare community and the public in a more proactive way.

The increase will enable FDA to:

• Enhance postmarket surveillance by improving electronic receipt and review of ADR reporting under the Adverse Event Reporting System (AERS);
• Increase ability to provide manufacturing quality assurance;
• Maximize external collaboration and cooperation with the pharmaceutical industry, consumers, academia, and other governmental organizations.
• Increase the quality of scientific information learned from clinical trials while decreasing drug development and review times while;
• Continue to convert from a paper intensive application process to an electronic submission and review system;
• Improve the infrastructure which supports the postmarket surveillance program;
• Develop analytical data warehouse capacity and design the data configuration for routine reports and analyses to be used by the Centers.
• Improve the quality and scope of adverse event reporting by the health care community, and to communicate safety issues through broader communications with health care professionals ensuring that improved knowledge about product injuries actually improves people's health.
• Develop computer and information systems to handle electronic submission and analysis of adverse event data, including desktop access to outside sources of information, hardware and software upgrades and training, gateways with automated editing templates, and linkages to the premarket review area.
• Acquire a sufficient cadre of drug evaluators trained to manage and track the flow of reports and conduct evaluations, and to expand capabilities to share information within the Agency and with other government agencies and FDA stakeholders.
• Establish contracts for systems design and support, developing more cooperative agreements with other government and health agencies, which will allow FDA would gain access to existing databases which contain adverse event reaction information from various sources including managed care organization data systems. and
• Establish contractual agreements with industry and academia involved in postmarket surveillance activities which will allow a cross-agency research contract will be put in place to improve the quality of reports, including identification of products involved, the nature of the injury, and improving compliance with reporting requirements.

Product Safety Assurance -- ($ 5.3 million, 17 FTE)

FDA is requesting $ 5.3 million and 17 FTE to ensure the quality and performance of drug products for the American people and to minimize the cost of drug development and the regulatory burden through product quality research in a research-to-policy-to-review paradigm.

Research advances the scientific basis for regulatory policy and ensures that policy and decisions are based on the best available science. Through the development of external collaborations with industry, academia, professional societies and other government laboratories, applied research has expanded significantly. After many years of coordination, FDA is in the final stages of creating the Product Quality Research Initiative (PQRI). FDA, the pharmaceutical industry, and academia will collaborate on research to support regulations and guidance for the types of product quality information that should be submitted in a regulatory filing. This will enable consistent and reasonable requirements for all product quality information submitted in a regulatory filing, and will streamline the drug development and approval processes or industry and FDA.

This increase will enable FDA to:

• Advance the scientific basis for regulatory policy through research and ensure that policy and decisions are based on the best available science.
• Bring closer the creation of the Product Quality Research Initiative (PQRI) which will significantly expand external collaborations with industry, academia, professional societies and other government laboratories in the area of applied research.
• Collaborate with the pharmaceutical industry and academia on research to support regulations and guidance for the types of product quality information that should be submitted in a regulatory filing which will enable consistent and reasonable requirements for all product quality information submitted in a regulatory filing, and will streamline the drug development and approval process for industry and FDA.
• Implementation of the Office of Research and Testing Plan, a formal research planning process that is updated annually and filed with the FDA Office of Science. Goals have been established in the following areas: clinical pharmacology, product quality, toxicology, and regulatory testing. FDA's research program reflects an obligation to respond to the need for a strong scientific foundation for identifying and responding to policy for pharmaceutics regulation.
• Provide additional funding for international harmonization of regulation activities and permit import regulatory resources to keep pace with the growth of drug import entries;
• Fund the mandatory link between the electronic import data system and the U.S. International Trade Data System now being established in the Department of Commerce;
• Provide enhancements to the electronic entry review system that permits us to triage import entries by public health risk as they are offered for import. Although the electronic system has increased the speed of decisions on entries, the continuing growth in imports places a heavy demand on the staff making entry decisions for drugs based on information appearing on electronic screens and evaluating import filers submitting the data into the system. This extensive use and the quantity of detailed information submitted and reviewed burden the existing electronic system -- which requires an upgrade to bear the increased load.

Goal: Complete 75 percent of projects identified in CDER's OTR Research Plan (dated November 24, 1997) designed to lead to appropriate policy for applying modern in vitro and ex vivo technology to assessment of drug metabolism and drug interactions.

Goal: Complete 75 percent of research projects identified in the OTR Research Plan (dated November 24, 1997) designed to develop rational, scientific-based requirements for drug substances, drug products and excipients to ensure a high standard of drug product quality and product performance for making regulatory decisions.

Goal: Complete 25 percent of the research projects started in FY 1999 under the auspices of the Product Quality Research Initiative (PQRI), a collaboration among FDA, industry and academia established to provide a scientific basis for policy and guidance development in CDER on issues of drug product quality and performance.

Premarket Application Review -- ($ 2.4 million, 13 FTE)

The Human Drugs Program requires an additional $ 2.4 million and 13 FTE for premarket application review activity. Of this, $ 1.9 million, 11 FTE is for the Office of Generic Drugs.

FDA reviews generic drug applications to ensure that the chemistry, manufacturing and control information, proposed labeling, and bioavailability and bioequivalence data meet the same standards as the innovator products. These products must have the equivalent therapeutic effect of the innovator drug and the generic firm must demonstrate that their products are the same in all aspects as the approved innovator product and would have an equivalent therapeutic effect -- in other words these products must be bioequivalent. The generic firm must also demonstrate evidence of its compliance with the good manufacturing practice requirements. Establishment inspections are conducted to monitor the manufacturing process and compliance with current good manufacturing practice regulations. FDA also review supplements, required annual reports and ADR reports subsequent to the approval of generic drug applications.

This increase for the Office of Generic Drugs will provide:

• Improved general information technology (IT) infrastructure environment which currently resulting in delays in approvals of generic products.
• Expedite the transition toward electronic review.
• Allow the Office to recruit, hire and train new generic drug reviewers.
• Maintain the system for electronic reviews and the database for use by reviewers, or archival submissions for the Entry Validation Application (EVA) program introduced by CDER's Office of Pharmaceutical Science in 1997 for electronic structured submissions of bioequivalence data that accompanies generic drug applications. Without additional resources, the Office cannot fully utilize the expanded system functions, which include access tochemistry, manufacturing and controls data.
• Enhance systems to includeelectronic microbiology and labeling data and other related initiatives (e.g., online copies of labeling).

Goal: Increase the average monthly number of actions completed on ANDAs (approvals, tentative approvals, not approvals and facsimile requests) completed by 3.2 percent from the FY 1997 level.

Prescription Drug User Fee Act (PDUFA) -- ($ 11.0 million, 52 FTE)

The Food and Drug Administration Modernization Act of 1997 (FDAMA) reauthorized the collection of prescription drug user fees (PDUFA) to enhance the human drug review process, including some biological products, through FY 2002. The Act established fees for applications, establishments, and approved products. PDUFA is a model for reinventing government with Congress, the Agency, the industry and consumer groups working together providing necessary resources, setting performance goals, and holding the Agency accountable. The user fees have enabled FDA to improve its performance for drug review and approval times. The median approval time for human drug applications in 1991 was 21 months. Since the enactment of PDUFA, the median approval time for PDUFA original applications in the FY 1993 and FY 1994 cohorts have decreased to 17 months. Approval time for priority applications have been even quicker, averaging only 12 months for the 22 priority applications approved under PDUFA.

The fees collected in FY 2000 will enable the FDA to continue to meet its PDUFA II performance goals, which are as follows:

• Review and act on 90 percent of standard original NDA and PLA/BLA submissions filed during fiscal year 2000 within 12 months of receipt, and review and act on 50 percent within 10 months of receipt.
• Review and act on 90 percent of priority original NDA and PLA/BLA submissions filed during fiscal year 2000 within 6 months of receipt.
• Review and act on 90 percent of standard efficacy supplements filed during fiscal year 2000 within 12 months of receipt, and review and act on 50 percent within 10 months of receipt.
• Review and act on 90 percent of priority efficacy supplements filed during fiscal year 2000 within 6 months of receipt.
• Review and act on 90 percent of manufacturing supplements not requiring prior approval filed during fiscal year 2000 within 6 months of receipt.
• Review and act on 90 percent of manufacturing supplements filed during fiscal year 2000 within 6 months of receipt and review and act on 50 percent of manufacturing supplements requiring prior approval within 4 months of receipt.
• Review and act on 90 percent of Class 1 resubmitted original NDAs filed during fiscal year 2000 within 4 months of receipt, and review and act on 50 percent within 2 months of receipt.
• Review and act on 90 percent of Class 2 resubmitted original NDAs filed during fiscal year 2000 within 6 months of receipt.
• Respond to 80 percent of meeting requests within 14 calendar days.
• Schedule 80 percent of Type A, Type B and Type C meetings within 30, 60 and 75 days, respectively.
• Make 80 percent of meeting minutes available to sponsors within 30 days after the meeting.
• Respond to 90 percent of the responses to clinical holds within 30 days of the receipt of a complete response.
• Make assessments of and agreements to 70 percent of the special protocols within 45 days of receipt.

Physicians' Pay - - $ 1.27 million

The FY 2000 request includes a physician compensation growth guideline to limit the escalation of HHS physicians payroll (base salaries and special pays). The Human Drugs portion of this reduction is $1.27 million.

JUSTIFICATION OF BASE

In FY 1999 and FY 2000, the Human Drugs Program will continue to work on specific goals begun in FY 1998. They are as follows:

Premarket Application Review

Application Review: New Drugs: The prompt approval of safe and effective new drugs is vital to the improvement of the public health so patients enjoy the benefits provided by these therapies to treat and prevent illness and disease. Continued high-quality and timely review of an increasing number of premarketing applications for new drugs as well as supplemental applications remains one of the Agency's highest priorities. The Agency has proposed and implemented numerous initiatives to improve efficiency and streamline premarket drug review:

FDA Modernization Act of 1997 reauthorizes the prescription drug user fees (PDUFA), adds new goals for Agency achievement, and makes some of the PDUFA time frames more stringent. The Agency will improve its drug review performance at an even more rapid pace than under PDUFA I. For example, by the end of PDUFA II, the Agency's review time for a standard new drug application (NDA) will decrease from 12 months to 10 months. Following are specific objectives for FY 1999:

• Improve patient access to promising new cancer therapies by shortening approval times for cancer treatments and work with pharmaceutical companies to make promising cancer therapies approved by foreign countries available to cancer patients before the product is approved in the U.S.
• Full implementation of the Agency's New Use Initiative, announced in March 1997, will focus on helping new drug sponsors establish proof that their products are effective without excessive or redundant studies.
• Continue the implementation of Good Review Practices designed to enhance clinical review practices by standardizing many review procedures and providing a mechanism for ongoing feedback.
• Publish guidance on fast-track policies and procedures for drugs that demonstrates the potential to address unmet medical needs and are intended to treat serious or life-threatening diseases.
• Continue the Electronic Document Management System (EDMS) which provides for the electronic storage, routing, tracking and retrieval of documents generated during the drug review process.

OTC Drugs Program: FDA regulates over-the-counter (OTC) drugs, in addition to prescription and generic drugs. Review of OTC drug products ensures each ingredient's safety and effectiveness and helps consumers understand how to best use these products. There are currently more than 100,000 OTC products on the market. Several important initiatives will enhance the safe and effective use of all OTC drug products:

• Meet the new PDUFA goals for new drug products which are intended to be marketed OTC.
• Finalize new OTC labeling requirements, which ensure readable and understandable OTC drug labels.
• Establish in rulemaking, a monograph procedure for OTC drugs which have been internationally marketed for material, time, and extent.

Application Review: Generic Drugs: FDA continues to support an active generic drugs program by working to expand the supply of high quality generic drug products to the public. The Agency has increased annual approvals of generic drug applications despite a significant increase in the overall workload. In addition, a number of initiatives have reduced the time FDA takes to approve generic drugs.

Goal: Reduce the number of post-approval changes requiring chemistry supplements per application.

• Initiation of a procedure to contact applicants that undergo two or more major deficiency cycles. Applicants are requested to contact the Office of Generic Drugs (OGD) for discussion or clarification regarding the deficiencies. If OGD is not contacted, the Office will contact the applicant within 30 days to see if any further discussion, or perhaps a meeting, is necessary. OGD is attempting to reduce or eliminate additional review cycles and move the applications to approval more quickly.
• Public release of bioequivalence protocols and protocol reviews. It is anticipated that by providing access to this information, there will be fewer protocols submitted to the Division of Bioequivalence for review, thus decreasing the Division's protocol workload and allowing more time to be spent on application reviews.
• Implement a pilot for accepting and archiving electronic ANDAs.

Postmarketing Surveillance

FDA monitors adverse drug events to assess performance of approved products to detect safety problems that only become evident with actual use. FDA will continue to monitor, evaluate and enhance the reporting of adverse events, medication errors and product defects associated with drug products using postmarketing surveillance reporting, collecting and analyzing drug product samples to evaluate their compliance with quality standards and labeling requirements; conducting inspections to determine if fraudulent drugs are marketed in commercial channels; and evaluating foreign and domestic compliance with Good Manufacturing Practices (GMPs).

The Agency has long recognized the need to develop partnerships with state, local and other federal governments as well as with both the pharmaceutical industry and consumers. FDA is accelerating the development of collaborations. Partnerships are being pursued in a number of areas, including training, communication, and shared operations and information.

Important initiatives in these areas are:

• Explore more effective ways of sharing regulatory information regarding FDA inspected manufacturers through contracts with foreign governments. One potential avenue involves the increased use of the Compliance Status Information System (COMSTAT) database.
• Participate in discussions and negotiations with trading partners or trade-related organizations to develop a consensus on technical regulations and standards and/or determine the equivalence of regulatory systems.
• Enter into formal cooperative agreements and Memoranda of Understandings (MOU) with foreign governments.
• Develop and implement the pilot for the First Party Audit Program (FPAP) to leverage the inspectional resources required to ensure the quality and purity of drug products.

Human Drugs

Program Activity Data

/1 Total of approvals, not approvals, tentative approvals, and facsimile requests. Actions projections reduced from earlier reports due to changes in FDA's policy on abbreviated application cycles and responses to applicants.
/2 Total time to approval. Includes firm time to respond to deficiencies.
/3 All types of supplements.
/4 Original supplements only.

Note: Receipt and action totals based on the old counting system.
Reference to AADAs has been deleted. AADAs are now counted with ANDAs.