The availability of safe and effective biological products for disease prevention and treatment and the assurance of the safety of America's blood supply are essential elements of the nation's health care delivery system. FDA ensures that blood and blood products, blood test kits, bacterial vaccines and antigens, viral vaccines, therapeutic agents, and other biological products intended for use in the prevention, diagnosis, and treatment of disease in humans are pure, potent, safe, and effective, as well as properly labeled for their intended uses.

FDA's biologics program includes registration and inspection of blood banks and other firms processing blood; licensing and inspection of firms collecting human source plasma; evaluating and licensing biologics manufacturing firms and products; lot release of licensed products; removal of ineffective, unsafe, or improperly labeled products from the market; development of necessary regulations, compliance programs and guidelines; and the conduct of research, in concert with other DHHS public health agencies, academia, and industry, to further the development of new products and to provide a sound scientific basis for their regulation. FDA ensures that childhood vaccines are safe and effective through evaluation of products, their manufacture, and by monitoring adverse events associated with immunization.

INCREASES:

PUBLIC HEALTH INFRASTRUCTURE -- + $ 11.7 million, + 55 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 -- ($ 1.5 million, 2 FTE)

FDA plans to move as rapidly as possible to an integrated, fully electronic adverse event reporting system. This will reduce overall costs by allowing reporters to submit electronically, directly into agency systems, and will eliminate or substantially reduce the data entry and record handling costs. In addition, the uniform coding and nomenclature systems being developed will allow regulated industry and other reporters to accurately describe their products and events experienced, improving accuracy of reports and decreasing Agency costs for coding and additional follow-up.

Accurate, complete, and efficient operation of adverse event reporting systems is only the first step in the management of product injury. Reported events must be analyzed, and other sources of data must be accessed to make sense of the reports and to determine what action is needed. The need for access to various medical databases spans all FDA safety programs. Successful use of these databases requires investment of time by FDA project managers, programmers, and epidemiologists, as well as investment in computing equipment.

As a part of this Intra-Agency crosscutting initiative, the Biologics program will design an automated system for adverse event reporting of biological products. FDA will:

• Develop an automated system and computer software customized for adverse events of biological products, to search databases, find patterns, and highlight clusters of similar events. With this new system FDA will be able to:
  • Monitor the lot-to-lot variability in adverse event reporting of biologics products.
  • Improve assessment of manufacturer compliance with reporting regulations.
  • Expand the ability of the primary report reviewers to identify potential problems and act swiftly on information that indicates a problem with the safety of a biologics product.
• Improve AERS/external databases. FDA will develop an analytical data warehouse capacity. The goal of this program is to establish an automated system and computer software customized for adverse events of biological products.
  • Successful implementation of the AERS system is resulting in massive amounts of data that are available for searches and analysis.
  • Optimize analysis speed. Store data in an analytical warehouse.
  • Design the data configuration for routine reports and analyses needed by various components.

Product Safety Assurance -- ($ 6.2 million, 37 FTE)

FDA is responsible for providing regulatory oversight for licensed biological manufacturing establishments as well as for regulating the safety and quality of imported products. FDA's surveillance responsibilities include the inspection of manufacturing facilities for compliance with regulations, verification that product lots conform to preapproval standards and product consistency prior to their release into distribution, and evaluation of surveillance reports, such as adverse experience reports and blood fatality reports.

FDA is requesting $ 6.2 million to meet the statutory biennial inspection requirement for registered blood banks, source plasma operations and manufacturing establishments. FDA conducts postmarket research on biologics products primarily to ensure the continued quality and safety of the previously approved product. Because biological products are derived from living organisms, they do not have the same manufacturing consistency as pharmaceutical products derived from chemical combinations. FDA must conduct post-approval research to develop and validate test methods and establish standards for biological products.

The Food and Drug Administration Modernization Act of 1997 (FDAMA) provides FDA with the statutory requirement to biennially perform good manufacturing practices (GMP) inspections of registered biologic firms (50 percent annually). To accomplish this statutory mandate, FDA will:

• Provide the personnel, supplies for research and lot release activities, as well as monitoring the safety of products and related costs for these activities aimed at meeting the biennial inspection statutory requirement of inspecting 50 percent of registered blood banks, source plasma operations, and manufacturing establishments.
• Provide intensive risk based compliance oversight to selected biological product industry segments. This is a very expensive, labor intensive process due to the complexity of the industry segments to be targeted, for example source plasma operations.
• Improve monitoring of imported products for public health risk.
• Develop a training initiative in preparation for a pilot program for state public health agency contract inspections of unlicensed blood banks.

FDA does not and cannot test samples of each blood product. The only quality assurance available is through rigid adherence to GMPs by each blood establishment.

• These practices are what ensure that donors are properly screened; that HIV and other screening tests yeild accurate results; and that each and every unit of processed blood can be identified and connected with a donor and a set of test results.
• The adequacy of the system is increasingingly dependent on computerization which must have reliable and validated software.
• GMPs also require comprehensive standard operating procedures (SOPs) and employee training.

FDA will contract with several states to enforce GMPs and federal regulations for unlicensed blood banks during fiscal year 2000. Under the contract, state public health agencies will inspect unlicensed blood banks throughout their states.

• The state inspectors will be trained and accompanied by FDA inspectors during the pilot inspections. Information about the inspections will be forwarded to FDA, which will review the information and issue an establishment inspection report (EIR) outlining any correctional actions necessary for the blood bank to come into compliance.
• The state contracts will vary depending upon the number of blood banks located within the states.
• These contracts will pass approximately $2.0 million to the pilot state health agencies.

Goal: Meet the biennial inspection statutory requirement by inspecting 50 percent of registered blood banks, source plasma operations and biological manufacturing establishments.

Premarket Application Review -- ($ 4.0 million, 16 FTE)

A recent survey conducted by PhRMA found 350 new biotech medicines in development. There are questions related to the safety and effectiveness of these new biological products. The agency needs to know the public health impact and associated risks of products. Additionally, the agency must prepare to identify and combat emerging public health threats such as bloodborne infectious diseases and adventitious agents. FDA needs expertise in these product lines to expeditiously review these applications to ensure quick availability of new therapies to patients and to protect the public health. In FY 2000, a primary focus for FDA will be premarket research on blood, blood products and tissues including cell and gene therapy products.

The current application process is administratively complex and inefficient. FDA will reduce the number of pending blood applications and complete a systematic update of blood regulations.

• FDA will provide additional research/reviewers for the review of blood applications (PLAs/BLAs, PMAs and 510(k)s), update obsolete requirements, develop product standards, and convert guidance into regulations.
• FDA will develop a streamlined application procedure and increase self-auditing of quality assurance by industry.
• FDA will develop expertise in new and evolving biological product areas through research and more frequent dialogue/interaction between sponsors and FDA staff during early stages of review which will better equip reviewers to perform on-going reviews of these new product areas.

FDA will gain expertise in new and evolving biological products by providing research/reviewers opportunities to conduct regulatory related research to ensure safe products with the opportunity for fast approval.

• Proposed projects include adventitious agent projects such as porcine endogenous retroviruses and yersinia enterocolitica, and infectious disease projects such as the avian influenza.
• Development of expertise in new and evolving areas of biological products is crucial to reviewers who are adequately trained and knowledgeable about the products they are reviewing for approval to market.

A new field of medicine involving the use of animal cells or organs for human transplantation, broadly termed xenotransplantation, has been rapidly developing since the development of effective immunosuppressive therapies. FDA has recently begun to receive INDs to use animal cells or tissues in human clinical trials.

• As FDA scientists review these applications, they have concern that animals carry adventitious agents. Infection by retroviruses are known to cause a variety of pathologic conditions, such as hematological abnormalities, malignancies, and neurological disorders, in appropriate animal models.
• Primary animal cells will be examined for activation and expression of retroviruses infectious for human cells to determine whether the use of animal cells for human transplantation poses a risk to the patient and the public at large.

Goal: Review and act on 85 percent of complete blood bank and source plasma PLA/BLA submissions and 90 percent of PLA/BLA major supplements within 12 months after submission date.

PRESCRIPTION DRUG USER FEE ACT (PDUFA) -- + $ 1.9 MILLION, 8 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.

An increase of $ 1.9 million is requested for FY 2000, for a total of $ 30.7 million and 187 FTE in the Biologics program. The total PDUFA budget request for the Agency for FY 2000 is $ 145.4 million and 788 FTE. The revenues generated from the fees, paid by the pharmaceutical and biological prescription drug industries, will be dedicated to continuing to improve and expedite the prescription drug application review and approval process.

The collection of fees in FY 2000 will enable the FDA to continue to meet its 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.
• 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 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 I resubmitted original applications filed during fiscal year 2000 within 4 months and review and act on 50 percent within 2 months of receipt.
• Review and act on 90 percent of Class 2 resubmitted original applications filed during fiscal year 2000 within 6 months of receipt.

Physicians' Pay - - $ 0.55 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 Biologics portion of this reduction is $ 0.55 million.

JUSTIFICATION OF BASE

FDA will continue to ensure that blood and blood products, blood test kits, bacterial vaccines and antigens, viral vaccines, therapeutic agents, and other biological products intended for use in the prevention, diagnosis, and treatment of disease in humans are pure, potent, safe, and effective, as well as properly labeled for their intended uses.

FDA will continue its activities associated with the biologics program, including:

• Registration and inspection of blood banks and other firms processing blood
• Licensing and inspection of firms collecting human source plasma
• Evaluating and licensing biologics manufacturing firms and products
• Lot release of licensed products
• Removal of ineffective, unsafe, or improperly labeled products from the market
• Development of necessary regulations, compliance programs and guidelines
• The conduct of research, in concert with other DHHS public health agencies, academia, and industry, to further the development of new products and to provide a sound scientific basis for their regulation

FDA will continue its activities to ensure that childhood vaccines are safe and effective through evaluation of products, their manufacture, and by monitoring adverse events associated with immunization.

/1 Total of approval, approvable, not approvable and complete decisions. Does not include refuse-to-file decisions or withdrawals.

/2 Includes IND, IDE, Master File and license master files receipts.

/3 FDA estimates an increase from 15,000 to 116,000 error and accident reports from FY 1999 to FY 2000 upon implementation of a September 23, 1997 proposed rule to expand the scope of establishments required to report errors and accidents to FDA.

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