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FY 2007 Table of Contents

BIOLOGICS PROGRAM

^1/ Includes a one percent rescission.

Statement of Budget Request

The Biologics Program is requesting $210,000,000 for its mission activities including:

• To ensure the safety, efficacy, potency and purity of biological products including vaccines, cells, tissues, gene therapies, and related drugs and devices intended for use in the prevention, diagnosis and treatment of human diseases, conditions or injuries;
• To ensure the safety of the Nation's supply of blood and blood products;
• To evaluate the safety and effectiveness of biological products before marketing, and monitor the pre-clinical and clinical testing of new biological products;
• To license biological products and manufacturing establishments, including plasmapheresis centers, blood banks, and vaccine and biologic product manufacturers; and,
• To conduct regulatory research to establish product standards and develop improved testing methods.

Program Description

The Biologics Program is responsible for addressing regulatory challenges related to ensuring the safety and efficacy of a wide range of biologic products including: blood and blood products, human tissue, cell and gene therapies, vaccines, and allergenic products. The products regulated by the Center for Biologics Evaluation and Research (CBER) touch the lives of people everyday. Some examples include: over 14 million units of blood and blood components transfused yearly in the U.S.; more than 235 million vaccinations administered; and greater than one million human tissues transplanted last year. In addition, there were over 800 active human trials studying experimental cell and gene therapies, vaccines, and blood products for serious diseases such as HIV, cancer, diabetes and heart disease.

The Office of Regulatory Affairs (ORA) Field staff supports CBER by conducting premarket activities such as: bioresearch monitoring of clinical research, preapproval inspections and laboratory method validations needed for application decisions, and inspecting manufacturing facilities to ensure their ability to manufacture the product to the specifications stated in the application. ORA also conducts risk-based domestic and foreign postmarket inspections of medical products to assess their compliance with Good Manufacturing Practice requirements.

In addition to overseeing regulated products on a surveillance or "for cause" basis, ORA staff also respond to emergencies and investigate incidents of product tampering, terrorist events and natural disasters. To complement the regular field force, the Office of Criminal Investigations investigates instances of criminal activity in FDA regulated industries. In FY 2006, ORA will expend an estimated $30,315,000 in support of the Biologics Program.

Performance Analysis

During the latest completed performance period, (FY 2004), the Biologics Program successfully achieved all seven performance targets. So far, the Biologics program successfully achieved the only FY 05 target that has data available. The Biologics program expects to meet the other six targets when data becomes available later in FY 2006. For more information about these performance goals and results, please see the Performance Detail section.

The performance targets for implementing the Prescription Drug User Fee Act (PDUFA III) are very high. To sustain these ambitious targets, adequate funding must be assured.

Performance Highlight:

Program Resource Changes

Budget Authority

Pandemic Preparedness (Influenza) + $ 14,920,000 and + 56 FTE

FDA plays a unique and vital role in the Nation's preparedness for an influenza pandemic. We facilitate the development and availability of safe and effective vaccines in the event of an outbreak of an influenza pandemic.

FDA is requesting resources for an enhanced and sustained preparedness effort to:

• Facilitate rapid development, evaluation and availability of new influenza vaccines to prepare for a pandemic, including using new technologies such as cell culture and recombinant production, as well as antigen sparing approaches.
• Provide extensive outreach and training in manufacturing quality. Conduct timely and efficient inspections of manufacturing facilities to assure product quality and prevent problems that threaten safety or availability of products essential to respond to the pandemic threat. Assure that vaccines meet manufacturing and testing specifications and build sufficient surge capacity for such evaluation.
• Monitor the safety and effectiveness of vaccines administered to patients using improved information technology systems, electronic reporting mechanisms and analytic tools to identify vaccine safety signals.
• Through reverse genetics and other emerging technologies, prepare a library of pandemic influenza virus high growth reassortants (seed strains) and needed reagents for rapid response and manufacturing when a pandemic strikes.
• Assure that all strains and reagents used for manufacturing are high quality, safe and suitable for high-yield, large-scale manufacturing.
• Promote international regulatory cooperation, harmonization and information sharing in vaccine evaluation and safety activities.

Human Tissues Safety: + $ 2,475,000 + 18 FTE

FDA is implementing a new, risk-based approach to assure the safety of the human cells, tissues, and cellular and tissue-based products (HCT/Ps) used for human tissue transplants. This initiative will allow FDA to address issues related to safety and effectiveness of a rapidly growing industry.

The FDA has finalized three new rules that give the Agency more authority and oversight over a broader range of tissues and the establishments that process them. The rules also expand on the communicable diseases that are checked for, and they strengthen procedural and recordkeeping requirements for facilities that handle tissues. The three rules concern registration and listing, donor eligibility, and good tissue practices related to HCT/Ps. The Agency has tailored the regulations to the degree of risk posed by each product.

This initiative will fund monitoring and follow-up of adverse events and deviation reports, inspections of HCT/P establishments, guidance for the tissue industry and outreach activities. The human tissue safety initiative is funded at $2.5 million. This request includes $1.237 million, 8 FTE for the Center for Biologics Evaluation and Research and $1.238 million, 10 FTE for the Field portion supporting CBER.

Cost of Living-Pay: + $1,937,000

FDA's request for pay inflationary costs is essential to accomplishing its public health mission. Payroll costs account for over sixty-percent of our total budget, and the Agency is no longer able to absorb this level of inflation on such a significant portion of its resources. The increase will allow FDA to maintain staffing levels, including a national cadre of specially trained scientific staff. The total estimate for pay increases is $20,267,000. The Biologics portion of this increase is $1,937,000. These resources are vitally important for FDA to fulfill its mission to protect the public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use.

Biologics Reductions -$7,766,000 and -30 FTE

To fund FY 2007 priority initiatives such as Pandemic Preparedness and the Human Tissues Initiative, FDA re-deployed resources from base programs. To accomplish this strategic redeployment and fund new, high priority initiatives, CBER reductions include: guidance development, early interactions with sponsors, non-emergency communications and outreach, activities related to blood and to cell and gene therapy products, and certain related post-market, safety, research and international harmonization activities.

User Fees

Prescription Drug User Fee Act: +$2,194,000 and +10 FTE

PDUFA authorized FDA to collect fees from the pharmaceutical industry to augment appropriations spent on drug review. These fees expand the resources available for the process of reviewing human drug applications including reviewers, information management, space costs, acquisition of fixtures, furniture, equipment and other necessary materials so that safe and effective drug products reach the American public more quickly. In 2002, the Bioterrorism Act included reauthorization 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 (PDUFA III). The reauthorization directs FDA to strengthen and improve the review and monitoring of drug safety; consider greater interaction with 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. The increases will contribute to meeting these mandated directives. In FY 2007 FDA will work with Congress on the reauthorization of the Prescription Drug User Fee Act. This increase of $2,194,000 will cover inflationary costs, as well as overhead and rent costs, for additional staff associated with the Act.

Medical Devices User Fee and Modernization Act: +$748,000 and + 3 FTE

The Medical Device User Fee and Modernization Act of 2002 (MDUFMA), P.L. 107-250, amends the Federal Food, Drug, and Cosmetic Act to provide FDA important new responsibilities, resources, and challenges. MDUFMA was signed into law October 26, 2002 and was amended by the Medical Device User Fee Stabilization Act of 2005. MDUFMA has three particularly significant provisions. These provisions allow for the collection of user fees for premarket applications, allow establishment inspections to be conducted by third parties and place new regulatory requirements on reprocessed single use devices. The revenues from these fees, and the appropriated trigger amounts will allow FDA to pursue a set of ambitious performance goals that will provide patients earlier access to safe and effective technology, and will provide more interactive and rapid review to the medical device industry. In FY 2007 FDA will work with Congress on the reauthorization of the Medical Device User Fee and Modernization Act. This increase of $748,000 will cover inflationary costs, as well as overhead and rent costs, for additional staff associated with the Act.

Proposed User Fees (Reclassified as Mandatory): (Non-Add)

Reinspection User Fee (Mandatory): + $410,000 and + 3 FTE (Non-Add)

The Administration is proposing authorizing legislation that requires establishments to pay the full costs of reinspections and associated follow-up work when FDA reinspects facilities due to failure to meet Good Manufacturing Practices (GMPs) or other important FDA requirements. Under this proposal, these activities will be reclassified as mandatory user fees in FY 2007. FDA currently funds this activity through discretionary appropriations. Imposing a fee would generate $22.0 million in revenue, an estimated amount sufficient to fund the FY 2007 reinspections. The Field - Office of Regulatory Affairs component of this user fee is $410,000 and 3 FTE.

Justification of Base

Protecting and promoting the public health in the 21st Century is a great responsibility. Mastering it requires meeting some unprecedented challenges: attracting and retaining the most talented scientists; utilizing dynamic and responsive regulation to reduce risks; promoting quick access to needed new medical technologies that are safe and effective; assuring the continuing safety and availability of regulated products; helping consumers get true and useful information about the products they use; and facilitating quick responses to the challenges of bioterrorism as well as emerging infectious diseases. The Biologics Program will continue to play both a facilitating and a leadership role in meeting these challenges, including seeking input from and having effective collaboration with our partners.

The Biologics Program also is responsible for addressing regulatory challenges related to ensuring the safety and efficacy of biological products. Meeting these challenges successfully will require knowledge and utilization of scientific advances in areas such as proteomics, genomics and gene therapies, xenotransplantation, new vaccine technologies and delivery methods, and novel cellular and tissue therapies. In these and other areas, CBER research, often in collaboration with others, helps to identify opportunities to advance new and emerging technologies, and provide needed standards, assays and models to better measure and assure product safety, efficacy and consistency. These contributions move innovative products more rapidly along what has been termed the "critical path" to availability for patients who can benefit from them, consistent with FDA's Critical Path Research Initiative (http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf).

FDA Strategic Goal: Enhancing Patient and Consumer Protection and Empowering Them with Better Information about Regulated Products

Communications with Stakeholders and Consumers

• Collaborates with scientists to support regulatory decisions by assessing risks associated with regulated products; sets standards that minimize risk and tests products against those standards; improves the usefulness and precision of risk assessment methods; and develops methods to increase the accuracy of sample analysis and detection of biological substances.
• Provides information on research projects and scientific articles emphasizing the importance of our regulatory research as mission critical work underpinning regulatory decisions.
• Provides access to new guidance documents, safety information and the opportunity to discuss important issues with Agency experts at numerous trade associations, scientific, and community meetings.
• Maintains outreach with industry and provides training as required by FDAMA and the Small Business Regulatory Enforcement Fairness Act.

FDA seeks continuous improvements in patient and consumer safety by reducing risks associated with FDA-regulated products. FDA's work on medical errors and SARS are examples of efforts in this area.

Medical Errors

The prevalence of avoidable health complications involving the use of FDA-regulated products presents a challenge for the Biologics Program. Our central public health role is to help ensure that biologic products are safe and effective. Therefore, we must ensure that quality standards are adhered to by the various biological product establishments by:

• Conducting product safety biomedical research in areas such as new cells used to produce drugs and biologics; rapid advances in technology and the evolving HIV pandemic necessitate the need to use new types of cell substrates and to develop new assays and assess the reliability of current assays used to monitor product safety.
• Developing new, specific and sensitive techniques and assays to validate and detect a greater variety of known potentially infectious viruses.
• Enhancing vaccine and biologic safety surveillance through implementation of ongoing programs of cutting edge technology; including increasing use of healthcare databases.
• Maintaining the system of post-market surveillance and risk assessment program to identify adverse events that did not appear during the product development process by collecting, evaluating and acting on information of Adverse Event Reports (AERS) associated with marketed products.
• Sustaining reporting systems to collect biological product deviation events that occur during manufacturing processes or storage of biological products.
• Establishing contracts for safety monitoring data links that include product exposure and extensive patient information To enhance FDA's ability to monitor public health impact, the Agency is developing access to external databases with other government agencies, states, academia and independent health organizations such as hospitals.

Counterterrorism

The Agency's strategic goal to "Protect America from Terrorism" focuses on preparation and response to a terrorist attack on the U.S. population. FDA plays a crucial role in protecting the public health by ensuring the availability of safe and effective medical countermeasures for mitigating the public health consequences of a bioterror event.

The Biologics Program is responsible for regulating the development and licensure of new biological products including vaccines, blood products including antisera for diseases such as botulism and anthrax, human tissues, cells and gene therapies. By working closely with industry and government agencies, FDA helps to assure an adequate supply of these products, which include immunization against anthrax, smallpox and other bio-threats that might be used by terrorists as well as products to treat burn, blast and trauma injuries. FDA also collaborates closely with other federal agencies to develop protocols, conduct animal studies, and define reference databases on treatment and alternative therapies for infectious diseases caused by the intentional use of biological agents. FDA also monitors adverse events to identify patterns of significant reactions to these new vaccines. Finally, support has been increased for the protection of regulated products from contamination and tampering to ensure availability of products. More specifically, the Biologics Program works to:

• Ensure the safety and efficacy of biological products, including vaccines, blood and blood products, and diagnostic countermeasures to support the development, maintenance and deployment of stockpiles of medical countermeasures.
• Help ensure that sufficient quantities of medical products are available; and implement post-event follow-up and data collection for these products, some of which are investigational.
• Conduct and support active applied research programs directed toward optimizing the availability of safe and effective new products for the treatment, prevention or cure of diseases in humans.
• Evaluate the types of non-clinical data that may be acceptable for product licensure if pre-licensure clinical studies are not feasible or ethical.
• Evaluate over 100 active investigational new drug applications on products under development for use either to mitigate or prevent the pathological effects of terrorism-related pathogens in humans.
• Participate in activities to facilitate the availability of the currently approved vaccine for anthrax; and continue counterterrorism activities associated with the development of new smallpox and anthrax vaccines; vaccines for plague, tularemia, and Venezuelan Equine Encephalitis, as well as other encephalitis-causing viruses.
• Monitor production of biologics from the early stages all the way through post marketing with lot release testing to ensure the individual lots continue to meet safety, purity, potency and efficacy requirements.

Science Based Review

CBER's Critical Path research program ensures efficient evaluation of the safety, efficacy and manufacturability of complex biological products that are aimed at prevention or treatment of life-threatening diseases.

CBER science based evaluation aimed at ensuring safety and efficacy of complex biological products for the public encompasses:

• Development, evaluation and application of formal risk assessments and methods to develop risk reduction strategies for licensed products, e.g., protecting the blood supply from TSE (Mad Cow Disease) and from vaccine-associated adverse events.
• Continuing evaluation of vaccine safety after licensure by identifying and studying adverse events in patients receiving these products in the clinical setting, e.g., rotavirus and intestinal disease, pneumococcal vaccine allergic responses, influenza vaccine/meningitis vaccine and neurological diseases.
• Development and evaluation of tests to better predict the protective response to biodefense vaccines, e.g., smallpox, botulism, anthrax.
• Development and evaluation of biomarkers for product efficacy and to support personalized medicine, e.g., better targeting of vaccines, and blood products for hemophilia.

FDA Strategic Goal: Increasing Access to Innovative Products and Technologies to Improve Health

Base resources will be used to conduct science-based risk management in all Agency regulatory activities so that the Agency's resources can provide the most health promotion and protection at the least cost to the public. These activities include the efforts discussed below.

Gene Therapy

One of the most exciting and highly publicized areas in biomedical research today is human gene therapy - the replacement of a person's faulty genetic material with normal genetic material to treat or cure a disease or abnormal medical condition. Over time and with proper oversight, this may become an effective weapon in modern medicine's arsenal to help fight diseases such as cancer, diabetes, high blood pressure, heart disease and other genetic disorders.

Since FY 2000, FDA has received over 489 requests from medical researchers and manufacturers to study gene therapy and to develop gene therapy products. Presently, FDA is overseeing approximately 249 active investigational new drug gene therapy studies.

Human Cells, Tissues and Cellular and Tissue Based Products

The term "human cells, tissues, and cellular and tissue-based products (HCT/P's)" covers many products transplanted for medical uses, such as skin replacement following severe burns, tendons and ligaments to repair injuries, bone replacement, and corneas to restore eyesight. In this rapidly growing industry, the number of musculoskeletal tissue transplants increased from approximately 350,000 in 1990 to over 1 million conducted annually. Over the past decade advancing technology and improved techniques have expanded the therapeutic uses of tissue-based products.

FDA seeks to accomplish three primary goals with respect to human tissues while not discouraging the development of new products: (1) to prevent the spread of communicable diseases; (2) to ensure that safety and efficacy are demonstrated for cellular and tissue-based products that are also drug, biological, and medical device products; and, (3) to help enhance public confidence in these products so that, where appropriate, they can fulfill their great potential for improving and saving lives.

CBER scientists:

• Actively advise national and international public health groups such as WHO, CDC, NIH, and the National Vaccine Program Office on selecting new influenza viruses to be used in annual vaccine production and in preparing for an influenza pandemic..
• Review extensive manufacturing and clinical information, and conduct several inspections of the manufacturing facilities of additional sponsors of influenza vaccine INDs. ;
• Actively engage with sponsors and manufacturers interested in developing new technologies for influenza vaccine manufacture, including cell-based and recombinant vaccines, in addition to interacting closely and proactively with the four currently licensed influenza vaccine manufacturers, Chiron, GSK, Aventis Pasteur and MedImmune on a variety of issues related to their vaccine manufacturing.
• Expedite lot release of influenza vaccine through the manufacturing time period; the process of manufacturing these vaccines is very complex, and is complicated by the large number of doses administered in a very short time frame.
• Work with manufacturers throughout the year to collect information on the capability of new influenza viruses to be used for large-scale production.

[D]

Blood Safety

The blood supply is a critical underpinning of our Nation's health care system and of our emergency preparedness. Our U.S blood system continues to be the world's safest. FDA's goal is to ensure this remains true by minimizing the risk of infectious disease transmission and other hazards. FDA continues to strengthen efforts to protect the blood supply, and to minimize any emerging risk to patients of acquiring HIV, hepatitis, Creutzfeldt-Jakob Disease (CJD), the human form of Mad Cow Disease, West Nile Virus (WNV) and other emerging blood-borne diseases, including potential agents of bioterrorism. These efforts include:

• Promulgating and enforcing standards for blood collection and for the manufacturing of blood products, including transfusible components of whole blood, pharmaceuticals derived from blood cells or plasma, as well as related medical devices and screening tests.
• Facilitating the development and review of innovative products to improve blood safety and availability such as new immunoglobulin and clotting factors, new methods to preserve blood cells and related products, artificial blood substitutes, new blood testing and safety technologies, as well as improved HIV tests for blood and for public health screening.
• Updating existing guidance so it is consistent with new scientific information and eliminate guidance documents where enforcement is either no longer required or not practical.
• Addressing emerging infectious diseases by ensuring compliance of plasma fractionation establishments, blood donor/recipient notification and look back, and FDA emergency and Class I recalls affecting blood safety response procedures.
• Responding to emerging potential threats to the blood supply, such as WNV, SARS, HIV variants; new hepatitis agents; human herpes virus-type 8; and CJD, in a timely and coordinated approach. For example, under the Medical Device User Fee Act FDA has dramatically shortened review times for blood related devices, many of which help test blood or otherwise assure its safety and availability.
• Emphasizing the need to protect the nation's blood supply, and minimizing any risk of acquiring the human form of BSE, CJD, and other blood-borne diseases.

Through enhanced testing and other improvements in blood safety, the risk of transmission of viruses such as HIV, and hepatitis B and C through blood transfusion has been dramatically reduced. The risks of HIV and of HCV have been reduced from 1/100 units in the 1980's to less than 1-in-a-million at present.

Imports, Import Monitoring and Foreign Inspections

The explosion in the number of imports combined with the security concerns raised by terrorism and counterfeiting incidents has increased the need to physically assess the status of imported products, including biologics, as part of the Agency's emerging import strategy. Base funding will enable FDA to improve the safety of imported and domestic biological products and tissues by increasing the surveillance of human tissues and biological products and coordinate domestic field investigational analytical compliance activities.

Prescription Drug User Fee Act (PDUFA)

The Biologics Program has met or exceeded most of its PDUFA performance goals from FY 1994 through 2004. The BT Act reauthorized 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 reauthorization is 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 with sponsors during the review of drugs and biologics intended to treat serious and life-threatening diseases; and, develop principles for improving first-cycle reviews. Review performance monitoring is being done in terms of fiscal-year cohorts. The FY 2006 cohort performance goals include:

• Complete review and action on 90 percent of standard original NDA/BLA submissions within 10 months; and complete review and action on 90 percent of priority original NDA/BLA submissions within six months of receipt.
• Complete review and action on 90 percent of standard efficacy supplements within 10 months; and complete review and action on 90 percent of priority efficacy supplements within six months of receipt.
• Complete review and action on 90 percent of manufacturing supplements within six months of receipt; and complete review and action on 90 percent of manufacturing supplements requiring prior approval within four months of receipt.
• Complete review and action on 90 percent of Class 1 resubmitted original applications within two months; and complete review and action on 90 percent of Class 2 resubmitted original applications within six months of receipt.

Science Based Review

The Center for Biologics Evaluation and Research (CBER) has an experienced staff of research-regulators with expertise in complex biological product evaluation science who works with product sponsors, scientific experts and the public to resolve challenges in development of complex biological products (e.g., vaccines for adults and children, blood and blood products and cell, tissue and gene therapies). CBER science based evaluation activities aimed at ensuring safety and efficacy of complex biological products for the public:

• Improve access to life-saving blood products for trauma victims by developing and evaluating animal and cell-based tests for the safety of blood substitutes.
• Evaluation and qualification of biomarkers predictive of medical product safety to streamline clinical trials and support personalized medicine, e.g., of cancer or autoimmune risk following cellular therapies and of enhanced disease following tuberculosis vaccination.
• Development and evaluation of animal and cell-based models of disease used to predict the safety of gene therapy vectors, e.g., adenovirus gene vector-associated lung disease.
• Ensure safety and availability of the blood supply by evaluating improved blood donor testing kits for detection of malaria and other parasites.
• Development and evaluation of animal and cell-based models of disease used to test the efficacy of vaccines for biodefense, e.g., anthrax, plague, smallpox, ebola.

FDA Strategic Goal: Improving Product Quality, Safety, and Availability through Better Manufacturing and Product Oversight

Science Based Review

CBER science based evaluations develop and evaluate the scientific tools needed to maintain and improve the safety, efficacy and manufacturing quality of the licensed products, and to support efficient and effective evaluation of the novel products that are the fruit of the biotechnology research boon. CBER scientific evaluation activities:

• Ensure that better products reach the patient faster by modernizing and streamlining rapid tests of product quality, e.g., moving from animal-based to non-animal based vaccine potency testing, genomics microarray testing of biodefense vaccines.
• Develop and evaluate tests for contamination of complex biological products, including TSE (Mad Cow Disease), viruses, bacteria in blood, vaccine and cell therapies.
• Evaluate methods to improve consistency of manufacturing and reduce shortages of medical products, e.g., complex protein-carbohydrate meningitis vaccines.
• Develop and evaluate reference standards for biological products, including vaccines such as influenza and blood donor test kits.

FDA Strategic Goal: Transforming FDA Business Operations, Systems, and Infrastructure to Support FDA's Mission in the 21^st Century

The Agency strategic goal, "Improving FDA's Business Practices," focuses on the critical infrastructure that provides scientific support and administration to FDA's programs. This will ensure a world-class professional workforce, effective and efficient operations, and adequate resources to accomplish the Agency's mission. The managerial and operational efficiencies being pursued under this goal are aligned with the President's Management Agenda, the Secretary's priority of strengthening management by creating a more streamlined, cost-effective, and accountable organization, and the DHHS strategic goal to achieve excellence in management practices.

Selected FY 2005 Accomplishments

FDA Strategic Goal: Enhancing Patient and Consumer Protection and Empowering Them with Better Information about Regulated Products

West Nile Virus (WNV)

In 2002, FDA and CDC, working together, identified transmission of WNV by blood transfusion. In response, FDA encouraged the development of investigational WNV Nucleic Acid-based Test (NAT) as screening tests and facilitated the widespread study of these investigational tests by blood establishments. Beginning in July 2003, investigational WNV NAT was available throughout the country to screen the blood supply in a minipool format, and more than 95% of the blood supply was tested. In 2005, WNV continued to spread across the lower 48 continental states with about 2,300 cases of WNV illness and 66 deaths reported in the general population. Blood screening for WNV detected more than 350 viremic donors and prevented their donations from entering the blood supply. No cases of transfusion-transmitted WNV were reported in 2005.

Counterterrorism

FDA plays a crucial role in protecting the public health by ensuring the availability of safe and effective medical countermeasures for mitigating the public health consequences of a bioterror event. The Agency's responsibility is to regulate the development and licensure of new biological products, including vaccines, blood and blood products, human tissues and cells and gene therapies. FDA also collaborates closely with other federal agencies, such as DOD, NIH, and CDC to develop protocols, conduct animal studies, and define reference databases on treatment and alternative therapies for infectious diseases caused by the intentional use of biological agents. Major counterterrorism activities during FY 2005 included:

• Issued draft guidance on July 5, 2005 CBER issued addressing FDA's policies for authorizing the emergency use of medical products.
• Issued a direct final rule and accompanying guidance for revision to allow for greater flexibility when manufacturing with spore-forming microorganisms in the production of vaccines and counter-terrorism products.
• Approved two Biologic License Applications (BLAs) for Vaccinia Immune Globulin (VIG), one for DynPort Vaccine Company LLC in February 2005 and the other for Cangene Corporation in May 2005. Both were granted priority review and approved under the accelerated approval mechanism in the regulations.
• CBER reviewed and recommended the authorization of Emergency Use Authorization (EUA) of Anthrax Vaccine Adsorbed for persons in the military at high risk of exposure to a possible attack with anthrax.
• CBER provided extensive support through reviewing and providing technical input on multiple Requests for Proposals for acquisition of additional countermeasures for the SNS (anthrax therapeutics, new smallpox vaccines, botulinum antitoxin, neuropenia), providing information regarding the types of data needed to consider use of unapproved countermeasures under an EUA, and participating in the Project Coordination Team efforts for the first contract awarded under Project Bioshield to VaxGen for Recombinant PA (rPA) Anthrax Vaccine.

FDA Strategic Goal: Increasing Access to Innovative Products and Technologies to Improve Health

In alignment with the Agency's Critical Path Initiative, the Biologics Program employs science-based approaches to solve current problems and anticipate future barriers to biologics product development and licensure. The Program strives to identify and work collaboratively to develop the scientific knowledge and tools to determine the safety and efficacy of products.

Cell and Gene Therapy: Outreach and Partnerships

The Biologics Program has provided proactive scientific and regulatory guidance in areas of novel product development. Openly communicating regulatory expectations and encouraging dialogue on points of cutting edge product development helps define the best scientific approaches and reduces product development time and risk. Focusing on how to best evaluate the most important issues in safety and efficacy helps avoid unnecessary regulatory burdens. In addition, engaging and supporting broad public interactions helps FDA and product developers to better address difficult issues involving risks and benefits of novel products. Examples during the past year include:

• Held a workshop in October 2004, entitled "From Concept to Consumer: Center for Biologics Evaluation and Research, Working with Stakeholders on Scientific Opportunities for Facilitating the Development of Vaccines, Blood and Blood Products, and Cellular, Tissue, and Gene Therapies.".
• Attended the Cell Therapy/FDA Liaison Meetings on November 5, 2004 and June 24, 2005 . The objectives of the liaison meetings were to discuss emerging manufacturing and regulatory issues related to somatic cell therapy products and to provide an avenue for open discussions and outreach between CBER, industry, and academic sponsors.
• Attended and presented, in April 2005, at a meeting held by the American Society of Gene Therapy in Arlington VA, entitled "Challenges in Advancing the Field of Gene Therapy: A Critical Review of the Science, Medicine and Regulation-Stakeholders Meeting." The objectives of the meeting were to bring members of the gene therapy community together to critically review the issues and consider ways to move the field forward and specifically facilitate the initiation and successful conduct of gene therapy clinical trials.
• Attended and co-chaired, in May 2005, the International Conference on Harmonization (ICH) Gene Therapy Discussion Group (GTDG) meeting held in Brussels, Belgium. At this meeting the group discussed issues related to the potential for inadvertent germline transmission of gene therapy products and the safety and benefit of using oncolytic viruses for use in oncology clinical trials.
• Attended and co-chaired, on September 22 and 23, 2005, the Korean FDA (KFDA) International Symposium and gave the special lecture entitled, "Current Issues on Xenotransplanation." CBER staff also presented a talk entitled, "Overview of Xenotransplanation Regulation in the US," at the follow-up seminar: Colloquium on the regulatory aspects on Xenotransplanation. This two day meeting allowed the U.S. FDA and KFDA to participate in ongoing discussions on the safety concerns surrounding clinical trials using xenotransplanation products.

Prescription Drug User Fee Act (PDUFA)

PDUFA has provided FDA with needed resources for the review of human drug and biologic applications. Fees collected have been used to help reduce the time required for evaluating human drug and biologic applications and to improve review quality. FDA has submitted annual performance and financial reports to Congress on application review performance and use of PDUFA fees. PDUFA has been amended and extended through September 30, 2007. The amended Act is now referred to as PDUFA III.

In April, 2005, Guidance for Review Staff and Industry entitled "Good Review Management Principles and Practices (GRMPs) for PDUFA Products" was released. The guidance is intended to support the FDA's primary public health mission for human drug and biologic products, help the FDA continue to define processes that fulfill the Agency's PDUFA mandates, promote efficient use of the FDA's resources, and define ways in which both FDA review staff and applicants can further the effectiveness and efficiency of the review process. This guidance is expected to lead to greater consistency and efficiency of the review process within individual review divisions and between CDER and CBER. The GRMPs in this guidance are based on the collective experience of CDER and CBER with review of applications for PDUFA products and are intended to promote the practice of good review management based on sound fundamental values and principles.

Representatives from CBER, CDER, ORA, and OC are currently preparing for negotiations with industry on PDUFA IV.

Medical Device User Fee and Modernization Act (MDUFMA)

In the last three years, the Biologics Program has worked intensively and sought input from both inside and outside the Agency to strengthen the quality, efficiency and timeliness of its device review process. The resulting increased effectiveness of device review in CBER is illustrated by the fact that CBER has met FY 2005 MDUFMA goals for all types of submissions in 2004. In many cases, these approvals relate directly to innovations that enhance the safety and efficacy of blood and tissue products. Timely approvals included products for which we received modular pre-market approval applications (PMAs).

Additionally, effective, expert interaction with government partners and industry have facilitated the recent approval of rapid tests for HIV and of tests to monitor HIV drug resistance, examples of successful regulation under the framework established by MDUFMA.

In the spirit of the least burdensome approach to regulating devices, on November 17, 2004, CBER/CDRH issued guidance to industry that provided FDA's recommendations on the timeliest and most effective way to resolve disputes concerning FDA actions that affect payment or refund of a user fee assessed under MDUFMA.

The Biologics Program has met or exceeded the MDUFMA review performance goals, most of which did not become effective until FY 2005. For the first two years of MDUFMA, only two of the performance goals were in place. In FY 2005, 20 MDUFMA goals were in place, and the Agency is collecting data on its performance against these goals. The Agency's MDUFMA performance and finance reports can be accessed at www.fda.gov/oc/mdufma/.

Blood Safety

Bacterial contamination, especially of platelets, remains among the top three causes of transfusion-related fatalities in the United States. To address this problem, FDA has encouraged the development of bacterial detection devices that can be used to release platelets. To date, FDA has approved three devices for quality control monitoring of the platelet collection process (bioMeriuexBacT/Alert, Pall eBDS, Hemosystems Scansystem). In February 2005, the FDA approved Gambro BCT single-donor platelets for 7-day storage. The FDA approved the extension of platelet shelf life from 5 days to 7 days when the Gambro BCT collection bag is used along with the bioMeriuex BacT/Alert Microbial Detection System using both aerobic and anaerobic culture bottles. FDA is also encouraging studies to validate prestorage pooling of platelets derived from platelet-rich plasma.

The Department of Health and Human Services (DHHS), FDA and the Centers for Medicaid and Medicare Services (CMS) received reports that health care providers were having difficulty obtaining immune globulin intravenous (IGIV) for some patients. FDA worked cooperatively with DHHS and the Plasma Protein Therapeutics Association (PPTA) to monitor the IGIV supply and facilitate its availability. While there does not appear to be a severe product shortage, there have been reports of difficulties obtaining the same product in the same treatment center that patients customarily use. Monthly distribution of products has not increased over the last 24 months, while demand has historically increased by 7% - 10% per year. At its July 2005 meeting, the Blood Products Advisory Committee (BPAC) announced the closure ofthe Massachusetts Public Health Biological Laboratories (MPHBL), the primary manufacturer of varicella-zoster immune globulin (VZIG), which is used to treat complications of varicella-zoster infection.) In response, FDA sought the Committee's advice on options for efficacy determination for new BLA applications for VZIG because of concerns about a potential upcoming shortage of this product. The FDA will work with manufacturers to approve other VZIG products or to use investigational mechanisms to make the product available.

Tissue Action Plan

The final rule on current good tissue practice (GTP), the last of three rules to be issued as part of FDA's overall plan to make human cells and tissues even safer, was published in the Federal Register on November 25, 2004. GTP governs the methods used in, and the facilities and controls used for, the manufacture of these products. With this final rule, FDA's efforts to establish a new, comprehensive, and risk-based approach to this promising and innovative field of medicine can be realized. The new approach became effective on May 25, 2005.

The new rule, entitled "Current Good Tissue Practice for Human Cell, Tissue, and Cellular and Tissue-Based Product Establishments; Inspection and Enforcement," requires manufacturers to recover, process, store, label, package and distribute HCT/Ps, and screen and test cell and tissue donors, in a way that prevents the introduction, transmission, or spread of communicable diseases. The regulations apply to a broad range of these products including musculoskeletal tissue, corneas, human heart valves, dura mater (lining of the brain) and cellular therapies.

Two other related proposed rules to implement the proposed regulatory approach to HCT/Ps have previously been finalized. The first final rule, "Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing," was issued on January 19, 2001. It became effective on April 4, 2001, and requires HCT/P establishments to register with the FDA and list their products.

[D]

The other final rule, "Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products," was issued on May 25, 2004, and focuses on donor screening and testing measures to prevent the unwitting use of contaminated tissues with potential to transmit infectious diseases. It became effective on May 25, 2005. .

Significant Biologics Approvals in FY 2005

One of the goals of the Biologics Program is to provide timely, high quality, cost-effective process for the review of new technologies/pre-market submissions. Several important new Biologics Licensing Applications were approved in FY 2005 as shown in the table below:

FDA Strategic Goal: Increasing Access to Innovative Products and Technologies to Improve Health

The FDA must ensure that the biological products put on the market for U.S. consumers are both safe and effective. FDA must also ensure the safety of the nation's blood supply by minimizing the risk of infectious disease transmission and other hazards. The Field supports the Biologics Program in improving the safety of both imported and domestic biologics through a variety of activities. Examples of accomplishments and activities appear below organized by strategic goal.

Human Tissue Inspections

The Field inspects human tissue establishments to increase the safety of transplanted human cells, tissue, and cellular and tissue based products, while encouraging the development of new products.

Human Tissue Safety

The Field ensures that clinical safety and efficacy are demonstrated at tissue establishments and that appropriate review is performed for Human Cellular and Tissue Products (HCT/P's).

National Vaccine Stockpile

The Field inspects vaccine manufacturers whose products may be stockpiled as part of the Government's counter terrorism efforts. To ensure that the Government has sufficient quantity of safety and effective vaccines, the Field also monitors and inspects all vaccine stockpile facilities.

Blood Safety Activities

Blood and blood products are vitally important products in medical treatment. The Field monitors the collection of whole blood and the processing of products derived from human blood and assures consumer protection from defective products which may endanger public health.

FDA Strategic Goal: Transforming FDA Business Operations, Systems, and Infrastructure to Support FDA's Mission in the 21^st Century

Biologics Investigational New Drug Management System (BIMS)

The Biologics Investigational New Drug Management System (BIMS) supports high-level tracking and summarization of CBER regulatory efforts associated with Investigational New Drugs (INDs), Master Files (MF), and Investigational Device Exemptions (IDEs). The system was enhanced to support the review, management and tracking of Emergency Use Authorization (EUA) submissions. There were five other software releases implemented providing numerous process modifications, including changes for product data-entry, data quality, and handling original submissions and amendments which greatly reduced processing time by reviewers. BIMS is used by over 600 CDER and CBER medical product reviewers.

Biologics License Application (BLA)

The Regulatory Management System for the Biologics License Application (RMS/BLA) provides an automated system to support the tracking of BLAs, their review, and their associated data. Three major software upgrades were successfully implemented comprising over 100 user and programmer generated change requests, 350 data change requests, 2 data migration related requests, several performance related enhancements, and 15 special report requests. Among these enhancements were modifications to support MDUFMA, promotional materials review, foreign inspections, routing request capability, and additional search and reporting capabilities.

Lot Release System (LRS)

The Lot Release System (LRS) supports the processing of lots and issuance of release notifications. LRS also supports inventory, routing, and laboratory sample tracking. There were two major software releases, comprising of nearly 50 user-requested and programmer-generated improvements. One of the major enhancements, a new Milestones Module for the purpose of tracking and reporting on performance throughout the lot review and approval process, will enable the Product Release Branch (PRB) to track and report on time between events and actions taken for a given lot.

CBER's Electronic Document Room (EDR)

CBER's Electronic Document Room (EDR) functions as an electronic library for reviewers, distributing and storing electronic submissions of IND, BLA, NDA, 510(k), PMA, regulatory correspondence, and other types of submissions defined by CBER. EDR enhancements include the integration of the FDA electronic Common Technical Document (eCTD) review tool that allows for the receipt of eCTD-based submissions, hardware and operating system upgrades, software modifications to the Electronic Secure Email system (ESM), ability to receive and extract data from PDF forms received on physical media, capability to process trans-BLA submissions, and PDF link checking software for the submission processing.

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

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

3/Includes MedWatch, Foreign reports and VAERs reports. Does not include Fatality Reports or Medical Device Reports for CBER-regulated medical devices.

FY 2007 Table of Contents

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