Center for Biologics Evaluation and Research FY 2003 Annual Report Innovative Technology Advancing Public Health Vision and Mission Vision- The Center for Biologics Evaluation and Research (CBER) uses sound science and regulatory expertise to: Protect and improve public and individual health in the U.S. and, where feasible, globally; and Facilitate the development, approval and access to safe and effective products and promising new technologies. Mission- To ensure the safety, purity, potency, and effectiveness of biological products including vaccines, blood and blood products, and cells, tissues and gene therapies for the prevention, diagnosis, and treatment of human diseases, conditions or injury. Through our mission, we also help to defend the public against the threats of emerging infectious diseases and bioterrorism. In fulfilling our mission as a Center in the Food and Drug Administration, we apply the following principles with the highest ethical standards and integrity: Develop, maintain, and support a high quality and diverse work force; Ensure compliance with laws and regulations through review, education, surveillance, and enforcement; and Conduct research as an essential element of science-based decision-making. From the Director   Center for Biologics Evaluation and Research Food and Drug Administration Rockville, MD 20857 March 2004 Dear Colleagues in the Biologics Community: I am pleased to provide the seventh annual report from the Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER). This report provides highlights from CBER’s activities during Fiscal Year (FY) 2003 and introduces some key new directions and initiatives for 2004. FDA’s new strategic framework establishes five broad strategic goals to frame the Agency’s future. The framework lays out an action plan to accomplish FDA’s primary mission to protect and promote the public health. The plan’s goals cut across all of FDA’s Centers, many of which include extensive inter-Center collaboration. The five goals are: Efficient Risk Management Improving Healthcare through Better Information Improving Patient and Consumer Safety Protecting America from Terrorism Smarter Regulation through a Stronger Workforce CBER’s FY 2003 annual report is organized within these five critical goals/areas. CBER embraces each goal and is working closely with other organizations to achieve them. Protecting and promoting the public health in the 21st Century is a great responsibility. Mastering it requires meeting some unprecedented challenges: having a strong organization that attracts and retains the most talented scientists; utilizing dynamic and responsive regulation for new and better ways to reduce risks; promoting quick access to needed new medical technologies that are safe and effective; helping to assure the continuing safety and availability of CBER regulated products; helping consumers get truthful and useful information about the products they use; and facilitating quick responses to the challenges of bioterrorism as well as emerging infectious diseases. These are among the many critical challenges we face as we look forward into the 21st Century. CBER can and will continue to play both a facilitating and a leadership role in meeting these challenges, seeking input from, and effective collaboration with, partners within and outside of government. The Center is responsible for addressing regulatory challenges related to ensuring the safety and efficacy of a wide range of biologic products including blood, blood products, human tissue, cell and gene therapies, vaccines, and allergenic 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. As you will see in this report, in both these and other areas, CBER research, often performed in collaboration with partners in government, academia and industry, helps to identify opportunities to advance new and emerging technologies, providing needed standards, assays and models to better measure and assure product safety, efficacy and consistency. These scientific contributions help to more safely and efficiently move innovative products along what has been termed the “critical path” to availability for patients who can benefit from them. In 2004 CBER will further sharpen its focus, and seek continuing input and collaboration, in utilizing its scientific resources and expertise to facilitate the development of products that are safe and effective – consistent with the FDA’s Critical Path Research Initiative (http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf). Nowhere is both the efficiency and quality of FDA’s product review more important than in the assessment of products such as CBER’s that are usually essential for the health of the public, may be given to healthy people (e.g. vaccines) and frequently address otherwise unmet medical needs. Therefore, we are fully committed to quality improvement and excellence in all of our review processes, including enhanced efficiency, management and consistency of review that incorporates best practices, such as the tradition of fostering early interactions during the review process. CBER has met or exceeded most of the higher performance goals in the Prescription Drug User Fee Act (PDUFA) III. In addition, through improvements in training, management, and the hard work and commitment of reviewers, CBER has demonstrated that it has the ability to provide timely review of device submissions, consistent with the Medical Device User Fee and Modernization Act (MDUFMA) goals. The Agency’s report to Congress on CBER’s work during the first year of MDUFMA indicates that the device program in Biologics has already improved its timeliness and responsiveness. My first year as CBER’s Center Director has been both challenging and productive. We anticipate another active year in FY 2004 as new scientific breakthroughs and discoveries continue, and we are fully committed to meeting the challenges of the 21st Century. In the coming year, we expect to make significant progress on a number of important CBER initiatives that both support the FDA Strategic Plan and further our critical public health mission, helping to protect and improve the health of Americans, and, wherever possible, people everywhere. Examples of important activities that have been or will be initiated this year include: Our new Review Template Initiative, to institutionalize best review practices and improve the consistency, quality, ease and efficiency of review, while supporting the Agency’s quality initiatives. Implementation of a Tissue Safety System, including finalization of FDA’s regulatory framework for tissue safety, continuing outreach to the tissue industry, and development of an interdisciplinary Tissue Safety Team. Formation of a Policy Coordinating Council, to address cross-cutting Center issues and better assure the development of important Center-wide policies. Development of a Counterterrorism Product Safety and Integrity Plan to put measures in place to help better assure the availability and safety of needed products during potential terrorist events. A management training initiative, to help provide CBER managers and leaders with the updated tools they need to make the best use of our available human and material resources. Implementation of a formal reviewer training program in fundamentals of Risk Management, Assessment and Communication. Enhanced external interactions: Bringing the outside in - increased opportunities for input and transparency of CBER programs, including opportunities for Advisory Committee and stakeholder input into programmatic efforts, such as defining future scientific needs and directions to enhance preparedness for and development of new products. Bringing the inside out - increased programs that foster continued career development for CBER staff, such as opportunities for continuing clinical and teaching activities for medical personnel, a program of blood bank rotations for blood product and device reviewers, and programs such as sabbaticals and interagency agreements to foster career development of our staff. Strategic focus of our international activities to achieve the best possible public health outcomes in areas such as emerging infectious diseases and global vaccine development. This includes providing enhanced and carefully targeted regulatory and technical assistance in the development of vaccines to meet global public health needs. Meeting the challenges of issues such as emerging infectious diseases and bioterrorism requires that we have state of the art, safe and effective medical products, and preparedness to keep these products safe and available to support our public health and medical systems. To achieve the incredible promise of new technologies, from novel vaccines to blood replacements to cell and gene therapies, requires continuously improving and evolving scientific expertise, cross-disciplinary teamwork and creatively defining new approaches to product development and regulation. We must do all this while maintaining our critical objective and independent role in assessing product safety and effectiveness. We look forward to working with all of you in achieving this critical mission. Sincerely, --- signature --- Jesse L. Goodman, M.D., M.P.H. Director Center for Biologics Evaluation and Research TABLE OF CONTENTS Who We Are Efficient Risk Management: The Most Public Health Bang for Our Regulatory Buck Empowering Consumers: Improving Healthcare Through Better Information Improving Patient and Consumer Safety Protecting America From Terrorism Smarter Regulation Through a Stronger Workforce Contact Us Appendix A Appendix B Appendix C WHO WE ARE The products regulated by CBER are most often critical to public health, on the leading edge of technology, or both. Rapid scientific advances in biochemistry, molecular and cellular biology, microbiology, immunology, genetics, and information technology are transforming biologics discovery and development, paving the way for unprecedented progress in developing new medicines to prevent and treat disease. While innovative new biological products promise great health benefits for U.S. consumers, and CBER seeks to facilitate their timely development and availability, we also must ensure that these products are safe and effective. Biological Products Regulated by FDA Blood Derivatives Whole Blood Blood Components Devices Tissues Vaccines Allergenic Extracts Somatic Cell & Gene Therapy Xenotransplantation   Blood FDA is responsible for ensuring the safety of the nation's blood supply by minimizing the risk of infectious disease transmission and other hazards, while facilitating the maintenance of an adequate supply of blood and blood products. CBER regulates the collection of blood and blood components used for transfusion or for the manufacture of other related products, such as clotting factors, and establishes standards for the products themselves. CBER also regulates products that are used to prepare blood and cellular products and to ensure the safety of the blood supply - for example, products such as cell separation devices, blood collection containers, and HIV and other blood donor screening tests.1, 2 CBER develops and enforces quality standards, inspects blood establishments, and monitors, analyzes and acts on reports of biological product deviations or unexpected events in manufacturing as well as adverse clinical events. As an example, in order to establish controls to monitor the performance of sensitive HIV and HCV-detection methods for blood (nucleic acid amplification technique or NAT), collaborative studies were carried out to harmonize international standards by calibrating international reagents, including the CBER standard. A study was also conducted to compare the sensitivity of different assays for hepatitis B virus (HBV) as a screening test for blood donors.   CBER works closely with other parts of the Public Health Service (PHS) to anticipate, identify and respond to potential threats to blood safety, to develop safety and technical standards, to monitor blood supplies and to help industry maintain an adequate supply of blood and blood products. While a blood supply with zero risk of transmitting infectious disease may not be possible, the blood supply is safer than it has ever been. Over a period of years, FDA has progressively strengthened the overlapping safeguards that protect patients from unsuitable blood and blood products. Blood donors are now asked specific and very direct questions about risk factors that could indicate possible infection with a transmissible disease. This "up-front" donor screening eliminates approximately 90 percent of unsuitable donors. FDA facilitates the development and implementation of sensitive tests to detect infectious agents in blood. These tests help assure that even donors without known risk factors do not transmit known infectious agents. FDA requires blood centers to maintain lists of unsuitable donors to prevent the use of collections from them. In addition to strengthening these safeguards, FDA has significantly increased its oversight of the blood industry. Blood donations are tested for seven different infectious agents. The Agency inspects all blood facilities at least every two years, and those for which previous inspections raised concerns may be inspected more often. Five Layers Of Blood Safety: First, donor screening - Potential donors are provided educational materials and asked specific questions by trained personnel about their health and medical history. Second, the blood is tested. Third, blood establishments must keep current a list of individuals who have been deferred as blood or plasma donors. Fourth, blood products are quarantined until the products have been thoroughly tested and the donation records have been verified. Fifth, blood establishments must investigate any breaches of these safeguards and correct system deficiencies. Some products also undergo viral inactivation procedures. The Impact of Testing for HIV and Hepatitis Viruses (HBV, HCV) on the Safety of the U.S. Blood Supply 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. For example, as shown in the graph, 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. Vaccines And Vaccine Safety CBER regulates vaccine products. Many of these are pediatric vaccines that have contributed to the dramatic reduction of dreaded childhood diseases such as polio and measles. Vaccines, as with all products regulated by FDA, must undergo rigorous review of laboratory and clinical data to ensure the safety, efficacy, purity3,4 and potency of these products. Vaccines may also be required to undergo additional studies even after they are approved for marketing in order to further evaluate the vaccine and often to address specific/additional questions about the vaccine's safety,5,6,7 and effectiveness.8 FDA also regularly inspects vaccine manufacturing facilities to ensure continued high quality production. Some examples of CBER's contributions to facilitating vaccine development include: To facilitate regulation and availability of vaccinia virus-based smallpox vaccines, CBER developed a new standardized, high-throughput, quantitative assay to measure the serum immune response to vaccinia vaccines and the potency of vaccinia-virus antibodies in human immunoglobulin preparations.9 Studies of the correlation of vaccine gene changes with attenuation and virulence may lead to rapid and more sensitive ways for detecting undesirable neurovirulence and assuring the safety of live viruses used in the manufacturing of live viral vaccines, such as oral poliovirus vaccine and mumps vaccine. Correlating immune responses to vaccines with protection from infectious disease was discussed in a World Health Organization (WHO) workshop to identify measures of immunity to use in clinical trial studies of pneumococcal vaccines, a strategy that can help speed and reduce the costs of needed product development. CBER and the Centers for Disease Control & Prevention (CDC) jointly manage the Vaccine Adverse Event Reporting System (VAERS), a cooperative program for vaccine safety. VAERS is a post-marketing safety surveillance program that collects information about adverse events (side effects) potentially related to vaccination, reported after the administration of U.S. licensed vaccines.10 In collaboration with CDC, State health departments and other partners, the VAERS system was used to compare differences in vaccine adverse event reports for various vaccine forms as a possible indicator of differences in vaccine safety.   Vaccines have reduced preventable infectious diseases to an all-time low and now few people experience the devastating effects of polio, measles, pertussis and other vaccine-preventable illnesses. CBER scientists have also developed a method to engineer Influenza B virus so that potential candidates that would be suitable for inclusion in vaccines and meet proper manufacturing specifications can be generated rapidly. Using these methods, CBER can provide influenza vaccine manufacturers with reference strains tailored to evolving public health needs. CBER scientists collaborate with NIH, other government agencies and departments, academic institutions, and industry to facilitate the rapid development of vaccines to counter emerging potential threats to public health. For example, dengue, a mosquito borne viral infection usually affecting those in tropical areas, has recently emerged as a threat to people in the continental USA. Currently, there are no effective treatments or preventive measures to combat this infection. CBER and NIH scientists collaborated to design and facilitate initial testing of a new, multivalent live attenuated dengue virus vaccine that may ultimately help to counter this threat in the future. Reports to the VAERS program are welcomed from all concerned individuals: patients, parents, health care providers, pharmacists, and vaccine manufacturers. (VAERS http://www.fda.gov/cber/vaers/vaers.htm) Information concerning preventive vaccines and vaccine-preventable diseases is available at the CDC National Immunization Program WWW site: http://www.cdc.gov/nip/ Cellular And Gene Therapies And Cancer Vaccines CBER regulates cutting edge medicines for the 21st Century. Among these, cellular and gene therapies and tumor vaccines stand out. Cellular and gene therapies are unique in their promise and potential to not only treat diseases, but to permanently correct them. Cell therapy products introduce cells into the body and thereby harness the power of different cell types to fight disease, restore normal function, repair injuries, replace lost cells, or regenerate failing organs. Stem cell-based therapies have the potential to repair many different cells in the body. Gene therapy products introduce genetic material into the body to replace faulty or missing genetic material, thus treating or curing a disease or abnormal medical condition. Human embryonic stem cells provide potential sources of differentiated cells for a variety of uses, and have the potential to treat a host of diseases including Alzheimer disease, Amyotrophic Lateral Sclerosis (ALS) - Lou Gehrig's disease, Parkinson's disease and diabetes. CBER has had, and continues to have, an active regulatory outreach program for sponsors and academic health centers to discuss product, preclinical and clinical requirements for these novel stem cells. This outreach includes the Cellular and Gene Therapy Working Group, established through a memorandum of understanding between CBER and the National Institute of Neurologic Diseases and Stroke. CBER also brings its research expertise to bear in solving problems and helping move new technologies forward. For example, CBER and NIH published one of the first comprehensive microarray analyses identifying unique "stemness" genes expressed by the Federally funded human embryonic stem cells lines,11 work that should help better assure the identity, safety and effectiveness of future stem cell treatments. FDA has not yet approved any human gene therapy product. However, the amount of gene-related patient research and development occurring in the United States continues to grow rapidly. FDA reviews many requests from researchers to study gene therapy and to develop gene therapy products, and actively oversees any studies that are in progress. Such research could lead to gene-based treatments and cures for a wide variety of disorders, including immune deficiencies, cancer, cystic fibrosis, heart disease, hemophilia, wounds, and infectious diseases such as AIDS, and graft-versus-host disease.12 CBER also regulates therapeutic vaccines for cancer treatment and prevention. A number of studies involving cellular and acellular tumor vaccines have advanced to the Phase III stage of clinical development (controlled clinical studies). CBER has maintained extensive interactions with academia, industry, government agencies and other regulatory bodies to enhance international awareness of the need for early product characterization (e.g., identity and potency) to help in the successful development of these products. CBER has also emphasized the need for identification of biological/immunological end points at early stages of tumor vaccine clinical trials13, 14 in order to more accurately and quickly identify effective treatments.   Tissues Tissue transplantation has come to play a major role in modern medicine with materials such as tendons, heart valves, skin and blood vessels being used to repair and restore normal function and to treat life-threatening diseases. The number of tissue transplants performed annually has grown from 350,000 in 1990, to greater than 1,000,000 in 2004. CBER requires tissue establishments to screen and test donors and to prepare and follow written procedures to prevent the spread of communicable disease and to prevent contamination during all stages of tissue recovery, processing and manufacturing. In response to the increased role and complexity of tissue transplants and the need to prevent communicable disease transmission, FDA is in the process of updating its regulation of human tissues, cells, and cellular- and tissue-based products. The proposed regulatory approach would address a broader scope of products, include more comprehensive yet adaptable requirements to prevent the transmission of existing and newly emerging communicable diseases, and apply tiered, risk-based requirements based on the characteristics of such products.   CBER Regulated Human Tissues Xenotransplantation CBER also regulates xenotransplantation, which is any procedure that involves the transplantation, implantation, or infusion into a human recipient of either: (a) live cells, tissues, or organs from a nonhuman animal source; or, (b) human body fluids, cells, tissues or organs that have had any contact with live nonhuman animal cells, tissues, or organs. Xenotransplantation offers the potential promise of providing needed organs and tissues to thousands who await transplants of scarce human organs. However, it raises a number of scientific and public health challenges, most notably the risk of transmission of new infectious diseases from animals to humans. Therefore, careful oversight and caution are critical to protect public health.   Xenotransplantation, using animal derived cells and tissues, has been used experimentally to treat certain diseases such as neurodegenerative disorders, liver failure and diabetes, where sufficient human organs and tissues are not usually available. Devices CBER regulates medical devices used in the collection, processing, testing, manufacture and administration of blood, blood components and cellular products. CBER also regulates all HIV and other infectious disease test kits used to screen donor blood, blood components and cellular products, as well as HIV tests used to diagnose, treat and monitor therapy in persons with HIV and AIDS. CBER collaborates closely with FDA's Center for Devices and Radiological Health in the regulation of these medical devices and of combination products that combine cellular therapies with devices, including so-called "tissue engineering" products which offer innovative and promising approaches to tissue repair and restoration.   The device above is a modular, microprocessor-controlled bench top instrument designed to automate routine testing in blood bank laboratories. Allergenics There are currently two types of allergenic products licensed for use: allergen patch tests and allergenic extracts. Allergen patch tests are diagnostic tests applied to the surface of the skin. Patch tests are used by physicians to determine the specific causes of contact dermatitis, and are manufactured from natural substances or chemicals such as nickel, rubber and fragrance mixes, that are known to cause contact dermatitis. Allergenic extracts are used for the diagnosis and treatment of allergic diseases such as allergic rhinitis ("hay fever"), allergic sinusitis, allergic conjunctivitis, bee venom allergy and food allergy.15 To help improve product quality and consistency, in 2003, CBER initiated a study to examine the levels of a common substance (endotoxin) in allergenic extracts that may affect performance. The results show the presence of variable amounts of endotoxins in some allergenic extracts. Further evaluation is underway to understand possible effects on their performance and safety. Allergenic extracts are currently manufactured in two forms: standardized and unstandardized. Prior to release, standardized allergenic extracts are compared to U.S. reference standards for potency. CBER maintains these reference standards and distributes them to manufacturers. Reference standards are critical for safe and reliable manufacturing. There are currently 19 standardized allergenic extracts. Extracts for which there are no current U.S. reference standards are termed unstandardized.   Allergenic extracts are injectable products that are manufactured from natural substances, such as molds, pollens, insect venoms, animal hair, and foods, known to elicit allergic reactions in susceptible individuals. Food extracts are only used to diagnose food allergies, but other allergenic extracts may be used for both diagnosis and treatment of allergic disease. Table of Contents EFFICIENT RISK MANAGEMENT: THE MOST PUBLIC HEALTH BANG FOR OUR REGULATORY BUCK Use science-based efficient risk management in all Agency regulatory activities, so that the Agency's limited resources can provide the most health promotion and protection at the least cost to the public. CBER's approach to risk management for biological products focuses on advancing public health through innovation. Our approach involves the use of the most current science, standards, and industry communications to avoid unnecessary regulatory burdens; improve compliance with the law; and achieve greater and faster improvements in public health through safe, effective and more affordable biological products. CBER is committed to enhancing its review process to help bring safe and effective biologics to market more quickly. Enhancements to the review process will include a quality systems approach and enhancements to our oversight of industry's activities to reduce risks, including expansion of risk-based approaches to inspection programs. We are also engaged in developing strategies and analyses to optimize pre- and post-marketing regulatory decisions related to biologics. CBER can also identify areas where risk management would benefit from standards and therefore, participates in producing them. For example, the Adenovirus Reference Material produced by an international working group is used to reduce risks of gene therapy vector- associated toxicity.16 Following the death of a recipient of adenovirus vectored gene therapy from a therapy-related toxicity, it became clear that a better understanding of such possible adverse effects was needed. Because this patient had underlying liver disease, CBER scientists sought to develop models to study adenovirus vector adverse effects in the setting of such pre-existing liver disease. Using a rat model, CBER scientists found that liver damage was associated with an increased sensitivity of the lungs to adverse outcomes following adenovirus vector administration. This model may help identify specific risk-associated factors in the patient and in the vector that will help in defining the best use of these therapies and in preventing future serious adverse events. Selected Biologics Approvals in FY 2003* Product Indication/Purpose Public Health Impact OraSure OraQuick Rapid HIV-1 Antibody Test OraSure Technologies, Inc., Bethlehem, PA For the detection of antibodies to HIV-1 in human finger-stick whole blood specimens An innovative rapid HIV diagnostic test kit that provides results with 99.6 percent accuracy in as little as 20 minutes. Pediarix DTaP & Hepatitis B (Recombinant) & Inactivated Polio Virus Vaccine GlaxoSmithKline Biologicals, Rixensart, Belgium Combination vaccine for childhood immunization The only vaccine marketed in the U.S. that offers protection against all of these infections in a single injection. Amevive Alefacept Biogen, Inc., Cambridge, MA Treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy Psoriasis affects many as 5.5 million people. Plaque psoriasis is the most common form of psoriasis, a chronic relapsing disease of the skin that is characterized by scaling and inflammation. Fabrazyme agalsidase beta Genzyme Corporation, Cambridge, MA For treatment of Fabry disease to reduce globotriasylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types The first treatment for patients with Fabry disease, a serious metabolic genetic disorder affecting approximately one in 40,000 males. Fabry disease causes certain fats to accumulate in the blood vessels, which can then lead to organ failure. Patients often must cope with pain and disability and typically have a shortened life span. FluMist Influenza Virus Vaccine Live, Intranasal MedImmune Vaccines, Inc., Mountain View, CA For active immunization for the prevention of disease caused by influenza A and B viruses in healthy children and adolescents, 5-17 years of age, and healthy adults, 18-49 years of age The first live virus influenza vaccine approved and the first nasally administered vaccine in the U.S. Flu is responsible for approximately 36,000 deaths per year in the U.S. Advate Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method Baxter Healthcare Corp., Westlake Village, CA Indicated in hemophilia A (classical hemophilia) for the prevention and control of bleeding episodes, and in the perioperative management of patients with hemophilia A A new recombinant DNA-derived clotting factor to treat people with hemophilia A. The first produced without using additives derived from human or animal blood in the manufacturing process, providing added protection against any unknown potential future infectious disease risks that may arise from the use of blood-derived additives. ORTHO Antibody to HBsAG ELISA Test System 3 Ortho-Clinical Diagnostics, Inc., Raritan, NJ Detection of hepatitis B surface antigen in human serum or plasma as a screening test and an aid in the diagnosis of potential hepatitis B infection Increase the safety of the blood supply. Dryvax Smallpox vaccine, dried, calf lymph type; 100 dose-kit (approval of supplements addressing issues such as extension of dating, etc.) Wyeth Laboratories, Marietta, PA Active immunization against smallpox disease The only currently licensed smallpox vaccine in the U.S. *See Appendix C for a list of CBER FY 2003 Major Approvals.   User Fee Programs PDUFA In 1992, Congress passed the Prescription Drug User Fee Act (PDUFA). This was reauthorized by the Food and Drug Modernization Act of 1997, and again by the Public Health Security and Bioterrorism Preparedness and Response Act of 2002. PDUFA authorizes FDA to collect fees from companies that produce certain human drug and biological products. When a company seeks FDA approval for a new drug or biologic prior to marketing, it must submit an application along with a fee to support the review process. In addition, companies pay annual fees for each manufacturing establishment and for each prescription drug product marketed. Previously, taxpayers alone paid for product reviews through budgets provided by Congress. In this program, industry provides added resources needed to meet review performance goals, which emphasize timeliness.   CBER has met or exceeded most PDUFA performance goals in the cohort FY 1994 through FY 2002. PDUFA Reports on Performance, Finance, and the Five-Year Plan can be accessed at www.fda.gov/oc/pdufa/reports.html.     PDUFA II Performance Goal: 90% (Indicated by Green Line)     Data thru 09/30/03 PDUFA has provided FDA with increased resources for the review of human drug and biologic applications. Fees collected from 1993 to 2002 were used to help reduce the time required for evaluating human drug applications without compromising review quality. FDA has submitted annual performance and financial reports to Congress on progress in streamlining the drug review process 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.   MDUFMA The Medical Device User Fee and Modernization Act of 2002 (MDUFMA) recognizes that "the public health will be served" by providing additional funds to FDA for "the process for the review of devices and the assurance of device safety and effectiveness so that statutorily mandated deadlines may be met." FDA's medical device program resources have been reduced in recent years, and there were indications that review performance had begun to decline. The user fees provided by MDUFMA, and the additional appropriations that go with the new law, should provide these significant benefits: Safe and effective devices used to diagnose and treat disease will reach the public more rapidly; Greater certainty that manufacturers will receive timely, high quality reviews; and Assurance that devices marketed in the United States continue to meet high standards for safety and effectiveness. The Act has three particularly significant provisions: User fees for reviews of premarket applications (PMAs), product development protocols (PDPs), premarket reports (a new category of premarket application for reprocessed single-use devices), biologic license applications (BLAs), certain supplements, and 510(k)s. Establishment inspections may be conducted by accredited persons (third-parties), under carefully prescribed conditions. New regulatory requirements for reprocessed single-use devices including a new category of premarket submission, the premarket report. In the last two years, CBER has worked intensively and sought input from both inside and outside the Agency to strengthen its device review process. The resulting increased effectiveness of device review in CBER is illustrated by timely product approvals and clearances in the first three quarters of FY 2003. In many cases, these approvals relate directly to innovations that enhance the safety and efficacy of blood and tissue products. Timely approvals included the implementation of modular premarket approval applications (PMAs). Additionally, CBER expertise in retrovirus marker detection and related fields has contributed to effective development and regulation of HIV diagnostic tests. Effective interaction with government partners and industry facilitated the recent approval of rapid tests for HIV and tests to monitor HIV drug resistance, both recent examples of successful regulation at CBER under the framework established by MDUFMA.   The Medical Device User Fee and Modernization Act of 2002 (MDUFMA), P.L. 107-250, amends the Federal Food, Drug, and Cosmetic Act (FD&C; Act) to provide FDA new responsibilities, resources, and challenges. MDUFMA was signed into law October 26, 2002. Additional information about MDUFMA can be accessed at www.fda.gov/oc/mdufma. Examples of recent timely approvals that have had a significant impact on public health included two rapid HIV tests, OraQuick and Reveal. In addition, the Clinical Laboratory Improvement Act (CLIA) waiver of the OraQuick rapid HIV test now enables the test to be used in a larger number of sites in the United States, including physicians' offices, community-based organizations and outreach clinics, not just clinical laboratories. Other recent approvals include the approval of Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) nucleic acid tests (NAT) for blood donor screening; rapid development and implementation under Investigational New Drug (IND) of donor screening for West Nile Virus (WNV) by NAT; and two quality control devices for detection of bacterial contamination in platelets. Pharmaceutical Good Manufacturing Practices FDA has undertaken and CBER is fully engaged in a significant initiative to enhance the regulation of pharmaceutical manufacturing and product quality, and to bring a 21st Century focus. The initiative focuses on FDA's current good manufacturing practices (cGMP) program and includes biological products such as vaccines. This initiative is designed to improve public health promotion and protection by focusing on three major goals to augment FDA's pharmaceutical product quality assurance programs across the board: Enhance the focus of the Agency's cGMP requirements more squarely on potential risks to public health, by providing additional regulatory attention to and Agency resources for those aspects of manufacturing that pose the greatest potential risk; Help ensure that FDA's essential work in establishing and enforcing pharmaceutical product quality standards does not impede innovation and the introduction of new manufacturing technologies in the pharmaceutical industry; and Enhance the consistency and predictability of FDA's approach to assuring production quality and safety among FDA's centers and field components. CBER has a history of innovation in GMPs, and many of these innovations will be carried further in the Agency-wide cGMP initiative including: Risk-based inspections; Participation of product specialists on inspection teams; Use of comparability protocols; Integrated cGMP prelicense review and inspection; Center review of warning letters; and Specialized training of investigators.   "Americans expect that their medicines will be of the highest quality, and assuring that quality is one of FDA's core missions," said FDA Deputy Commissioner Dr. Lester M. Crawford. "FDA's regulatory and quality control systems for pharmaceutical products have become a gold standard for the world, and we Americans should be proud that the quality of the medicines we have available to us and our animals is second to none. Any system can be improved upon, however, and with this risk-based, highly integrative cGMP initiative we intend to do just that. We know we can make even a very good system better…" Systems-Based Blood Program Compliance Guide To further CBER's risk-based approach to assuring the safety of biological products, CBER and the Office of Regulatory Affairs jointly developed and on September 1, 2003 implemented an updated systems-based Compliance Program Guide entitled "Inspection of Licensed and Unlicensed Blood Banks, Brokers, Reference Laboratories, and Contractors - 7342.001." This compliance program identifies five critical systems in a blood establishment operation for inspection: quality assurance, donor suitability/eligibility, product testing, quarantine/inventory management, and production and processing. The program directs an in-depth audit of critical areas in each of these systems. The critical areas, identified through risk assessment, are those that may affect safety and quality of the product if procedures are not performed properly or the system controls are inadequate or not functioning correctly. The compliance program builds on the knowledge gained during previous inspections of the blood industry and recent scientific developments, refining and updating CBER's risk-based approach. The program provides FDA investigators a method to determine the appropriate level of inspectional coverage and resources for each inspection based on factors such as the number of operating systems within the particular blood establishment and the establishment's compliance history.   New Recombinant Antihemophilic Factor On July 25, 2003, CBER licensed a new recombinant DNA-derived clotting factor to treat people with hemophilia A. This new antihemophilic human factor VIII product is the first produced without using materials derived from human or animal blood in the manufacturing process. This advance provides added protection against any unknown potential future infectious disease risks that could arise from such materials. The new product, called ADVATE Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (rAHF-PFM), was approved to prevent and control bleeding episodes or to prepare persons with hemophilia for surgery. It is produced by genetically engineered Chinese hamster ovary cells that produce factor VIII. Advate is manufactured by Baxter Healthcare Corporation, Deerfield, IL. Current factor VIII products (both plasma-derived and recombinant) are considered very safe as a result of many technological advances in the last two decades. These include viral inactivation and removal steps in manufacturing that are believed to effectively prevent transmission of hepatitis B, hepatitis C or HIV from plasma-derived products. These same procedures are also considered effective to minimize any infectious risks from products made by DNA technology, which uses living cells. Since 1987, there have been no reported cases of infectious disease transmission of HIV, HBC, or HCV from such products. New Rapid HIV Test Kit On November 7, 2002, CBER approved an innovative rapid HIV diagnostic test kit that provides results with 99.6 percent accuracy in as little as 20 minutes. Using less than a drop of blood, this new test detects antibodies to HIV-1, the virus that causes HIV infection and AIDS in most cases in the U.S. Unlike other HIV antibody tests, the kit can be stored at room temperature, requires no specialized equipment, and may be considered for use outside of traditional laboratory or clinical settings. The newly approved HIV test is called the OraQuick Rapid HIV-1 Antibody Test, manufactured by OraSure Technologies, Inc., Bethlehem, PA. To perform the test, a finger-stick sample of blood is collected from an individual and transferred to a vial where it is mixed with a developing solution. The test indicates whether HIV-1 antibodies are present by displaying two reddish-purple lines in a small window on the device. Although the results of rapid screenings will be reported in point-of-care settings, as with all screening tests for HIV, positive results must be confirmed with an additional specific test. The OraQuick test has not been approved to screen blood donors. New Pediatric Combination Vaccine On December 13, 2002, CBER announced the approval of a new combination vaccine that protects infants against diphtheria, tetanus, pertussis (whooping cough), polio, and hepatitis B virus. The vaccine is marketed as Pediarix by GlaxoSmithKline Biologicals. Pediarix is the only vaccine marketed in the U.S. that offers protection against all of these infections in a single injection, thus providing increased convenience for patients and health care providers. First Nasal Mist Flu Vaccine On June 17, 2003, CBER approved FluMist, an influenza vaccine that is the first live virus influenza vaccine approved in the U.S. It is also the first nasally administered vaccine to be marketed in the U.S. The strains of live virus used in the vaccine are modified so they do not grow well at body temperature but replicate enough to induce protective immunity. Each dose of FluMist is formulated to contain the three influenza virus strains recommended by the U.S. Public Health Service for the 2003-2004 influenza season: two strains of influenza A, to protect against the virus that causes the most severe and widespread outbreaks; and one strain to protect against influenza B, which usually causes a milder illness. CBER has been active in working with and educating stakeholders in the influenza vaccine production and licensing process.17 FluMist (Influenza Virus Vaccine Live, Intranasal) was approved to prevent influenza illness due to influenza A and B viruses in healthy people ages 18-49. Children 5-8 years old need two doses of FluMist at least 6 weeks apart in their first year of vaccination, while individuals 9-49 years old need only one dose. FluMist is manufactured by MedImmune Vaccines Inc., Mountain View, CA, and is marketed by MedImmune and Wyeth, Philadelphia, PA. Copyright (c) Russian Hemophilia Society 2001 A number of human factor VIII products have been approved to treat hemophilia A, an inherited disorder in which the blood clotting protein factor VIII is deficient or abnormal. Affected persons are unable to form blood clots normally and therefore risk serious and life-threatening bleeding episodes and the chronic damage to tissues, such as joints, that bleeding can cause. Replacement therapy with any of the factor VIII products, which requires intravenous administration, corrects the defect only temporarily. For this reason, factor VIII products frequently must be given several times a week, or more often, to prevent or treat bleeding episodes. Gene therapy holds future promise for replacing the missing or defective factor VIII gene in such patients and, it is hoped, may someday reduce or eliminate the need for chronic factor replacement. The first recombinant antihemophilic factor was approved in 1992. However, up until now, all recombinant factor VIII products were made with the use of blood-derived additives of human or animal origin, such as albumin, in manufacturing. These additives were needed to keep the cells viable so they could make the factor VIII protein. In this new product non-human and non-animal materials replaced these additives, further reducing potential risks to product safety. CDC has estimated that one-fourth of the approximately 900,000 HIV-infected people in the U.S. are not aware that they are infected. Because of the potential public health benefits of rapid HIV testing (providing immediate results to patients and their health care providers), CDC and the Centers for Medicare and Medicaid Services (CMS) are working with state and other health officials to make the test widely available, and to offer technical assistance, counseling and training for its use. Immunization has played a critical role in protecting individuals from potentially deadly diseases. In addition, vaccines safeguard the public from infectious diseases, proportionately decreasing the risk of disease spreading as vaccination rates increase. DTaP vaccine, Hepatitis B vaccine and inactivated poliovirus vaccine (IPV) are all currently available in the U.S. as separate vaccines. A Hepatitis B (recombinant) and Haemophilus influenzae type b combination vaccine is also available in the U.S. Pediarix, recently approved by the FDA, provides protection against all 5 infections. Influenza, or "flu," is responsible for an average of approximately 36,000 deaths per year in the U.S. Rates of infection are highest among children ages 5-14 years; however most severe illness and deaths occur among individuals with underlying medical conditions, children less than 2 years, and adults over 65. "This new vaccine (FluMist) provides another option for protection against influenza and will potentially increase the availability of the injected killed virus vaccine for those people at highest risk," said FDA Commissioner Mark B. McClellan, M.D., Ph.D. "Having enough supplies of flu vaccine available has sometimes been a challenge because there are few manufacturers, the vaccine needs to be changed every year, and certain strains of the virus grow slowly during the vaccine development process." Cell And Gene Therapy: Outreach And Partnerships CBER has provided proactive scientific and regulatory guidance in areas of novel product development. We have found that openly communicating regulatory expectations and encouraging continuing 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: Biological Response Modifiers Advisory Committee (BRMAC) meetings: February 2003: meeting on umbilical cord blood for hematopoietic reconstitution. During the meeting, patients, parents and families of patients addressed the Committee regarding their experiences and views on cord blood transplantation to treat oncologic, genetic and metabolic disorders. The BRMAC discussions highlighted concerns related to licensing, ethnic and racial issues in availability, impact on families and patients, age of recipients and informed consent. Advice from the BRMAC is being used by FDA to move ahead with the promulgation of appropriate regulatory approaches to facilitate the availability of consistently safe and effective cord blood. October 2003: meeting on islet cell transplantation. Promising results were presented showing that islet cell therapy can provide long-term normalization of glucose control in some patients with severe, difficult to treat, diabetes. FDA discussed and BRMAC provided advice on issues such as: acceptance criteria for source organs, criteria for islet isolation/processing, product potency and comparability, acceptable clinical outcomes and risk-benefit assessment of islet products. The American Society for Gene Therapy and CBER jointly sponsored a workshop on Non-Clinical Toxicology in Support of Licensure of Gene Therapies March 13-14, 2003 in Arlington, VA. This meeting discussed FDA expectations for preclinical studies needed for potential future licensure of gene therapy products in depth.   Tissue Action Plan The purpose of the Tissue Action Plan (TAP) is to develop the policies, regulations and guidance documents needed to implement the "Proposed Approach to the Regulation of Cellular and Tissue-based Products" (Proposed Approach) announced by FDA in February 1997, and in response to the recommendations made by the Government Accounting Office in its 1997 report, "Human Tissue Banks: FDA Taking Steps to Improve Safety, but Some Concerns Remain." FDA is making significant progress towards implementing the TAP. FDA published the third of three proposed rules intended to implement the Proposed Approach. This rule will require establishments that recover, process, store, label, package, or distribute tissue, or that screen or test donors, to follow current good tissue practice requirements. The proposed rule also contains provisions for FDA inspection of establishments and enforcement of the regulations.   FDA published a final rule requiring human cell, tissue, and cellular and tissue-based product (HCT/P) establishments to register with the Agency. This rule also establishes the criteria for regulation of HCT/Ps under section 361 of the Public Health Service Act and describes which HCT/Ps are regulated as biological products, drugs, and/or devices under the Federal Food, Drug, and Cosmetic Act and section 351 of the Public Health Service Act. FDA and CBER have placed their highest priorities in finalizing and publishing the remaining 2 rules governing donor suitability and good tissue practices. First Biologic Therapy For Psoriasis On January 31, 2003, CBER announced the approval of Amevive (Alefacept), an injected medication for adults with moderate to severe plaque psoriasis. Amevive is manufactured by Biogen, Inc., of Cambridge, MA. Amevive treats psoriasis through a unique immunosuppressive mechanism. Specifically, Amevive is believed to work by simultaneously blocking and reducing the cellular component of the immune system thought to play a significant role in the disease process.   According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, psoriasis affects between 1 and 2 percent of the United States population, or as many as 5.5 million people. First Treatment For Fabry Disease On April 24, 2003, CBER approved Fabrazyme (agalsidase beta), the first treatment for patients with Fabry disease, a serious metabolic genetic disorder affecting approximately one in 40,000 males. While it is believed that fewer females suffer the most serious consequences of the disease, they can be seriously affected as well. Because of an enzyme deficiency (alpha-galactosidase A), Fabry disease causes certain fats to accumulate in blood vessels over many years, involving various tissues and organs of the body, including kidneys and heart, which can then cause organ failure. Patients with Fabry disease often must cope with significant pain and disability, and typically have a shortened lifespan. Fabrazyme is a protein identical to the natural human enzyme but is produced by recombinant DNA technology. Fabrazyme is manufactured by Genzyme Corporation, Cambridge, MA. This replacement of the missing enzyme reduces harmful lipid (fat) accumulation in many types of cells, including blood vessels in the kidney and other organs. It is believed that this reduction of fat deposition should prevent the development of life-threatening organ damage. Fabrazyme was approved under FDA's accelerated approval mechanism. This policy allows for expediting the approval of therapies that treat serious or life-threatening illnesses when studies of the products indicate early favorable outcomes that are likely to predict clinical benefit. The approval is based on "surrogate endpoints" - laboratory measurements or physical signs - for evidence of effectiveness.   "This priority approval of an orphan drug illustrates FDA's commitment to approving innovative new therapies for patients with serious and life-threatening diseases quickly, based on response to treatment of biological markers likely to predict long-term clinical benefit." said FDA Commissioner Mark B. McClellan, M.D., Ph.D. "The orphan drugs program provides crucial incentives for innovators to develop new treatments for rare diseases. By approving this new biotechnology therapy under the 'accelerated approval' process, we are making this product available more quickly to patients who need it." "A key part of our accelerated approval process involves further study of the new treatment after approval, to confirm clinical benefit," said Dr. Jesse Goodman, Director of FDA's CBER. "In this case, FDA has worked closely with the product developer to make sure that, despite the relatively small number of patients with this disease, all reasonable steps will be pursued to make sure that we learn more about the product's clinical benefits and long-term safety once it is on the market." First Biologic For Allergy-Related Asthma On June 20, 2003, CBER approved the first biotechnology product to treat patients with asthma related to allergies. The product, Omalizumab (Xolair), is a monoclonal antibody that has been shown to be safe and effective in treating people 12 years of age or older with moderate to severe allergy-related asthma inadequately controlled with inhaled steroid treatments. In these patients, Omalizumab has been shown to decrease the number of asthma exacerbations or episodes of airway narrowing that result in wheezing, breathlessness, and cough. Xolair is manufactured by Genentech, Inc., San Francisco, CA, and marketed in conjunction with Novartis Pharmaceutical Corporation, East Hanover, NJ. While the cause for most forms of asthma is unclear, asthma caused by allergies results from the immune system's reaction to inhaled allergens such as dust mites or animal dander. The body forms antibodies in response to the allergen, and this immune reaction prompts inflammation causing airway narrowing, wheezing and other symptoms. Xolair is a genetically engineered protein that blocks this immune response.   Asthma is an airway disease affecting approximately 17 million Americans. It is estimated that a relatively small percentage of these people would be appropriate candidates for this new drug. It is currently recommended only for patients with moderate to severe allergy-related asthma after first-line treatments failed, and is not approved for children under the age of 12. Table of Contents EMPOWERING CONSUMERS: IMPROVING HEALTHCARE THROUGH BETTER INFORMATION Enable consumers to make smarter decisions by getting them better information to weigh the benefits and risks of FDA-regulated products. CBER is working to provide useful and accurate information to consumers to allow for better informed decisions. Communication with the public is integral to keeping constituents well-informed and ensuring transparent regulatory processes. A key component in regulating biological products is ensuring consumers, health professionals and others have accurate and timely information about potential health benefits and health consequences associated with these products so that they can make prudent decisions. The Center continues to support a multi-system approach to convey important messages to the public regarding product approvals, safety and related emerging risk management considerations. FDA Initiative Against Counterfeit Medical Products Counterfeit biological products are not only illegal, but also are potentially or inherently unsafe. On July 16, 2003, FDA launched a major initiative to more aggressively protect American consumers from counterfeit drugs. CBER is an active partner in this initiative and has played a leadership role in developing processes to respond to and address potential and actual counterfeiting events. At CBER, the initiative is designed to: Better identify the risks and threats from counterfeit biological products; Establish a public and private coalition to fight biological product counterfeiting and distribution; and Develop and implement new tools to aid in identifying, deterring and combating counterfeiting. As part of the initiative, CBER participates on the Commissioner’s Task Force and working groups, to further the use of modern technologies and other measures, including stronger enforcement and information dissemination, and to help prevent the distribution of counterfeit biological products to consumers. The Task Force issued a final report on February 18, 2004 (www.fda.gov/oc/initiatives/counterfeit/report02_04.html) that identifies ways to combat the growing public health problem of counterfeit prescription drugs in the U.S. The final report describes steps to protect against counterfeit drugs in the years ahead and identifies specific steps needed to secure the U.S. drug distribution system. Outreach During FY 2003, CBER’s electronic communication mechanisms reached their widest audiences. There were over 23.5 million hits on CBER’s internet site. CBER's website has proven to be a powerful communications tool for rapidly disseminating important information. When Hurricane Isabel hit the East Coast, CBER was prepared - the Center posted information about the impact of severe weather on biological products (http://www.fda.gov/cber/weatherimpact.htm). The number of hits to the web page spiked as the storm hit; the activity slowed once conditions improved. CBER continually seeks out and welcomes new opportunities for developing and providing useful information to the general public. For example, this year two educational brochures were updated: one providing general information about CBER; and the other on the Vaccine Adverse Event Reporting System (VAERS). The VAERS brochure, developed in partnership with the CDC, represents the inauguration of CBER efforts to develop outreach information for the Spanish-speaking community. CBER has also partnered with the National Hemophilia Foundation to develop three information sheets on gene therapy trials targeted to addressing the questions and interests of patients with hemophilia who hope to benefit from new experimental treatments. In addition to these proactive efforts, the Center responded to over 14,000 specific inquiries from consumers and health care professionals. During FY 2003, the FDA Science Forum on Protecting America's Health was coordinated by CBER. The annual FDA Science Forum is critical in sharing results of cutting-edge science focused on development of safe, effective and innovative products. Of equal importance, the forum also demonstrates to the public and our partners how FDA's scientific research contributes to improved medical products and outcomes. Many outreach efforts to regulated industry were conducted in FY 2003. CBER also organized information-sharing liaison meetings with organizations such as the Pharmaceutical Research and Manufacturers of America; the Plasma Protein Therapeutics Association; the American Blood Resources Association (joint meeting); the Biotechnology Industry Organization; the American Association of Blood Banks; and the Department of Defense Armed Services Blood Program. CBER also responded to over 8,000 inquiries from industry for general and technical assistance. CBER developed co-sponsorship agreements for six different major meetings. These meetings offer additional opportunities to share perspectives on a variety of issues, ranging from transfusion safety to regulatory issues for scientists and clinicians studying somatic cell therapy to facilitating product development. For example, one such collaborative event provided a forum for FDA and regulated industry to discuss the latest bioanalytical methods and their practical application to biotechnology pharmaceuticals and other related products. CBER also participates on planning committees to aid in program development for important industry educational conferences, meetings and symposia that offer the potential to improve the product development process and the safety and effectiveness of regulated products. CBER’s exhibit program is another important part of the Center’s outreach activities. During FY 2003, CBER exhibited at 13 consumer, health professional and industry meetings in 8 cities, reaching thousands of conference attendees and providing an avenue for direct communication between Center staff and the public. Please see Appendix B for the exhibit list. Table of Contents IMPROVING PATIENT AND CONSUMER SAFETY Seek continuous improvements in patient and consumer safety by reducing risks associated with FDA-regulated products. All FDA-regulated products have both benefits and risks, and CBER plays an important role in detecting and preventing injuries and deaths related to these products. According to some published estimates, adverse drug events alone may result in 770,000 injuries and deaths each year. Sometimes problems arise when medical products are misused because consumers or doctors do not have the right information about a new treatment. But adverse events that are preventable are not just caused by human error. Even with the best available data, products are sometimes found to have side effects that were not predictable or detected in clinical trials and other studies prior to product use in real-world conditions. Because virtually all medical therapies have side effects and risks, it is important for these side effects to be detected and well understood so that CBER can be sure that the benefits of the products we approve outweigh the risks and continue to do so after approval. This includes improving our ability to understand particular risks in specific populations, e.g., elderly patients, patients from particular demographic groups, or those carrying certain genes that may be associated with differences in risks. More mortality, morbidity, and related costs could be avoided as the management of product-related risks improves. On March 13, 2003, FDA proposed a new regulation that would require bar codes be placed on all prescription drugs (including biological products, such as vaccines) and some over-the-counter drugs. The bar code would, at a minimum, contain the drug's National Drug Code number, which uniquely identifies the product, its strength, and its dosage form. This rule will help to prevent medication errors associated with drug products. Monitoring Emerging Safety Information On Licensed Products While biological products must meet extremely high safety standards and present a positive benefit-to-risk ratio in order to be marketed, CBER continues to monitor products for important new safety and effectiveness information even after they are licensed. Biological products are complex and require vigilant post-marketing safety surveillance. CBER is working not only to improve current passive reporting systems for vaccines and biological therapeutics but to supplement and update our product safety activities by partnering with health care systems and others to use external medical databases that provide rapid and reliable information on product safety. Pilot projects assessing tissue transplant safety, as well as, vaccines given to older adults, have been initiated. CBER is also partnering with an expert constituent group to develop and evaluate new analytic tools for automated screening, or “data mining” of submitted adverse event reports. These techniques are already being applied to existing databases so, that new potential safety concerns can be recognized and analyzed earlier. In order for new information to improve consumer safety and patient outcomes, it must be quickly and clearly made available to health practitioners and the public. CBER post-marketing safety findings may lead to rapid implementation of changes in product labels and manufacturers’ communications with health practitioners. In addition, CBER epidemiologists report important safety findings directly to the medical community through presentations at scientific meetings and publication in medical journals, further increasing awareness and the potential for affecting practice. In some cases, it may be helpful to convey results of post-marketing surveillance even when no new safety concerns have been uncovered. This can be especially important for products, such as vaccines, that are widely used in healthy populations. CBER routinely conducts intensive monitoring of safety reports for new vaccines and publishes its findings, making the information widely available.18-27 For example, a summary of post-marketing experience with the pneumococcal conjugate vaccine, a new and universally recommended vaccine for infants, has recently been completed. This detailed review of adverse events reported to FDA during the first two years post-licensure confirmed the product's strong benefit-to-risk ratio, and should further enhance confidence in its use.   Response To Emerging Infectious Diseases And Other Public Health Threats West Nile Virus And Blood Safety The first domestically-acquired human cases of West Nile Virus (WNV) infection were documented in 1999, in the New York City region. In 2002, WNV activity was identified in 44 states and the District of Columbia, involving more than 4,000 human cases. According to the U.S. Centers for Disease Control and Prevention (CDC), the outbreak was the largest recognized arboviral meningoencephalitic epidemic in the Western Hemisphere. In 2002, in response to the growing epidemic, CBER and CDC promptly recognized the potential threat to the blood supply posed by blood from donors who felt well but could still potentially have the virus in their blood. CBER and the CDC alerted physicians, the blood community, and the public to the potential threat, while emphasizing that the benefits of medically indicated transfusions still far outweighed the risks, and that WNV could not be acquired by donating blood. For the first time ever, human WNV transmission through blood transfusions29 and organ transplantation30 were documented by CDC, FDA and State Health Departments. Responding quickly to the threat, FDA provided guidances on donor deferrals and product retrieval. FDA worked closely with CDC (who had proactively developed useful laboratory testing methodologies for its public health activities), the States, and the blood and diagnostics industries to identify the likely need for donor testing, engage all partners, and develop appropriate tests based on existing platform DNA detection methodologies. FDA and CDC provided needed technical assistance, virus and plasma samples, and standards for this effort and FDA performed highly interactive and rapid review of developmental testing methods and evaluation plans. As a result of this collaborative effort, within 8 months of identifying the risk of WNV exposure from blood, and before the start of the 2003 epidemic, universal investigational blood donor screening for WNV was made available, preventing the introduction of over 1,000 units of potentially infectious blood into the blood supply. In addition, the WNV blood screening efforts have contributed to CDC’s surveillance system providing very early identification of asymptomatic WNV infection in humans, a unique new real-time contribution of blood screening to acute infectious disease surveillance and control. This cooperative effort has provided a new model for rapidly addressing emerging infectious disease threats to blood safety. CBER is continuing to work with multiple partners to evaluate and implement effective WNV donor testing and is also involved in facilitating other efforts relevant to WNV, including vaccine development and potential immune therapies.   Because no screening tests were available at the time the threat of WNV to blood safety was first recognized, recommendations for donor deferral and product retrieval were especially important. So, FDA rapidly provided guidance, updated in 2003, which can be found on FDA’s website at http://www.fda.gov/cber/gdlns/wnvguid.htm FDA, worked closely with the blood and diagnostic industries, in an unprecedented team effort that result in the development and implementation of investigational WNV blood donor screening (nucleic acid testing) within 8 months of when the threat was first recognized. As a result, in 2003 over 1,000 units of potentially WNV infected blood were identified and removed before they could be transfused. “….testing blood donations for West Nile Virus RNA would have the potential benefit of removing viremic donations from the supply. Remarkably, such screening was initiated nationwide in late June 2003, as a result of tremendous effort on the part of the manufacturers of test kits and blood collectors, with the enthusiastic support and encouragement of the Food and Drug Administration.“ Dodd, R., in New England Journal of Medicine, 200328 In November 2002, in Bethesda, MD, FDA, CDC, HHS and NIH hosted a scientific workshop, attended by over 200 people, to share evolving information and to define and facilitate accelerated pathways needed for the development and implementation of WNV testing of blood donors. Severe Acute Respiratory Syndrome (SARS) In February 2003, CBER was notified of an outbreak of a new disease, Severe Acute Respiratory Syndrome (SARS). CBER immediately took steps to evaluate and help assure the safety of the blood supply against any potential risk. Existing FDA regulations require that a donor be in good health at the time of donation. These standard procedures already in place served as a safeguard against donation by a potential donor with symptoms from SARS. However, the degree of the outbreak and the nature of the disease were largely unknown. On April 17, 2003, CBER issued guidance to the Nation's blood establishments on measures to further safeguard the blood supply against the potential threat of SARS. CBER took this interim measure to assure the safety of the blood supply while more was learned about the disease. Scientific studies are continuing to evaluate whether SARS may be transmitted through blood and if so, the degree of risk and how best to address it. The Center also worked with its partners to proactively identify needs and help jumpstart and facilitate medical product development. For example, given the life threatening nature of SARS and its potential to rapidly spread globally, the Center is working with other government agencies and the private sector to address many of the challenges for development of a SARS vaccine. CBER and the CDC worked together to quickly make suitable seed-virus stocks available to manufacturers interested in producing a SARS vaccine. The CBER Director, Secretary Thompson, and NIH and CDC officials met with vaccine manufacturers to share information, encourage action and offer assistance to speed vaccine development. CBER has provided guidance on the use of animal test data and on safe manufacturing practices. CBER will also provide guidance on the design of clinical trials.   Severe acute respiratory syndrome (SARS) is a viral respiratory illness caused by a coronavirus, called SARS-associated coronavirus (SARS-CoV). SARS was first reported in Asia in February 2003. Over the next few months, the illness spread to more than two dozen countries in North America, South America, Europe, and Asia. The SARS global outbreak of 2003 was contained; however, its reemergence is an ongoing threat. As SARS vaccine development is in its infancy, much critical work must be accomplished as quickly as possible to assure that development and manufacturing processes meet the standards required to produce safe and effective vaccines. While significant scientific issues remain to be addressed, CBER and the Department of Health and Human Services (DHHS) are fully committed to facilitating the development of a safe and effective SARS vaccine as quickly as possible. CBER has formed a SARS Research Working Group composed of Center staff who meet regularly to communicate about SARS science, collaborate with partners at NIH, CDC, and the World Health Organization, and pro-actively prepare for anticipated development and evaluation needs for SARS-related biologics products. Hurdles to the identification and testing of effective and safe SARS vaccines include the need for rapid and accurate diagnosis of SARS infection, immune measures of vaccine effectiveness, assays for vaccine purity and potency, and evaluation of possible vaccine safety concerns. CBER scientists have formed a research consortium, in collaboration with NIH and CDC, to develop the tools necessary to support efficient and rapid SARS vaccine development White Particulate Matter In Blood On January 31, 2003, the American Red Cross (ARC) reported to FDA its observation of unexplained white particulate matter in blood and blood components contained in a small percentage of one type of blood bag. Subsequent reports revealed this phenomenon in blood and blood components collected in bags made by other companies in multiple areas of the country. FDA regulations call for visual inspection of blood and blood components during storage and immediately prior to distribution. CBER requested that blood establishments expeditiously quarantine any products raising concerns and report to the FDA their findings, as well as adverse events potentially related to the presence of particulate matter. Reports were rapidly investigated by FDA resulting in no evidence that the particulate matter causes any unusual problems. On February 7, 2003, FDA announced that it was issuing recommendations to the blood industry for additional blood inspection measures and would issue interim guidance recommending enhanced visual inspection of all blood and blood components. This interim guidance was a precautionary measure as FDA continued to actively investigate reports of units of blood and blood components containing white particulate matter. Several FDA laboratories worked closely with numerous outside investigators including blood bag manufacturers, NIH, CDC, State health authorities, ARC, American Association of Blood Banks (AABB), America’s Blood Centers (ABC) and academic transfusion experts to determine the nature of the particles and the possible cause of their formation. The findings of these investigations were discussed with FDA’s Blood Products Advisory Committee on June 19, 2003. These studies ruled out infectious agents including bioterrorism agents, chemical contaminants, and manufacturing changes or errors as possible causes. The findings suggested the white particles were simply clumps of platelets, white blood cells, and fibrinous materials, which might have been noted at an increased frequency due to a gradual increase in the use of certain blood preparation methods that are known to be safe. Investigations by FDA, the Georgia Department of Public Health, CDC and blood centers that may have received affected products, found no evidence of adverse events due to the particles, and no increase in the frequency of adverse events from transfusion. Based on the studies mentioned, FDA concluded that there was no additional value provided by the enhanced visual inspection measures and suggested that blood establishments discontinue that procedure. Although the cause of the particulate matter was not fully explained, throughout the investigations, FDA provided public risk communication not only of the initial reports and concerns but also of ongoing studies. The studies included those showing lack of contamination and absence of any attributable adverse events. CBER also emphasized that blood donation is a safe procedure and that continued donations were critical to maintaining a safe and adequate blood supply. By working together with multiple partners to rapidly investigate reports and communicate findings, major disruptions to the blood supply were avoided.   Blood Storage And Container Labeling Requirements On July 29, 2003, FDA issued a proposed rule to revise the labeling and storage requirements for blood and blood components including source plasma. FDA’s new policy would combine, simplify and update regulations related to blood container labeling and to the storage and shipping temperatures of frozen blood components. This new policy will make it easier for the blood industry to comply with existing regulations and manage the supply of plasma, while further enhancing the safety of the blood supply and reducing the cost of regulatory compliance through greater efficiency. The proposed new regulations would: Consolidate labeling requirements for blood and blood components into a single section of the regulations; Provide flexibility to allow use of an internationally standardized container label format that will harmonize with other countries the placement of important information such as blood type on the label, which should help reduce the risk of medical errors; Include provisions for changing some storage and shipping temperatures for certain frozen blood components to help ensure the potency of these components by preventing degradation of heat sensitive factors such as factor VIII (used to treat hemophilia); and Allow other safe changes in shipping and storage to provide blood establishments greater flexibility in inventory management, conserving product and helping prevent shortages.   Plasma is the fluid portion of blood collected from donors that can be used for transfusion purposes or further manufactured into blood derivatives such as anti-hemophilic factor. Source Plasma is plasma that is collected by plasmapheresis (automated collection) for further manufacturing. The proposed rule can be found on the FDA website at http://www.fda.gov/cber/rules/labelstorbldcor.htm Smallpox Vaccine Guidance To Protect Blood Safety On December 30, 2002, FDA issued guidance regarding procedures for potential blood donors who have recently been inoculated with the smallpox vaccine (vaccinia virus) or those who may have had other exposure to smallpox vaccine. This guidance was provided because of concerns that some people recently immunized with the live virus vaccine might have vaccine in their blood for a short period after immunization, and, if they donated blood, could unintendedly risk infecting some blood recipients. The recommendations, which delay blood donation following vaccination, were developed in consultation with vaccinia virus experts at CDC and the Department of Defense. These preventive measures pertain to non-emergency smallpox vaccination. In the event of widespread emergency vaccination due to an actual or impending smallpox outbreak, the procedures outlined in the guidance could be modified to adapt to changing risk-to-benefit assessments and other public health considerations.   The vaccinia virus used in smallpox vaccine is related to the smallpox virus (variola) and induces an immune response that is protective against the disease. Smallpox vaccine has been used with great success for over 100 years to protect against smallpox. FDA issued this guidance as a precautionary measure to reduce the very slight risk of unintended transmission of the vaccine virus by blood transfusions. To better guide blood safety policy, CBER scientists are currently performing laboratory studies to better determine if there is a risk and if so, its degree. Influenza An influenza pandemic occurs when a new influenza virus appears against which the human population has little or no immunity, resulting in several, simultaneous epidemics worldwide with enormous numbers of deaths and illnesses. With the increase in global transport and communications, as well as urbanization and overcrowding conditions, epidemics due to a new influenza virus are likely to quickly take hold around the world. During the last century, three influenza pandemics caused millions of deaths, social disruption and profound economic losses worldwide. Influenza experts agree that another pandemic is likely to happen. The 1918 Spanish flu pandemic is an example of a worst-case scenario because the strain was highly contagious and quite deadly. This pandemic killed more Americans than all the wars of the 20th Century. Since our world today is vastly more populated, and people travel the globe with ease, the spread of a next pandemic could be more rapid than that of previous pandemics. When a major change in one or both Influenza A surface proteins occurs spontaneously, no one will have partial or full immunity against infection because it is a new virus. If this new virus also has the capacity to spread from person-to-person, then a pandemic is most likely to occur. Preparation for the next pandemic of influenza requires action in the inter-pandemic period. Production of influenza vaccines is unique in that the viruses in the vaccine are changed on a frequent basis and the time available for making each year’s new vaccine and then distributing the vaccine for use is only 6-8 months. Infrastructure to permit support of manufacturing plays a vital role in ensuring that new vaccines can be produced in time to respond to a pandemic situation. Although vaccine production for a pandemic situation may be monovalent (a single strain), to accommodate increased vaccine production needs, non-pandemic (i.e., epidemic) strains with significant health impact are also likely to circulate, so that a multivalent (multiple strain) vaccine may be indicated for use. Increased awareness of the health impact of the flu epidemics and interest in pandemic preparedness has stimulated activity by manufacturers seeking approval for new influenza vaccines. Recent technical advances and product changes in the manufacture of influenza vaccines include development of live vaccines and tissue-culture-derived inactivated vaccines. A high probability of a successful response in a pandemic situation can be achieved when the response activities are developed and implemented during the inter-pandemic period. In general, at least one component of the trivalent influenza vaccine is changed every year. Therefore, CBER is highly experienced in rapidly supporting and reviewing yearly changes to large-scale manufacture of the vaccines. Most of the effort relates directly to new strains recommended for incorporation in vaccines. The regulatory process and CBER contributions to needed product availability for flu vaccines used in the U.S. include: Preparing new reference influenza virus reassortants for use in manufacturing (i.e. combining antigenic properties of wild type viruses with high growth characteristics of laboratory strains); Contributing to determinations about whether the current vaccine needs to be changed by evaluating antibody responses produced by current vaccines/strains against new strains that may be circulating and are being considered for use in new vaccines; Preparing information on influenza vaccine responses, on the status of reference strains and on the status of potency test reagents for use in influenza vaccine composition recommendations made by the FDA/USPHS and WHO; Testing and approving manufacturers’ seed viruses for new strains; Testing influenza virus vaccines and releasing the vaccines for distribution; Preparing strain-specific antiserum and antigen reagents that are recognized by WHO for use in vaccine potency tests used; and Enhancing uniformity of standards for vaccines manufactured worldwide by collaborating with WHO-sponsored international partners in calibration of key antigens used for testing. Currently, two inactivated influenza vaccines and one live attenuated influenza vaccine are licensed in the U.S., and other influenza vaccines are being developed. CBER researchers test and approve seed viruses (i.e., assays to confirm the antigenic characteristics of the viruses), test potency and approve release of manufactured vaccine. In addition to the laboratory based regulatory activities, ongoing review responsibilities relate to increasing capacity of current licensed manufacturers and licensing of new manufacturers. This includes review of IND studies, license applications and supplements, labeling and package insert documents, and participation in inspections of manufacturing facilities.   CBER scientists have developed new assays to confirm the genetic identity and evaluate the potency of potential constituents of new influenza vaccines. This provides pivotal support for the efficient development of safe and effective new vaccines. CBER scientists are applying innovative technologies to help speed the process of developing new strains of virus that are frequently needed for updating vaccines to respond to changes in the strains of virus that predominate in causing most influenza cases. The viruses that cause influenza outbreaks undergo rapid changes. This makes it necessary to regularly modify influenza vaccines so that they include the new properties to protect from the current virus. However, these new vaccine viruses also must be able to grow in the large quantities needed for vaccine manufacture. CBER scientists are working to expedite the development of new, effective vaccine strains through new molecular techniques. For example, growth properties needed for manufacture can be specifically engineered in a targeted fashion or viruses can be specifically assembled to contain the necessary properties rather than relying on random virus interactions. The large-scale preparation of inactivated influenza vaccines is highly dependent on the availability of influenza virus high-growth reassortants, which are influenza viruses that have been produced in the laboratory to incorporate the hemagglutinin and neuraminidase of the wild type strain with the growth properties of an egg adapted donor. CBER has been one of a few sources of new influenza A high- growth reassortants since the mid-1990’s. CBER scientists are applying innovative molecular technologies to provide the basis for resources and methods that will speed future availability of required strains for vaccines and avoid “bottle necks” in vaccine production that have sometimes occurred in the past. CBER works closely with NIAID/NIH, CDC, WHO, and other key organizations worldwide to develop well-coordinated, collaborative responses to potential pandemic strains. CBER scientists continue to make contributions to the development of critical virus strains and assays required for vaccine development and evaluation of therapies in response to worldwide threats to human public health, such as the 2004 “bird flu” virus raising concerns in Asia or other emerging potential pandemic influenza virus strains. Future global pandemics of flu are a constant threat and are likely to occur when genes from flu viruses affecting other species combine with human flu viruses. CBER plays an important role in identifying needed strains and in helping preparedness for influenza epidemics and pandemics. Gene Therapy Patient Tracking System Development The Gene Therapy Patient Tracking System (GTPTS) is a comprehensive, integrated system for the collection and analysis of information to assess and improve the safety of gene therapy. The GTPTS represents a comprehensive evaluation and re-engineering of FDA approaches to data pertinent to the safety of recipients of gene therapies, including collection of data from gene therapy studies; transmitting those data to FDA; storage of data in electronic databases; analysis of data; use of the data and analyses to make the best possible regulatory decisions; and to increase the understanding of researchers, subjects, and the public.   The Genetic Modification Clinical Research Information System (GeMCRIS) is one of several databases that will be part of the GTPTS. GeMCRIS is designed to provide protocol and adverse event information, and includes a browse function to review specific gene therapy trial information. FDA has worked closely with the NIH Office of Biotechnology Activities (OBA) to develop GeMCRIS, which provides: An important new electronic tool to facilitate the reporting and analyses for adverse event reporting; and Public access to non-confidential adverse event information as well as information on gene therapy clinical trials. GeMCRIS facilitates the generation of pre-formatted reports. GeMCRIS also allows selected non-confidential information about gene-transfer trials to be available to the public via the Internet. In 2003, CBER and NIH OBA shared the Secretary’s Distinguished Service Award for joint progress on GeMCRIS. Gene Therapy Clinical Trials For any FDA regulated product, the continuous balancing of risks and benefits and the assurance of protection of human subjects are essential parts of successful and safe product development. Gene therapy clinical trials, and their accompanying successes and adverse events, have stimulated broad public interest and discussion. CBER learned that a second child treated in a French gene therapy trial had developed a leukemia-like condition. Both this child and another who had developed a similar condition previously had been successfully treated by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID), also known as "bubble baby syndrome." In response, as an interim measure, in January 2003, CBER placed on "clinical hold" all active gene therapy trials using retroviral vectors to insert genes into blood stem cells. While CBER believes that the two leukemia cases reported from that clinical trial were related to the gene therapy mediated insertion of certain genes into high risk areas of the cell’s DNA, a continuing review of adverse events from somewhat different U.S. studies involving retroviral vectors found no evidence of leukemia due to the gene therapy. CBER reviewed the scientific evidence and the discussions and advice of the Biological Response Modifiers Advisory Committee (BRMAC) and of the NIH Recombinant DNA Advisory Committee. The Center continues to work closely with sponsors to facilitate development of innovative new treatments while doing everything possible to better understand and minimize the potential for serious adverse events. CBER, NIH, academic and industry scientists are sharing information and research to develop effective gene transfer methods that are designed to avoid problems, such as those previously described. While this process continues, CBER actively considers specific requests for retroviral gene therapy trials involving fatal or life-threatening disorders for which there currently are no viable alternative treatments.31   Gene Therapy: Promise and Concerns. The French SCID trial is a remarkable example of both the promise of gene therapy and of potential risks. Nine of 11 children treated for what is normally an otherwise fatal immune deficiency had their immune deficiency successfully corrected through gene replacement, promising normal lives. However, in 2 cases to date, the genes unintentionally became inserted in specific areas of the patient’s own DNA where they had the undesired effect of stimulating leukemia-like proliferation of other cells. CBER research is underway to help improve the safety of gene and cell therapy. For example, flow cytometry is a common but complex method of evaluating and selecting cells for use in gene and cell therapies. For use in the clinical setting, and to help improve the ease of development and quality and consistency of such products, CBER helps develop, standardize and calibrate methods for flow cytometry.32 Xenotransplantation Action Plan Xenotransplantation is any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs. The development of xenotransplantation is, in part, driven by the fact that the demand for human organs for transplantation far exceeds the supply. It is estimated that ten patients die each day in the U.S. while on waiting lists to receive life-saving vital organ transplants. Moreover, recent evidence has suggested that transplantation of needed cells and tissues may be therapeutic for certain diseases such as neurodegenerative disorders and diabetes. Unfortunately, sufficient supplies of the most promising human cells and tissues are not usually available. Although the potential benefits are considerable, the use of xenotransplantation raises concerns regarding the potential infection of recipients with both recognized and unrecognized infectious agents from animals, and the possible subsequent transmission to their close contacts and spread into the general human population.33, 34 One example of public health concern is the potential for cross-species infection by retroviruses, which may be latent (present but not apparent) and lead to disease years after infection. In addition, new infectious agents may not be readily identifiable with current techniques.   While xenotransplantation offers promise and hope to people waiting for lifesaving transplants, the possibility of infectious diseases jumping from animals to humans is real. Both SARS and monkeypox diseases were spread to humans from small animals, thus illustrating the need for stringent measures, testing and monitoring to help assure the safety of any animal organs or cells considered for transplantation to humans. Highlights of significant accomplishments in the oversight of xenotransplantation in FY 2003 include: Final Guidance: “Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans,” published on April 3, 2003. This document provides guidance on the production, testing and evaluation of products intended for use in xenotransplantation, as well as advice on the design and conduct of xenotransplantation pre-clinical and clinical studies. The Xenotransplantation Product IND Reviewer Focus Group, consisting of the cross disciplinary medical, veterinary, and review staff responsible for the review of xenotransplantation submissions meets regularly to discuss: application of the principles set forth in relevant FDA regulations; current scientific and medical data and literature relevant to transplantation; current status of xenotransplantation applications submitted to the Agency, and the unique issues that these products may present; and to highlight areas of concern where further expert advice may be needed. The Secretary’s Advisory Committee on Xenotransplantation (SACX) met on February 3-4, 2003. The meeting agenda included industry updates on xenotransplantation studies, discussion of SACX draft reports, and meeting updates, news items, and activity updates. CBER collaboration with CDC in the development of a proposal for a National Biological Specimen Archive for Xenotransplantation (NBAX) to be administered by CDC. The NBAX is planned as a repository for biologic samples from source animals and recipients so that the Public Health Service agencies are well poised to investigate a xenogenic infectious incident, should one occur. Continued CBER involvement in international activities for the safety and regulation of xenotransplantation products. Xenotransplantation offers hope for those in need of transplants, but understanding the risks of animal pathogen transmission to humans is critical if safe xenotransplantation methods are to be developed. CBER scientists found that a retrovirus carried by pig cells, PERV, could infect human cells under specific conditions. In addition, they developed a test that can detect PERV in blood and blood products that may be useful in screening blood, cells and tissues prior to use as medical products. Product Shortages A shortage occurs when a biological product is not commercially available in sufficient quantity to meet demand. A biological product is considered medically necessary when it is used to treat, cure, mitigate, prevent, or diagnose a serious or life-threatening disease or medical condition and there is no other available source or alternative therapy. CBER works to help prevent or alleviate shortages of biological products, and to work with all parties involved to do whatever is possible to help keep medically necessary products available. We place a high priority on preventing and responding to product shortages that threaten public health.   To report a biological product shortage by email, you may send an email to CBERProductshortages@cber.fda.gov. Biological product manufacturers and healthcare personnel may also report a known or suspected biological product shortage by calling (301) 827-6220. http://www.fda.gov/cber/shortage/shortage.htm. Causes Of Shortages Manufacturing problems are the most common causes of biological product shortages. Manufacturing issues may be brought to FDA’s attention by the manufacturer or as a result of an FDA inspection. Examples of other activities that may contribute to or cause product shortages include corporate decisions to discontinue a product, manufacturing supply or product distribution disruptions, critically needed regulatory actions, or natural or man-made disasters. To assist in better responding to inquiries about the availability of certain biological products and in managing potential shortages of medically necessary products, CBER has: Designated a responsible product shortage coordinator; Implemented a new website for sharing product shortage information; and Clarified the internal procedures to be used for the identification and management of product shortage events.   Table of Contents PROTECTING AMERICA FROM TERRORISM Strengthen FDA’s capacity to identify, prepare for, and respond to terrorist threats and incidents. CBER plays an important role in protecting America from terrorism. A major focus for the Center is the expeditious development and licensing of products to diagnose, treat or prevent disease from exposure to the pathogens that have been identified as bioterrorist agents. These products must be carefully reviewed and risk-to-benefit issues carefully considered throughout their development, manufacturing and use life-cycles. Staff must guide the products through the regulatory process, including manufacturing, pre-clinical testing, clinical trials, and the licensing and approval processes. Experts in diverse areas are needed to expedite the development, evaluation and licensing processes. Time is often of the essence and the scientific and product issues are extremely challenging. Early involvement by scientific, statistical/epidemiologic and clinical review staff is crucial to the success of the expedited development and review processes. Preparedness for and response to an attack involving biological agents are complicated by the large number of potential agents (most of which are rarely encountered naturally) and delivery methods, nonspecific symptomatologies and diagnostic challenges, variable incubation periods, and their potential for secondary transmission. In addition to naturally occurring pathogens, agents used by bioterrorists may be genetically engineered to resist current therapies and evade vaccine-induced immunity. Pathogens that have been identified as potential biological warfare agents include those that cause smallpox, anthrax, plague, tularemia, and hemorrhagic fevers,35, 36 as well as toxins such as botulinum and ricin, and may also include potential use of existing common public health threats such as influenza and tuberculosis. CBER works closely with other government agencies and with industry to facilitate needed product development and to help assure an adequate supply of safe and effective biological products to counter terrorism. These include products for immunization and treatment against anthrax, smallpox and other biothreats that might be used by terrorists, as well as steps to assure the safety and availability of blood, tissues and needed cellular therapy products. CBER scientists and their collaborators perform needed research focused on advancing product development and safety. In order to optimize product use, CBER also evaluates product effectiveness and adverse events experienced during use. Counterterrorism Accomplishments CBER plays a crucial and increasing role in protecting public health by helping to ensure the availability of safe and effective medical countermeasures for preventing and treating the public health consequences of a bioterror event. CBER’s efforts focus on facilitating the development, availability and licensure of safe and effective new and existing biological products, including vaccines, blood and blood products, human tissues, and cell and gene therapies. In addition to facilitating product development and availability, CBER works to help assure that products critically needed to respond to catastrophic events, such as blood and tissues, are kept safe from terrorist threats. CBER collaborates closely with other Federal agencies such as DOD, NIH, and CDC to: identify unmet product needs; address regulatory issues at the investigational and licensing stages; develop clinical protocols and needed product standards; conduct laboratory and animal studies; and define reference databases on treatment and alternative therapies for infectious diseases caused by the intentional use of biological agents. Emergency response proficiency is also being addressed through reassessing and strengthening capabilities and the development of continuity of operations plans. Support has been increased for the protection of regulated products from contamination and tampering to ensure the availability of products for use against biological, chemical or nuclear agents. CBER activities encompass the areas of prevention, protection, surveillance and detection, response and recovery, and future threats.   After 9/11, CBER’s involvement in a broad range of activities to help protect our population from terrorist threats, including bioterrorism, has dramatically increased. The work commitments involved in these activities have more than doubled and now account for approximately 25% of the Center’s total efforts, from product review research needed to help successfully develop new products, safety and post-marketing activities, to inspections and compliance. A significant amount of time is devoted to participation in multidisciplinary, multi-Agency efforts to identify product needs and approaches to meeting them, and to successfully help move products efficiently from early stages along the “critical pathways” toward availability and licensure. These team approaches are time and resource intensive but have been critical in expediting the availability of key needed products. Biologic Approvals Smallpox Vaccine - In October 2002, FDA approved a license supplement for a 100-dose kit of Dryvax, with a new supply of diluent (the liquid that is mixed with dried vaccine before it is administered) and needles for administration. Before the approval of this supplement, Dryvax was previously available only under an investigational new drug (IND) application. This action allows the vaccine to be distributed and used as any other licensed product; something critically important to allow flexibility in emergency public health response situations. Along with Dryvax, there are several other smallpox vaccines that are being evaluated under INDs. As a result of these efforts, U.S. troops were able to receive licensed smallpox vaccine in response to the threat of smallpox as a biological weapon, and there are now sufficient doses of smallpox vaccine available to protect all Americans in the event of an emergency. Meanwhile, FDA, NIH, CDC and industry partners are working together to facilitate the development of newer smallpox vaccines, including vaccines that are cell culture based and some that may be able to be used safely in immunocompromised individuals. Anthrax Vaccine - There is currently one anthrax vaccine, Anthrax Vaccine Adsorbed (AVA), licensed in the U.S. which is manufactured by BioPort Corporation, located in Lansing, MI. The facility halted production of the anthrax vaccine in 1998 to begin a comprehensive renovation. Due to the complex nature of biological products, the Public Health Service Act and FDA require approval of an application for major changes made to a facility in which a licensed product is manufactured. On December 27, 2001, after a pre-approval inspection, FDA approved BioPort's Lansing, MI facility. On January 31, 2002, FDA took the final action necessary to allow BioPort Corporation to begin routine distribution of licensed anthrax vaccine from its renovated facility. This action was the approval of a supplement to BioPort's biologics license approving Hollister-Stier Laboratories, LLC in Spokane, WA, as a contract filling facility for the AVA. FDA also approved a supplement from BioPort revising their potency test for the anthrax vaccine. This test enables comparison of each lot to the reference lot, which is of known acceptable potency, using state of the art statistical analyses.   The last confirmed case of smallpox in the U.S. occurred in 1949, and the last naturally occurring case in the world was recorded in Somalia in 1977. Three years later, the World Health Organization declared that smallpox had been eradicated. Experts say that if terrorists were to intentionally introduce just a single case of smallpox today, it could mushroom into a public health emergency. Following the 9/11/01 attacks, Secretary Tommy Thompson made a commitment to obtain a sufficient stockpile of smallpox vaccine to protect every American in the event of an emergency. Working together, FDA, CDC, NIH and segments of the vaccine industry have helped meet this challenge. FDA identified existing stocks of older vaccines and, where needed, evaluated them for potency and purity. Working with NIH, the effectiveness of diluted smallpox vaccine was evaluated in an effort to extend supplies further. As a result of this teamwork, and FDA’s efforts, the U.S now has enough smallpox vaccine to immunize the entire population, were this ever to be needed. Other major counterterrorism activities have included: Creation of the CBER Counterterrorism Coordinating Committee (CTCC), which maintains a database of CT products, both licensed and under development, and provides a cross-cutting policy forum for the Center. In addition, in 2004, the CTCC will identify pertinent issues and develop a roadmap for protecting the safety and availability of CBER’s countermeasures and of biologic products, such as blood and tissues, whose safety may be affected by agents of terrorism; Issuing guidance for the blood industry regarding potential blood donors who have recently received the smallpox vaccine (vaccinia virus). The recommendations were developed in collaboration with smallpox experts at the CDC and the DOD. FDA issued the guidance as a precautionary measure because the presence of vaccinia virus in transfused blood or plasma could be harmful to some recipients (December 2002); Issuing the guidance document “Recommendations for Assessment of Donor Suitability and Blood and Blood Product Safety in Cases of Possible Exposure to Anthrax.” This provides FDA recommendations for assessment of donor suitability and product safety for donors potentially exposed to Bacillus anthracis, the agent of anthrax (October 2001); Working with HHS and industry to develop new approaches to increase Vaccinia Immune Globulin (VIG) stockpiles as well as new manufacturing capability and capacity in the U.S. VIG is used to treat adverse reactions to the vaccine. All VIG currently in existence in the U.S. was made available under IND for emergency use for treatment of smallpox vaccine adverse events;   As part of an overall Agency effort, CBER is in the process of developing Continuity of Operations Plans so that essential counter-terrorism related functions can still be performed during a local or national crisis. Developing a new assay for measuring antibodies in vaccinated people to determine how well smallpox vaccines work and how long the antibodies last after vaccination.37 This new assay speeds the large-scale evaluation of many samples in clinical trials. The assay was transferred to outside laboratories playing key roles in new smallpox vaccine trials and production; Designing and developing scientific assessment approaches to determine the usefulness of commercially available intravenous immunoglobulin (IGIV) as a viable treatment for certain smallpox vaccine adverse events in the absence of an adequate VIG supply; Working actively with HHS/CDC, DOD, NIH and industry on development of new recombinant vaccines for anthrax; Providing expert consultation to HHS, DOD and industry to assist in the development of future programs for production of new countermeasures; Implementing potency assay testing for smallpox vaccines. As part of this work, internal standard operating procedures, study plans, and internal reference standards were developed. In addition, scientists are collaborating in a World Health Organization/National Institute for Biological Standards and Control (WHO/NIBSC) sponsored study to assess the relative sensitivity of different assay techniques for potency determination. This study will also assess the suitability of vaccine candidates for a new international standard for smallpox vaccine; Participating on the Select Agent Interagency Workgroup, which provided expert scientific and policy guidance to the CDC necessary to draft the final rule "Select Biological Agents and Toxins." This rule defines the select agents and describes requirements for their registration, storage and transfer; and Collaborating in the development and preliminary animal testing of a live oral, attenuated S. typhi Ty21a-vectored vaccine for protection against Shigella sonnei. This work was published in the journal Infection and Immunity38 and a patent application was submitted in 2002. Work has begun, using this live oral vaccine model, to develop vaccines for protection against other major serotypes of Shigella and against anthrax. New CBER-developed immunoassay for measuring the potency of antibodies induced by smallpox vaccine. CBER participates in national risk management groups to discuss opportunities to leverage existing supplies of available medical countermeasures while identifying needs and gaps in current medical therapies. Project BioShield In February 2003, President Bush announced Project BioShield during his State of the Union Address. He proposed the creation of a permanent indefinite funding authority for purchase of needed medical countermeasures. This promises to further increase the pace of product development and create additional needs for proactive CBER activities, including, assistance to other agencies and to manufacturers to help develop such products effectively, evaluate and assure their safety and effectiveness, and to help make sure that they are properly manufactured and available as needed. In addition, the BioShield program would establish a new approach to facilitating the emergency availability of medical countermeasures prior to their licensure, under a mechanism called Emergency Use Authorization (EUA). Although Congress has not passed BioShield legislation, in November 2003, the President signed into law the National Defense Authorization Act for Fiscal Year 2004 (P.L. 108-136) that allows FDA to issue an EUA in a declared military emergency based on certain criteria. FDA would evaluate the product to determine whether its known and potential benefits outweigh its known and potential risks under the circumstances. FDA would also evaluate the information proposed to be communicated to providers and patients. The EUA provisions in the National Defense Authorization Act will terminate when BioShield legislation is enacted if that legislation provides effective emergency use authority for military personnel. CBER is currently working with the other Centers and the Office of the Commissioner to develop appropriate principles and procedures for the EUA. FDA’s role in assessing availability of products for emergency use, particularly when not yet licensed, is critical. Not only is it vital in meeting the threats of terrorism, but also in helping to assure to the best extent possible, that all available data are objectively reviewed in evaluating such a potential emergency use determination, that communication to the public is as clear and complete as possible about what is known, and that public safety and confidence in all medicines are safeguarded. Table of Contents SMARTER REGULATION THROUGH A STRONGER WORKFORCE Ensure a world-class professional workforce, effective and efficient operations, and adequate resources to accomplish the Agency’s mission. FDA’s continued ability to carry out its mission of protecting and advancing America’s health rests squarely on its most important resource: talented and dedicated staff. FDA is taking steps to improve retention and training, and is implementing new activities to augment the Agency’s capabilities through use of outside experts and collaborations. FDA is also implementing steps toward completing the consolidation of much of its workforce in a new campus in White Oak, MD. Jesse Goodman, M.D., M.P.H., Named Director Of CBER On December 16, 2002, the Commissioner of Food and Drugs, Dr. Mark McClellan appointed Jesse Goodman, M.D., M.P.H., as the Director of the Center for Biologics Evaluation and Research (CBER). Dr. Goodman served as CBER's Deputy Director (Medicine) and is a virologist who is board certified in internal medicine, oncology, and infectious diseases. Educated at Harvard, he earned his medical degree from the Albert Einstein College of Medicine, and did residency and fellowship training at the University of Pennsylvania and UCLA. Dr. Goodman joined FDA as a Senior Advisor to the Commissioner for medical programs in 1998, on leave from the University of Minnesota School of Medicine, where he was Professor of Medicine and Chief of Infectious Diseases, and an active clinician and researcher. In the Commissioner’s Office, he co-directed the U.S. Government's Interagency Task Force on Antimicrobial Resistance, working with CDC, NIH and others in developing the nation’s Public Health Action Plan to Combat Antimicrobial Resistance. He later moved to CBER, where he has been active in a wide variety of clinical and public health issues including bioterrorism preparedness and response, product development, and blood and vaccine safety. Dr. Goodman succeeds Dr. Kathryn Zoon, who joined FDA in 1980 and served as Director of CBER since 1992. Dr. Zoon announced her resignation to return to NIH, as Principal Deputy Director for Research in the Center for Cancer Research, at the National Cancer Institute. During Dr. Zoon's tenure, CBER licensed approximately 320 products, and successfully implemented the prescription drug user fee program for biological products. She was critical to the success of biotech products such as recombinant proteins and monoclonal antibodies, and played a key role in the Center’s proactive and effective post-9/11 response to bioterrorism threats, working closely with Dr. Goodman and other senior staff in those efforts. The first woman to serve as director of an FDA center, Dr. Zoon has been an outspoken advocate for strong science-based regulation and expertise at FDA.   "Jesse Goodman possesses the ideal credentials and experience to serve the American public as an empowered director of FDA's biologics center," said Dr. McClellan. "This is a critical time for biologics, with technologies like cellular and gene therapies holding the promise of transforming medical care in the 21st Century, and with new challenges including countering terrorism and protecting the blood supply from new threats. Dr. Goodman is absolutely committed, as am I, to meeting these challenges through sound regulation based on the best science and risk assessment models." Management Initiatives At CBER CBER is taking a number of steps to support and strengthen its workforce, encourage cross-disciplinary and collaborative approaches to its increasing product and public health challenges, and to improve its management to meet new responsibilities. These steps have included: Institution of monthly interdisciplinary Center-wide Grand Rounds Case Studies; Development of a science database that tracks research projects and their impact on public health and product development; Development of a clinical skills database and enhancement of opportunities for continuing clinical and teaching opportunities for CBER medical officers; Initiation of site visit programs for CBER reviewers to keep up-to-date with respect to industry and medical practices and options for and impacts of existing or contemplated regulatory strategies (e.g. the new CBER-Blood Bank Rotation Program); Increasing transparency and input- examples include: supporting sabbaticals at CBER for outside scientists and clinicians; regular high level CBER participation in medical device industry meetings and roundtables; planned Advisory Committee meetings to include presentations of and input into CBER’s broad scientific programs; and diverse input in designing needed tissue safety programs; Movement of review management and quality assurance senior leadership and staff to co-locate with product reviewers and review teams; and augmentation of its staff to begin enhanced review management and quality control efforts (e.g. the review template initiative); Streamlining, focusing and strengthening the Center Director’s Office with consolidation of managerial, business support and administrative functions in appropriate program and management offices; and Strengthening of the Center Director’s Office core functions with needed project management, counterterrorism, medical/scientific and support staff.   CBER Grand Rounds is a new interdisciplinary monthly case conference that brings together product scientists, clinical and statistical reviewers, scientists, epidemiologists, and administrative and policy staff to consider issues and products that cut across the Center’s interests. Grand Rounds held have included discussions such as: Emergency response to emerging infectious diseases Statistical analysis of lot release tests Development of cellular therapies for cardiac disease Human subjects protection Issues in vaccine development for global public health needs Electronic Document Room (EDR) And Other E-Initiatives: Using IT To Facilitate Efficient And Timely Product Review And Safety Monitoring The EDR is a collection of systems that enables the regulatory process by storing, retrieving, and distributing electronic submissions to reviewers. The EDR is integrated with the CBER regulatory databases to allow for advanced searches based on data in the CBER databases. The EDR automates processing of application submissions and automatically sends notifications to reviewers. The EDR also serves as a repository for CBER-generated final documents. Three software upgrades were made to the EDR during FY 2003. Enhancements include the addition of electronic routing of amendments to the IND and BLA electronic submissions processes, and Smart PDF forms containing business rules that ensure forms are completed appropriately, as well as, allowing the information to be extracted automatically into the EDR. These enhancements allow for a completely electronic process from submission, processing, routing, and review of amendments. This year alone, more than 1,100 submission documents with an electronic component were available in the EDR, including 8 original BLAs, 430 BLA amendments, 25 original INDs, 465 IND amendments as well as 262 supplements, annual reports, product correspondence, and post-marketing commitments. CBER is pleased that 5 (of 8) BLAs (62%) and 14 (of 25) INDs (56%) were compliant with our electronic submissions guidance, supporting fully electronic submissions. Submission of an eIND or BLA and amendments allows reviewers to immediately review or include new information within minutes, saving days usually spent in mailing in hard copies and routing them to appropriate FDA personnel. CBER encourages electronic format submissions and invites sponsors who are considering electronic submissions to work with us early in the application process. Significant progress has been made this year in compliance, blood and tissue systems with 1,630 new users registering with CBER to use these e-business systems: Electronic Biologic Product Deviation Report system (eBPDR) has received 18,243 reports; eBPDR supports the submission of Biological Product Deviation reports over the Internet; Electronic Blood Establishment Registration system (eBER) has received 1,437 registrations (includes 12 Initial Registrations); eBER is a web-based registration system to allow blood bank establishments to register on-line with FDA; and Electronic Human Cell and Tissue Establishment Registration system (eHCTERS) has received 17 registrations; eHCTERS is web-based registration system for establishments to register on-line with FDA.   CBER’s e-business team won the Secretary’s award for distinguished service. They have lead the way in integrating digital signatures using Public Key Infrastructure (PKI) with electronic medical imaging, statistical data, and supporting information to allow E-business transactions for key business services including IND studies, BLA’s and NDA’s. CBER has reduced the time to move information from industry medical professionals to HHS medical professionals from five to six days to five to six minutes. This near real-time exchange of secure business is accelerating both the quality and speed of medical products being made available to the public. FDA Completes Consolidation Of Certain Products From CBER To CDER FDA completed the third phase of the transfer of certain product reviews (monoclonal antibodies and recombinant therapeutic proteins other than blood products) from CBER to the Center for Drug Evaluation and Research (CDER) on June 30, 2003. This third phase dealt primarily with logistical and administrative issues involved in the product consolidation.   International Activities Highlights We are living in a global environment in which pharmaceutical and device development, including clinical trials and manufacturing, is increasingly international. It is beneficial to all nations to have the highest quality products developed for global use utilizing harmonized high quality research and manufacturing. In addition, we are in an age of global emerging infectious diseases that can rapidly spread around the world. SARS and avian influenza are only two recent examples. The Center undertakes a range of international activities as it pursues its mission within the larger FDA Strategic Plan. In FY 2003, the Agency embarked upon an effort to exercise greater coordination of cross-cutting international activities to assure their consistency with FDA’s mission and the international agenda of HHS. Specific goals were established whereby FDA would strive to enhance its ability to: Effect an affirmative public health agenda in the international arena; Enhance and maximize FDA’s global communication and interactions, assuring they reflect the Agency's policies and best thinking; Assure consistency of FDA international communications and interactions with the Department’s public health objectives; and Leverage resources with counterpart agencies and within FDA on a risk-based basis. CBER supports these objectives. CBER products such as blood, vaccines and products to address bioterrorism are critical to global public health. Increased global cooperation and harmonization in the development and availability of these products can benefit everyone. CBER has worked with the Office of International Programs in the Office of the Commissioner in its efforts. The Center supported Agency and Department international efforts in FY 2003, particularly in providing scientific and technical expertise in needed areas. Support was provided in many countries, including: Afghanistan, Argentina, China, Dominican Republic, Iraq, Italy, Korea, Taiwan, Singapore, South Africa, Uruguay, and Zimbabwe. Of particular significance has been CBER’s support of the Department’s international counterterrorism efforts. In FY 2003, CBER joined FDA in planning exercises under the Department’s Global Health Security Action Group (GHSAG). The GHSAG was created by formal agreement on November 7, 2001, in Ottawa, Canada, between the health ministers of the United States, Canada, France, Germany, Italy, Japan, Mexico, the United Kingdom, Mexico, the European Commission and WHO. The purpose of the GHSAG is to improve health security worldwide by increasing preparation for biological, chemical or nuclear attacks. In FY 2003, CBER also contributed significantly to the efforts of HHS as it addressed emerging infectious disease issues. Most notably, CBER contributed to addressing the emergence of SARS in Asia, providing support and scientific advice as appropriate. With respect to the recent H5N1 avian influenza outbreak, CBER is playing an important role in helping expedite the development of a vaccine to enhance preparedness in case this or a related flu strain threaten a global pandemic. A number of other important international activities, including extensive international collaboration and assistance in blood safety and xenotransplantation are described elsewhere in this report.   WHO And PAHO Activities In 1998, CBER was designated for the first time as a PAHO/WHO Collaborating Center for Biological Standardization. Designation as a PAHO/WHO Collaborating Center is not a status given in perpetuity, but one that must be renewed by PAHO/WHO based on an evaluation of work contributions by the Collaborating Center. On October 6, 2003, CBER received this redesignation. In FY 2003, CBER continued its substantial commitment to WHO/PAHO efforts to improve global public health by providing technical and scientific input on specific topical issues, as well as providing input on strategic policy matters. CBER has had substantial involvement in numerous WHO Expert Consultations in FY 2003, including: Transmissible spongiform encephalopathies (TSEs) in relation to biological and pharmaceutical products; Requirements for production and quality control of smallpox vaccine; Composition of influenza vaccines; Revision of WHO recommendations for production and quality control of inactivated influenza vaccine; Human papilomavirus vaccine efficacy; Requirements for production and quality control of dengue fever vaccine; Monitoring group on gene therapy; Serological criteria for evaluation and licensure of pneumococcal conjugate vaccines; and Preparation, characterization and establishment of WHO international standards and other biological reference materials.   Bacterial meningitis due to meningococcus is a major domestic and international health problem in children and young adults. The development of conjugate vaccines has decreased serious disease by over 50%. However, synthesis of these complex protein-carbohydrate conjugates can be time consuming costly, and inefficient. Scientists at CBER have developed a novel method for rapid and more efficient conjugation of glycoprotein vaccine candidates, supporting cost reduction in vaccine manufacture and avoidance of vaccine shortages. A patent is pending for this method and it is being incorporated into a WHO international testing program for meningococcal vaccines. International Conference On Harmonisation (ICH) The Center continued its commitments as a Steering Committee member to the International Conference on Harmonisation (ICH), a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration. CBER provided leadership and technical expertise to the various Expert Working Groups, Implementation Working Groups, and technical discussion groups over the course of FY 2003. CBER originated and leads the ICH gene therapy discussion group. The mission of this group is to discuss and share scientific and regulatory information on the emerging issues surrounding gene therapy. One outcome will be to reach consensus on novel emerging technologies and gene therapy related safety issues.   As part of the Agency’s cGMPs for the 21st Century initiative, FDA opened discussions in the ICH forum on those areas within the initiative with potential for harmonization. Following a brainstorming session at the July meeting, general agreement was reached on a high level vision: a harmonized pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to risk management. Global Harmonization Task Force The Global Harmonization Task Force (GHTF) is an international harmonization initiative intended to respond to the growing need for international harmonization in the regulation of medical devices. Regulation of devices is primarily the purview of the Center for Devices and Radiological Health (CDRH). However CBER has a portfolio of devices as well, including in vitro diagnostics (IVDs) used in blood donor screening and for HIV. CBER collaborates closely with CDRH in its role as the lead FDA center for the GHTF.   Enhancing CBER’s International Public Health Role In 2004 To further enhance our international activities, and make the best use of limited resources, CBER is taking the following actions: Development of goals and priorities and a global action plan with timelines in each product area (e.g., blood, vaccines, gene and cell therapies, tissues); and Consolidation, coordination and enhancement of high priority activities in global vaccine development - focusing available resources on providing effective regulatory and consultative assistance to address the need for vaccines targeting diseases of global significance. Table of Contents Contact Us Consumers and Health Professionals 800-835-4709 or 301-827-1800 fax 301-827-3843 / octma@cber.fda.gov www.fda.gov/cber Manufacturers and Distributors 800-835-4709 or 301-827-1800 fax 301-827-3843 / matt@cber.fda.gov Ombudsman 301-827-0379 / fax 301-827-2920 lard@cber.fda.gov or balick@cber.fda.gov Blood and Plasma Products Information 888-CBER-BPI or 301-827-4604 Freedom of Information Act (FOIA) Requests 800-835-4709 or 301-827-1800 www.fda.gov/opacom/backgrounders/foiahand.html VAERS 800-822-7967 / fax 877-721-0366 info@vaers.org / www.Vaers.org www.fda.gov/cber/vaers/vaers.htm MEDWATCH 800-FDA-1088 or 301-827-7240 fax 301-827-7241 or 800-FDA-0178 www.fda.gov/medwatch/index.html Biological Product Deviation Reporting 301-827-6220 / bp_deviations@cber.fda.gov www.fda.gov/cber/biodev/biodev.htm E-Mail Distribution Lists To subscribe, click on www.fda.gov/cber/pubinfo/elists.htm FPRECALL Recalls and market withdrawals of fractionated blood products. BLOODINFO Includes FPRECALL and all blood-related documents. CBERINFO Includes FPRECALL, BLOODINFO, and all other new CBER documents. Table of Contents Appendix A Calibration of HIV-1 working reagents for nucleic acid amplification techniques against the 1st international standard for HIV-1 RNA. Davis C, Heath A, Best S, Hewlett I, Lelie N, Schuurman R, Holmes H. J Virol Methods 2003 Jan;107(1):37-44. Comparative sensitivity of HBV NATs and HBsAg assays for detection of acute HBV infection. Biswas R, Tabor E, Hsia CC, Wright DJ, Laycock ME, Fiebig EW, Peddada L, Smith R, Schreiber GB, Epstein JS, Nemo GJ, Busch MP. Transfusion 2003 Jun;43(6):788-798. Genetic and phenotypic analysis of reassortants of high growth and low growth strains of influenza B virus. Vodeiko GM, McInnis J, Chizhikov V, Levandowski RA. Vaccine 2003 Sep 8;21(25-26):3867-3874. A Live, Attenuated Dengue Virus Type 1 Vaccine Candidate with a 30-Nucleotide Deletion in the 3' Untranslated Region Is Highly Attenuated and Immunogenic in Monkeys. Whitehead SS, Falgout B, Hanley KA, Blaney Jr JE Jr, Markoff L, Murphy BR. J Virol 2003 Jan 15;77(2):1653-1657. Microarray analysis of evolution of RNA viruses: Evidence of circulation of virulent highly divergent vaccine-derived polioviruses. Cherkasova E, Laassri M, Chizhikov V, Korotkova E, Dragunsky E, Agol VI, Chumakov K. Proc Natl Acad Sci U S A 2003 Aug 5;100(16):9398-403. Changes in mumps virus gene sequence associated with variability in neurovirulent phenotype. Rubin SA, Amexis G, Pletnikov M, Vanderzanden J, Mauldin J, Sauder C, Malik T, Chumakov K, Carbone KM. J Virol 2003 Nov;77(21):11616-24. Identification of a new genotype H wild-type mumps virus strain and its molecular relatedness to other virulent and attenuated strains. Amexis G, Rubin S, Chatterjee N, Carbone K, Chumakov K. J Med Virol 2003 Jun;70(2):284-6. Correlates of immunity for pneumococcal conjugate vaccines. Lee LH, Frasch CE, Falk LA, Klein DL, Deal CD. Vaccine 2003 May 16;21(17-18):2199-205. Development of a novel vaccinia-neutralization assay based on reporter-gene expression. Manischewitz J, King LR, Bleckwenn NA, Shiloach J, Taffs R, Merchlinsky M, Eller N, Mikolajczyk MG, Clanton DJ, Monath T, Weltzin RA, Scott DE, Golding H. J Infect Dis 2003 Aug 1;188(3):440-8. Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)--United States, 1991-2001. Zhou W, Pool V, Iskander JK, English-Bullard R, Ball R, Wise RP, Haber P, Pless RP, Mootrey G, Ellenberg SS, Braun MM, Chen RT. MMWR Surveill Summ 2003 Jan 24;52(1):1-24. Gene expression in human embryonic stem cell lines: Unique molecular signature. Bhattacharya, B. Takumi M, Brandenberger R, Mejido J, Luo Y, Yang AX, Joshi BH, Ginis I, Thies RS, Amit M, Lyons I, Condie BG, Iskovitz-Eldor J, Rao MS, Puri RK. Blood, First edition paper, prepublished online December 30, 2003: DOI 10.1182/Blood-2003-09-3314. FDA educational partnerships to improve the development of cell and gene therapy products. Weber D, Simek S, Puri RK. Bioprocessing Journal 2003. Regulatory issues affecting tumor vaccines. Thornton MO, Worobec A, Wonnacott K, Puri RK. in Handbook of Cancer Vaccines. MA Morse, TM Clay and HK Lyerly (editors). Human Press Inc., Totowa, NJ. 2004:563-576. Regulatory expectations during product development for tumor vaccines. Kawakami K, Puri RK in Development of Biologicals. 2003. Endotoxin content of standardized allergen vaccines. Trivedi B, Valerio C, Slater JE. J Allergy Clin Immunol 2003 Apr; 111(4):777-83. FDA perspectives on the use of the adenovirus reference material. Simek S, Byrnes A, Bauer S. BioProcessing 2002;1:40-42. The influenza vaccine licensing process. Wood JM, Levandowski RA. Vaccine 2003 May 1;21(16):1786-8. Development of resistance to acyclovir during chronic infection with the Oka vaccine strain of varicella-zoster virus, in an immunosuppressed child. Levin MJ, Dahl KM, Weinberg A, Giller R, Patel A, Krause PR. J Infect Dis 2003 Oct 1;188(7):954-9. Adverse event reporting rates following tetanus-diphtheria and tetanus toxoid vaccinations: data from the Vaccine Adverse Event Reporting System (VAERS), 1991-1997. Lloyd JC, Haber P, Mootrey GT, Braun MM, Rhodes PH, Chen RT; VAERS Working Group. Vaccine 2003 Sep 8;21(25-26):3746-50. US Vaccine Adverse Event Reporting System. Prevalence of anti-gelatin IgE antibodies in people with anaphylaxis after measles-mumps rubella vaccine in the United States. Pool V, Braun MM, Kelso JM, Mootrey G, Chen RT, Yunginger JW, Jacobson RM, Gargiullo PM, VAERS Team. Pediatrics 2002 Dec;110(6):e71. Tumor necrosis factor antagonist therapy and lymphoma development: Twenty-six cases reported to the Food and Drug Administration. Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Arthritis Rheum 2002 Dec;46(12):3151-8. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Kwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Ann Intern Med 2003 May 20;138(10):807-11. Infectious complications of biologic treatments of rheumatoid arthritis. Mohan AK, Coté TR, Siegel JN, Braun MM. Curr Opin Rheumatol 2003 May;15(3):179-84. Pharmacoepidemiologic implications of erroneous varicella vaccinations in pregnancy through confusion with varicella zoster immune globulin. Wise RP, Braun MM, Seward JF, Mootrey GT, Shields KE, Salive ME, Krause PR. Pharmacoepidemiol Drug Safety. 2002 Dec;11(8):651-4. Extensive limb swelling after immunization: reports to the Vaccine Adverse Event Reporting System. Woo EJ, Burwen DR, Gatumu SN, Ball R, Vaccine Adverse Event Reporting System Working Group. Clin Infect Dis. 2003 Aug, 1;37(3):351-8. Postmarketing safety surveillance for typhoid fever vaccines from the Vaccine Adverse Event Reporting System, July 1990 through June 2002. Clin Infect Dis 2004 Mar 15;38(6):771-9. A review of rotavirus vaccine reports to the Vaccine Adverse Event Reporting System: more than intussusception alone? Haber P, Zanardi LR, Chen RT, Mootrey GT, English R, Braun MM, VAERS Working Group. Pediatrics, in press. Emerging infections, transfusion safety, and epidemiology. Dodd RY. N Engl J Med 2003 Sep 25;349(13):1205-1206; published at www.nejm.org on Sep 18, 2003 (10.1056/NEJMp038138). Transmission of West Nile Virus through blood transfusion in the United States in 2002. Pealer LN, Marfin AA, Petersen LR, Lanciotti RS, Page PL, Stramer SL, Stobierski MG, Signs K, Newman B, Kapoor H, Goodman JL, Chamberland ME, the West Nile Virus Transmission Investigation Team. New Engl J Med 2003 Sep 25;349(13):1236-1245. Transmission of West Nile Virus from an organ donor to four transplant recipients. Iwamoto M, Jernigan DB, Guasch A, Trepka MJ, Blackmore CG, Hellinger WC, Pham SM, Zaki S, Lanciotti RS, Lance-Parker SE, DiazGranados CA, Winquist AG, Perlino CA, Wiersma S, Hillyer KL, Goodman JL, Marfin AA, Chamberland ME, Petersen LR, the West Nile Virus in Transplant Recipients Investigation Team. N Engl J Med 2003 May 29;348(22):2196-2203. Risks and benefits of gene therapy. Noguchi P. N Engl J Med 2003 Jan 16;348(3):193-4. Clinical quantitative flow cytometry: "Identifying the optimal methods for clinical quantitative flow cytometry”. Marti GE, Vogt RF Jr, Stetler-Stevenson M. Cytometry 2003 Sep;55B(1):59. Detection of porcine endogenous retrovirus in cultures of freshly isolated porcine bone marrow cells. McIntyre MC, Kannan B, Solano-Aguilar GI, Wilson CA, Bloom ET. Xenotransplantation 2003 Jul;10(4):337-342. Xenotransplantation--federal regulatory considerations. Bloom ET. Curr Top Microbiol Immunol 2003;278:239-51. Innate and adaptive immune responses to an intracellular bacterium, Francisella tularensis live vaccine strain. Elkins KL, Cowley SC, Bosio CM Microbes Infect 2003 Feb;5(2):135-42. Detection and discrimination of orthopoxviruses using microarrays of immobilized oligonucleotides. Laassri M, Chizhikov V, Mikheev M, Shchelkunov S, Chumakov K. J Virol Methods 2003 Sep;112(1-2):67-78. Development of a novel vaccinia-neutralization assay based on reporter-gene expression. Manischewitz J, King LR, Bleckwenn NA, Shiloach J, Taffs R, Merchlinsky M, Eller N, Mikolajczyk MG, Clanton DJ, Monath T, Weltzin RA, Scott DE, Golding H. J Infect Dis 2003 Aug 1;188(3):440-8. Molecular cloning and characterization of genes for Shigella sonnei form I O polysaccharide: Proposed biosynthetic pathway and stable expression in a live Salmonella vaccine vector. Xu D-Q, Cisar JO, Amboulas N Jr., Burr DN, Kopecko DJ. Infect Immun 2002 Aug;70(8):4414-4423. Table of Contents Appendix B CBER Exhibit Program FY 2003 Meeting Dates     American Association of Blood Banks Orlando, FL October 26-29, 2002     Society for Neuroscience Orlando, FL November 2-7, 2002     American Public Health Association Philadelphia, PA November 9-13, 2002     BioSecurity 2002 Las Vegas, NV November 19-21, 2002     American Society of Hematology Philadelphia, PA December 6-10, 2002     National Consumers League Washington, D.C. February 27-28, 2003     Engineering Tissue Pittsburgh, PA March 19-20, 2003     FDA Science Forum Washington, D.C. April 24-25, 2003     American Society for Microbiology Washington, D.C. May 19-21, 2003     BioDefense Vaccine Washington, D.C. June 2-4, 2003     American Society for Gene Therapy Boston, MA June 5-7, 2003     BIO Washington, D.C. June 22-25, 2003     International Society for Cellular Therapy Cambridge, MD September 13-15, 2003 Table of Contents Appendix C CBER Major Approvals – FY 2003 CBER’s Fiscal Year 2003 major approvals include all approvals for original new BLA’s (except those for blood banking), and other approvals for original biologic, drug, or device applications or supplements that are expected to significantly enhance the public health (e.g., for new/expanded indications, new routes of administration, new/improved tests, new dosage formulations and regimens). Although most of the Office of Therapeutics Research and Review’s applications were transferred to the Center for Drug Evaluation and Research on June 30, 2003, all major BLA approvals are included in this list for both centers. Biologics License Applications Tradename/ Proper Name Indication for Use Manufacturer Pegasys Peginterferon alfa-2a Treatment of adults with chronic hepatitis C who have compensated liver disease and who have not been previously treated with interferon alfa Hoffmann-La Roche Inc.Nutley, NJ COBAS Ampliscreen HCV Hepatitis C Virus (Hepatitis C Virus/Polymerase Chain Reaction/Blood Cell Derived) For the detection of HCV RNA, in human plasma Roche Molecular Systems, Inc. Pleasanton, CA Pediarix DTaP & Hepatitis B (Recombinant) & Inactivated Polio Virus Vaccine Combination vaccine for childhood immunization GlaxoSmithKline Biologicals Rixensart, Belgium COBAS Ampliscreen HIV-1 Human Immunodeficiency Virus Type 1 (HIV-1/Polymerase Chain Reaction) For detection of Human Immunodeficiency Virus (HIV-1) in human plasma using Polymerase Chain Reaction Roche Molecular Systems, Inc. Pleasanton, CA Aralast Alpha-1-Proteinase Inhibitor (Human) Chronic replacement therapy (augmentation) in patients having congenital deficiency of Alpha-1-Proteinase Inhibitors with clinically evident emphysema Alpha Therapeutic Corporation Los Angeles, CA HUMIRA Adalimumab Reducing signs and symptoms and inhibiting the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more disease modifying antirheumatic drugs (DMARDs) Abbott Laboratories Abbott Park, IL Amevive Alefacept Treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy Biogen, Inc. Cambridge, MA Crosseal Fibrin Sealant (Human) Adjunct to hemostasis during liver surgery OMRIX Biopharmaceuticals, Ltd. Fairfax, VA Peroxidase Conjugate ORTHO Antibody to HBsAG ELISA Test System 3 Antibody to Hepatitis B Surface Antigen (Mouse Monoclonal) Enzyme-Linked Immunosorbent Assay (ELISA) (Antibody to HBsAg/Enzyme Immuno Assay (EIA), Version 3.0/Monoclonal) Detection of hepatitis B surface antigen in human serum or plasma as a screening test and an aid in the diagnosis of potential hepatitis B infection. Ortho-Clinical Diagnostics, Inc. Raritan, NJ Fabrazyme agalsidase beta For use in patients with Fabry disease to reduce globotriasylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types Genzyme Corporation Cambridge, MA Aldurazyme Laronidase For treatment of patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. Biomarin Pharmaceutical, Inc. Novato, CA FluMist Influenza Virus Vaccine Live, Intranasal For active immunization for the prevention of disease caused by influenza A and B viruses in healthy children and adolescents, 5-17 years of age, and healthy adults, 18-49 years of age MedImmune Vaccines, Inc. Mountain View, CA XOLAIR Omalizumab For adults and adolescents (12 years of age and above) with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Genentech, Inc. South San Francisco, CA BEXXAR Tositumomab and Iodine I 131 Tositumomab Treatment of patients with CD20 positive, follicular, non-Hodgkin's lymphoma, with and without transformation, whose disease is refractory to Rituximab and has relapsed following chemotherapy. Corixa Corporation Seattle, WA Zemaira Alpha-1-Proteinase Inhibitor (Human) To use as chronic augmentation and maintenance therapy in individuals with Alpha-1-Antitrypsin Deficiency and evidence of emphysema Aventis Behring L.L.C. King of Prussia, PA Advate Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method Indicated in hemophilia A (classical hemophilia) for the prevention and control of bleeding episodes, and in the perioperative management of patients with hemophilia A Baxter Healthcare Corporation Westlake Village, CA Genetic Systems HIV-1/HIV-2 Plus O EIA Human Immunodeficiency Virus Types 1 and 2 (HIV-1 and HIV-2/Enzyme Immunoassay (EIA)/Recombinant and Synthetic) For detection of antibodies to human immunodeficiency types 1 and 2. Bio-Rad Laboratories, Inc. Hercules, CA GAMUNEX Immune Globulin Intravenous (Human), 10% by Chromatography Process Indicated in primary humoral immunodeficiency and idiopathic thrombocytopenic purpura Bayer Corporation Berkeley, CA   Biologics License Supplements (for New Indications, New Routes of Administration, New Dosage Forms, Improved Safety) Tradename/ Proper Name Indication for Use Manufacturer Prevnar Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein) New indication for the prevention of otitis media Lederle Laboratories Division Pearl River, NY Avonex Interferon beta-1a Package insert revised to include updated information regarding serum neutralizing antibodies Biogen, Inc. Cambridge, MA Pegasus Peginterferon alfa-2a Combination therapy with Ribavirin, USP (COPEGUS), for the treatment of chronic Hepatitis C Virus infection in adults Hoffmann-La Roche Inc. Nutley, NJ Aranesp Darbepoetin alfa Darbepoetin alfa Albumin (human) formulation in single dose prefilled syringes for six dosage strengths (60, 100, 150, 200, 300 and 500 micrograms) Amgen, Inc. Thousand Oaks, CA Simulect Basiliximab Addition of new single dose 10 mg strength of drug product Novartis Pharmaceuticals Corporation East Hanover, NJ Avonex Interferon beta-1a Package insert revised to include safety and efficacy data from a study of patients who experienced a single clinical exacerbation of multiple sclerosis and to provide a Medication Guide Biogen, Inc. Cambridge, MA Betaseron Interferon beta-1b To revise the Clinical Studies section to include data from two studies conducted in patients with secondary progressive multiple sclerosis (MS), also to update the Adverse Reactions and Warnings sections to include new safety information, and to provide a Medication Guide Chiron Corporation Emeryville, CA Remicade Infliximab For reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing Crohn’s disease Centocor, Inc. Malvern, PA Rebif Interferon beta-1a Final pivotal study report that confirms the results of 48 week data Serono, Inc. Rockland, MA Avonex Interferon beta-1a HAS-free liquid formulation in a prefilled syringe as an alternate dosage form and to provide for a Medication Guide Biogen, Inc. Cambridge, MA Dryvax Smallpox Vaccine, Dried, Calf Lymph Type Active immunization against smallpox disease Wyeth Laboratories, Inc. Marietta, PA Dryvax Smallpox Vaccine, Dried, Calf Lymph Type Include new safety information for the recent reports of cardiac events and updated storage period for the vaccine after reconstitution from 15 days to 90 days Wyeth Laboratories, Inc. Marietta, PA Infanrix Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed To include in the indication a fifth dose at 4-6 years of age after 4 prior doses of Infanrix GlaxoSmithKline Biologicals Rixensart, Belgium Enbrel* Etanercept To expand the rheumatoid arthritis indication to include improving physical function Immunex Corporation Seattle, WA Enbrel* Etanercept For reducing signs and symptoms in patients with active ankylosing spondylitis Immunex Corporation Seattle, WA Enbrel* Etanercept To expand the indication to include inhibiting the progression of structural damage of active arthritis in patients with psoriatic arthritis Immunex Corporation Seattle, WA Kineret* Anakinra To expand the indication to include slowing the progression of structural damage in moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed one or more DMARDs Amgen, Inc. Thousand Oaks, CA Synagis* Palivizumab To expand the indication to include children with hemodynamically significant congenital heart disease MedImmune,Inc Gaithersburg, MD *OTRR product applications transferred to CDER on 6-30-03.   New Drug Applications Tradename/ Proper Name Indication for Use Applicant triCitrasol Anticoagulant Sodium Citrate Conc. 46.7% Trisodium Citrate, 30 mL Anticoagulant Sodium Citrate Solution triCitrasol, after dilution of a rouleaux agent, is an anticoagulant used in granulocytapheresis procedures Cytosol Laboratories, Inc. Braintree, MA Anticoagulant Citrate Dextrose Solution, Solution A, U.S.P., (ACD-A). 50 mL, PN 6053 Anticoagulant Citrate Dextrose Solution (ACD) To provide for the use of Anticoagulant Citrate Dextrose Solution, Solution A, U.S.P., (ACD-A) 50 mL for the extracorporeal processing of blood with Autologous PRP systems in production of platelet rich plasma (PRP) for in vitro use. Cytosol Laboratories, Inc. Braintree, MA   Supplemental New Drug Applications Tradename/ Proper Name Indication for Use Applicant Abbokinase Urokinase Improvements in the manufacture and testing of the bulk drug substance and drug product, and withdrawal of the indication for coronary artery thrombosis indication (CAT) and the Open-Cath dosage strengths Abbott Laboratories Abbott Park, IL   Device Applications Tradename Description and Indication for Device Applicant OraSure OraQuick Rapid HIV-1 Antibody Test For the detection of antibodies to HIV-1 in human finger-stick whole blood specimens OraSure Technologies Bethlehem, PA MedMira Rapid HIV Test For detection of HIV-1 and HIV-2 Antibodies MedMira labs Bayers Lake Halifax, Canada Ortho ProVue, Software Version: 2.10 Modular, Microprocessor-controlled instrument designed to automate in vitro immunohematological testing to human blood utilizing the ID MTS/Gel Technology. Micro Typing Systems Inc. Pompano Beach, FL Vironostika HIV-1 Plus O Microelisa System For the qualitative detection of antibodies to Human Immunodeficiency Virus Type 1 (HIV-1), including Group O, in human specimens collected as serum, plasma, or dried blood spots BioMerieux, Inc. Durham, NC   Device Supplements (for New Indications, Improved Safety) Tradename Description and Indication for Device Applicant Calypte HIV-1 Urine EIA HIV-1 Urine EIA to include changes to the black box warning statement Calypte Biomedical Corporation Alameda, CA Table of Contents

Updated April 30, 2004

CBER Home Page | CBER A-Z Index | CBER Search | Contact CBER FDA Home Page | Search FDA Site | FDA A-Z Index | Contact FDA | Privacy | Accessibility | HHS Home Page FDA / Center for Biologics Evaluation and Research