Center for Biologics Evaluation and Research

FY 2006 Annual Report
Innovative Technology Advancing Public Health

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Table of Contents

Vision and Mission

A Message from the Director

Our Products

• Blood and Blood Products
• Vaccines and Vaccine Safety
• Cellular and Gene Therapies
• Tissues
• Xenotransplantation
• Devices
• Allergenics

National Preparedness And Security

• Pandemic Influenza Preparedness
• Vaccine Production and Supply
• Ensuring a Safe and Available Blood Supply
• Protecting America from Terrorism
  • Anthrax
  • Smallpox
  • Blood Supply
  • Other Counterterrorism Activities

Enhance Patient And Consumer Protection And Empower Them With Better Information About Regulated Products

• Improving the Safety of the Blood Supply with Novel Donor Screening Tests
  • Hepatitis B
  • West Nile Virus
• Monitoring the Availability of Blood and Blood Components
• Enhancing the Safety of Blood and Development of the CBER Blood Safety Team
• Biological Safety Activities
• CBER Outreach Update

Increase Access To Innovative Products And Technologies To Improve Health

• Initiatives to Strengthen, Diversify, and Increase Capacity for Influenza Vaccines
• The 2005-2006 Influenza Season
• FDA Issues Advice to Facilitate Influenza Vaccine Development
• Technology for New-Generation Vaccines for Viral Infectious Diseases
• Critical Path Initiative: Personalized Medicine
  • Research Management Advances
  • Scientific Expertise Teams
  • Scientific Training Initiatives
• PDUFA
• MDUFMA
• Cellular and Gene Therapies: Facilitating Availability and Development of Safe and Effective Products through New Technologies
  • Genomics and Proteomics
  • Tissue Engineering
  • Cellular and Gene Therapies: Outreach and Partnerships
• FDA Approves Gardasil
• FDA Approves Zostavax
• FDA Approves RotaTeq
• FDA Approves Vivaglobin
• FDA Approves New Manufacturer for Cytogam
• FDA Approves ADVIA Centaur HIV 1/O/2 Assay A

Improve Product Quality, Safety, And Availability Through Better Manufacturing And Product Oversight

• Ensuring Safety of Recipients of Donor Tissue
  • Donor Referral Services
• Immune Globulin Availability and Demand
• TSE Safety for Biological Products
  • Blood Donor Deferral for Transfusion in France
  • TSE Research and Risk Estimation
• Workshop on Testing for Malarial Infections in Blood Donors

Transform Administrative Systems And Infrastructure To Support FDA Operations

• Globalization of Public Health and Product Development: International Activities
• Highlights
  • WHO and PAHO Activities
  • Global Collaboration on Blood Safety
  • International Conference on Harmonisation
  • International Partnering
  • Pharmaceutical Inspection Cooperation Scheme (PIC/S)
  • Global Harmonisation Task Force
  • International Outreach
• Review Management Initiatives
  • Agency Harmonisation Initiatives
  • Quality Systems Initiatives
  • Electronic Standards Initiatives
  • Outreach Initiatives
• CBER Review Business Process Efforts
• Quality Assurance
• Management Systems Initiatives
• IT and System Enhancements
  • eSystems
  • EDR and FDA Gateway
  • Other System Enhancements
  • Security

Contact Us

Appendix A (CBER Publications)

Appendix B (CBER Exhibit Program - FY 2006)

Appendix C (CBER Major Approvals - FY 2006)

Appendix D (Rulemaking and Guidance Documents - FY 2006)

Appendix E (Advisory Committee Meetings - FY 2006)

Appendix F (Organizational Chart)

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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 United States (U.S.) and globally
• facilitate the development of, approval of, and access to safe and effective products and promising new technologies
• strengthen CBER as a pre-eminent regulatory organization for biologics.

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 injuries. 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 U.S. Food and Drug Administration (FDA), we apply the following principles with the highest ethical standards and integrity:

• develop, maintain, and support a high-quality and diverse workforce
• ensure compliance with laws and regulations through review, education, surveillance, and enforcement
• conduct research as an essential element of science-based decision-making.

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A Message from the Director

July 2007

Dear Colleagues in the Biologics Community:

It is my pleasure to share the tenth annual report from the Food and Drug Administration's (FDA's) Center for Biologics Evaluation and Research (CBER). This report focuses on accomplishments and on-going initiatives during Fiscal Year 2006 (FY 2006). CBER's products touch people's lives on a daily basis and they play a critical role in the nation's public health preparedness, where they are critical in addressing threats from emerging infectious diseases, like pandemic influenza, and terrorism. They include a wide range of both essential and highly innovative products, including vaccines and allergenic products, blood and blood products, tests used in assuring the safety of transfusion, and human tissues, cell and gene therapies. The goals of the Center align with those established by the FDA to accomplish our mission and protect public health. CBER's FY 2006 annual report is organized within the FDA's four goal areas and highlights accomplishments in the area of Public Health Preparedness and Security. CBER works closely with multiple partners to achieve the following goals:

1. Enhance Patient and Consumer Protection and Empower Them with Better Information about Regulated Products
2. Increase Access to Innovative Products and Technologies to Improve Health
3. Improve Product Quality, Safety, and Availability through Better Manufacturing and Product Oversight
4. Transform Administrative Systems and Infrastructure to Support FDA Operations.

In each of these areas, as well as in the area of Public Health Preparedness and Security, CBER has made substantial accomplishments and exceeded goals. We continue to meet or exceed the user fee performance goals in the Prescription Drug User Fee Act (PDUFA III), and the Medical Device User Fee and Modernization Act (MDUFMA). Our success in accomplishing thorough but timely scientific review of biological products and related devices has resulted in safe and effective products reaching those in need more efficiently and rapidly. CBER's interactions with applicants, our application review efforts, and proactive monitoring and transparency regarding product quality and safety issues, have helped to keep needed vaccines, tissues and blood products both safe and available, thus maintaining public confidence and trust.

Safety expectations for blood, tissues and vaccines are particularly high; and product availability, critical for our nation's health and medical infrastructure, is also frequently a challenge. Our product safety activities emphasize effective, interdisciplinary, proactive approaches using modern methods to prevent, detect, and promptly investigate potential problems, and assure needed supplies, while providing effective and transparent communication to consumers and health professionals. Among our recent safety innovations and accomplishments have been the implementation of a new regulatory framework to provide enhanced oversight of tissue safety and the creation of formal interdisciplinary product safety teams (e.g. the Tissue Safety Team and the Blood Safety Team). These teams meet regularly and in emergencies to bring together diverse disciplines (e.g. product scientists, clinicians, epidemiologists, manufacturing experts, and communications experts) to share, analyze and act on safety information and develop needed strategic and scientific approaches to enhance safety. The safety teams collaborate with other FDA components and colleagues at other agencies, particularly the Centers for Disease Control and Prevention (CDC). In addition, we have pioneered the use of large medical databases to detect and investigate product safety issues. We have also pioneered the use of risk assessment computer modeling to evaluate risk and help inform patients and health care providers of effective approaches to help reduce risk (e.g., an assessment of the potential risk from the agent of variant Creutzfeld-Jacob disease, the cause of "Mad Cow" disease, to blood plasma product safety).

To address the global threat of pandemic influenza, and position us to better respond to other future emerging threats, CBER has taken a proactive leadership role and worked with the World Health Organization (WHO), the Department of Health and Human Services (DHHS), other Federal agencies, particularly CDC and the National Institutes of Health (NIH), industry, and sister regulatory authorities from other nations. We have acted with these partners to foster information sharing, rapid development, evaluation and U.S. and global availability of pandemic influenza vaccines that will be effective, safe and high quality. We conducted outreach to major manufacturers throughout the world to stimulate interest in producing vaccines for the U.S. market for both annual and pandemic influenza. We have taken a number of steps aimed at enhancing manufacturers' capacity to produce more doses every year of annual vaccine. As a result, the United States has advanced from a vaccine supply of 3 manufacturers and approximately 63 million doses in the 2004-2005 season to 5 manufacturers and 120 million doses in the 2006-2007 season. We also co-sponsored a series of meetings with vaccine regulators from around the world to establish agreed upon standards for human avian influenza vaccines and have published guidances, including provisions for accelerated approval based on immunogenicity, to speed and assist manufacturers' development of vaccines for both seasonal and pandemic influenza. We are also strengthening our emergency response infrastructure and processes (e.g. IT, communications) and our laboratory testing, standards and methods activities, including use of quality systems approaches. This strengthening will allow us to be better prepared with the tools and capacity we, and industry, will need to help assure vaccine and other critical product availability and quality should a pandemic occur.

Our international activities have become increasingly critical and have had growing impacts as emerging health threats, product manufacturing and use, and innovation and advances have all become more prevalent. CBER is highly engaged in global information sharing, capacity building and harmonisation to benefit global health. We actively participate in the Regulatory Preparedness Workshops on Human Vaccines for Pandemic Influenza. These workshops aid in the development of guidelines and standards for global regulatory information sharing, coordination and pandemic vaccine evaluation and quality and have provided input to the WHO for the development of, "WHO Guidelines on Regulatory Preparedness for Human Pandemic Influenza Vaccines." Additionally, we have engaged in regulatory outreach, with respect to avian influenza preparedness, to our counterparts in Asia. This is just a snapshot of our commitment to protecting and promoting global health and addressing major neglected diseases such as tuberculosis, HIV, and malaria, which is essential to improve lives throughout the world and protect our nation and its people. We do this through a large inventory of activities that range from helping to build regulatory capacity in developing countries, collaborating with WHO and other partners on sound global public health policy and working with industry, NIH, nongovernmental organizations and others to promote the development of safe and effective products to address unmet global needs.

Through the advancement of new technologies, we have helped make available a number of products that are both the first of their kind and represent significant advances in public health. We approved a human papillomavirus vaccine to prevent cervical cancer and precancerous lesions caused by certain human papillomaviruses. We approved several new blood tests that help make the blood supply even safer, such as a test to detect West Nile virus infection, a fully automated diagnostic test for antibodies to HIV-1, HIV-2, and HIV-I Group O in human serum and plasma, and a fully automated product combining screening and confirmatory testing for hepatitis B (HBsAg). CBER co-developed the Blood Availability and Safety Inventory System (BASIS) used by DHHS to monitor the availability of blood components at major hospital centers and blood establishments throughout the United States. We published a new guidance on umbilical cord blood, increasingly used in treatment of diseases such as cancer and leukemia, which is designed to foster the availability of these stem cells, while assuring their effectiveness and safety.

With dedication, hard work, and team effort from our remarkably diverse and knowledgeable staff, CBER continues to achieve outstanding accomplishments in promoting innovation while ensuring the quality, safety and availability of the products we regulate. We strive for continuous quality improvement, including enhanced efficiency. Each of us at CBER is committed to our mission and we all appreciate your essential input, support and participation in achieving our goals. I welcome your feedback and ideas to strengthen the mission of the Center, and our common public health goals, and look forward to working with you in the coming year.

Jesse L. Goodman, M.D., M.P.H.
Director
Center for Biologics Evaluation and Research

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Our Products

Blood and Blood Products*

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 blood and blood components that are used for transfusion and for manufacture into products such as plasma derivatives. CBER also regulates the resulting blood products, such as clotting factors, concentrates, immune globulins, albumin and protease inhibitors. CBER also establishes product standards and performs lot release testing. CBER regulates devices used to prepare blood products, including blood establishment computer software (BECS), cell separators, and blood collection containers, as well as tests to screen blood donors for human immunodeficiency virus-type 1 (HIV1) and other viruses, such as hepatitis B virus (HBV) and hepatitis C virus (HCV), West Nile virus (WNV), human T-lymphotropic virus types I and II (HTLVI/II), and for syphilis. CBER develops and enforces quality standards, monitors, analyzes, and acts on reports of biological product deviations and adverse clinical events. Biological product deviations are the result of unexpected or unforeseeable events in the manufacturing process.

For example, FDA encouraged development of highly sensitive nucleic acid tests (NATs) for the detection of HIV-1 and HCV. These tests are now FDA-approved and recommended for use in screening blood donors to reduce the risk of transmission of these infectious agents. To standardize the performance of these tests, CBER developed essential lot release reagents. FDA also encouraged the development of NATs for WNV in response to the epidemic in the U.S. Close coordination with other U.S. Public Health Service (PHS) agencies, device manufacturers and blood establishments resulted in the development and use of investigational WNV tests in blood establishments within 8 months of recognition of this new transfusion transmission risk. As a result of these efforts, FDA approved a WNV NAT for use in blood screening within the goal timeframe established for licensure of the test.

Over a period of years, FDA has progressively strengthened the overlapping safeguards that protect patients from unsuitable blood and blood products. Blood donors are asked specific questions and review educational materials about risk factors that could indicate possible infection with a transmissible disease. This upfront donor screening helps to reduce risk from infectious agents by identifying and deferring potentially high-risk donors prior to testing and is especially important in the absence of donor screening tests for emerging infectious diseases. CBER has worked actively with the blood community over the past decade to redesign, streamline and cognitively assess a standardized donor-screening questionnaire. This questionnaire now is in broad use throughout the U.S. for the screening of blood donors.

FDA facilitates the development and implementation of sensitive tests to detect infectious agents in blood. Testing of donors for infectious agents is a critical safeguard for blood safety. To further enhance blood safety, FDA requires blood centers to maintain lists of donors considered unsuitable to donate blood because of test results or risk factors for infectious diseases that can be transmitted by blood. Blood establishments also quarantine units of blood until they determine the units are suitable for release. In addition, FDA has significantly increased its oversight of inspections of blood collection and manufacturing facilities.

*See Appendix A References 1-6

Vaccines and Vaccine Safety*

CBER regulates vaccine products. Many of these products are pediatric vaccines that have contributed to the dramatic reduction or elimination of life-threatening childhood diseases in the U.S. (e.g., diphtheria, measles, and polio). Newer vaccines are playing an increasing role in protecting and improving the lives of adolescents and adults and include vaccines to prevent meningococcal disease, shingles, and cervical cancer. In addition, there are vaccines under development that offer the promise of preventing serious infectious diseases, such as pandemic influenza viruses and severe acute respiratory syndrome (SARS), HIV-1, and malaria. As with all medical products, highly-trained scientists and clinicians rigorously review laboratory and clinical data in assessing the safety, effectiveness, and quality of vaccines. FDA also reviews additional studies after some vaccines are approved to further evaluate their safety and effectiveness (e.g., in broader population groups). Both before and after a vaccine is licensed, FDA inspects vaccine manufacturing facilities to help ensure continued high quality and safe production.

The U.S. Centers for Disease Control and Prevention (CDC) and CBER jointly manage the Vaccine Adverse Event Reporting System (VAERS), a cooperative program for vaccine safety. VAERS is a postmarketing safety surveillance program that collects information about adverse events (side effects) potentially related to vaccination and reported after the administration of U.S. licensed vaccines. In collaboration with CDC, state health departments, and other partners, CBER uses VAERS to monitor vaccine adverse event reports for possible indicators of vaccine safety concerns.

*See Appendix A References 7-15

Cellular and Gene Therapies*

CBER regulates cellular and gene therapy products including therapeutic cancer vaccines. Somatic cells, vectors expressing certain gene products, and genetically manipulated cells offer the promise of harnessing the power of different cell types to fight disease, restore normal function, repair injuries, replace lost cells, or regenerate failing organs. CBER is aware of both the promise of gene therapy and its potential to cause serious adverse events and works closely with the National Institutes of Health (NIH), academia, and industry on these products. For example, FDA and NIH have collaboratively developed a Web-accessible database on human gene transfer—the Genetic Modification Clinical Research Information System (GeMCRIS). GeMCRIS enables faster reporting of adverse events in human gene transfer trials and is a unique public information resource. The system provides information to the public directly via the Internet at www.gemcris.od.nih.gov and improves the government's ability to monitor adverse events in gene therapy. Manufacturers of gene and cellular therapy products must study their products in the laboratory for safety before beginning studies in humans under an Investigational New Drug Application(IND) or an Investigational Device Exemption (IDE). Like all biological products, gene and cellular therapies need to meet statutory and regulatory requirements for safety, purity, and potency before the products can be licensed for commercial distribution in the U.S. Through FY 2006, CBER has received 517 gene therapy INDs and is currently overseeing approximately 270 active INDs. CBER has also received 1,171 INDs and IDEs for somatic cellular therapies through FY 2006, and approximately 437 are still active. There have been a total of 40 INDs and IDEs for xenotransplantation products, and approximately 14 of them were active at the end of FY 2006.

CBER has provided proactive scientific and regulatory advice to manufacturers in areas of novel product development. Focusing on how best to evaluate essential issues of safety and efficacy, while facilitating product development, we are also committed to protecting human study subjects. Our involvement in broad public interactions helps CBER and product developers address important issues involving the development of novel gene and cellular therapy products.

Tissues* Tissue transplantation is a rapidly growing industry. The number of musculoskeletal tissue transplants increased from approximately 350,000 in 1990 to more than 1.6 million in 2006. CBER is responsible for regulating many different types of human tissue and cells that are transplanted during various types of medical procedures (e.g., skin replacement following severe burns, tendons and ligaments used to repair injuries, bone replacement, and corneas used to restore eyesight). Transplantation of human tissues presents unique safety challenges, in particular the risks of transmitting infectious diseases from donor to recipient and the contamination of tissues during processing. These risks can be reduced significantly, but not completely eliminated. Since 1993, CBER has also required tissue establishments to screen and test donors. Since 1997, CBER has required tissue establishments to prepare, validate, and follow written procedures to prevent contamination and cross-contamination during processing. In response to the increased use, role, and complexity of tissue transplants, and the recognition of threats to tissue safety, FDA developed and has implemented a comprehensive new framework, which went into effect in May 2005, for the regulation of human cells, tissues, and cellular- and tissue-based products. The new framework promotes the use of the most up-to-date tools and methods to reduce risks of infectious disease transmission and contamination. FDA's regulatory framework includes a broad range of tissues (e.g., hematopoietic stem cells and reproductive tissues, the latter covered primarily for donor eligibility and testing issues). The new regulations encourage a comprehensive, yet flexible, approach to quality throughout the entire manufacturing process, from donor assessment to the final product, including adverse event reporting. CBER conducted extensive outreach and sought stakeholder input as we developed the regulatory approach, and we continue to seek input in this important area.

On August 30, 2006, the FDA established a multidisciplinary task force on human cell and tissue safety. The FDA Human Tissue Task Force (HTTF) was established as part of the Agency's efforts to strengthen its comprehensive, risk-based system for regulating human cells and tissue. The main priority of HTTF is to assess the effectiveness of new tissue regulations, and conduct a review of recent reported findings that some tissue recovery establishments are not following federal requirements for tissue recovery. The HTTF is led by senior FDA officials from CBER and the Office of Regulatory Affairs.

Xenotransplantation*

CBER regulates products used in xenotransplantation, which is any procedure that involves the transplantation, implantation, or infusion into a human recipient of either: (1) live cells, tissues, or organs from a nonhuman animal source; or (2) human body fluids, cells, tissues, or organs that have had contact with live, nonhuman animal cells, tissues, or organs. Xenotransplantation offers the promise of providing needed organs and tissues to thousands of individuals who await transplants of scarce human organs. It holds the potential for the treatment of a wide range of conditions and disorders, including diabetes, degenerative neurological disorders, and other diseases involving tissue destruction and organ failure. Currently, the demand for human organs for clinical transplantation far exceeds the supply. Although xenotransplantation's potential benefits are considerable, it raises a number of complex scientific and public health challenges, most notably the risk of transmission of infectious diseases from animals to humans and the failure of such transplants due to rejection. CBER's continued careful oversight is critical to protecting public health while exploring the potential of these investigational therapies. CBER continues to be a leader in international activities aimed at the safety and regulation of xenotransplantation products.

Devices

CBER regulates many medical devices used in the collection, processing, testing, manufacturing, and administration of blood, blood components, human cells, tissues, and cellular- and tissue-based products. The Center's activities include regulation of HIV-1 and other infectious disease test kits used to screen donor blood, blood components, and cellular- and tissue-based products. CBER also regulates HIV-1 tests used to diagnose, treat, and monitor therapy in persons infected with HIV. CBER collaborates closely with FDA's Center for Devices and Radiological Health (CDRH) on cross cutting issues. We also work with CDRH and the Office of Combination Products in the regulation of combination products, such as tissue-engineering products. The Center has also leveraged its resources by working with the National Toxicology Program (NTP), a joint FDA-NIH venture, to evaluate safety issues associated with materials used in blood collection and transfusion devices.

*See Appendix A References 18-20

Allergenics*

Licensed allergenic products include: (1) allergen patch tests, and (2) 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 (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 (or hay fever), allergic sinusitis, allergic conjunctivitis, bee venom allergy, and food allergy. CBER has been proactive in evaluating novel technological approaches for improving allergenic product development and standardization, as well as characterizing these complex biological products. Some allergenic extracts are currently standardized, whereas others are nonstandardized. Standardized allergenic extracts are compared to U.S. reference standards for potency before release. CBER maintains these reference standards and distributes them to manufacturers. There are currently 19 standardized allergenic extracts.

*See Appendix A References 21-24

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National Preparedness And Security

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 bioterror threats. CBER plays a crucial role in protecting public health by ensuring the availability of safe and effective medical countermeasures for mitigating the consequences of a pandemic, natural, or deliberate disaster. The Center also works to ensure the continuity of mission critical operations in the face of disasters.

Pandemic Influenza Preparedness*

Vaccine Production and Supply

Pandemic influenza is a significant public health threat to our nation and the world. The supplemental funding that CBER received in 2006 allowed us to significantly increase the resources that we direct to the review and development of guidance for influenza vaccines, and the research that supports these activities. Around the globe, different nations are developing plans to prepare for, and respond to, the next influenza pandemic. Although no influenza pandemic has occurred in the U.S. in decades, scientists are concerned that the highly pathogenic avian influenza virus (H5N1), which is currently circulating in wild and domestic birds in Asia, Europe, the Middle East, and Africa, and has caused deaths in humans, may mutate into a form capable of efficient and sustained human-to-human transmission, thereby resulting in a global outbreak (or pandemic). Preparedness planning is imperative to lessen the impact of such a pandemic.

CBER is engaged in a leadership role to prepare for and respond to the risks of a pandemic influenza outbreak. To safeguard Americans from the danger of pandemic influenza, CBER is working with industry, with other agencies in the Department of Health and Human Services (DHHS), and global partners to facilitate the development and availability of pandemic influenza vaccines in the shortest time possible to protect the largest number of people using a vaccine that is safe, effective, and easy to deliver.

As a result of our intense efforts to help build manufacturing capacity for pandemic and seasonal influenza vaccines, CBER has made many strides in aiding vaccine manufacturers. In March 2006, the Agency published two draft guidances outlining specific approaches that influenza vaccine developers can follow to show the safety and effectiveness of new seasonal and pandemic influenza vaccines in support of licensure. These guidances also provide flexible regulatory pathways for getting influenza vaccines on the market, including an accelerated approval process that can substantially reduce the development time for a new vaccine.

Currently, influenza vaccines licensed in the U.S. are produced using fertile hens' eggs as part of a complex and exacting process. These guidances also apply to vaccines made with new manufacturing methods, such as cell culture-based and recombinant technologies, and adjuvants (substances that may enhance the body's immune response to a vaccine, making the vaccine more effective). In September 2006, CBER issued draft guidance on the production of viral vaccines in cell cultures, which is directly applicable to, and should help facilitate, the development of cell-culture based pandemic and seasonal influenza virus vaccines.

Responding to the threat of a pandemic strain of influenza will require an expedited evaluation and licensure of new vaccines to ensure adequate supplies of influenza vaccine during the pandemic period. CBER's scientific research program contributes to pandemic influenza preparedness by facilitating the availability of influenza vaccine. CBER is involved in the following activities:

• preparing strain-specific antisera that are used to determine the potency of vaccines against a pandemic strain
• examining the genetic makeup of potential high-growth viruses to develop reference vaccine viruses that grow optimally in either eggs or cell cultures
• exploring what is needed to prepare libraries of potential pandemic influenza viral strains
  that could be readily available to begin manufacturing vaccines.

CBER also collaborates to develop safety tests that help evaluate whether cell cultures that have the potential for tumorigenicity can be used to manufacture vaccines. Activities also included in the development of assays to detect infectious agents that could potentially contaminate cell cultures. In addition, the Division of Product Quality, created in the Office of Vaccines Research and Review, has the responsibility for facilitating the lot release testing for influenza vaccines. By doing this work now, we hope to have the necessary tools in hand to respond to a pandemic before it occurs.

Seasonal influenza vaccine manufacturers will likely produce pandemic influenza vaccines, therefore increases in manufacturing capacity and improvements to existing processes could enhance the ability to produce pandemic influenza vaccines. CBER uses knowledge gained from past experience with counterterrorism products and with the 2004-2005 influenza vaccine shortage to facilitate the regulatory review of new Biologic License Applications (BLA) and supplements of existing applications for influenza vaccines. In response to the 2004 influenza vaccine shortfall, FDA contacted major manufacturers of influenza vaccine throughout the world to stimulate interest in producing vaccine for the U.S. market, including the provision of an accelerated approval pathway. As a result, licensed influenza vaccines have risen from three to five within a two-year period. Having additional manufacturers enhances the capacity to produce more doses of seasonal influenza vaccine every year, provides better protection against future interruptions in supply, and enhances the manufacturing capacity to produce pandemic influenza vaccines.

CBER is working with multiple partners, including manufacturers, to transform the influenza marketplace, reinvigorate influenza vaccine infrastructure through promising new technologies, secure additional licensed vaccines and medicines, and prepare stronger response plans and capacity. With the goal of increasing access to safe and effective pandemic vaccines worldwide, CBER has been working with the World Health Organization (WHO) and foreign regulatory counterparts to develop international convergence with regard to the scientific and regulatory standards for safety, effectiveness, and manufacturing quality of pandemic influenza vaccines. Together with the WHO and Health Canada, CBER co-sponsored two workshops, one in Canada in March 2006, and the second in the U.S. in June 2006, where regulatory authorities from developed and developing nations provided input that formed the basis for WHO's draft guidelines for pandemic influenza. This draft, together with comments from manufacturers, will be further discussed at a workshop in Geneva in 2007.

Ensuring a Safe and Available Blood Supply

At CBER, preparedness for pandemic influenza also includes ensuring a safe and available blood supply. We are carefully developing our own internal Continuity of Operations Plan for pandemic influenza, as well as coordinating with other federal agencies and national organizations. Key partners in this effort include the DHHS, Office of the Secretary and Public Health Science (OSPHS), CDC, and the American Association of Blood Banks (AABB). These collaborative activities are a critical and continuous part of CBER's pandemic influenza preparedness. To ensure timely communication and information sharing, CBER staff led the DHHS/PHS Pandemic Influenza Working Group that shares information and develops pandemic influenza preparations related to the blood supply. In addition, CBER leads a monthly PHS blood meeting that includes pandemic planning as a standard topic. The Center participates actively as a liaison with the AABB Disaster Task Force and the AABB Pandemic Influenza Task Force, both of which are proactively planning responses to the threat of pandemic influenza.

Center staff are considering potential regulatory approaches to the prompt evaluation and approval of new therapeutics (e.g., hyperimmune globulins), and new in vitro diagnostics (e.g., an H5N1 blood donor screening assay) that might be submitted to FDA. Within FDA, CBER strives to coordinate a safe, effective, and balanced plan in the event of a public health crisis of pandemic influenza. CBER investigates the feasibility of using newer technologies to detect contamination of the blood supply with bioterror/biowarfare infectious agents.

*See Appendix A References 25-29

Protecting America from Terrorism*

CBER is responsible for helping to ensure safe and effective biological products are available for treating and preventing illness due to terrorist agents. These products include vaccines, blood and blood derivatives, gene therapies, and cells and tissues for transplantation.

These biological products are carefully reviewed, and risk-to-benefit issues are carefully considered throughout their development, manufacturing, and clinical testing. CBER staff guide the products through the regulatory process, including manufacturing, preclinical testing, clinical trials, and the approval and licensing processes. Experts from diverse areas help expedite the development, evaluation, and approval processes. Often, time is of the essence, and the scientific and product issues are extremely challenging. Early involvement by scientific, statistical/ epidemiological, and clinical review staff is crucial to the success of the expedited development and review processes.

As part of national policy, a high priority is placed on category A agents—a CDC designation given to the greatest public health threats. Category A agents include organisms that cause anthrax, plague, smallpox, tularemia, and viral hemorrhagic fevers, as well as botulinum toxin. Emergency response proficiency is also being addressed through reassessing and strengthening capabilities and the development of continuity of operations plans. In addition, CBER has been proactive in identifying gaps that exist and in medical countermeasures against biological agents.

Anthrax

Anthrax is an infectious disease caused by the spore-forming bacterium, Bacillus anthracis. There are three forms of anthrax infection: (1) cutaneous; (2) gastrointestinal; and (3) inhalational, the latter of which is associated with the highest death rates. Currently, there is one anthrax vaccine—BioThrax, manufactured by BioPort Corporation, that is licensed in the U.S. This vaccine is indicated for pre-exposure prophylaxis against Bacillus anthracis (the causative agent of anthrax) in individuals between 18 and 65 years of age who are at risk of exposure. CBER has approved supplements to the BLA for BioThrax to increase the manufacturing capacity and extend the dating period of the product to 36 months.

FDA also issued a Proposed Rule and Order regarding the safety and efficacy of certain bacterial vaccines and toxoids, including the licensed anthrax vaccine that was published December 29, 2004. After reviewing the comments submitted to the docket, CBER, together with other FDA components, issued a Final Rule and Order regarding the safety and efficacy of certain licensed biological products. A Final Order was issued on December 15, 2005 regarding the authorization of emergency use of anthrax vaccine.

CBER is part of an interagency working group—with NIH, CDC, the Department of Defense (DoD), and DHHS—focused on encouraging the development of new, recombinant anthrax vaccines intended to prevent anthrax both before and after exposure. Such vaccines, being developed under INDs, present many challenges, especially in terms of developing reproducible animal models for demonstrating efficacy. The genetic makeup of anthrax is being studied to help improve vaccines and treatments.

DHHS awarded the first contract under Project Bioshield for a recombinant protective antigen (rPA) anthrax vaccine. CBER has devoted extensive resources to assist and guide manufacturers through the regulatory process in the development of their rPA anthrax vaccines and has provided extensive technical input to the Office of Public Health Emergency Medical Countermeasures (OPHEMC) in the Office of the Assistant Secretary for Public Health and Emergency Preparedness (OASPHEP), DHHS. New immune-based therapies for treating anthrax are also under development. For example, anthrax immune globulin is under evaluation as a potential treatment of anthrax disease. CBER has been working with the Center for Drug Evaluation and Research (CDER) to develop a draft guidance that addresses the development and licensure of immune-based therapies to treat anthrax disease. CBER has also provided technical input to DHHS the Strategic National Stockpile.

Smallpox

Smallpox, caused by the variola virus, is highly contagious and can be spread by close contact with an individual who has smallpox symptoms: high fever, fatigue, headaches, backaches, vomiting, rash, and pus-filled blisters. There is no proven treatment. The last confirmed case of smallpox in the U.S. was in 1949, and the last naturally occurring case in the world was recorded in Somalia in 1977. The death rate in the past was about 30% for the general population, and death rates can be higher for infants and young children.

Smallpox can be prevented through vaccination. Dryvax (dried, calf lymph type smallpox vaccine), made by Wyeth Laboratories, is the only smallpox vaccine currently licensed and is no longer being manufactured. Smallpox vaccines that are related to the same vaccine strain used in Dryvax, but grown in cell culture, are being developed. CBER is studying the safety, efficacy and manufacture of smallpox vaccines to facilitate regulation of these important products.

Blood Supply

Any time there are large emergencies or outbreaks of diseases, the blood supply is threatened. In the case of mass vaccinations, those who receive some vaccinations containing live viruses cannot be blood donors for a period of time because of the potential to transmit the vaccine virus. The Center has issued guidances on reducing the risk of transmitting diseases through blood donated by infected individuals, either by vaccination (anthrax and smallpox) or by exposure to a bioterrorist agent (bacilius anthracis). Recommendations have also been made for national emergency planning to ensure that vaccination campaigns consider impacts on the blood supply. Efforts are also underway to produce diagnostic assays to detect bioterrorist agents in blood donations.

CBER works in close liaison with the AABB-sponsored Interorganizational Task Force on Domestic Disasters and Acts of Terrorism. This task force defines a disaster or act of terrorism as an event that requires a much larger amount of blood than usual; one that temporarily restricts blood collection, testing, and distribution; or one that creates a sudden influx of donors requiring accelerated drawing of blood. CBER also works with multiple other partners to help ensure blood donations remain safe and plentiful in times of disaster.

Other Counterterrorism Activities

CBER continues to interact intensively with DHHS, the Department of Homeland Security (DHS), DoD, and industry on a broad array of projects to help make our nation better prepared for threats of biological, chemical, and radiological/nuclear terrorism. Accomplishments include the following:

• co-developed the Blood Availability and Safety Inventory System (BASIS) used by DHHS to monitor the availability of blood components at major hospital centers and blood establishments throughout the U.S.
• established the CBER Blood Safety Team to improve CBER's response to blood safety issues, and to enhance external outreach, evaluation, and risk communications
• facilitated continual development of new medical countermeasures (e.g., rPA vaccines, anthrax immune globulin, new smallpox vaccines, and botulinum antitoxin) through expedited regulatory review and assistance to manufacturers
• completed the Final Order on the Efficacy Review of Bacterial Vaccines and Toxoids, including the anthrax vaccine—this review was published in the Federal Register on December 19, 2005 (Biological Products, Bacterial Vaccines and Toxoids, Implementation of Efficacy Review, Anthrax Vaccine Adsorbed, Final Order)
• reassessed and strengthened response capabilities including the development of continuity of operations plans
• proactively identified gaps that exist related to needed medical countermeasures against biological agents that could be used in an attack
  lead effort to finalize new labeling regulations for medical products purchased for the Strategic National Stockpile
• studied/developed improved immunological assays for anthrax vaccines, the protective isotypes of vaccinia immune globulin, correlates of immunity for tularemia, the cellular trafficking of botulinum toxin, and stimulation of innate immunity against various agents
• held numerous pre-IND/technical meetings with potential manufacturers of medical countermeasures to assist in their development and the submission of INDs, as well as development of their licensure path.

*See Appendix A References 30-38

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Enhance Patient And Consumer Protection And Empower Them With Better Information About Regulated Products

CBER actively addresses the highest public health priorities through collaborative, innovative and cooperative actions. The Center has emphasized the importance of outreach, new paths to product evaluation, increased access to products, and safety. Improving blood safety through new blood donor screening tests and safety surveillance of licensed biological products to detect new information about adverse events have significantly increased public health protections. Increasing the amount of information available to guide consumer decisions on product use and the elimination of false and misleading product information contribute to a public better informed about biologic products.

Improving the Safety of the Blood Supply with Novel Donor Screening Tests*

Improvements in blood donor screening and testing over the last few years have helped make the nation's blood supply safer from infectious diseases than it has been at any other time in history. A number of products and product supplements have been approved in the last fiscal year that contribute to this effort.

Hepatitis B

Hepatitis B (HBV) is caused by a virus that infects the liver. The virus, which is transmitted by blood, can, in some cases, cause lifelong infection, cirrhosis (scarring) of the liver, liver cancer, liver failure, and death. This past year, CBER approved the first fully automated tests for hepatitis B virus (the Abbott Prism HBcore assay, the Abbott Prism HBsAg assay, and the Abbott Prism HBsAg Confirmatory assay). The Abbott Prism automated test system increases the efficiency and convenience of screening blood, tissue, and organ donors for HBV. The Abbott Prism tests are fully automated, thus reducing the potential for operator errors. They are tamper-resistant, with redundant checks to ensure integrity of the testing system, and highly sensitive and specific for detection of infection with HBV.

West Nile Virus

WNV is typically transmitted to humans by mosquito bites. It was first detected in the U.S. in 1999, and the virus has recurred each year for seven consecutive years, causing close to 20,000 human cases of disease and at least 762 deaths since 2002. It has been estimated between 1 and 2 million people have been infected with WNV. In 2002, it was discovered the WNV could be transmitted in blood, and an urgent effort to develop a blood test began. With support from FDA, CDC, and NIH, manufacturers developed investigational WNV NATs that were rapidly put in place to evaluate their effectiveness and (as an interim measure) to protect the blood supply. Blood banks across the U.S. participated in these efforts, to safeguard the blood supply.

CBER approved the first WNV blood test to screen donors of blood, organs, cells, and tissues in December 2005. The Procleix WNV assay, developed by Gen-Probe, Inc. and marketed by Chiron Corporation, detects viral genetic material (ribonucleic acid or RNA). This new test will help protect patients who receive blood and other biologic products against WNV infection. This approval is the result of a tremendous cooperative effort among FDA, other public health agencies, state health departments, test kit manufacturers, and the blood industry. With the approval of a screening test for WNV, CBER is developing guidance for industry on the implementation of these tests.

Despite all the progress in testing and improvement in the understanding of WNV, scientific questions still remain. CBER is also conducting studies on the partitioning of WNV in blood components to determine whether new approaches to testing, including the use of whole blood as the test sample, could increase the sensitivity of WNV NAT, thereby further reducing the risk of WNV from NAT screened donations.

*See Appendix A References 39-40

Monitoring the Availability of Blood and Blood Components*

The TRANS-Net Blood and Reagent Shortage Monitoring System, designed and piloted by CBER, has been incorporated into the DHHS Public Health Emergency Management System. Blood and blood components are critical biological products that provide life support to patients in the U.S. each year and are frequently needed in large quantities during times of natural disaster and other emergencies. More than 29 million units of whole blood, red blood cells, and platelets are transfused each year. However, these products have relatively limited storage times and are critically dependent on the routine availability of eligible donors, as well as supplies for collection of blood and reagents for testing.

Systems for assessing national blood supply inventories, while successfully measuring historical trends in collection and utilization, have not previously had the capability to assess local, regional, and national blood component shortages in real time. In response to the September 2001 tragedy, TRANS-Net was designed at CBER as a Web-based system that provides a mechanism for voluntary real-time reporting of shortage information to a central site from the nation's 1,848 registered blood collection sites and 2,348 transfusion services. These reports are received electronically and mapped at a central data monitoring facility. Data are then assessed manually and electronically through the use of software that recognizes the geospatial density and frequency of information received. This software creates an alert message when a predetermined shortage threshold is reached. It also creates geospatial maps reflecting shortage levels that can be integrated with other mapped data (e.g., hospital census) that are also part of the BASIS blood inventory monitoring system, which is housed in the DHHS Secretary's Operations Center. Incoming data also contain information that helps to indicate the seriousness of a reported shortage event, for example:

• delayed surgery or medical procedure (number of events per reporting day)
• support of Rh-negative patients with Rh-positive blood (number of events per reporting day)
• unfilled (or underfilled) blood orders (e.g., <50% of requested blood received)
• triage of available supply
• insufficient blood to meet emergency needs.

As part of the TRANS-Net design, summary reports of appropriate blood availability information will be made available on the Web to public health stakeholders and eventually to the general public as an aid in recruiting blood donors.

*See Appendix A Reference 41

Enhancing the Safety of Blood and Development of the CBER Blood Safety Team

The CBER Blood Safety Team was launched in July 2006. Led by the Office of Blood Research and Review (OBRR), the interdisciplinary Blood Safety Team is comprised of experts from several CBER offices, including the Office of Compliance and Biologics Quality (OCBQ), the Office of Communications, Training, and Manufacturers Assistance (OCTMA), Office of Biostatistics and Epidemiology (OBE), and the Immediate Office of the Director (IOD). Four main goals of the Blood Safety Team are to:

• improve CBER's response to blood safety issues
• improve the availability and quality of CBER's blood safety information
• improve processing of blood safety information
• enhance CBER's external outreach, evaluation, and risk communication.

Current objectives of the Blood Safety Team include the following four areas:

• finalizing the blood safety reporting rules and guidances
• evaluating methods to improve the collection and assessment of adverse events, transfusion related fatalities, and Biological Product Deviation Reports (BPDRs)
• developing pathways to track plasma derivatives
• increasing access and partnerships with other DHHS agencies.

We anticipate the activities of the Blood Safety Team will enhance CBER's ability to monitor and respond to blood safety issues and further protect the nation's blood supply and blood products from infectious diseases and other emerging threats.

Biological Safety Activities*

A fundamental aim in CBER's continuous safety surveillance of licensed biological products is to enhance our understanding of the safety profile of the products we regulate and to provide updated safety information to the public. Our efforts can help physicians weigh a product's risks and benefits and help patients to use these products as safely as possible. CBER also presents information to advisory committees and publishes articles in the medical literature about the safety of biological therapeutic and prophylactic products.

CBER has played an important new role in implementing the International Conference on Harmonisation's (ICH) Pharmacovigilance Planning Guidance. CBER recognizes the importance of pharmacovigilance plans submitted as part of the license application, and our review of such plans is an important activity in the area of postmarketing safety.

*See Appendix A References 42-44

CBER Outreach Update

CBER's outreach efforts during FY 2006 focused on improving the Center's communication through innovative communication strategies. CBER's outreach program reaches tens of thousands of stakeholders annually, both directly and indirectly, including consumers, health care professionals, regulated industry, members of Congress, and the media.

During FY 2006, CBER began an initiative to improve the organization and quality of information on its website. The website serves as a focal point for obtaining information from the Center. The redesign will make information easier to find. There were almost 18 million hits to the site during FY 2006, averaging approximately 43,000 hits per day. The Center also maintains three automated e-mail distribution lists, which now reach more than 8,000 subscribers. These "listservs" allow CBER to proactively distribute information electronically, reaching a wide audience quickly and efficiently.

Over the past several years, CBER has enjoyed a successful exhibit program, and FY 2006 was no exception. The Center participated in annual meetings, conferences, and workshops. The Center's exhibit program reaches a vast array of constituents, including those working in regulated industry, counterterrorism research, infectious diseases and infection control, and parents' groups (see Appendix B).

CBER held several workshops in FY 2006 that were intended to provide important information to researchers, product sponsors, and the public on key topics related to product development and licensure. CBER also participated in information-sharing liaison meetings with trade associations and developed several co-sponsorship agreements for workshops as avenues to disseminate important regulatory and policy information. In addition, CBER contributed a number of important updates on product approvals and safety information to FDA Patient Safety News, a monthly broadcast produced by the Agency and delivered to hospital networks around the country.

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Increase Access To Innovative Products And Technologies To Improve Health

CBER continues to meet or exceed the fee performance goals for drugs and devices, thereby increasing the number of biological products and related devices available to those in need

. Newly approved products, such as RotaTeq to prevent rotavirus gastroenteritis in infants, Gardasil to prevent cervical cancer caused by certain human papillomaviruses (HPV), and Zostavax to reduce the risk of shingles all address important public health needs. The Critical Path initiative focuses on facilitating innovative products for the 21st Century. The Center is working to advance the development of more efficient vaccine production which will benefit the public health in many areas, including strengthening our capacity to deal with seasonal and pandemic influenza.

Initiatives to Strengthen, Diversify, and Increase Capacity for Influenza Vaccines

The 2005-2006 Influenza Season

Seasonal influenza is a significant cause of morbidity and mortality in the U.S. According to CDC, every year on average in the U.S., approximately 5 percent to 20 percent of the population get sick with influenza, more than 200,000 people are hospitalized from its complications, and approximately 36,000 people die from it. Some individuals, such as the elderly, children, and people with certain chronic medical conditions, are at high risk for serious complications from influenza. Ninety percent of influenza-related deaths occur in individuals aged 65 or older; however healthy children under 2 years of age are as likely to be hospitalized because of influenza as older adults.

Influenza vaccine is unique because its active ingredients, the virus strains used to manufacture the vaccine, change almost every year. Because the circulating viruses are constantly mutating, each year's vaccine usually differs from the preceding year. Therefore, manufacturers must produce tens of millions of doses of a new vaccine each year. Promising technologies (e.g., cell culture and recombinant protein and DNA-based influenza vaccines) are in the research and development stages. In September 2006, CBER issued draft guidance on development of cell culture vaccines that is applicable to the development of influenza vaccine. CBER is working with our DHHS colleagues and with manufacturers to advance their development. The vaccine manufacturing process is complex and can create uncertainty for the vaccine supply. Preparing for the influenza season each year is a time-critical, collaborative effort involving FDA, CDC, NIH, WHO, vaccine manufacturers, and the health care community.

The strain selection process usually occurs in February when an FDA advisory committee meets to recommend which three strains of the virus should be included in the vaccine, based on data from WHO laboratories in more than 80 countries. FDA makes the final decision on which strains will be included in the vaccine for the
U.S. population.

FDA, CDC, other WHO collaborating centers, and other partners produce reference influenza viruses that represent the selected strains and are adapted to high growth in eggs. The reference influenza viruses are provided to the licensed vaccine manufacturers to generate the "seed virus" for further manufacturing the influenza vaccine. Manufacturers then inject the seed viruses into fertilized chicken eggs, and the virus multiplies.

CBER produces and provides manufacturers with antiserum that is used to test vaccine potency for each influenza strain used in the manufacture of trivalent inactivated influenza vaccines. Manufacturers of both inactivated and live attenuated influenza vaccines ship samples of vaccine from each lot, along with their test results, to CBER for lot release. CBER reviews the manufacturer's test results and also may perform its own tests on the vaccine before releasing each lot for distribution.

It takes about 6 months to complete influenza vaccine production, from egg to vial, each season. FDA interacts extensively with licensed manufacturers to address issues that may arise during annual production and to facilitate resolution of these issues. In addition, since 2004, FDA has conducted inspections of influenza vaccine manufacturers on an annual basis to identify problems earlier and prevent them whenever possible. Although some lots of vaccine may be released as early as July, manufacturing usually continues until October or later to produce and test the large volume of vaccine required for the U.S. population.

In August 2005, FDA announced the approval of Fluarix, an influenza vaccine for adults that contains inactivated virus. Fluarix is approved to immunize adults 18 years of age or older against influenza virus subtypes A and type B contained in the vaccine. The approval of Fluarix broke new ground in that it was the first vaccine approved using FDA's accelerated approval process. Accelerated approval allows FDA to approve products for serious or life-threatening diseases based on early evidence of a product's effectiveness; therefore reducing the time it takes for needed medical products to become available to the public. In this case, the manufacturer demonstrated that, after vaccination with Fluarix, adults made levels of protective antibodies in the blood that FDA believes are likely to be effective in preventing influenza. GlaxoSmithKline, manufacturer of Fluarix, is performing further clinical studies as part of the accelerated approval process to verify the clinical benefit of the vaccine. In the fall of 2006 and in time for the 2006-07 influenza season, FDA approved ID Biomedical's trivalent inactivated influenza vaccine, FluLaval, to immunize adults 18 years of age and older against influenza disease caused by virus subtypes A and type B. FDA again used the accelerated approval pathway.

Four manufacturers distributed influenza vaccine for the 2005-2006 season:

1. sanofi pasteur;
2. MedImmune Vaccines, Inc.;
3. GlaxoSmithKline Biologicals; and
4. Chiron

The estimated supply of vaccine for the 2005-2006 season was 86 million doses, approximately 40 percent more than the 2004-2005 season's 61 million doses. Demand for vaccine averages 70 million to 75 million doses annually.

The peak demand for influenza vaccine is in October and November. Because the influenza disease season usually peaks in January or later in the U.S., FDA and CDC support extending vaccination into January and February of each year.

FDA Issues Advice to Facilitate Influenza Vaccine Development

In March 2006, CBER's Office of Vaccines Research and Review (OVRR) released two draft guidance documents, one for seasonal influenza vaccines (annual trivalent inactivated) and the other for pandemic influenza vaccines, to aid manufacturers in evaluating seasonal and pandemic influenza vaccines for safety and effectiveness. FDA's goal is to increase the supply of safe and effective influenza vaccines by outlining the regulatory pathway for the rapid development and approval of influenza vaccines. The two guidances provide manufacturers with guidelines on the clinical data needed to show safety and effectiveness for new influenza vaccines. Consistent with the goals of FDA's Critical Path Initiative to get products to market more quickly and to advance the development and use of new technologies, these documents outline specific approaches for vaccine developers to follow. In essence, through the guidances, FDA provides a road map to assist industry and provides advice for new manufacturers on how to develop new and safe vaccine products more quickly.

Additional and more specific information on the guidances can be found on the CBER website at www.fda.gov/cber/guidelines.htm.

Technology for New-Generation Vaccines for Viral Infectious Diseases

In an effort to aid manufacturers in developing safe and effective cell-based viral vaccines, including those to address emerging and pandemic threats, FDA issued a new draft guidance in September 2006. "The guidance document…is a vital part of our overall efforts to help manufacturers develop new vaccines that are critical to meeting global public health needs," said then acting FDA Commissioner, Andrew von Eschenbach, M.D.

"This guidance promises to help modernize the development of life-saving vaccines for influenza and other diseases and facilitate the development of more plentiful, reliable supplies."

In the guidance, FDA provides manufacturers of viral vaccines with updated recommendations to the 1993 document, "Points to Consider in the Characterization of Cell Lines Used to Produce Biologics." The guidance document conveys information for determining the suitability of a cell culture for manufacturing, which includes testing and validating the safety and purity of the cells used in the development and production of viral vaccines.

While cell cultures currently are used in the manufacture of many licensed vaccines that help protect against diseases, such as polio, rubella, and chickenpox, the new guidance further helps facilitate the development of additional vaccines. The guidance outlines the best practices using current and emerging science. Cell-based vaccine manufacturing holds the promise of a reliable and flexible alternate method of producing influenza vaccines, which are currently produced in chicken eggs by a technique developed more than 50 years ago. With increasing demand for seasonal influenza vaccine and with the potential threat of a pandemic, as well as other emerging infectious diseases (e.g., SARS), more flexible approaches that allow surge capacity in an emergency are critical. With cell-based manufacturing, cells can be frozen, stored, and thawed as needed to produce more vaccine.

A copy of the draft guidance, "Guidance for Industry: Characterization and Qualification of Cell Substrates and Other Biological Starting Materials Used in the Production of Viral Vaccines for the Prevention and Treatment of Infectious Diseases," is available at www.fda.gov/cber/gdlns/vaccsubstrates.pdf.

Critical Path Initiative: Personalized Medicine*

Critical Path is FDA's premier initiative to identify and prioritize the most pressing medical product development problems and the greatest opportunities for rapid improvement in public health benefits. Its primary purpose is to ensure basic scientific discoveries translate more rapidly into new and important medical treatments by creating new scientific tools to develop and evaluate new medical products.

On March 16, 2004, FDA released a report, Innovation/ Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, addressing the apparent slowdown in innovative medical therapies submitted to FDA for approval. The report describes the urgent need to modernize the medical product development and evaluation process (the Critical Path) to make product development more predictable and efficient. Because of its unique vantage point, FDA can work with companies, patient groups, academic researchers, and other stakeholders to coordinate, develop, and/or disseminate solutions to scientific hurdles that are impairing the efficiency of product development industry-wide.

Through the Critical Path Initiative, FDA took the lead in the development of a Critical Path Opportunities List and Report. The report describes and provides examples of how new scientific discoveries in fields, such as genomics and proteomics, imaging, and bioinformatics, can be used in bringing products to market, and provide the right treatment at the right time to the right patient. The Opportunities List was released on March 16, 2006, by Secretary Leavitt and Commissioner von Eschenbach (then Acting Commissioner). The Opportunities List outlines an initial 76 projects to bridge the gap between the quick pace of new biomedical discoveries and the slower pace with which those discoveries are currently developed into therapies. The release of the Opportunities List marks a starting point in identifying priorities to be accomplished under the Critical Path Initiative. Government, industry, and academic experts estimate that, if accomplished, the new tests and tools developed under the Critical Path Initiative will modernize the drug development process by 2010 and help make treatments safe while bringing new medical discoveries to patients faster and at a lower cost. The Opportunities List is available at http://www.fda.gov/oc/initiatives/criticalpath/reports/opp_report.pdf.

CBER continues to leverage resources with other government agencies. In January 2006, FDA, the National Cancer Institute (NCI), and Centers for Medicare and Medicaid Services entered into a Memorandum of Understanding for the Biomarker Qualification Initiative. The three agencies collaborate and pursue specific projects aimed at improving the clinical utility of biomarkers as diagnostic and assessment tools that facilitate the development of safe and more effective cancer therapies.

CBER has a long tradition of research aimed at resolving challenges to biological product evaluation. Many of these are cited within the Annual Report text. Additional recent Critical Path achievements of CBER can be viewed at www.fda.gov/oc/initiatives/critical path/opportunities06.html.

Research Management Advances

FY 2006 marked a year of major milestones in CBER research management and successes. CBER research and scientific expertise contribute to facilitating product development and evaluation. CBER has expert medical, scientific, and technical staff who are members of interdisciplinary review teams. Some of these individuals also perform research to advance biological product safety, efficacy, and quality.

CBER uses the following principles to facilitate the management of research programs and objectives within the Center:

• The CBER research program is highly collaborative and includes laboratory, epidemiological, statistical, and clinical sciences.
• Its scope encompasses the scientific basis of preclinical and clinical studies, manufacturing, regulatory submissions, inspections, postmarketing surveillance, and stakeholder outreach (e.g., guidances).
• The research is high-quality, efficient, and provides outcomes that address scientific and regulatory challenges in product development, safety, efficacy, and quality.

This past year, CBER established a Research Leadership Council (RLC) to spearhead the CBER Research Management Initiative. The RLC developed and is implementing a transparent, mission driven research program management process. CBER is developing a center-wide Scientific Research Plan, for which input from CBER's Advisory Committees will be sought.

Scientific Expertise Teams

CBER has a wide range of scientific expertise. The RLC developed the Scientific Expertise Team Matrix to identify and manage the scientific and technical expertise within the Center. This matrix provides a mechanism to best utilize CBER scientific resources for product regulation by identifying specific scientific expertise within CBER.

CBER regularly invites external scientific experts on advisory committees to evaluate, through site visits, the achievements and future plans of the CBER Research Laboratories and research-regulator staffs. CBER expanded external review of research to include a broader programmatic assessment of each product office's research program (OVRR, OBRR, and the Office of Cell, Tissue, and Gene Therapy (OCTGT)). These evaluations are important tools in our annual research planning.

Scientific Training Initiatives

CBER also has a long tradition of collaborative research. In FY 2006, we developed a program to enhance research training of collaborative scientists. Through this program collaborative research opportunities are established with other domestic and international governmental and nongovernmental institutions. The Collaborative Scientific Training Program (CSTP) provides an opportunity for acquiring additional scientific expertise within CBER, as well as training a cadre of researchers (e.g., postdoctoral students) in the science of product development and regulatory research. Inaugural CSTP partners include the Korean FDA and the University of Yokohama in Japan, and further outreach is underway with other domestic and international academic and regulatory institutions.

CBER medical, scientific, and technical staffs use their expertise to evaluate complex biological medical products. It is critical to continually update and advance their expertise in concert with the rapid advancements in 21st century science. In FY 2006, CBER developed a program to support continuing technical, scientific, and medical education initiatives for scientific staff. Through this program, these staff were able to attend seminars and educational meetings in their area of medical, scientific, and technical expertise.

To provide formal education in the science of leadership and management, CBER developed and offered a series of leadership and management training courses for all personnel. The courses included Productive Conflict Management, Situational Leadership, and Motivating Your People. These courses were well-attended and are an essential component in staff development and succession planning at CBER.
Selected FY 2006 research accomplishments at CBER include the following:

• established programs to develop and evaluate enhanced approaches to pandemic influenza vaccine manufacture, safety, and efficacy
• identified biomarkers that may serve as indicators of epithelial ovarian cancer disease progression/ response to therapy; identified portion of Ebola virus critical to cell entry, which may provide a target for vaccine development
• embarked on international study with the WHO to qualify a new, small animal mumps vaccine safety test
• developed a new assay to distinguish HIV-vaccinated subjects from HIV-infected subjects in clinical trials
• commenced a new proteomics coordination effort to enhance and modernize biological product characterization techniques, including influenza vaccine, cell substrates, and gene therapies.

Selected FY 2006 partnering relationships include the following:

• studies relating to cell substrate testing for vaccine manufacture, HIV-related biological product evaluation and development
• Interagency Oncology Taskforce fellowship program with the National Cancer Institute (NCI)
• support of CBER core biotechnology services with the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ongoing development of small animal models for preclinical testing of tularemia vaccines, aerosolized anthrax, smallpox vaccine, and SARS vaccine
• preclinical assay development for tuberculosis vaccines with the Aeras Global TB Vaccine Foundation
• proteomics for blood product characterization with the Alpha-1-Foundation
• transgenic mouse model development with the American Red Cross to address variant Creutzfeldt-Jakob disease (vCJD) contamination
• genomics analysis of cell substrate quality with the American Type Culture Collection
• development of DNA microarray system for detection of pathogenic agent contamination of biological products with Johns Hopkins University
• improvement of safety and production of pandemic flu vaccines with the National Vaccine Program Office, including improving cross-protection of influenza vaccines.

*See Appendix A References 45-51

User Fee Programs

PDUFA

In 1992, Congress passed the Prescription Drug User Fee Act (PDUFA). Congress reauthorized PDUFA in the FDA Modernization Act of 1997 (FDAMA), and again in the Public Health Security and Bioterrorism Preparedness and Response Act of 2004. The 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, the company 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. In this program, industry provides added resources needed to meet review performance goals, which emphasize timeliness while maintaining safety and efficacy of FDA-approved products.

PDUFA has provided FDA with needed resources for the review of human drug and biologic applications. Fees are used to help reduce the time required for evaluating human drug applications and to support review quality. FDA submits annual performance and financial reports to Congress on progress in streamlining the drug review process and use of PDUFA fees.

On November 10, 2005, FDA also issued a white paper entitled, "Adding Resources and Improving Performance in FDA Review of New Drug Applications." The document shows the evolution of the PDUFA program since its enactment in 1992 and progress to date. The paper also discusses how fees are collected and how the fees are utilized.

On November 14, 2005, FDA held a public meeting entitled, "Prescription Drug User Fee Act: Public Meeting." This meeting included presentations by FDA and a series of panels representing different stakeholder interest groups (e.g., patient advocates, consumers, industry members, health professionals, and academic researchers). The public meetings shared stakeholders views as FDA prepared to work on amended authorizing legislation for PDUFA.

The authority for PDUFA III expires in September 2007; without further legislation, FDA would no longer be able to collect user fees for the prescription drug program, and resources critical to running the program would become unavailable to FDA. Information on FDA's PDUFA performance and financial reports, including the white paper, can be accessed at www.fda.gov/oc/pdufa.

MDUFMA

The Medical Device User Fee and Modernization Act of 2002 (MDUFMA) is providing needed funds to FDA for "the review of devices and the assurance of device safety and effectiveness so that statutorily mandated deadlines may be met." MDUFMA user fees coupled with the additional appropriations required by MDUFMA, have helped reverse that trend and are providing the following continuing benefits:

• Safe and effective devices used to diagnose and treat disease are reaching the public more rapidly.
• Manufacturers are receiving timely, high-quality application reviews.
  Devices marketed in the U.S. continue to meet high standards for safety and effectiveness.

CBER interaction with government partners and industry has facilitated the recent approval of rapid tests for HIV and tests to monitor HIV drug resistance, examples of successful regulation under the framework established by MDUFMA. The Center aims to apply regulation in a risk-based manner. Certain areas in CBER's oversight, including blood-screening tests, raise unique concerns. CBER seeks to address these in a balanced, transparent, and least burdensome manner, and welcomes public and industry input as we develop guidance to industry on devices regulated by CBER. On April 28, 2006, CBER, in conjunction with CDRH, issued guidance to industry that provided information about the real-time review process for premarket approval application (PMA) supplements and outlined the procedures for requesting and submitting these types of documents. On August 1, 2006, CBER/CDRH also issued guidance to industry entitled, "Small Business Qualification Worksheet and Certification," that provided updated information regarding which firms qualify for small business fees and discounts for FY 2007.

On September 30, 2007, the user fee provisions of MDUFMA will expire. To help FDA and all stakeholders evaluate the program and prepare for possible new legislation to reauthorize MDUFMA, FDA sought input from interested parties about those aspects of MDUFMA that worked well and those areas for which change should be considered. FDA held its Third Annual MDUFMA Stakeholders meeting on November 17, 2005. The meeting provided a forum for industry, the general public, and all stakeholders to give feedback to FDA on how the user fee process is working and recommendations for improvement of the device review program.

Negotiations with industry for MDUFMA II include representatives from CBER, CDRH, Office of Regulatory Affairs (ORA), and the Office of the Commissioner. CBER has met or exceeded the MDUFMA review performance goals for FY 2005. FDA's MDUFMA performance and financial reports can be accessed at www.fda.gov/oc/mdufma.

Cellular and Gene Therapies: Facilitating Availability and Development of Safe and Effective Products Through New Technologies

Genomics and Proteomics

As hundreds and thousands of endpoints are analyzed simultaneously, genomics and proteomics technologies offer novel approaches to understanding biological processes. Not only are these technologies being incorporated into the routine of academic laboratories, but they are also becoming a tool for biotechnology, product characterization, and clinical research conducted by academia, government agencies, and industry. The results of genomic and proteomic studies have begun appearing in INDs and BLAs/New Drug Applications (NDAs) submitted to FDA. To facilitate development and availability of safe and effective technologies, CBER is engaged in the research and development of standards, performing critical path research to characterize cell substrates and products, including cellular and gene therapy products and developing guidance documents in the area of genomics and proteomics technologies. CBER is also engaged in developing expertise by providing a hands-on training program for regulatory scientists and research reviewers. More than 50 regulatory scientists/research reviewers have been trained through this program.

CBER helped develop FDA guidance for industry, "Pharmacogenomic Data Submissions," released in March 2005. CBER scientists are also involved in FDA's Interdisciplinary Pharmacogenomics Review Group (IPRG), which evaluates voluntary genomics data that sponsors submit to FDA. To keep pace as science and technology evolves, in the past year an expert working group on "Pharmacogenomics" was formed as part of ICH. Both CBER and CDER staff, along with representatives from Europe and Japan, participate in this group. The primary objective of this ICH group is to define basic terminology pertaining to pharmacogenomics, pharmacogenetics, and methods for coding of pharmacogenomic samples and data. Other objectives are to define terminology of genomic biomarker attributes. This group has begun drafting a guideline that will harmonize pharmacogenomic terminology and define consistent terms for use in regulatory documentation. This guideline will help facilitate integration of this evolving science into global drug development.

Tissue Engineering

In support of the critical path element entitled, "Tools for Assessing Safety, Demonstrating Medical Utility, and Characterization of Manufacturing," CBER, together with CDRH, is developing a partnership with other federal agencies to advance tissue-engineering science and to facilitate the development of safe and effective tissue-engineered products. The CBER/CDRH Tissue Engineering Steering Committee promotes inter-center interactions on topics of mutual interest. CBER staff also participate on the CDRH Specialty Task Group on Tissue Engineering, which is responsible for coordinating Agency interactions with the American Society for Testing and Materials International (ASTM) in the development of their international standards for Tissue-Engineered Medical Products (TEMP). CBER and CDRH staff attended the inaugural Tissue Engineering/ Regenerative Medicine (TERM) liaison meeting on April 28, 2006. Topics included FDA regulatory review process specific to cell scaffold products, key clinical challenges, unique product testing paradigms, and manufacturing issues in development of TERM products.

CBER staff participate in the Multi-Agency Tissue Engineering Science (MATES) Interagency Working Group, organized under the auspices of the Subcommittee on Biotechnology, National Science and Technology Council (NSTC). The primary goal of MATES is to facilitate communication across departments/ agencies by regular information exchanges and to enhance cooperation through co-sponsorship of scientific meetings and workshops. This past year, members of the MATES Working Group have been preparing a document entitled, "Strategies for Advancing Tissue Science and Engineering: Foundation for the Future." This document, when completed, will provide a strategic plan for the advancement of tissue engineering in the federal government. CBER has met with product manufacturers currently developing these innovative products and has a unique perspective pertaining to the issues associated with the early phases of developing tissue-engineered products. The need to provide a clear strategy that defines the types of studies and data essential for supporting regulatory submissions has been consistently noted. For example, CBER has identified a need for criteria suitable for the characterization of final manufactured cell-scaffold, tissue-engineered products. Key issues being considered include the following:

1. What questions should be asked and addressed by testing, and at what stage of product assembly?
2. What testing methods are available and what methods need to be developed?

Cellular and Gene Therapies: Outreach and Partnerships

CBER has provided proactive scientific and regulatory guidance in areas of novel product development. The Center communicates regulatory expectations and encourages dialogue on cutting-edge product development to help define the best scientific approaches and reduce product development time and risk. Early and continuing interactions with stakeholders and the public have proven to be an effective means of communicating, and addressing issues regarding potential risks and benefits, thus avoiding unnecessary regulatory burdens.

Following are some examples of these interactions during the past fiscal year:

• On January 27, 2006 and June 16, 2006, CBER staff attended the Cell Therapy/FDA Liaison Meetings. Topics discussed included HIV and HCV NAT testing for donor of human cells and tissues, and microbial contamination of peripheral blood progenitor cell products.
• In February 2006, CBER staff held a Cellular, Tissues, and Gene Therapies Advisory Committee meeting to discuss the complex and difficult area of potency assay development for cell and gene therapy products. CBER staff discussed a matrix approach to potency assays to spur development of complex products. The meeting also included a session on the NTP Proposed Study on Retroviral Vector-Mediated Insertional Mutagenesis.

As part of the NTP, and in collaboration with the National Institute of Environmental Health Sciences (NIEHS), CBER initiated studies to develop approaches to reduce the risk of cancer following retroviral gene therapy. Included in this collaboration are preclinical studies involving DNA-based therapeutics, specifically focusing on retroviral vector safety aimed at reducing the risk of retroviral-mediated tumorigenesis following administration into humans. The goal of the project is to reduce the uncertainty in the risk assessment/risk benefit analysis; enable a better estimate of risk; and establish high-quality, science-based safety assessments/risk management decisions for the consumer.

As part of our outreach efforts, CBER staff participated in numerous national, international, trade, and industry meetings. CBER has also been involved with liaison meetings within FDA involving Alzheimer's disease and the use of cellular therapy in cardiovascular disease. Much of our effort has been directed toward specific disease processes or emerging technologies. CBER staff has also worked extensively with the NIH extramural program on trials to establish the safety and efficacy of pancreatic islet cell transplantation for the treatment of diabetes mellitus.

To further communicate our regulatory expectations, CBER has issued the following guidances: "Chronic Cutaneous Ulcer and Burn Wounds—Developing Products for Treatment" (with CDRH) and "Guidance for Industry: Gene Therapy Clinical Trials— Observing Participants for Delayed Adverse Events." On July 27, 2006, CBER staff presented a talk entitled, "National Policies for Xenotransplantation Studies in the USA." In addition, CBER represented DHHS at a WHO consultation on September 27-29, 2006, entitled, "Second Global Consultation on Critical Issues in Human Transplantation," in which international policies for xenotransplantation oversight were discussed.

FDA Approves Gardasil

On June 8, 2006, FDA approved Gardasil, the first vaccine developed by Merck & Co., Inc. to prevent cervical cancer; precancerous genital lesions; and genital warts due to human papillomavirus (HPV) types 6, 11, 16, and 18. The vaccine is approved for use in females 9-26 years of age. HPV types 16 and 18 account for approximately 70 percent of cases of cervical cancer, whereas HPV types 6 and 11 cause approximately 90 percent of genital wart cases. HPV is the most common sexually transmitted infection in the U.S. CDC estimates that about 6.2 million Americans become infected with genital HPV each year and that more than half of all sexually active men and women become infected at some time in their lives. Most infected women will clear the virus and do not develop related health problems. However, some HPV types can cause abnormal cells on the lining of the cervix that can turn into cancer years after infection with the virus. In the U.S., on average, there are 9,710 new cases of cervical cancer and 3,700 deaths attributed to it each year. Worldwide, cervical cancer is the second most common cancer in women and is estimated to cause more than 470,000 new cases and 233,000 deaths each year.

The license application for Gardasil was evaluated and approved in 6 months under FDA's priority review process, which is targeted to products that provide significant health benefits over existing products. Gardasil is a recombinant protein vaccine (genetically engineered) that is given as three injections over a 6-month period. In women who were not already infected with HPV, Gardasil was nearly 100 percent effective in preventing precancerous cervical lesions, precancerous vaginal and vulvar lesions, and genital warts caused by the HPV types against which the vaccine is directed. Immunization with Gardasil also is expected to prevent most cases of cervical cancer due to HPV types targeted by the vaccine. "This is the first vaccine licensed specifically to prevent cervical cancer. Its rapid approval underscores FDA's commitment to help make safe and effective vaccines available as quickly as possible. Not only have vaccines dramatically reduced the toll of diseases in infants and children, like polio and measles, but they are playing an increasing role protecting and improving the lives of adolescents and adults," said Jesse Goodman, M.D., M.P.H., Director of CBER.

FDA Approves Zostavax

On May 25, 2006, FDA approved Zostavax manufactured by Merck & Co., Inc., which is the only vaccine indicated to prevent shingles (herpes zoster) in people 60 years of age and older. Zostavax, a live virus vaccine, boosted immunity against varicella-zoster virus, the same virus that causes chickenpox. The studies showed, overall, in those ages 60 and above, the vaccine reduced the occurrence of shingles by about 50 percent. The vaccine is given as a single injection under the skin, preferably in the upper arm.

After an attack of chickenpox, the varicella-zoster virus lies dormant in certain nerve tissue but can reactivate and appear as shingles years later. Shingles can occur in people of all ages, but most commonly in those greater than 60 years of age. The risk of singles increases as people get older, and shingles is estimated to affect 2 in 10 people in their lifetime. When shingles develops, a rash or blisters appear on the skin, generally on one side of the body. This is a sign the virus, that has been dormant in the nerve cells, has reactivated and traveled from the nerves and followed a path out to the skin. Because the nerves along the path become inflamed, shingles can also be painful. Pain that lasts for months after the rash has healed is called postherpetic neuralgia. For some people, this pain can be severe and chronic. "This vaccine gives health care providers an important tool that can help prevent an illness that affects many older Americans and often results in significant chronic pain," said Jesse L. Goodman, M.D.,
M.P.H.

FDA Approves RotaTeq

On February 3, 2006, FDA announced the approval of RotaTeq manufactured by Merck & Co., Inc. for preventing rotavirus gastroenteritis in infants between the ages of 6 and 32 weeks. RotaTeq is a live-virus vaccine that is given by mouth in three doses. Infection with rotavirus is a leading cause of severe diarrhea in infants and young children in the U.S. and worldwide and may also cause vomiting, fever, and dehydration. CDC has estimated that rotavirus infection results in approximately 55,000 hospitalizations annually of infants and young children in this country. Death from rotavirus is rare in the U.S. However, in developing countries, rotavirus gastroenteritis has been estimated to cause several hundred thousand deaths annually in infants and young children. "This vaccine gives health care providers an important new tool that can effectively prevent an illness that affects almost all children within the first few years of life," said Jesse L. Goodman, M.D., M.P.H.

Overall, approximately 72,000 healthy infants were studied in the United States and other countries in randomized placebo-controlled studies to look at the safety of RotaTeq. Of these infants, almost 7,000 from the U.S. and Finland were also studied for efficacy. In these studies, RotaTeq prevented 74 percent of all rotavirus gastroenteritis cases and 98 percent of the severe cases. In addition, RotaTeq prevented approximately 96 percent of hospitalizations due to rotavirus gastroenteritis.

In 1998, FDA approved a different live vaccine against rotavirus that was later withdrawn from the market because of its association with an increased risk of intussusception, a rare, life-threatening type of blockage or twisting of the intestine. Intussusception occurs spontaneously in approximately 1 in 2,000 healthy young infants and children per year, but occurred at an increased rate during the first week or two following vaccination with the previous rotavirus vaccine.

"Although this large study did not show an increased risk of intussusception associated with RotaTeq, given the experience with the previous vaccine, safety of this vaccine will be closely monitored in additional studies conducted after licensure," said Dr. Goodman. The manufacturer has committed to conducting a post-licensure study of approximately 44,000 children. CDC will also conduct a large study designed to rapidly detect any association of intussusception with RotaTeq through its Vaccine Safety Datalink Program, which evaluates vaccine safety in approximately 80,000 U.S. infants every year. In addition, for the first 3 years of licensure, the manufacturer will report cases of intussusception and all serious and unexpected adverse events to FDA within 15 days of receiving them, and all other side effects on a monthly basis.

FDA Approves Vivaglobin

On January 9, 2006, FDA announced the approval of the first immune globulin product for subcutaneous injection for the prevention of serious infections in patients with primary immune deficiency diseases (PIDDs). Vivaglobin, manufactured by ZLB Behring from human plasma collected at U.S.-licensed plasma centers, provides new delivery options for PIDD patients. It is given under the skin (subcutaneously) on a weekly basis using an infusion pump, allowing patients to self-administer the product at home. Some patients develop problems that make chronic intravenous administration of needed medicines difficult, and Vivaglobin may be helpful in providing them with an alternative route of administration.

PIDDs are genetic disorders that affect an estimated 50,000 people in the U.S. and include X-linked agammaglobulinemia (Bruton's disease), common variable immune deficiency, and severe combined immune deficiency (boy-in-the-bubble disease), among others. Patients with PIDD require regular treatment with immune globulin to fight off or prevent potentially serious or life-threatening infections. Other immune globulin products are administered either into the vein (intravenously) or into the muscle (intramuscularly).

"This is an important approval for patients who need lifesaving immune globulin products," said Jesse Goodman, M.D., M.P.H. "This new product provides a unique new treatment delivery option to patients and their physicians."

FDA Approves New Manufacturer of Cytogam

On August 16, 2006, CBER announced the licensure of a new facility and manufacturer, MedImmune, for production of Cytomegalovirus Immune Globulin Intravenous (Human) (Cytogam). Cytogam is a purified antibody preparation made from the plasma of donors with high antibody levels against cytomegalovirus (CMV). Cytogam is used to prevent severe infections with CMV disease in people with kidney, liver, pancreas, lung, and heart transplants. There is no other anti-CMV product licensed in the U.S. and there is no other similar treatment for transplant patients.

The previous sole manufacturer, Massachusetts Public Health Biologic Laboratories, planned to cease production in August. CBER worked with MedImmune to enable timely licensure of Cytogam manufacture at a new facility to avert a shortage of Cytogam for patients in need. Licensure occurred in a timely fashion, precluding any shortage of this important product.

FDA Approves ADVIA Centaur HIV 1/O/2 Assay

On May 18, 2006, FDA approved the first fully automated, random access system for detection of antibodies to HIV-1 group M/HIV-O and HIV-2 in serum and plasma, based on chemiluminescent reactions. The ADVIA Centaur HIV 1/O/2 Assay, manufactured by Bayer Diagnostics, is expected to increase the capability of high-volume testing for HIV in clinical laboratories and to allow for HIV antibodies to be tested along with other analytes in a random access mode. The test is highly sensitive and specific for the detection of antibodies to not only HIV-1, the most common form of HIV in the U.S., but also to the less common HIV-2 and HIV-1 Group O. As with other test systems, this fully automated test system reduces the risk of operator error. There are numerous features to protect the integrity and security of the test system.

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Improve Product Quality, Safety, And Availability Through Better Manufacturing And Product Oversight

CBER has emphasized the development and implementation of product safety teams to address areas, such as adverse events, product manufacturing and quality issues, and response to emerging threats. The Center has addressed issues related to safety of human tissue transplants, increased demand for immune globulin products and platelets, as well as risks to the blood supply from Transmissible Spongiform Enchephalopathies (TSE) agents.

Ensuring Safety of Recipients of Donor Tissue

On October 25, 2005, FDA notified the public of its investigation of human tissue recovered by Biomedical Tissue Services Ltd. (BTS) and sent to tissue processors. The tissue was recovered by BTS from human donors, who may not have met FDA donor eligibility requirements, and who may not have been properly screened. The tissue processors voluntarily recalled all unused tissue remaining in inventory, and worked cooperatively with FDA to ensure the implanting physicians whose patients may have received the products were properly notified.

On January 31, 2006, FDA issued an Order to Cease Manufacturing and to Retain Human Cells, Tissues, and Cellular- and Tissue-Based Products (HCT/P) to BTS. This was the first Order that FDA has issued under the HCT/P regulations, which went into effect May 25, 2005. The Order was issued after FDA's inspection of BTS uncovered serious violations of the regulations governing donor screening and record-keeping practices.

On March 2, 2006, FDA issued an update strongly recommending that health care providers inform their patients who received tissue implants prepared from BTS donors, that they may be at increased risk of communicable disease transmission and to offer them testing. This update was based on additional information that called into question the reliability of some of the donor samples submitted for communicable disease testing from BTS tissue donors. In some instances, blood samples did not come from the same donor as the linked tissue. Therefore, the results of communicable disease tests obtained from the blood samples may not correctly reflect the status of the donor. FDA's investigation into BTS activities is ongoing. FDA continues to work cooperatively with tissue processors and appropriate federal, state, and local authorities in this matter.

Donor Referral Services

On August 18, 2006, FDA issued an Order to Cease Manufacturing and to Retain HCT/Ps to Donor Referral Services (DRS). The Order was issued after an FDA inspection, and a concurrent investigation revealed the human tissues recovered by DRS may not have met FDA requirements for donor eligibility and was sent to tissue processors. The tissue processors voluntarily recalled all unused tissue remaining in inventory and worked cooperatively with FDA to ensure the implanting physicians whose patients may have received the products were properly notified. FDA continues to investigate DRS activities, working with the appropriate federal and state authorities in this matter.

On August 30, 2006, FDA issued a public health notification informing the health care community that human tissues recovered by DRS may not have met FDA requirements for donor eligibility and there is a potentially increased risk for infectious disease transmission. FDA and CDC strongly recommended that health care providers inform their patients who received tissue initially recovered by DRS that they may have received tissue from donors for whom adequate donor eligibility determinations were not performed and offer patients access to appropriate infectious disease testing.

Immune Globulin Availability and Demand

During FY 2006, FDA and the Centers for Medicaid and Medicare Services (CMS) received reports that health care providers were having difficulty obtaining immune globulin intravenous (IGIV) for some patients. FDA worked cooperatively with DHHS and the Plasma Protein Therapeutics Association (PPTA) to monitor the IGIV supply and facilitate its availability. Although there does not appear to be a severe product shortage, there have been reports of difficulties obtaining the same product in the same treatment center that patients customarily use. FDA, with the DHHS Office of Public Health and Science (OPHS), contacted responsible officials of all IGIV manufacturers to discuss the market situation. As a result, the average IGIV distribution increased by 12 percent in the last 4 months of 2005, compared with the previous 12-month average. Additionally, PPTA listed hotline numbers on its manufacturers' website for physicians to acquire IGIV for emergency use.

At its July 2006, meeting, the Blood Products Advisory Committee (BPAC) discussed the availability of varicella-zoster immune globulin (VZIG) because of the decision of the Massachusetts Public Health Biological Laboratories (MPHBL) to discontinue manufacturing the products. MPHBL was the only licensed U.S. manufacturer of VZIG, which is used to prevent life-threatening varicella-zoster infections in immune-compromised children and adults exposed to chickenpox. FDA sought the Committee's advice on options for efficacy determination for new BLA applications for VZIG because of concerns about a potential upcoming shortage of this product. FDA is working with sponsors and manufacturers, and has allowed an expanded access IND protocol for VZIG from a new manufacturer, to ensure availability under an IND until a new product is licensed. FDA and OPHS will continue to monitor IGIV availability and work with manufacturers, distributors, and others in the product distribution chain toward increasing availability.

TSE Safety for Biological Products*

Blood Donor Deferral for Transfusion in France

Since 2002, FDA has recommended the deferral of blood donors who resided in the United Kingdom (U.K.) for more than 3 months and elsewhere in Europe for more than 6 months because of a potential dietary exposure to vCJD, as a precautionary measure to prevent its possible transmission through blood. Although 90 percent of vCJD cases have occurred in the U.K., FDA has periodically reviewed and updated its recommendations on donor deferral. At the TSE Advisory Committee (TSEAC) meeting in February 2005, FDA shared with the committee a concern about the growing number of vCJD cases recognized in France. FDA requested advice on whether to recommend deferral of blood donors with a history of blood transfusion in France. A majority of TSEAC members recommended that FDA defer donors transfused in France.

Accumulating evidence suggests the time from exposure to vCJD to the onset of symptoms of vCJD develop may be very long, sometimes exceeding 12 years. The risk of dietary exposure to the bovine spongiform encephalopathy (BSE) agent in France, as in the U.K. and other European countries, has almost certainly decreased in recent years due to efforts to control the BSE epidemic in cattle and to protect food from contamination with the BSE agent. However, an unknown but possibly significant number of potential U.S. blood donors might have already been infected due to residence in France during the peak years of the BSE outbreak in Europe. There have been three reports in the U.K. of probable transmission of vCJD through transfusion of blood cells, including a case of blood collected 3 years before the blood donor showed any sign of illness.

These considerations led FDA to conclude it would be a prudent preventive measure to indefinitely defer whole blood and source plasma donors who have received a transfusion of blood or blood components in France since 1980. For source plasma donors, however, FDA concluded an exception can be made if blood components are collected solely for manufacturing into noninjectable products (e.g., materials used in the in vitro diagnostic test kits). To address this deferral, the draft guidance entitled, "Amendment (Donor Deferral for Transfusion in France Since 1980) to Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products," was published on August 8, 2006. FDA will continue to monitor the BSE epidemic and re-evaluate the necessity of deferring donors transfused in other European countries. CBER continues to evaluate technologies for clearance of infectious agents, including TSEs, from biological products.

TSE Research and Risk Estimation

FDA has continued to work with manufacturers to determine the role of plasma fractionation in reducing TSE risk. Laboratory studies using model TSE agents have demonstrated TSE infectivity may be reduced by certain plasma fractionation manufacturing steps. Although experimental studies are reassuring, not all products have been thoroughly studied. In addition, it remains uncertain if the models accurately reflect the form of infectivity in blood, which has not been characterized. FDA evaluates submissions containing experimental data on TSE clearance for specific products. Based on such data, FDA has approved labeling for several products. In September 2006, CBER asked TSEAC for advice on whether standardized methods and assessment criteria are feasible and appropriate for determining removal of TSE in the manufacturing processes for certain products made from human plasma. At the same meeting, CBER asked TSEAC for advice on potential approaches and issues to consider when validating candidate screening tests for vCJD and other TSE infections in donors of blood, plasma and human cells, tissues, and cellular- and tissue-based products.

FDA attempts to improve the definition of possible risk to the blood supply posed by vCJD and design approaches to reduce that risk. FDA also conducts collaborative research projects to investigate the role of various abnormal forms of the prion protein in TSEs, to explore the potential for accidental contamination with TSE agents of various cell lines used to manufacture biologic products, and to identify methods for reducing the risk of contamination and cross-contamination with TSE agents.

At the TSEAC meeting in February and October 2005, FDA asked the Committee for advice on a computer-assisted probabilistic model for estimating the potential risk of vCJD to recipients of U.S. licensed human plasma-derived coagulation factor VIII products. CBER has taken the advice of TSEAC to refine the model further, and the results of the study will be presented at a future TSEAC meeting and made publicly available.

*See Appendix A Reference 52

Workshop on Testing for Malarial Infections in Blood Donors

On July 12, 2006, CBER organized a workshop to discuss the scientific developments that might support donor testing for malarial infections as a part of predonation screening, or, alternatively, follow-up testing of deferred at-malaria-risk donors to permit a reduced deferral period. Currently, in the U.S., no laboratory test is approved to screen donors for malarial infections and at-malaria-risk donors are identified by donor questionnaires. Although donor deferral polices have been effective in reducing the incidence of transfusion-transmitted malaria (TTM) (16 cases of TTM in the last 15 years), this approach has led to the loss of more than 120,000 otherwise suitable blood donors each year. The outcome of the discussion at the workshop revealed the problems associated with malaria test sampling and sensitivity issues, and concluded nucleic acid-based tests are not ready for use in screening of blood donors for malaria parasite infections. However, several European countries, Australia, and New Zealand now test deferred at-malaria-risk donors, which shortens the deferral period for some donors without malarial antibodies. The antibody based test, used in those countries, detects antibodies to only 2 of 4 human Plasmodium species (Plasmodium falciparum and Plasmodium vivax), allowing the earlier re-entry of 97% of the otherwise deferred donors. Workshop participants discussed the merits of such antibody-based tests and possible algorithms of implementation in the U.S. blood-banking industry. FDA is currently discussing malaria antibody test development and donor testing algorithms with various stakeholders, including the blood-banking industry.

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Transform Administrative Systems And Infrastructure To Support FDA Operations