Table of Contents
Message from the Director
CBER Vision and Mission
Tissue Safety Team
Blood Safety Team
Vaccine Safety Team
Office of Vaccines Research and Review
Office of Cellular, Tissue and Gene Therapies
Office of Blood Research and Review
Office of Biostatistics and Epidemiology
Office of Compliance and Biologics Quality
Office of Communication, Outreach, and Development
Guidances of Note
White Oak Planning
Critical Path Research
I am pleased to issue this annual report of the Center for Biologics Evaluation and Research (CBER) for fiscal year 2010, which presents the center’s many significant accomplishments that supported our mission to protect and improve health in the United States and globally.
Some important efforts that are detailed in the report include a continued and sustained response to the H1N1 influenza pandemic as well as preparedness steps for potential future pandemics, intensive efforts to facilitate the development of medical countermeasures to combat bioterrorism and emerging infectious diseases, an increasingly robust international program rooted in international collaboration, and the successful initial implementation of a quality systems approach to CBER laboratories. And, of course, CBER continued to perform its day-in, day-out workload of product reviews, risk assessments, compliance activities, and much more that assures the availability of safe and effective biological products to the American public.
In addition, CBER’s work over FY 2010 supported over-arching priorities of the Food and Drug Administration (FDA), including efforts to advance regulatory science and research, with particular focus on facilitating the development of new biological products.
FY 2010 was an extremely productive year that reflected the continuing dedication of our outstanding staff to our mission. I would like to take this opportunity to acknowledge and thank our talented and committed staff at CBER, whose efforts made possible the many achievements noted in this report.
Karen Midthun, MD
Center for Biologics Evaluation and Research
Food and Drug Administration
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 and, where feasible, globally
- Facilitate the development, approval of, and access to safe and effective products and promising new technologies including those enabling personalized medicine
- Strengthen CBER as a preeminent regulatory organization for biological products
The mission of CBER is to ensure the safety, purity, potency, and effectiveness of biological products including vaccines, blood and blood products, and cells, tissues, and gene therapies for the prevention, diagnosis, and treatment of human diseases, conditions, or injury. Through our mission, we also help to defend the public against the threats of emerging infectious diseases and bioterrorism.
In fulfilling our mission as a Center in the US Food and Drug Administration, we apply the highest ethical standards and integrity to:
- 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
The International Program at CBER works proactively with other centers in the agency and the Office of the Commissioner to anticipate and respond to emerging global regulatory and public health issues. Its inter-office activities represent the center’s efforts to improve public health both nationally and globally.
The International Program achieves its strategic goals through several strategies:
Harmonization of international standards and technical requirements for product development and approval can facilitate streamlined global product development and more timely introduction of new medical products. Among the major harmonization efforts of CBER, together with other Agency components, are:
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
- Global Harmonisation Task Force
- Asia-Pacific Economic Cooperation Life Sciences Innovation Forum Regulatory Harmonization Steering Committee
Sharing scientific and regulatory information with foreign counterparts broadens and deepens our knowledge of products, enhances our insights into global regulatory aspects of products, helps to coordinate a rigorous approach to emergency event planning and response, enhances our ability to detect adverse event signals and enables and supports best regulatory practices. The European Medicines Agency is one of FDA’s key regulatory partners with whom we exchange information ranging from specific product submissions to scientific advice and policy development. In FY 2010, CBER and EMA launched the new area of focus for information exchange devoted to blood products.
International Standards Development
Written and physical standards are fundamental to regulatory control of biologic products. In FY 2010, CBER continued its significant support for international standards. A cornerstone of this work is the center’s role as a Pan American Health Organization/World Health Organization Collaborating Center for Biological Standardization.
Global Regulatory Capacity Building
CBER includes regulatory capacity building in its international program because the center recognizes that protection of US public health is inextricably linked to that of global public health. For example, the center’s portfolio of regulated products includes vaccines to protect against infectious diseases. The development of these products has global relevance, and clinical trials for vaccines are undertaken in areas where the disease is endemic, often in developing countries.
CBER conducted its second Foreign Regulators Seminar October 5-8, 2009 in Rockville, Maryland with 24 foreign regulatory participants from 13 different countries. The CBER seminar allows CBER staff to provide information about the US biologics regulatory processes in an efficient, organized, and integrated way. CBER experts explain the regulatory role of CBER, as well as the science, technology, regulations, and processes the center uses. The seminar provides the opportunity for foreign regulatory counterparts to hear from a broad array of CBER experts, and for CBER staff and their foreign counterparts to meet and discuss topics of mutual interest.
CBER actively engages with the WHO Developing Country Vaccine Regulator Network (DCVRN), a network of national regulatory authorities (NRAs) from Brazil, China, Cuba, South Korea, India, Indonesia, the Russian Federation, South Africa, and Thailand. The DCVRN builds regulatory capacity among vaccine-producing developing countries through information-sharing, training, and organizing activities. DCVRN country representatives meet approximately on a biannual basis to get timely information from independent experts and developers on issues relating to vaccine trials occurring in developing countries. They also devise institutional plans and other activities with the aim of strengthening the regulatory capacity of developing country NRAs.
In addition, CBER helps the WHO-coordinated African Vaccine Regulatory Forum (AVAREF) define the oversight roles of the NRAs of its member nations. These roles include regulating clinical trials of vaccines, interacting with national and local IRBs and ethical committees, and strengthening NRA capacity to regulate new medical products.
In this capacity, FDA and other experienced NRAs, such as the EMA, participate as expert advisers to share the regulatory mechanisms for evaluating the safety and efficacy of investigative products. The Forum includes representatives from seventeen African nations including Botswana, Burkina Faso, Cameroun, Ethiopia, Gabon, Gambia, Ghana, Kenya, Malawi, Mali, Mozambique, Nigeria, Rwanda, Senegal, Tanzania, Uganda, and Zimbabwe, as well as expert advisers from the US FDA, EMA, and Health Canada.
An important part of regulatory capacity building is assessing an organization’s ability to identify gaps and needs, as well as to set benchmarks. While WHO has employed an assessment tool (criteria for judging the competency of an NRA) for some time in its vaccine prequalification process, there is growing attention to the concept of good regulatory practice and the use of associated assessment tools. CBER has been active in the area of regulatory assessment in a variety of forums and has served on a number of WHO assessment teams.
A Global Collaboration: The MenAfriVac Meningitis Vaccine
A new meningococcal A conjugate vaccine, MenAfriVac, was developed by the Meningitis Vaccine Project (MVP), a partnership between WHO and PATH funded by the Bill and Melinda Gates Foundation, and is manufactured by Serum Institute of India, Ltd. In December 2010, this affordable vaccine was introduced in mass immunization campaigns in several countries in the “meningitis belt” of Africa, and the hope is that wide-spread use of this vaccine in sub-Saharan Africa will prevent epidemics caused by this deadly organism, meningococcus group A. Scientists at CBER made an important contribution to the development of this vaccine by providing the conjugation technology used to manufacture the vaccine.
The story of the MVP and the role CBER and many others played in developing this vaccine is a dramatic example of how international collaborations can make significant contributions to global public health.
Facilitating the Development of Medical Countermeasures to Combat Bioterrorism and Emerging Infectious Diseases
The possible threat of terrorist attacks in the United States using biological, chemical or radiological/nuclear agents, and the emergence of new infectious diseases, have prompted government and health officials to promote and support research and development of prophylactic and therapeutic drugs and biological products to diagnose, prevent, treat, or mitigate medical problems caused by either threat.
CBER has responded to the need for timely, science-based regulatory oversight of such new biological products by establishing close working relationships with academic and other federal institutions, as well as industry. These relationships are designed to facilitate the development of safe and effective biological products for diagnosing, preventing, and treating illness as a result of terrorism with biological, chemical or radiological/nuclear (CBRN) agents or emerging infectious diseases. These products include vaccines, blood and blood derivatives, gene therapies, and cells and tissues for transplantation.
The development of these products can be extremely challenging: the only way to demonstrate efficacy of some of the products might be by testing in animal models. To facilitate this process, FDA published in 2009 the draft guidance “Animal Models – Essential Elements to Address Efficacy Under the Animal Rule.” In November 2010, FDA’s Center for Drugs Evaluation and Research (CDER) and CBER held a public meeting to obtain stakeholder input on the draft guidance and re-opened the docket for comments; these comments are currently under review.
Anthrax Vaccine and other Immune-Based Therapies
In the absence of known exposure, vaccination is the only effective means of preventing anthrax disease. There is currently one anthrax vaccine, BioThrax, manufactured by Emergent BioSolutions, licensed for pre-exposure prophylaxis in the United States.
However, efforts are underway to pursue licensure of an anthrax vaccine, to be used in conjunction with approved antibiotics, for post-exposure prophylaxis in the event of an aerosol attack with Bacillus anthracis.
At the November 2010 meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC), CBER presented a strategy for demonstrating the efficacy for post-exposure prophylaxis of certain anthrax vaccines under the Animal Rule. The advisory committee concurred with the proposed strategy (http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/
CBER is also facilitating the development of immune-based therapies for treating anthrax disease, such as anthrax immune globulin
Smallpox, caused by the variola virus, is highly contagious and can be spread by close contact with infected individuals. Smallpox can be prevented through vaccination. There is one licensed smallpox vaccine (ACAM2000) based on vaccinia virus for people at high risk of exposure to smallpox. CBER is facilitating efforts to develop and make available in an emergency an additional smallpox vaccine for certain populations.
CBER continued to work with its federal partners, through the Public Health Emergency Medical Countermeasure Enterprise (PHEMCE)and industry on a broad array of projects aimed at making our nation better prepared for CBRN threats and emerging infectious diseases through the development of new countermeasures.
CBER has been a full and active participant in FDA’s Medical Countermeasure Initiative. This work includes establishing a Public Health and Security Action Team for our biological medical countermeasures (MCMs), engaging in numerous research projects to identify gaps and further our understanding in the area of regulatory science, and participating in meetings to evaluate the legal, regulatory and policy implications on the development and approval of MCMs.
In FY 2010 CBER continued to use its scientific expertise to facilitate the development of safe and effective products for bioterrorism defense preparedness, as part of an interagency agreement with the National Institute of Allergy and Infectious Diseases. Notable among these accomplishments were the following developments:
- Improved understanding of assays that will enable scientists to better evaluate and compare the ability of animal or human antibodies to neutralize anthrax toxin.
- New methods to measure antigenicity of botulinum vaccine antigens and to produce new botulinum toxoids (weakened bacterial toxins) that are significantly more effective in eliciting anti-botulinum protective antibodies.
- Improved animal models for testing smallpox and anthrax vaccines.
(For more details on the counterterrorism activity at CBER see: http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ProductSecurity/ucm110322.htm)
CBER monitors postmarketing product safety in a number of ways, including through the evaluation of reports of potential adverse effects (i.e., safety signals) submitted by healthcare workers, manufacturers, and the public.
CBER responds to product safety issues through one its three multidisciplinary review teams, depending on whether the biological product is a blood, tissue, or vaccine product. Each Safety Team includes product scientists, clinicians, epidemiologists, and manufacturing and communications experts who share, analyze, communicate, and respond to safety issues. These specialized Safety Teams coordinate investigations with other agencies and regulatory partners, formulate appropriate responses, and communicate with stakeholders.
Safety teams meet regularly and during emergencies; they also help develop and guide strategic and scientific approaches to enhance safety, collaborating closely with other FDA components and other agencies, particularly CDC.
Human cells and tissues present unique safety challenges, especially the risk of transmitting infectious diseases from donor to recipient, and the risk of contamination during processing. In FY2010, the Tissue Safety Team (TST) received an average of eight reports per month of infectious disease in tissue recipients; most reports were from cell and tissue manufacturers. Reports of infectious disease in tissue recipients do not necessarily represent confirmed cases of disease transmission by the tissue; some cases represent common post-surgical infections or exposure to other sources of infection.
After reviewing the reports to determine if there was a relationship between the tissues and the reported infections, the TST did not identify any significant public health threats requiring regulatory action.
The TST had noted an increase in reports of fungal infections after cornea transplant procedures in 2008 and 2009 compared to the previous three years. A TST member reviewed these cases to identify any association with donor, recipient, and manufacturing factors, particularly an association with pre-cutting of the cornea for endothelial keratoplasty. This review was completed in FY 2010. Due to the small number of cases and incomplete information about the hypothesized risk factors, it was not possible to find a clear association with specific donor or recipient factors. The TST continues to monitor reports of post-transplant cornea infections and is pursuing efforts to improve recognition and reporting of these events.
Safety alert on fibrin-sealant spray device
FDA received reports of air or gas embolisms occurring during or immediately after application of fibrin sealants using air- or-gas pressurized sprayers. These adverse events appeared to be related to the use of spray devices inconsistent with the approved product labeling and instructions for use. In response, the team worked with the manufacturers to revise the Warnings and Precautions section of the labeling for fibrin sealant products to emphasize the recommended spraying pressure and appropriate distance between the sprayer and the target tissue (November 2009). BST also helped to coordinate an FDA Safety Alert on July 9, 2010, regarding use of fibrin sealant spray devices.
Blood Safety Team (BST) monitors MAUDE
Since the Office of Blood Research and Review (OBRR) oversees most blood-related devices, the BST took the lead in FY 2010 to manage OBRR device-related safety issues. OBRR staff will establish a more standardized reporting system and identify possible adverse events for inclusion in the FDA Manufacturer and User Device Experience (MAUDE) database (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm).
In FY 2010, the VST played an important role as a forum for discussing and enhancing cross-center communication regarding various vaccine safety topics. Throughout the year, VST kept key CBER staff informed of important ongoing public health activities throughout the center, communication efforts, and safety surveillance initiatives. This included a cross-office, center-wide case seminar on the center’s response to pandemic H1N1 influenza. These discussions contributed to decisions made by CBER in response to potential vaccine safety issues.
In FY 2010, the VST informed and contributed to CBER decisions on:
- safety surveillance of individuals who received pandemic H1N1 influenza vaccine;
- adverse events (including febrile seizures) associated with pediatric influenza vaccines;
- finding of porcine circovirus (PCV) in rotavirus vaccines;
- development of strategies to enhance testing for novel adventitious agents that could theoretically contaminate vaccines;
- strategies for communicating information on the safety of vaccines;
- review of Biological Deviation Reports and assessment of impact on vaccine safety.
The mission of the Office of Vaccines Research and Review (OVRR) is to protect and enhance public health by ensuring the availability of safe and effective vaccines, allergenic extracts, and related products.
Major Leadership Activity of FY 2010
In March, FDA provided a public communication regarding Rotarix, (GlaxoSmithKline Biologicals), concerning the presence of DNA from porcine circovirus type 1 (PCV1), a virus not known to cause disease in people. Rotarix is a vaccine for infants to prevent rotavirus disease, which can cause severe diarrhea and dehydration. As part of this communication, FDA recommended that health care providers in the United States temporarily suspend the use of Rotarix while the agency investigated the finding of PCV1 in the vaccine.
OVRR immediately began a thorough scientific evaluation and assessment of risk to infants. This included studies of the vaccine in OVRR laboratories, a review of scientific literature, and consultation with external experts. Following the announcement pertaining to Rotarix, FDA learned that studies conducted by Merck & Co, Inc. on RotaTeq, another rotavirus vaccine, indicated the presence of fragments of DNA from PCV1 and a related porcine circovirus type 2 (PCV2); FDA informed the public of this finding.
In May, FDA’s Vaccines and Related Biological Products Advisory Committee convened to discuss the complex scientific findings of PCV and PCV DNA in rotavirus vaccines and provide recommendations to FDA. Based on a careful evaluation of information and data, a thorough review of the scientific literature, and input from scientific and public health experts, on May 14, 2010, FDA revised its recommendation to suspend the use of the Rotarix vaccine. The agency informed clinicians and health care professionals to resume the use of Rotarix and to continue the use of RotaTeq. FDA made this recommendation based on the demonstrated benefit of the vaccines, which outweighs the theoretical risk of PCV.
Details of the FDA and OVRR response to this issue can be found at the following Web site: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm205539.htm
Scientific Working Group on Cell Substrates and Adventitious Agents
With guidance from OVRR, CBER established a center-wide Cell Substrate and Adventitious Agent Working Group that will be responsible for ensuring that the best science is applied appropriately to assess cell substrates, improve characterization, and make recommendations for integrating novel technologies, such as molecular, genomic, and proteomic, into CBER policy and regulatory decisions and actions.
Cervarix (GlaxosmithKline; October 16, 2009)
Agriflu ( Novartis Vaccines and Diagnostics, Inc.; November 27, 2009)
Menveo (Novartis Vaccines and Diagnostics, Inc.; February 19, 2010)
Prevnar 13 ( Wyeth Pharmaceuticals, Incorporated; February 24, 2010)
Seasonal Influenza vaccines, 2010-2011 - Six manufacturers; eight influenza vaccines for the prevention of influenza in children, adolescents, and adults, including the elderly. (July 2010)
Key Regulatory Science Accomplishments
Alternative Method for Preparation of Pandemic Influenza Strain-Specific Antibody for Vaccine Potency Determination
Developing reagents to assess influenza vaccine potency is a key step for production of seasonal and pandemic influenza vaccines. The traditional assay used to measure potency of inactivated influenza vaccines is a single-radial immunodiffusion (SRID) assay that uses an influenza strain-specific antibody to measure the content of virus hemagglutinin (HA) in the vaccine in comparison to a homologous HA reference antigen.
Since timely preparation of potency reagents by regulatory authorities is a key step for influenza vaccine production, it is extremely important that additional approaches to reagent development be available, particularly in the event of an emerging pandemic influenza virus. OVRR developed an alternative method for preparing strain-specific antibody that did not require the presence or purification of influenza virus, and was not limited by the success of the traditional technique of bromelain digestion and purification of virus HA. The results demonstrate a feasible approach for addressing one of the challenges in producing inactivated pandemic influenza vaccines--the timely production of one of the critical potency-testing reagents. This is especially important in the case of an influenza virus that emerges suddenly and starts to spread very rapidly, as the pandemic (H1N1) 2009 influenza virus did, thus necessitating the rapid production of a vaccine . The new strategy could also be applied to seasonal influenza vaccines. Because the composition of these vaccines is evaluated annually and changed as necessary to protect against circulating influenza viruses, new potency reagents must also be generated to test these vaccines.
Development of a Non-Human Primate Model for Pertussis
Pertussis is a highly contagious, acute respiratory illness that can be fatal, especially in the vulnerable infant population. Despite near universal vaccine coverage, the incidence of pertussis in the United States has increased over the last twenty years. No correlate of protection has been established for pertussis vaccines, which represents a significant hurdle to the development and licensure of improved pertussis vaccines. Until now, progress to better understand the disease and the protective immune response has been hampered by the lack of relevant animal models. OVRR developed a non-human primate model for pertussis. This model should aid in the development of correlates of immunity for pertussis vaccines, increase our understanding of disease transmission, and provide a mechanism for generating proof-of-concept and pre-clinical data required for the development and licensure of new pertussis vaccines and effective pertussis therapeutics.
A Pseudotype Neutralization Assay for Pandemic 2009 H1N1
Influenza A viruses mutate rapidly, often requiring annual changes to the composition of influenza vaccines. Therefore there is a need to rapidly assess antigenic properties of newly emerging influenza viruses. Traditional methods of assessing antigenic relatedness rely on the use of live influenza viruses, which require using high-level biocontainment facilities to evaluate highly pathogenic and potential pandemic strains. To overcome this limitation, OVRR researchers developed a rapid, non-infectious, high-throughput assay to evaluate antigenicity and neutralization of pandemic 2009 H1N1. Without the need to work with live virus, OVRR used a synthetic 2009 H1N1 hemagglutinin gene to quickly generate pseudoviruses bearing hemagglutinin on their surface. Neutralization of these pseudoviruses was sensitive and specific.
The researchers further identified an adaptive mutation in the hemagglutinin that greatly enhances its function, mostly likely by improving use of sialic acid receptors on target cells. In addition, the easy genetic manipulation of pseudoviruses compared to live viruses allowed them to discover a new neutralization determinant (target of immune response) in the stem of the hemagglutinin molecule that controls cross-neutralization between the 2009 H1N1 and a recent seasonal H1N1 influenza strain that was used in influenza vaccines during the 2000/01 to 2006/07 influenza seasons. This finding suggests that immune responses to past seasonal influenza vaccines or infections may have contributed to protection against the 2009 H1N1 pandemic.
- Participation with the World Health Organization (WHO) in Geneva, Switzerland to assess improving world-wide the influenza strain selection process, the first step in influenza vaccine manufacturing. This meeting included international public health agencies and NRA’s. (June 2010)
- In 2010 OVRR and the Division of Product Quality (Office of Compliance and Biologics Quality) began collaborating with FDA’s Center for Food Safety and Applied Nutrition, Centers for Disease Control and Prevention, and the National Institute for Biological Standards and Control (UK) to work toward modernization of influenza reference antigen standard calibration. This entails evaluating a new Mass Spectrometry (MS) method for calibrating the antigen content of influenza potency reagents. Work is underway to compare results from the more rapid MS method to the traditional approach used for reagent calibration, a process that typically takes 3-4 weeks. This collaborative effort was described at a recent Health Canada/WHO/CBER workshop in Ottawa, Canada; the consensus of the workshop participants was that the results of this collaborative study would be evaluated and used to design any further experiments necessary for implementation of the new method.
- A 3-day w orkshop, jointly organized by Health Canada, CBER, and the WHO, was held in Ottawa, Canada in July 2010 to evaluate lessons learned from potency testing of pandemic (H1N1) 2009 influenza vaccines and considerations for future potency tests. The 2009 H1N1 influenza pandemic brought unprecedented attention to the methods and processes used in the release and licensures of pandemic influenza vaccines. In the context of a public health emergency, the suitability of existing potency assays had been questioned, and alternative approaches were used in some cases to supplement existing techniques.
The specific goals of the workshop were to:
- exchange knowledge and experience gained in vaccine release and immunization around the world throughout the 2009 influenza pandemic;
- formulate plans to address gaps in our knowledge of the use of alternative approaches to assess potency of influenza vaccines;
- identify possible ways to incorporate such assays into influenza vaccine regulation.
As a first step in the outcomes, a recommendation was made for improvements to the SRID assay, which is the standard to measure potency of inactivated influenza vaccines. In parallel, alternative methods should continue to be evaluated for potential future application.
In FY 2010 OVRR released OVRR issued two guidances for industry (one updated and one draft). For details see the “Guidances” section of this report.
Advisory Committee Meetings
OVRR convened the Vaccines and Related Biological Products Advisory Committee (VRBPAC) five times to obtain input on various topics such as two new vaccines (Prevnar 13 and FluBlok), the unexpected finding of DNA originating from porcine circovirus in rotavirus vaccines, the selection of strains for the influenza virus vaccine for the 2010-2011 influenza season, and the proposed licensure pathway using the animal rule for anthrax vaccines indicated for post-exposure prophylaxis.
For more information see OVRR Advisory Committee Meetings at
The mission of the Office of Cellular, Tissue and Gene Therapies (OCTGT) is to facilitate the development and approval of, and access to, safe and effective cellular and gene therapies, tumor vaccines and immunotherapies, tissue and tissue-based products, xenotransplantation products, combination products, and devices used with cells and tissues.
Major regulatory activities
- Provenge approval (April 2010)
OCTGT approved Provenge (Dendreon, Seattle, WA), an autologous cellular immunotherapy for certain men with advanced prostate cancer. Provenge is indicated for the treatment of asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment. Each dose is made by removing immune cells from the patient’s blood, treating them so they will respond to the prostate cancer cells, and then administering those activated immune cells intravenously to the patient.
Order to Cease Manufacturing of HCT/Ps to Newborn Blood Banking, Inc. (Feb. 23, 2010)
An FDA investigation of Newborn Blood Banking (Land O’ Lakes, FL) uncovered deviations from requirements regarding donor eligibility screening and testing, processing controls, environmental control and monitoring, equipment and facilities, supplies and reagents, process validation, labeling controls, and receipt of products. The consequent lack of adequate protections in place against the risks of communicable disease transmission from use of the product prompted FDA to issue an Order to Cease Manufacturing of HCT/Ps to Newborn Blood Banking. OCTGT staff evaluated the extent of the hazard to public health, advised on appropriate measures to mitigate the risk, and assisted with preparation of external communications and public notification materials.
For more information see the Office of Compliance and Biologics Quality section.
- Staff from the Division of Human Tissues (DHT) c ontributed to the review and licensure of the following infectious disease tests:
- Abbott Prism Chagas Trypanosoma cruzi (E. coli, Recombinant) Antigen (Abbott)
- Abbott ARCHITECT HIV Ag/Ab Combo (Abbott)
(For more information see “Office of Compliance and Biologics Quality” section of this report.)
IND and Related Review Workload
OCTGT staff reviewed numerous regulatory submissions throughout the year. Many of these submissions involved precedent-setting policy decisions. Staff continue to be actively involved in product review of Phase 3 clinical studies, end- of-Phase 2, Fast-track designations, and Special Protocol Assessments.
In FY 2010, the regulatory review effort continued to increase: the total number of active files was 1399, including 144 new IND, IDE, and Master File applications. (Master Files provide confidential, detailed information about facilities, processes, components, raw materials, and other proprietary data.) In addition, DCGT received 4530 amendments to existing applications.
- FDA-NCI Workshop on Therapeutic Cancer Vaccines: Considerations for Early Phase Clinical Trials Based on Lessons Learned from Phase 3 (Oct. 27, 2009)
OCTGT spearheaded the organization of an FDA-National Cancer Institute public workshop to facilitate development of safe and effective cancer vaccines by optimizing early-phase clinical trials based on lessons learned from completed Phase 3 studies. Participants discussed the role of randomized Phase 2 clinical trials and adaptive study designs. The workshop also emphasized the importance of monitoring immune responses in early phase trials in order to optimize immunological therapies. In addition, participants discussed the incorporation of pretreatment biomarkers in early phase clinical studies that could predict the effect of specific treatments in order to identify a population likely to benefit (predictive biomarkers).
Next Generation Beta Cell Transplantation (Nov. 9, 2009)
This workshop on the use of porcine islet cells and differentiated human stem cells to treat Type 1 diabetes was designed to coordinate product development efforts and provide advice on product development. Participants from CBER discussed regulatory considerations for manufacturing and testing beta cells, pre-clinical considerations for islet transplantation, transplantation using porcine islets, and planning and designing clinical trials for these products. A collaborative effort between two government agencies (FDA, NIH) and one non-government funding agency (Juvenile Diabetes Research Foundation), the workshop was an open meeting that included both experienced clinical researchers and potential new diabetes researchers.
Cord Blood Licensure: A Workshop (March 8, 2010)
FDA, CBER, and AABB hosted the workshop for manufacturers and physicians working with minimally manipulated allogeneic, unrelated cord blood. Participants learned about licensure requirements for the BLA process and the IND process for un-licensed allogenic hematopoietic progenitor cells from cord blood for specified indications.
Emerging Arboviruses: Evaluating the Threat to Transfusion and Transplantation Safety (Dec. 14-15, 2009)
Emerging Infectious Diseases: Evaluation to Implementation for Transfusion and Transplantation Safety Public Workshop (May 11-12, 2010)
For more information on the above emerging infectious diseases workshops see “Office of Blood Research and Review” section of this report.
- American Society of Gene and Cell Therapy, Clinical Trials Training in conjunction with ASGT Annual Meeting (May 17-18)
This course, taught by OCTGT, offered training to both sponsors and investigators in the gene therapy field in clinical trial design methodology and applicable IND and licensure regulations.
- Collaboration with other agencies of the Blood, Organ and Tissue Safety group
OBRR and OCTGT collaborated with researchers and staffs at the National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), Health Resources and Services Administrations (HRSA), Centers for Medicare and Medicaid Services (CMS), and the Department’s Office of the Assistant Secretary (OASH) to address blood, organ and tissue safety. A product of this collaboration was the white paper “ Biovigilance in the United States : Efforts to Bridge a Critical Gap in Patient Safety and Donor Health” issued October 2009:
- Liaison and outreach activities with tissue stakeholder groups
- OCTGT staff participated in national and international meetings and conferences as invited speakers, moderators, or planning committee members to share information about agency regulations and policies and communicate directly with a variety of stakeholders
Guidances and rules
In FY 2010, OCTGT issued two guidances (one in draft form) for industry. For details see the “Guidances” section of this report.
Advisory committee meetings
- Blood donation deferral of men who have sex with other men
HHS Advisory Committee on Blood Safety and Availability (ACBSA) meeting ( Rockville, MD; June 10-11, 2010)
(See “Advisory committee meetings” in Office of Blood Research and Review section.
- HHS Advisory Committee on Blood Safety and Availability (ACSBA) ( Rockville, MD; Nov. 19-20, 2009)
(See “Advisory committee meetings” in Office of Blood Research and Review section.)
- Pediatric Advisory Committee (Donor and banked human milk) ( Bethesda, MD; December 6, 2010)
The Office of Pediatric Therapeutics, OCTGT, and CFSAN, planned this inter-center group meeting, where they discussed human milk banking. The committee met to obtain and discuss information and data that would help FDA better understand current practices and potential benefits and risks associated with the donation and banking of human milk.
For more information see:
- Cellular, Tissue, and Gene Therapy (CTGT) Advisory Committee discussed azficel-T BLA (Oct. 2009)
For more information see:
- CTGT Advisory Committee (Testing of Replication Competent Retrovirus (RCR)/Lentivirus (RCL) in Retroviral and Lentiviral Vector Based Gene Therapy Products ( Gaithersburg, MD; Nov. 19, 2010)
CTGT discussed FDA recommendation for testing of replication competent retrovirus (RCR)/lentivirus in retroviral and lentiviral-vector-based gene therapy products, including background issues and recommendations for testing and patient monitoring.
The goal of the Office of Blood Research and Review (OBRR) is to protect both blood donors and recipients by ensuring the safety, efficacy, and availability of blood and blood products. OBRR fulfills this goal by regulating blood and blood components, plasma derivatives, blood donor screening tests, and other medical devices associated with blood and blood component collection, manufacture and distribution. OBRR scientists and staff also collaborate with numerous federal agency and industrial partners in the United States and internationally to maintaining a safe and adequate blood supply in the United States.
Major Accomplishments in FY 2010
The announcement in October 2009 of a possible association between chronic fatigue syndrome (CFS) and a retrovirus known as (XMRV) was a challenging emerging issue in FY 2010.
A study published in 2009 reported that XMRV was present in the blood of at least some persons with chronic fatigue syndrome CFS. This suggested that theoretically XMRV might be transmitted through blood and/or other bodily fluids. However, the results of subsequent studies have not definitively confirmed how XMRV is transmitted and its correlation, if any, with CFS or other disease states.
XMVR/ CDC OBRR devoted significant resources in FY 2010 to studying XMRV and the possibility of blood and/or blood product transmission. OBRR has been at the forefront of the federal government’s response to XMRV, working with the National Institutes of Health’s Blood XMRV Scientific Research Working Group, academic researchers, and blood establishments to determine whether XMRV is present in US blood donors and whether the virus is transmitted by transfusion. (See also “Advisory Committee Meetings,” below.)
In FY 2010, OBRR continued to work on important mission-related research and regulation of emerging infectious disease. For example, when there was a reported outbreak of dengue in Key West, Florida, and Puerto Rico, OBRR worked with blood establishments to prevent transmission of dengue fever through blood transfusion in at-risk areas. For instance, certain blood establishments in Puerto Rico, where dengue is endemic implemented additional donor screening measures. In addition, FDA and others are researching tests that could be used to detect dengue in blood.
Also in the area of emerging infectious disease, OBRR investigated evidence of a variant Creutzfeldt-Jakob Disease (vCJD) infection reported in a hemophiliac patient who had received plasma-derived Factor VIII, a blood-clotting protein, which was manufactured in the United Kingdom. FDA also revised and updated the guidance document for industry that recommended blood donor deferral for donors who have resided in France since 1980. FDA also revised labeling for transfusable blood components to reflect that vCJD as well as classic CJD could theoretically be transmitted through blood and blood products.
In addition, OBRR conducted research on the West Nile Virus which resulted in the issuance of a guidance document for blood establishments on using nucleic acid tests to screen blood donors for West Nile Virus.
Other major infectious diseases that OBRR studied in 2010 include malaria and hepatitis as well as other topics relevant to the safety of blood including pathogen reduction technology.
OBRR sponsored or participated in several public workshops on emerging infectious diseases such as Arboviruses (see “Outreach Efforts,” below).
Amyloid plaques with surrounding abnormal prion protein in cerebellar tissue of patient who died of variant Creutzfeldt-Jakob disease.
OBRR also approved several important new products (see “Major product approvals,” below).
Major product approvals
In FY 2010, OBRR approved a variety of important new products:
ALBAclone (Alba Bioscience Limited, UK; October 2009)
Verax Biomedical Platelet PGD Test System (Verax Biomedical; November 2009)
Wilate (von Willebrand Factor/Coagulation Factor VIII Complex [Human]) (Octapharma, USA; December 2009)
InterSol (Fenwal; December 2009) http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ ApprovedProducts/NewDrugApplicationsNDAs/ucm193789.htm
Hizentra Immune Globulin Subcutaneous (Human), 20% Liquid ( CSL Behring; March 2010)
Abbott Prism Chagas Trypanosoma cruzi (E. coli, Recombinant) Antigen (Abbott; April 2010)
TachoSil Absorbable Fibrin Sealant Patch (Nycomed; April 2010)
Abbott ARCHITECT HIV Ag/Ab Combo (Abbott; June 2010) http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/
Glassia, Alpha1-Proteinase Inhibitor (Human) (Kamada Ltd; July 2010)
Gamunex-C Immune Globulin Intravenous (Human), 10%, Caprylate/Chromatography Purified (IGIV-C) (Talecris Biotherapeutics; October 2010)
Recalls, safety alerts and labeling changes
- Risk of intravascular hemolysis from use of WinRho SDF Immune Globulin Intravenous (Human) (March 2010)
- Warning label changes for risk of air embolism with use of Evicel Fibrin Sealant and Artiss Fibrin Sealant (April 2010)
- Allergic reaction adverse event reports associated with two lots of GammaGard Liquid, Immune Globulin Intravenous (Human) (June 2010)
- Market withdrawal of Octagam (Immune Globuline Intravenous [human]) 5% Liquid Preparation due to risk of thromboembolism (September 2010)
Development of investigational assay for characterization of IGIV thrombogenicity
In response to an increased number of reports of thromboembolic (blood-clotting) adverse events in recipients of Octagam, Immune Globulin Intravenous (human) (IGIV), the manufacturer, Octapharma, initiated a voluntary market withdrawal of all product lots from the U.S. market as a precautionary measure.
OBRR researchers in the Division of Hematology developed an in vitro assay known as a thrombin generation test (TGT) that measures thrombin generation by IGIV products. FDA continues to collaborate with certain foreign regulatory counterparts and standards organizations in anticipation of larger collaborative studies aimed at developing standards and test methods to increase the safety of IGIV products.
Liaison work with organizations
OBRR participated in numerous meetings and conferences with stakeholders to share information about FDA regulations and policies. Some of the meetings and conferences attended by OBRR staff in FY 2010 included:
AABB Bi-annual liaison meeting (Jan. 2010);
- AABB annual meeting (Oct. 2009);
- Plasma Protein Therapeutics Association (PPTA) annual liaison; meeting and PPTA Plasma Protein Forum (Sept. 2010);
- Plasma Protein Forum meeting participation (June 2010);
- North American Thrombosis Forum (NATF) meeting (March 2010).
Collaboration with other agencies of the Blood, Organ and Tissue Safety group
OBRR collaborated with researchers and staff at the National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), Health Resources and Services Administrations (HRSA), Centers for Medicare and Medicaid Services (CMS), and the Department’s Office of the Assistant Secretary (OASH) to address blood, organ and tissue safety.
Collaboration with Blood XMRV Scientific Research Working Group
OBRR participated with other DHHS agencies, academic researchers and blood collectors in the working group, led by the National Heart, Lung, and Blood Institute, to determine whether XMRV is present in US blood donors and whether the virus is transmitted by transfusion.
- Response to H1N1
OBRR led the blood team for FDA’s response to the 2009 H1N1 Influenza virus pandemic, collaborating with other Federal agencies, industry, trade associations, and consumer groups. The office also cooperated with this group in preparing for future influenza seasons. OBRR developed guidance for blood establishments to help mitigate the impact of the pandemic on the blood supply and collaborated with CDC on their interim guidance on infection control for personnel in blood and plasma collection facilities.
See also “A Pseudotype Neutralization Assay for Pandemic 2009 H1N1” in the Office of Vaccine Research and Review” section.
- Public Workshop: Blood Establishment Computer Software: Understanding What to Include in a 510(k) Submission, Rockville, MD. Nov. 4 - 5, 2009 :
Public Workshop: Emerging Arboviruses: Evaluating the Threat to Transfusion and Transplantation Safety, Bethesda, MD. December 14-15, 2009 http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm187986.htm
Public Workshop: Emerging Infectious Diseases: Evaluation to Implementation for Transfusion and Transplantation Safety, Gaithersburg, MD. May 11-12, 2010
- Participation and leadership in HHS hemovigilance activities
In October 2009, FDA, CDC, NIH, and other agencies issued a landmark report entitled “Biovigilance in the United States: Efforts to bridge a critical gap in patient safety and donor health” (http://www.hhs.gov/ash/bloodsafety/biovigilance/index.html). This report discussed recommendations of the DHHS Biovigilance Working Group, which was co-chaired by an OBRR representative. The report, endorsed by the DHHS Advisory Committee on Blood Safety and Availability, identifies gaps in the effectiveness of current biovigilance activities and makes specific recommendations for improvement, such as enhanced integration of government and private sector reporting systems and allocation of resources to this effort. This report will form the foundation for developing an HHS action plan to promote hemovigilance.
New guidances & rules
OBRR issued several guidances for industry in FY 2010. For details see the “Guidances” section of this report.
Advisory committee meetings
- Blood Products Advisory Committee, Bethesda, MD. Nov. 16-17, 2009
At its November meeting, BPAC endorsed FDA’s proposal to adopt a risk-based approach to blood donor deferrals for malaria risk and allow blood collection, without deferral, for donors who visited Quintana Roo, the Mexican state that includes popular tourist destinations (e.g., Cancun). http://www.fda.gov/AdvisoryCommittees/Calendar/ucm184809.htm
- Blood Products Advisory Committee, Gaithersburg, MD. July 26-27, 2010
At the July 2010 BPAC meeting, FDA provided updates on XMRV and FDA’s collaborative efforts with other public health agencies and blood establishments to determine whether XMRV poses a safety concern for the blood supply.
The committee discussed blood donor hemoglobin and hematocrit standards, and the risk of Babesia transmission from blood transfusions and potential approaches to screening and testing blood donors for Babesia. http://www.fda.gov/AdvisoryCommittees/Calendar/ucm216470.htm
- Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC). Gaithersburg , MD. October 28-29, 2010
The committee advised FDA on the agency’s updated risk assessment for vCJD in U.S. licensed plasma-derived Factor VIII and labeling of plasma derivatives including albumin and products containing albumin. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/ BloodVaccinesandOtherBiologics/TransmissibleSpongiformEncephalopathiesAdvisoryCommittee/ucm225805.htm
- HHS Advisory Committee on Blood Safety and Availability (ACSBA)
- June 10-11, 2010, Rockville, MD
Developing reagents for panels to detect HIV variants and dengue virus
CBER has obtained the isolates for the four serotypes, expanded the virus in culture and produced viral stocks. Standardization of the stocks (sequencing, stability, viral load) is ongoing. The next step will be to validate the standards by doing multi-laboratory testing. Participants include CDC, NIH, the New York State Department of Health, Roche, and GenProbe.
Human Immunodeficiency Virus (HIV) Variants
CBER obtained the samples necessary to develop panels to determine whether new and existing assays are capable of detecting variant strains of HIV. OBRR is developing an HIV p24 antigen panel based on cultured virus isolates, initially for clade B viruses, followed by the other major subtypes.
OBRR developed a lot release panel for antibody to Human Immunodeficiency Virus Type 2 (anti-HIV-2 Lot Release Panel #17) for the qualitative and semi-quantitative evaluation of in vitro tests to detect antibody to HIV-2 in human serum or plasma. The test is now available for distribution by CBER.
Validation of novel sample preparation methods to improve detection of blood-borne pathogens to enhance blood safety and availability
OBRR developed a method of sample preparation designed to concentrate the Leishmania parasite from a large quantity of blood and further concentrate the specific DNA target for amplification using polymerase chain reaction. The new approach will facilitate detection of parasites with greater sensitivity than that of previously used techniques, and foster public health by allowing easier detection of this pathogen in blood and blood products.
The mission of the Office of Biostatistics and Epidemiology (OBE) is to protect and promote public health by facilitating the development, licensure, and post-licensure monitoring of safe and effective biologic products. The office pursues this mission by providing biostatistical and epidemiological expertise regarding the design, conduct, and analysis of laboratory experiments, clinical trials, and observational studies.
OBE provides decision support, applies new and advanced modeling and quantitative analytic methodologies to the tasks of assessing risks and benefits of biologics throughout the product lifecycle, and facilitates appropriate regulatory and risk communication actions.
OBE comprises the Division of Biostatistics, Division of Epidemiology, and the Risk Assessment group and Genomics Evaluation Team in the Immediate Office of the Director.
Major Leadership Activities in FY 2010
OBE continued to play a major leadership role in planning, coordination, and implementation of H1N1 vaccine safety surveillance and research,including continued collaboration with the National Vaccine Program Office, Centers for Disease Control and Prevention (CDC), Center for Medicare and Medicaid Services (CMS), Indian Health Service, Department of Defense and Veterans Administration.
OBE also continued to provide information on H1N1 influenza vaccine safety surveillance to the H1N1 Vaccine Safety Risk Assessment Working Group, established by the National Vaccine Advisory Committee.
OBE continues to explore new ways to improve the evaluation and monitoring of the safety of CBER-regulated products throughout their lifecycle. Improving access to and use of large health care databases for this purpose is a major activity in OBE. Two specific example of this work are:
- Expanded capacity for Vaccine Safety Surveillance
OBE led the integration of the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program, originally developed in 2009 for H1N1 influenza vaccine safety surveillance, into the FDA Mini-Sentinel Project. The goal of this project is to further develop and evaluate PRISM as a general vaccine safety surveillance tool.
- Improved ability to conduct Blood Safety Surveillance
OBE staff developed over 20 new blood safety International Statistical Classifications of Diseases (ICD-9-CM) codes to improve post-marketing monitoring of safety of these products that became effective October 1st, 2010.
Major Regulatory Activities in FY2010
OBE staff conducted statistical review of pre-licensure submissions for all products reviewed by CBER and played an important role in the approvals described in other sections of this report.
OBE staff collaborated with CBER product offices in reviewing and evaluating Phase 2 and 3 IND protocols, IDEs, BLAs, and 510K submissions. This included providing alternative design and analysis strategies as appropriate.
A major goal of the FDA Amendment Act of 2007 is to improve the ability of FDA to monitor safety of medical products throughout their life cycle. Section 921 of this act requires FDA to conduct regular, bi-weekly screening of the Adverse Event Reporting System (AERS) database and post a quarterly report on the AERS Web site with any new safety information or potential signal of a serious risk identified by AERS within the previous quarter. FDAAA Section 915 tasks FDA with providing the public with summary analysis of adverse drug reaction reports for each drug, including identification of any new risks not previously identified, potential new risks, or known risks reported in unusual numbers by 18 months after approval or after the use of the product by 10,000 individuals, whichever is later. In FY 2010, OBE staff contributed to the meeting these requirements and results are available online for section 921 and section 915.
The Risk Assessment Group within OBE conducted a one-day workshop on 13 May 2010 titled, “Quantitative Risk Assessment: Blood Safety & Availability” that brought together regulators, industry, and academia to discuss risk assessment methodologies used by CBER that impact both blood safety and availability.
The Division of Biostatistics provided outreach to diverse audiences this past year, reflecting the variety of products we regulate. CBER statisticians joined CDRH colleagues by presenting and participating in a two-day conference with industry on statistical methods for evaluation of medical devices. We joined CDER colleagues in the DIA-Statistics Forum addressing statistical issues in the context of drugs and biologics. The division staff also presented talks at meetings more focused on CBER regulated products (vaccines, allergenics, and bioassays for vaccine products).
OBE staff made numerous presentations at national and international scientific meetings
OBE staff contributed their expertise to the development of several FDA guidances, including those for adaptive design clinical trials, non-inferiority clinical trials, International Conference on Harmonization (pharmacogenetics, and early phase pharmacogenomics clinical studies.
For more information see the “Guidances” section.
Advisory committee meetings
OBE staff contributed their expertise to advisory committee meetings, including those on pneumococcal 13-valent vaccine (OVRR), transmissible spongiform encephalopathy (OBRR), blood donor testing for babesiosis (OBRR).
For more information see information on advisory committee meetings in the above-cited product offices.
Major changes in the structure or function of the office
The pharmacovigilance function integrated previously separate branches for vaccine and therapeutic product safety surveillance.
Review Management (RM), as part of the Office of the Center Director, oversees the business process of regulatory review and bioinformatics across CBER.
RM provides careful oversight of the rigorously detailed path to biological product approval and the post-marketing period. This oversight, called the Managed Review Process (MRP)
- ensures that sponsors and manufacturers of new biologics comply with regulatory requirements
- ensure that CBER reviewers follow best internal practices of product review
- manages efficiently and simultaneously the ongoing review of many biological products in various stages of the product lifecycle, a process that often requires using a variety of different regulatory pathways
The Managed Review Process
MRP thus provides a structured approach to the review and establishes timeframes for specific review tasks so the status of the application review can be tracked efficiently. It also helps CBER to coordinate and integrate the reviews of scientists, clinicians, epidemiologists, compliance and manufacturing experts, and others involved in the comprehensive assessment of the application.
In FY 2010, RM continued to enhance the robustness of the review process by:
- Increasing the effectiveness of regulatory review processes
- Improving the quality of reviews and the review process
- Facilitating development of standards
- Refining and implementing the CBER bioinformatics strategy
- Strengthening information technology
- Communicating with the health care industry and other international regulators
- Improving records management.
Identifying best practices for regulatory review
RM staff continually improves the MRP by identifying best practices, developing opportunities to simplify the process, and improving the quality and consistency of the review.
The staff worked closely with the center’s Review Management Coordinating Committee and its subcommittees to complete a comprehensive assessment of MPR, identification of these improvements, and consistent implementation of them throughout CBER. Ongoing implementation of recommendations based on a comprehensive assessment of the MRP continued to improve coordination and management of review activities at CBER.
RM continued its support of the center’s collaborations with various national and international organizations that create standards to guide development of biological products.
In FY 2010, approximately 110 CBER staff participated in over 133 global and domestic standards development activities. These interactions with national and international standards organizations led to new standards for clinical trials, pharmacology and toxicology studies of new products, bioinformatics, manufacturing, and product testing.
Among these cooperative interactions were
- collaborating with Foundation for the Accreditation of Cellular Therapy to establish product standards for cord blood progenitor cells used in life-saving transplantations
- serving as liaison to AABB scientific committees and reviewing standards for blood establishments
- collaborating with the American Association of Tissue Banks to help set industry standards for human tissue establishments
- collaborating with Clinical Data Interchange Standards Consortium (CDISC), which establishes standards to support acquisition, exchanges, submission, and archiving or clinical research data that can improve medical research and related areas of health care
Standards Management Coordinating Committee
CBER coordinates and manages the development of standards in CBER through the Standards Management Coordinating Committee (SMCC). In FY 2010, SMCC developed an internal standards web page and provided training for CBER staff who routinely use standards-- particularly staff who interact, with standard- development organizations, including the development of physical standards.
Bioinformatics and Information Technology
The RM staff continued to enhance the efficiency and quality of the regulatory process, including review activities, by coordinating and developing the CBER part of FDA enterprise bioinformatics. A major emphasis continues to be transitioning from paper to electronic submissions and records. This change required that RM organize development of acceptable data and content standards, regulations, policies and procedures, and infrastructure.
In addition, RM staff continued to standardize the formats in which public and private institutions and industry store and electronically transfer drug and biological product information. The staff also continued to provide expertise and guidance to the Healthcare Information Technology Standards Panel (HITSP) of the American National Standards Institute (ANSI) in the development of standard terminologies for drug review and regulation.
These standards are designed to simplify electronic communications among FDA, new product applicants, and other stakeholders, and to help to make processing and assessing data more efficient.
In collaboration with other national and international organizations, RM staff helped to implement standard communication formats and terminology for reviewing new product applications, performing safety studies, and communicating with stakeholders. Such standard formats will facilitate international cooperation, especially in response to emerging infectious disease outbreaks worldwide and threats of bioterrorism. (See also the “International Program” and “Counterterrorism” sections.)
The team initiated ongoing changes that increased the use of electronic communications for submission and review. Among the notable accomplishments of RM staff in support of the enterprise project are the following:
RM staff continued to participate in the development of the electronic inventory of all facilities, firms, points of contacts, and products linked to FDA regulatory activities.
Study Data Tabulation Model (SDTM)
In 2010, CBER implemented SDTM as the standard for the electronic submission of human clinical trial data. The clinical review staff was trained in the standard to help increase the efficiency and improve the quality of the review process. The implementation of the clinical data standard supports the reduction of paper- based submissions and enhances the quality of electronic submissions and subsequent data analysis.
Analysis Data Model (ADaM)
In 2010, the standard for analysis data, ADaM, was finalized and published by CDISC. CBER trained the statisticians that perform human clinical review and implemented the standard across the center.
Structured Product Labeling
On June 1, 2009, an electronic establishment registration and listing system went into effect for products regulated by CBER that are required to be registered and listed under 21 CFR 207 (e.g., vaccines, allergenics, and plasma derivatives).
A key part of the system is Structured Product Labeling (SPL), which is designed to establish a robust repository of establishments and products that facilitates storing, accessing, and evaluating product information, such as active ingredients, strengths, dosage forms, and routes of administration.
In FY 2010, CBER staff continued to improve the SPL by applying additional electronic validation criteria on data submitted to the center and developing standards for other CBER regulated product classes. For example, medical reviewers are now developing the necessary data elements and structures for indexing pharmacologic class. Indexing refers to the insertion of machine-readable tags, which do not appear in actual printed labeling, to enable users with clinical decision support tools and electronic prescribing systems to rapidly search and sort product information.
CBER also began expanding the SPL system to include blood and blood components to replace the current paper registration and listing now used for these products. CBER will continue to support stakeholders as they transition from paper to the electronic system.
Information Technology System Enhancements
In 2010, CBER upgraded most IT systems from older client server technology to Web-based technology. This upgrade makes the systems significantly more reliable, gives users greater access to the systems, and increases their security capabilities. Other technology upgrades included Oracle, Documentum, and architectural changes to comply with new FDA standards.
FDA Electronic Submission Gateway (ESG) is the central transmission point for sending information electronically to FDA, automatically routing submissions to the proper FDA center or office. CBER provided the project manager and the contracting officer technical representative for FDA on this project, which satisfied a PDUFA III IT goal. The electronic submission process informs the sender of the receipt of the submissions and notes any processing errors; it also routes the submission to a receiving center or office and notifies the recipient, and provides access to the review team of the electronic submission.
In FY 2010, CBER received 5700 completely electronic submissions via the FDA ESG.
Adverse Events Reporting and Follow-Up: MedWatch Plus and FAERS
RM staff and other subject matter experts in the center continued to improve adverse event reporting, which uses several systems for CBER products. Their activities included proactively identifying business requirements and conducting overall business management of the FDA Adverse Event Reporting system (FAERS) project, which will be the new repository for post-marketing adverse events reports (except, for now, vaccines).
The mission of OCBQ is to ensure the quality of products regulated by CBER over their entire lifecycle: through pre-market and post-market review, surveillance, inspection, outreach and compliance.
Major activities in FY 2010
CBER Lab Quality System receives ISO 17025 accreditation by the American Association for Laboratory Accreditation
In October 2010, the American Association for Laboratory Accreditation awarded CBER Laboratory Quality System (LQS) program accreditation to ISO/IEC 17025 for competence in testing, i.e., consistently producing valid results. CBER received accreditation in the fields of biological and chemical testing, specifically for the six in vitro methods used most frequently for evaluating the safety and effectiveness of influenza vaccines (including sterility), and seven methods for evaluating blood donor screening kits that test for the presence of HIV, HBV, HCV, HTLV-I/II, Trypanosoma cruzi, and West Nile virus.
The LQS program is the coordinated organizational structure, including procedures, processes and resources, that CBER uses to evaluate and test regulated biological products. This testing includes that performed in support of lot release or surveillance, licensing, supplements and amendments to licenses, official investigative actions, the development and characterization of official reference materials and physical standards, and other studies identified to be of relevance to product testing. The International Standards Organization and the International Electrotechnical Commission developed the international standard ISO/IEC 17025 (“General requirements for the competence of testing and calibration laboratories”) in order to merge requirements for technical competence in testing and calibration laboratories with requirements for quality systems.
CBER Electronic Lot Release Gateway Expansion
In FY 2010 OCBQ expanded the pilot program to allow electronic submission of lot release protocols through the agency’s electronic gateway, in order to facilitate the receipt and processing of lot release protocols and reduce the amount of time needed to release the lots.
In accordance with Title 21, Code of Federal Regulations, Section 610.2(a), manufacturers of licensed biological products may be required to send to CBER s amples of the product together with the protocols showing results of applicable tests, and may not distribute the product until the lot is released by CBER. Previously, industry submitted these protocols to FDA either in paper form or on electronic media such as CD-ROM. Beginning with the 2009 H1N1 influenza virus vaccine campaign, CBER made the submission of protocols quicker and more efficient by initiating a pilot program to allow electronic submission of the lot release protocols, using the agency’s electronic gateway .
Based on the effort to accelerate the availability of the products, this effort was expanded to include all manufacturers of seasonal influenza virus vaccine for the 2010 campaign. The use of the gateway for electronic lot release in these circumstances facilitated the receipt and processing of lot release protocols and resulted in a reduction of time needed to release the lots.
During FY2010 the Office completed 6749 final actions on lots submitted to CBER, of which 272 were influenza virus vaccine lots released by FDA and made available for distribution by the manufacturers.
Direct Recall Classification Initiative Results in Streamlined Process
CBER implemented Direct Recall Classification (DRC), an important initiative to streamline the processing and classification of certain biologics recalls (i.e., Class I, Class II, or Class III, depending on the relative degree of health hazard of the product being recalled or considered for recall.) DRC allows direct recall classification based on the information submitted to FDA in electronic Biological Product Deviation reports (eBPDR). DRC is currently available for recalls of blood and blood components (e.g. red blood cells, platelets, source plasma).
During the first full year after implementation, 65% of all recalls of blood and blood components (1191 of 1845 recalls) were classified using the Direct Recall Classification process. Of these recalls, 65% were classified by OCBQ within 45 days of receipt of additional information from each establishment through electronic means. This represents a substantial improvement in the time frame for classification of recalls of blood and blood components.
Significant Regulatory Activities
Order To Cease Manufacturing of HCT/Ps Issued to Newborn Blood Banking, Inc.
Newborn Blood Banking, Inc., located at Land O Lakes, Florida, is a registered manufacturer of human cells, tissues, and cellular and tissue-based products (HCT/Ps). Specifically, the firm performs donor eligibility determinations, processing and storage of umbilical cord blood. These products are stored in the event that the cord blood stem cells are needed for later use by the child or a close relative.
Based on the violations documented during its inspection, the agency determined that there were reasonable grounds to believe that the Newborn’s operations constituted a danger to health and accordingly, an Order to Cease Manufacturing was issued on February 19, 2010 to Newborn and to its Chief Executive Officer and Owner, Jon G. Suits. The Order related to conduct occurring on or after May 25, 2005, the effective date of the applicable regulations and required the firm to:
- immediately cease all manufacturing (including receipt of in-transit cord blood units) until compliance with the regulations in 21 CFR 1271 has been achieved and FDA has provided written authorization for them to resume operations;
- not distribute any HCT/Ps recovered on or after May 25, 2005 which are in their possession or received after the date of the order; and
- continue to store all HCT/Ps in their possession in compliance with the requirements of 21 CFR 1271.260.
The potential public health impact was for the families who have umbilical cord blood units recovered, processed and stored at Newborn, which were compromised by the firm’s manufacturing conditions. The FDA provided notification of the cessation order to all individuals who had stored, or intended to store blood with Newborn since May 25, 2005, by providing them a copy of the order. At the time of the order, none of the units stored at Newborn’s facility had been distributed.
For more information on this action, go to:
Warning Letters Issued to Two Reproductive HCT/P Establishments
On March 29, 2010, FDA’s Los Angeles District Office issued a Warning Letter to IVF Phoenix, Scottsdale, Arizona. FDA conducted an inspection of this reproductive HCT/P establishment from February 1 to February 5, 2010. FDA investigators documented deviations from the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps).
To view the full text of the Warning Letter go to:
On January 26, 2010, FDA’s Florida District Office issued a Warning Letter to Fertility and Reproductive Medicine Center for Women, Melbourne, Florida. FDA conducted an inspection of the establishment from November 4 through November 12, 2009. During this inspection, the FDA investigator documented significant deviations from the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps).
To view the full text of the Warning Letter go to:
Warning Letter Issued to Baxter Biosciences
On January 15, 2010 FDA issued a Warning Letter to Baxter Biosciences (Baxter), Lessines, Belgium. FDA conducted an inspection of Baxter between October 12 and October 19, 2009. During the inspection, FDA investigators documented significant deviations from current good manufacturing practice in the manufacture of Gammagard Liquid and Gammagard S/D intermediates. The deviations included
To view the full text of the Warning Letter go to:
Warning Letters Issued for Three Unapproved Influenza Virus Vaccines
As a result of coordinated internet surveillance by the FDA Flu Task Force, CBER issued Warning Letters to three websites for offering products for sale that are intended to diagnose, mitigate, prevent, treat or cure the H1N1 Flu Virus in humans. The products had not been approved, or otherwise authorized by FDA for use in the diagnosis, mitigation, prevention, treatment, or cure of H1N1 Flu Virus.
To view the full text of the Warning Letters go to:
Warning Letter Issued to a Clinical Investigator Conducting Studies with Investigational Biological Drugs
CBER issued a warning letter on March 11, 2010 to Charles H. Toledo, M.D., of Sylva, North Carolina. A Bioresearch Monitoring inspection showed that Dr. Toledo failed to conduct clinical investigations according to the investigational plan; failed to prepare and maintain adequate and accurate case histories; failed to maintain adequate records of the disposition of investigational products; and failed to retain records.
To view the Warning Letter, go to
Warning Letter Issued to an Institutional Review Board overseeing Clinical Research involving Investigational Biological Drugs
CBER issued a warning letter on November 10, 2009 to the Teneo Institutional Review Board of Tulsa, Oklahoma. A Bioresearch Monitoring inspection showed that the Teneo IRB failed to maintain adequate documentation of all IRB activities to include, but not limited to: documentation of the discussion, review, and approval of protocols and informed consent forms; reports of adverse events; IRB member discussion and vote on IRB-related matters such as Standard Operating Procedures; and minutes for all meetings conducted by the IRB. CBER placed restrictions on the IRB to halt enrollment of new subjects into FDA-regulated studies, and FDA will withhold approval of all new studies approved by this IRB.
To view the Warning Letter, go to
Former Clinical Investigator Alfred E. Chang is Disqualified
On April 7, 2010, FDA completed an agreement that disqualifies former clinical investigator Alfred E. Chang, M.D., of Ann Arbor, Michigan. Dr. Chang is no longer permitted to receive investigational biologics or drugs. This action is the result of an FDA inspection of Dr. Chang’s studies of investigational cell therapies and gene therapies.
Major Changes in the Structure or Function of the Office
During FY2010, the Division of Product Quality was transferred from CBER’s Office of Vaccines Research and Review to the Office of Compliance and Biologics Quality. The responsibilities and activities of the Division of Product Quality remain the same.
The Office of Communication, Outreach, and Development (OCOD) supports the broad mission of CBER through a variety of educational, media, governmental, and public interest activities.
On December 8, 2009, the Office of Management and Budget (OMB) issued the Open Government Directive (http://www.whitehouse.gov/open/documents/open-government-directive). This directive was based on an earlier memorandum from President Barak Obama to ensure that his administration takes appropriate action to disclose information the public can readily use and find.
HHS Secretary Katherine Sebelius formed a group to coordinate an overall HHS response to the Open Government Directive, and FDA Commissioner Dr. Margaret A. Hamburg launched the agency’s Transparency Initiative in June 2009. In early January 2010, FDA launched a web-based Transparency Initiative resource called FDA Basics (http://www.fda.gov/AboutFDA/Transparency/default.htm). This site includes Q&As, videos, and conversations with agency officials.
OCOD supported the efforts of FDA and CBER to comply with the transparency program launched by President Obama. The Open Government Directive, directed agencies to find new ways to make information available to the public rapidly and in forms that are easily accessible and user-friendly.
OCOD plays a significant role in leading and coordinating the Center’s outreach efforts. In addition to the Office’s work on transparency-related activities, OCOD works closely with the product offices and the Office of the Director to develop a variety of communication products to educate stakeholders about CBER’s regulatory, compliance, policy and research activities. This includes development content for the CBER website such as frequently asked questions on product approvals, product safety issues, emerging infectious diseases, enforcement actions. OCOD also responds to inquiries from the public, handling over 10,000 such requests during FY 2010.
OCOD also manages the Center’s exhibit program, participating in industry, health care professional, consumer and patient organization meetings to provide information on CBER-regulated products and Center policies, and works with the program offices to conduct liaison meetings with regulated industry.
Training and Development Activities
CBER staff must constantly hone their skills and knowledge in order to keep pace with the scientific and technical advances that impact the products they regulate. OCOD supports this cross-center training need, starting at orientation of new employees and continuing throughout their careers at CBER. In FY 2010, this support included coordinating internal and external training for staff such as technical training for reviewers, leadership for non-supervisors, coaching for supervisors and managers, and ongoing professional development.
Guidance documents, which represent FDA's current thinking on a topic, are prepared for FDA staff, applicants, sponsors, and the public to describe the agency’s interpretation of or policy on a regulatory issue. CBER addresses a variety of topics in guidance documents, such as development and manufacturing of products, and testing products for safety and efficacy. Below we highlight some guidances issued in FY 2010 that might be of special interest.
An Acceptable Circular of Information for the Use of Human Blood and Blood Components
Updated December 2009
This guidance recognizes that FDA has determined that the instruction circular entitled "Circular of Information for the Use of Human Blood and Blood Components" (dated December 2009) is acceptable for use by manufacturers of blood and blood components intended for transfusion.
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
This is the latest in a series of guidance documents addressing the risk of CJD and vCJD transmission by blood and blood products. This guidance amends the 2002 document by recommending, 1) deferral of donors who have received a transfusion in France since 1980 and 2) revised labeling of blood and blood components for transfusion to address the possible risk of transmission of CJD and vCJD.
Nucleic Acid Testing (NAT) for Human Immunodeficiency Virus Type 1 (HIV-1) and Hepatitis C Virus (HCV): Testing, Production Disposition, and Donor Deferral and Reentry
This guidance provides recommendations to blood and plasma establishments, manufacturers, and testing laboratories that are implementing a licensed method for Human Immunodeficiency Virus Type 1 (HIV-1) Nucleic Acid Test (NAT) and Hepatitis C Virus (HCV) NAT, for testing individual samples or pooled samples from donors of human blood and blood components for HIV-1 ribonucleic acid (RNA) and HCV RNA.
Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Donors of Whole Blood and Blood Components Intended for Transfusion
This guidance provides recommendations for testing donations of Whole Blood and blood components intended for transfusion for West Nile Virus (WNV), using an FDA-licensed nucleic acid test (NAT) to reduce the risk of transmission of WNV. The guidance does not apply to Source Plasma or plasma derivatives.
Requalification Method for Reentry of Blood Donors Deferred Because of Reactive Test Results for Antibody to Hepatitis B Core Antigen (Anti-HBc)
This guidance provides establishments that collect Whole Blood or blood components intended for transfusion with recommendations for reentry of deferred donors after it has been determined that they had repeatedly tested falsely positive for antibodies to hepatitis B core antigen (anti-HBc), and that there is no evidence of infection with hepatitis B virus (HBV).
Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications
This guidance recommends ways to enable manufacturers (generally a cord blood bank) to apply for licensure of minimally manipulated, unrelated allogeneic placental/umbilical cord blood, for specified indications.
Characterization and Qualification of Cell Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease Indications
This guidance applies to the development of viral vaccines for the prevention and treatment of infectious diseases. Its scope is limited to cell substrates (cells used to produce vaccines) of human or animal (including insect) origin and does not cover characterization of unicellular organisms, such as bacteria or yeast.
FDA-TRACK: An Agency-wide Program Performance Management System Encouraging Accountability and Tracking Progress
FDA-TRACK is a performance management system designed to encourage accountability among employees and track progress in key program areas. Launched in 2010, FDA-TRACK advances the commitment of President Barack Obama to transparency, public participation and collaboration in the work of the federal government.
FDA-TRACK incorporates the three main points of this agenda: 1) using performance information to lead, learn, enhance operational efficiency, and improve outcomes; 2) communicating performance coherently and concisely for better results and transparency; and 3) strengthening problem-solving networks.
FDA-TRACK monitors 110 FDA program offices by means of data collection using key performance measures that are chosen each year. Following data collection and analysis, FDA center directors and office directors meet quarterly with senior FDA officials to report performance and evaluate programs. The public can access both the agency's goals and progress on the FDA-TRACK website (http://www.fda.gov/AboutFDA/Transparency/track/default.htm).
For details on CBER FDA-TRACK see - http://www.fda.gov/AboutFDA/Transparency/track/ucm195010.htm
The Food and Drug Administration (FDA) and the General Services Administration (GSA) are working together to consolidate FDA Headquarters at the government owned White Oak Federal Research Center in Montgomery County, Maryland. The consolidation project was authorized by Public Law 101-635, (FDA Revitalization Act of 1990) and is funded through the GSA appropriation. This initiative directed the Secretary of Health and Human Services and the Administrator of GSA to consolidate FDA headquarters into modern office and laboratory facilities.
Currently, nearly 5,500 employees have been relocated to the White Oak campus.
Construction of laboratories for the Center for Biologics Evaluation and Research/Center for Drugs Evaluation and Research (CBER/CDER), the largest remaining laboratory to be built on the campus, are under construction. Clark Construction Company is the general contractor.
The Center for Biologics Evaluation and Research remains on schedule for its relocation to the White Oak Campus in mid-2014. Clark Construction, the general contractor, remains on schedule in its development of the Southeast Quadrant site.
FY 2010 events and accomplishments
- Following completion of the final design review of Building 75 (Southeast Quadrant laboratories and offices) by the CBER planning teams, the GSA prepared and released the construction bid documents through a formal issue for bid on FedBizOps (January 28, 2010). About 50 CBER employees attended the groundbreaking of the Southeast Quadrant on September 8, 1010.
- The Southeast Quadrant planning groups of CBER and CDER received an FDA group award in for their work during the planning and design of a state-of-the-art laboratory and office facilities on the campus (May 2010).
- A proactive outreach program was developed during the planning and design of the CBER facilities at White Oak to engage the CBER community and promote their commitment to the success of the consolidation. In addition, the White Oak Planning Team provided desk-to-desk information packets to CBER employees to ensure that center employees were kept up-to-date on White Oak planning activities.
CBER Research Prepares Reviewers to Evaluate Future Biologic Products
Breakthroughs in fields such as genomics, nanotechnology, and stem cell biology are creating the new knowledge needed to fulfill the promises of 21 st Century medicine.
Many of these new therapies, such as gene and stem cell therapies, are complex biologics-based products. These products will require that CBER regulator-scientists have state-of-the-art knowledge and skills to evaluate their safety, purity, potency, and effectiveness. Moreover, existing and emerging infectious diseases continually threaten the safety of the blood supply used for transfusions and the production of blood products. These threats necessitate careful screening of donor blood and plasma and therapeutic substances derived from them. CBER also targets infectious disease with its research in key areas of vaccine development: evaluating novel adjuvants and vaccine delivery systems, developing testing standards to screen vaccine substrates for bacterial and viral contamination, and applying new technologies to assess the safety and efficacy of certain vaccines.
Recognizing these challenges, CBER supports and pursues research that will enhance regulatory science: the science of assessing and evaluating the safety, effectiveness, potency, quality, and performance of biological products, as well as enhancing the design and evaluation of preclinical and clinical testing protocols.
Regulatory Science Supports the Critical Path Initiative
Regulatory science supports the goals of the agency's Critical Path Initiative (CPI), a national strategy for transforming the way FDA-regulated products are developed, evaluated, and manufactured (http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/ucm076689.htm). The agency launched CPI in 2004 because the number of submissions of new products for approval was significantly decreasing, despite major advances in medical science. FDA noted in the landmark report that launched CPI ("Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products") the rising cost, difficulty, and unpredictability of product development and the need for new in vitro tests and assays, computer modeling, qualified biomarkers, and innovative clinical trial designs.
CPI projects, some of which have received funding since FY 2008, represent the application of regulatory science to these real-world challenges as the center works to protect public health by ensuring the safety, efficacy, and security of biological products.
Among the key goals of CPI projects are to develop better evaluation tools like biomarkers and new assays
- streamline clinical trials by modernizing the clinical trial sciences to make trials safe and efficient
- move manufacturing into the 21st Century, using tools such as process analytic technology and nanotechnology
- develop products to address urgent public health needs, including improved antimicrobial testing, new animal models to test bioterrorism countermeasures, and vaccine testing
CBER Critical Path Project Summaries
Improving Vaccine Safety
- Predicting safety and efficacy of novel adjuvants and vaccine delivery systems
- Supporting the development of effective vaccines to prevent pneumococcal disease
- Developing standards for testing cell substrates
- Applying novel technology to assess the safety and efficacy of certain vaccines
- Developing a toxoid antigen research program
- Evaluating xenotropic murine leukemia retrovirus (XMRV) risk in vaccine cell substrates
- Characterizing novel live attenuated mycobacterial vaccines
Promoting Development of Innovative Therapies
- Regenerative medicine: Assessing safety and efficacy of stem-cell-derived products
- Improving animal models and biomarkers that can predict blood substitute toxicity
- 10. Developing a rapid in vitro screening method to detect insertional mutagenesis of integrating vectors
- Improving the safety and efficacy of adenovirus gene therapy vectors
- Developing preclinical models of vascular endothelial dysfunction to evaluate safety of hemoglobin-based products and aged red blood cells
Continuing Efforts to Ensure Blood and Blood Product Safety
- Improving detection of blood-borne pathogens
- Developing a comprehensive HIV variant viral reference panel
- Developing product quality biomarkers for stored blood cells
- Developing assays and reference reagents for blood donor surveillance and virus transmission
- Developing viral reagents to evaluate new and existing assays for detecting dengue and Chikungunya
- Evaluating blood and vascular biocompatibility of engineered nanomaterials
- Determining the role of platelet products in transfusion-related acute lung injury
- Improving the clinical efficacy of Hepatitis C immune globulin products
- Developing laboratory test to screen donors for babesia risk
Ensure Allergen Potency
- Application of the multiplex allergen extract potency assay