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FY 2011 CBER Annual Report: Innovative Technology Advancing Public Health

 

Table of Contents


Message from the Director
CBER Vision and Mission
Office of Vaccines Research and Review
Office of Cellular, Tissue and Gene Therapies

Office of Blood Research and Review

Countering Bioterrorism
International Programs

Safety Teams

Blood Safety Team
Tissue Safety Team

Vaccine Safety Team

Office of Biostatistics and Epidemiology 
Review Management 
Office of Compliance and Biologics Quality
Critical Path Initiative
Office of Communication, Outreach, and Development
Office of Management
Guidances of Note

White Oak Planning

 


A Message from the Director

 
Karen Midthun, MD
 
I am pleased to share the annual report of the Center for Biologics Evaluation and Research (CBER) for fiscal year 2011. The accomplishments noted in this report represent significant efforts in support of our mission to protect and improve health in the United States and globally. This work performed at CBER supported the overarching priorities of the Food and Drug Administration, including efforts to advance regulatory science and research, with particular efforts related to the development of new biological products. Among its many accomplishments in fiscal year 2011, CBER approved several vaccines that provide protection against a variety of diseases potentially impacting infants, toddlers, and adults. CBER also approved the first product intended to prevent bleeding in people with a rare genetic clotting factor deficiency. Other product approvals made available new products for HIV testing and the detection of mutations that confer resistance to HIV drugs. CBER also continued its important efforts aimed at supporting development of products intended to protect the public against agents of bioterrorism and chemical warfare. Such accomplishments, which reflect the Center’s broad mission, occurred as CBER carried on its daily responsibilities of product reviews, risk assessments, compliance activities, global collaborations, and other activities that ensure the delivery to the public of biological products that are safe and effective. I would like to take the opportunity to acknowledge and thank the many dedicated and talented employees at CBER for making FY 2011 such a productive year.
 
Karen Midthun, MD
Director
Center for Biologics Evaluation and Research
Food and Drug Administration

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CBER 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 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
 
Mission
 
The mission of CBER is to ensure the safety, purity and potency of biological products for the prevention, diagnosis, and treatment of human diseases, conditions, or injury. CBER-regulated products include vaccines, blood and blood products, and cells, tissues, and gene therapies. CBER also helps to protect 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 mission-related research as an essential element of science-based decision-making

     
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OFFICE OF VACCINES RESEARCH AND REVIEW
 
Mission
 
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.
 
OVRR accomplishes this by evaluating investigational new drug applications (INDs) and biologics license applications (BLAs) and supplements submitted by manufacturers for preventive vaccines and related biological products to determine their safety and effectiveness, and taking appropriate regulatory actions. In addition to its regulatory responsibilities, OVRR plans and conducts mission-oriented research related to the development, manufacture, and evaluation of safe and effective vaccines and related products. OVRR also develops guidance, policies, and procedures governing the pre- and postmarket evaluation of safety and effectiveness of vaccines and related biological products.
 
OVRR engages with the World Health Organization (WHO) and other international partners to help strengthen global regulatory and scientific infrastructure, including in less developed regions of the world. Additionally, OVRR serves as a key contributor to the worldwide efforts to select yearly seasonal influenza vaccine strains as an Essential Regulatory Laboratory in the WHO Global Influenza Surveillance and Response System (GISRS). In collaboration with the Office of Compliance and Biologics Quality, OVRR also is a key contributor to the worldwide efforts to generate appropriate reference virus strains and reference reagents for influenza vaccine production, both seasonal and pandemic.
 
Major Leadership Activity
 
A priority for OVRR is facilitating the development of safe and effective vaccines for infectious diseases that address important health concerns and would benefit public health. OVRR’s commitment to this priority was demonstrated by its work in bringing scientific experts together in the areas of group B Neisseria meningitidis and smallpox to help answer important scientific questions that will create a pathway towards licensure of these vaccines.
 
Group B Neisseria meningitidis vaccine
 
In April 2011, OVRR convened its Vaccines and Related Biological Products Advisory Committee (VRBPAC) to seek advice on the scientific strategy for the regulatory pathway for licensure proposed by OVRR for new vaccines to prevent group B Neisseria meningitidis, a significant cause of endemic and epidemic meningococcal disease world wide. Group B strains account for approximately one-third of invasive meningococcal disease overall, and over half of the disease in children under one year of age. In addition, it is also a significant disease burden in adolescents and young adults in the United States. FDA has not licensed any group B meningococcal vaccines.
 
Placebo-controlled clinical trials using meningococcal disease as an endpoint are not feasible because meningococcal disease strains are diverse and evolve over time, and the prevalence of the disease in the United States is low. Therefore, OVRR proposed that effectiveness be based on protective anti-meningococcal antibody titers measured by human complement serum bactericidal activity (hSBA) assays, combined with bridging of test-strain-specific hSBA to endemic disease isolates. The VRBPAC concurred and agreed that the types of studies that OVRR proposed could constitute a development pathway for manufacturers to facilitate the licensure and availability of this important vaccine.
 
Smallpox vaccine
 
Smallpox has the potential to be a terrorist weapon despite the fact that the World Health Organization declared the disease eradicated in 1980 and routine U.S. vaccination ended in 1972. Therefore, much of the population in the world has no immunity to smallpox virus and fatality rates could be high if smallpox were deliberately. released. Moreover, there are no FDA-approved treatments and the smallpox vaccines used to eradicated the disease are no longer licensed in the U.S. OVRR licensed a new smallpox vaccine, ACAM2000, in 2007; however, similar to previously licensed smallpox vaccines, this vaccine may cause serious adverse reactions in some recipients. Thus, smallpox vaccines with an improved safety profile are under development. To define the best approaches to evaluation and the licensure pathways for the next generation of smallpox vaccines, OVRR, in collaboration with the National Institutes of Health, convened a workshop with scientific experts in September 2011. The scientific discussions addressed the challenges and the experts proposed ideas for predicting the effectiveness of the vaccines, which cannot be directly evaluated in humans because smallpox has been eradicated.
 
Anthrax vaccine
 
Bacillus anthracis is a very serious potential bioweapon because this bacterium’s spores are very stable, easy to disperse, and the disease, especially the inhalation form, has a high mortality rate if not treated. The currently licensed anthrax vaccine is approved for pre-exposure prophylaxis and routinely administered to military personnel; however, an anthrax vaccine for a post-exposure prophylaxis (PEP) is not currently approved. Such a vaccine could protect against delayed onset disease caused by residual, germinating anthrax spores. In November 2010, OVRR convened its VRBPAC to present a pathway for developing such a vaccine under the Animal Rule. This strategy would use antibody titers to bridge animal protection data to the human immune response to support a PEP indication. The Committee agreed that the proposed strategy was scientifically sound, considering it is not ethical or feasible to conduct efficacy studies in humans.
 
(FDA’s regulations concerning the approval of new drugs or biological products when human efficacy studies are neither ethical nor feasible are known as “the Animal Rule” [21 CFR 314.600 for drugs; 21 CFR 601.90 for biological products]. The Animal Rule states that in selected circumstance, when it is neither ethical nor feasible to conduct human efficacy studies, FDA may grant marketing approval based on adequate and well-controlled animal studies when the results of those studies establish that the drug or biological product is reasonably likely to produce clinical benefit in humans. Demonstration of the product’s safety in humans is still necessary.)
 
Influenza vaccines
 
The development of alternative methods to replace the current single radial immunodiffusion (SRID) potency assay for influenza vaccines is critical for advancing pandemic preparedness. Therefore, OVRR initiated research pursuing various approaches for developing an alternative influenza vaccine potency assay.
 
In addition, OVRR developed the “Influenza Manufacturing Improvement Initiative,” a collaborative project with the Biomedical Advanced Research and Development Authority (BARDA) Centers for Disease Control and Prevention (CDC) and NIH, aimed at ensuring more rapid deployment of influenza virus vaccines for both seasonal and pandemic uses.
 
See selected research article summaries at: Innovations and Regulatory Science:http://www.fda.gov/Biologics BloodVaccines/ScienceResearch/ucm234680.htm).See more on vaccine research at:http://www.fda.govBiologicsBlood Vaccines/ScienceResearchBiologics ResearchAreasucm124378.htm
 
Mission-Related Research
 
In FY 2011, OVRR scientists authored or contributed to over 100 publications in peer-reviewed medical and scientific journals about vaccines and related products and the infectious diseases that they prevent. This research was pertinent to the development, manufacture, and testing of vaccines and related products, including those for pandemic influenza vaccines and those prepared by genetic engineering and synthetic procedures, to support the regulatory process, and to assist in establishing methodologies and standards to ensure the continued safety, purity, potency and effectiveness of vaccines and related products.For list of published articles in 2011 see CBER publications at: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm321284.htm

 
Key Approvals
 
  • Adenovirus Type 4 and 7, live, oral vaccine: for use in military populations 17 through 50 years of age for the prevention of febrile acute respiratory disease caused by adenovirus type 4 and 7.
  • Boostrix: first vaccine to prevent three diseases: tetanus, diphtheria, and pertussis (whooping cough) in people ages 65 and older. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2011/ucm262390.htm
  • Fluzone Intradermal: trivalent inactivated influenza vaccine for ages 18 through 64 years, administered into the skin, rather than the muscle, using a very small needle.
  • Gardasil: prevention of anal cancer and associated pre-cancerous lesions due to human papillomavirus (HPV) types 6, 11, 16, and 18 in people ages 9 through 26 years. http://www.fda.gov/NewsEvents/Newsroom/Press Announcements/2010/ucm237941.htm
  • Influenza vaccine: vaccines: approved 2011-2012 influenza vaccine formulation for all six manufacturers licensed to produce and distribute influenza vaccine for the United States. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm263319.htm
  • Menactra: for use in children as young as 9 months for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135. It was previously approved for use in people ages 2 through 55 years of age. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm252392.htm
  • Menveo: for use in children 2 through 10 years of age for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135. It was previously approved for individuals 11 through 55 years of age.
  • Spherusol: for the detection of delayed hypersensitivity to Coccidioides immitis in individuals, 18-64 years of age, with a history of pulmonary coccidioidomycosis.
  • Zostavax: for the prevention of shingles in individuals 50 to 59 years of age. It was previously approved for use in individuals 60 years of age and older. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2011/ucm248390.htm
 
Meetings of the Vaccines and Related Biological Products Advisory Committee
 
Discussed the pathway to licensure for protective antigen-based anthrax vaccines for a post-exposure prophylaxis indication using the animal rule. (See also, “Countering Bioterrorism”) (November 16, 2010)

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/
VaccinesandRelatedBiologicalProductsAdvisoryCommittee/ucm197728.htm
 
Discussed the effectiveness of vaccinating males and females with Gardasil for the prevention of anal dysplasia and anal cancer. (November 17, 2010)

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/
VaccinesandRelatedBiologicalProductsAdvisoryCommittee/ucm241549.htm
 
Discussed and made recommendations regarding selection of strains to be included in the influenza virus vaccine for the 2011-2012 influenza season. (February 25, 2011)

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/
VaccinesandRelatedBiologicalProductsAdvisoryCommittee/ucm241549.htm
 
Provided advice regarding the use of immunological markers to demonstrate the effectiveness of meningococcal serogroups A,C,Y and W-135 conjugate vaccines administered to children less than 2 years of age, and approaches to licensure of meningococcal serogroup B vaccines. (April 6-7, 2011)

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/
VaccinesandRelatedBiological ProductsAdvisoryCommittee/ucm241549.htm


 
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OFFICE OF CELLULAR, TISSUE, AND GENE THERAPIES
 
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 Leadership Activity
 
Cellular therapies, gene therapies and tissue engineered medical products are novel and rapidly developing classes of products being developed for the prevention and treatment of diseases and improvement of human health. The activities below summarize specific activities that OCTGT staff participated in to support development of these products.
 
  • Co-sponsored with NIH a public workshop “Pluripotent Stem Cells in Translation: Early Decisions” (Bethesda, MD, March 21-22, 2011)http://www.fda.gov/Biologics BloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm241380.htm
  • Participated in an Interagency collaboration on a framework for biovigilance of tissues, cells, and organs.
 
Key approvals
 
Laviv (Azficel-T)• OCTGT approved the biologics license application for Laviv (Azficel-T) on June 21, 2011. Laviv is an autologous cellular product indicated for improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults.http://www.fda.gov/BiologicsBlood Vaccines/CellularGeneTherapy Products/ApprovedProducts/ucm260485.htm
 
Mission-Related Research
 
An increasing number of cell, tissue, and gene therapy (CTGT) products are reaching phase 3 trials, and BLAs are being submitted. CBER is conducting research to address such issues as product characterization, lot release testing, and stability testing. In order to facilitate FDA approval of CTGT products, FDA and product sponsors must know: 1) how to achieve understanding of product behavior preclinically and predict performance; and 2) how to approach characterization and quality control testing of these novel products.
 
OCTGT research is addressing these questions, as well as other CBER public health priorities, such as medical countermeasures against bioterrorism and control of pandemic influenza.
 
See more on gene and cellular research at: http://www.fda.gov/BiologicsBlood Vaccines/ScienceResearch/Biologics ResearchAreas/ucm124376.htm
 
See more on tissue research at:
http://www.fda.gov/Biologics BloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm124377.htm
 
For list of published articles in 2011 see CBER publications at: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm321284.htm
 
  • Mesenchymal stem cell (MSC) product

    OCTGT is measuring MSC properties upon serial passage and with cells from different donors, to identify candidate predictive markers of cell quality. These candidate markers will then be compared to biological performance of the cells in a variety of in vitro and in vivo systems. http://www.fda.gov/Biologics BloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm124376.htm

     
  • Targeted cancer therapy and tumor vaccines

    OCTGT researchers showed that the protein IL-13PE works synergistically with gemcitabine to inhibit tumor growth in mice, and that inhibition of the nuclear enzyme histone deacetylase sensitizes pancreatic tumor cells to IL-13PE. http://www.fda.gov/Biologics BloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm127167.htm

     
  • Cell surface marker

    OCTGT scientists showed that the protein DLK, which is found on stromal cells used to support lymphoid cultures, plays an important role in neurogenesis (development of certain nerve cells in the brain). http://www.fda.gov/Biologics BloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm127182.htm

     
  • Ebola envelope glycoprotein

    OCTGT scientists used antibodies to detect and characterize a variety of filoviruses; this technique can be used in future studies of viral envelope structure and function, as well as diagnostic and screening assays. http://www.fda.gov/BiologicsBloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm127154.htm

     
  • Universal influenza vaccination

    OCTGT scientists showed in an animal model that vaccination against conserved influenza virus antigens protects against human and avian strains, as well as against the 2009 pandemic H1N1 strain. http://www.fda.gov/BiologicsBloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm127152.htm

    Meetings of Advisory Committees

  • Advisory Committee meeting on Cell and Gene Therapy Trials in Retinal Disease (Silver Spring, MD, June 29, 2011)

    Discussed cellular and gene therapy products for the treatment of retinal disorders.
  • Advisory Committee meeting on New York Blood Center BLA for umbilical cord blood (Gaithersburg, MD, September 22-23, 2011)

    Discussed biologic license application for a device indicated for variety of medical disorders, such as hematologic malignancies, bone marrow failure, and a nervous system disorder, as well as a medical device used to harvest HLA-matched hematopoietic stem cells for treatment of myelogenous leukemia.
  • Advisory Committee meeting on Miltenyi Biotec HDE for CliniMACS CD34 Selection System (Gaithersburg, MD, September 22-23,2011)

    Discussed CliniMACS CD34 Selection System, Miltenyi Biotec, for processing allogeneic HLA-matched hematopoietic progenitor cells-apheresis (HPC-C).
  • Advisory Committee meeting on Apligraf (Oral), Organogenesis, Inc (Silver Spring, MD, November 17, 2011)

    Discussed Apligraf (Oral), Organogenesis, Inc., BLA 125400, for the treatment of surgically created gingival and alveolar mucosal surface defects in adults.
 
All materials for the above advisory committee meetings can be found at: http://www.fda.gov/Advisory Committees/Committees MeetingMaterials/Blood VaccinesandOtherBiologics/Cellular TissueandGeneTherapiesAdvisory Committee/ucm249846.htm

 
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OFFICE OF BLOOD RESEARCH AND REVIEW
 
The mission of the Office of Blood Research and Review (OBRR) is to ensure the safety, purity, and potency of blood and blood components, plasma derivatives and analogous products, blood donor screening tests, retroviral diagnostic tests, and certain medical devices used to collect, process or store donated blood and plasma, such as blood establishment computer software and blood collection equipment (e.g., automated blood cell separator devices).
 
As part of this mission, OBRR reviews new product applications, helps to ensure the safety of currently marketed products and the safety of blood donation and collaborates with academia, blood establishments, patient organizations, product developers, and government agencies.
 
OBRR also conducts mission-related research on blood and blood products, emerging infectious diseases, and current and emergent technologies. OBRR contributes to FDA emergency preparedness activities, helping to ensure a safe and adequate blood supply during local, regional, and national emergencies.
 
OBRR also participates in both domestic and international initiatives to improve biological product safety, including standards development, and collaborates with the World Health Organization and regulatory agencies throughout the world.
 
Major Leadership Activities
 
Biovigilance
 
In October 2009, FDA and other federal agencies issued a report that discussed recommendations of the Department of Health and Human Services Biovigilance Working Group for maintaining the safety of blood, human cells, tissues, and cellular and tissue-based products and organs. An OBRR representative co-chairs this working group and the office continues this collaboration. (See report at: http://www.hhs.gov/ash/bloodsafety/biovigilance/ash_to_acbsa_oct_2009.pdf).
 
Hemovigilance pilot programs recommended in the report have been successful and participants have held discussions about potential public-private partnerships.
 
XMRV
 
The finding in 2009 of Xenotropic Murine Leukemia Virus-Related Virus (XMRV) in the blood of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) patients prompted concern that the virus, previously associated with prostate cancer, could be transmitted through blood.
 
In response, the federal government formed the Blood XMRV Scientific Research Working Group. (See the Working Group report: http://online library.wiley.com/doi/10.1111/j.1537-2995.2011.03063.x/pdf)
 
In 2011, OBRR scientists, working as part of this Working Group, reanalyzed samples from healthy blood donors and chronic fatigue patients previously found to be positive for XMRV. The reanalysis suggested the previously observed results were likely false positives.
 
Other laboratories found similar negative results. It now appears that the positive)association between XMRV and CFS/ME was probably mistaken and XMRV detected in the blood of CFS patients was due to laboratory contamination.
 
eSubmitter
 
In FY 2011, OBRR piloted and implemented modules for its eSubmitter electronic submission program for manufacturers of Whole Blood and blood components, including Source Plasma (http://www.fda.gov/ForIndustry/FDAeSubmitter/default.htm). OBRR also provided guidance to manufacturers that wish to use eSubmitter (see Guidance section of the annual report), which is designed to improve efficiency both for FDA and regulated industry).
 
Personalized Medicine
 
OBRR, with representation from other CBER offices, established a team that will interact with other centers at FDA to discuss the agency’s approach to personalized medicine, in order to harmonize the review processes for companion diagnostic devices, direct-to-consumer devices, and genetic tests.
 
New OBRR Laboratories
 
 The Division of Blood Applications in OBRR established the Laboratory of Immunohematology and Molecular Testing. Immunohematology and molecular testing more precisely match donor red blood cell (RBC) components to a specific recipient than is possible with current techniques. This is particularly important for chronically transfused patients, such as those with sickle cell disease, who often make multiple antibodies to RBC antigens, thus complicating transfusion.
 
The laboratory’s first project will be to develop quality control reference panels for blood group genotyping kits that will facilitate the review of submissions of these genotyping kits, and will advance regulatory science in this important area.
 
The office’s Laboratory of Emerging Pathogens (LEP), another recently established program, continued its efforts to develop tests designed to ensure the safety of the nation’s blood supply by detecting malaria parasites and antibodies against these parasites in blood donors.
 
The laboratory is also conducting research in support of the development of candidate vaccines by using assays and animal models to predict the safety of live attenuated malaria vaccines, determine immunological correlates of protection induced by recombinant malaria vaccine candidates in mice, and identify host factors associated with pathogenesis of cerebral malaria in a mouse model. These projects should help prepare FDA scientists to review the latest generation of malaria vaccines now being developed.
 
Mission-related research
 
 In FY 2011, OBRR researchers contributed about 70 publications to peer-reviewed medical and scientific journals on various topics including transfusion - transmitted pathogens, such as malaria, babesia, leishmania, and variant Creutzfeldt-Jakob disease, and new and emerging technologies such as nanotechnology, and biologic metabolism and pharmacokinetics. OBRR mission-related research contributed to general scientific knowledge and supported OBRR in its role as the regulator of blood and blood products in the U.S. by providing new insights about product safety and efficacy and potential new treatments and technologies.
 
See selected research article summaries at: Innovations and Regulatory Science:

http://www.fda.gov/BiologicsBloodVaccines/ScienceResearch/ucm234680.htm).
 
See more on blood and blood product research at: http://www.fda.gov/BiologicsBloodVaccines/Science Research/BiologicsResearchAreas/ucm124375.htmFor list of published articles in 2011 see CBER publications at:

 
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm321284.htm
 
Workshops

Public Workshop: Product Development Program for Interventions in Patients with Severe Bleeding Due to Trauma or Other Causes (December 9-10, 2010)
 
Helped manufacturers and researchers better understand the FDA approach to regulating new products for the treatment of severe bleeding due to trauma and other causes.
 
http://www.fda.gov/Biologics BloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm230217.htm
 
Public Workshop Risk Mitigation Strategies to Address Potential Procoagulant Activity in Immune Globulin Products (May 17-18, 2011)
 
Convened the first discussion among major immune globulin manufacturers in which participants discussed data about thrombogenicity in a public forum to help improve product safety.
 
http://www.fda.gov/Biologics BloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm247285.htm
 
Public Workshop: Quarantine Release Errors in Blood Establishments (September 13, 2011)
 
Held to help FDA and blood establishments better understand the root causes of quarantine release errors (QREs) and reduce the already low number of units of blood or blood components inadvertently released that do not meet FDA requirements; also examined how QREs might be impacted by any change in the current lifetime deferral from blood donation of men who have had sex with men.

http://www.fda.gov/Biologics BloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm263117.htm
 
Key Product Approvals
 
  • INSTI HIV-1 Antibody Test (November 2010)

    The INSTI HIV HIV Antibody Test (bioLytical Laboratories Inc, British Columbia, Canada) is a single use, rapid, in vitro qualitative immunoassay for the detection of antibodies to HIV-1 in human whole blood, finger stick blood, or plasma specimens. It is intended to be used by laboratory personnel to rapidly screen patients for HIV at point-of-care settings.
 
http://www.fda.gov/Biologics BloodVaccines/BloodBloodProducts/ApprovedProducts/Premarket ApprovalsPMAs/ucm235024.htm
 
  • Corifact (Factor XIII Concentrate [Human]) (February 2011)
 
Corifact (CSL Behring, Marburg, Germany) is an orphan drug for the treatment of congenital factor XIII deficiency, a condition in which patients lacking Factor XIII form unstable blood clots and may experience bleeding episodes and complications. It is the only product approved in the US for this condition and was approved under accelerated approval regulations.
 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm243856.htm
 
  • LifeTrak®/Plasma (March 2011)
 
This approval was for a 510(k) supplement for a stand-alone blood establishment computer software (BECS) that is designed to help manage data related to Source Plasma donors, processing, management, inventory and shipping.
 
http://www.fda.gov/Biologics BloodVaccines/BloodBlood Products/ApprovedProducts/Substantially Equivalent510kDeviceInformation/ucm246436.htm
 
 
  • TRUGENE® HIV-1 Genotyping Kit and OpenGene® DNA Sequencing System (March 2011)

These devices are indicated for use in detecting HIV genomic mutations that confer resistance to specific types of antiretroviral drugs, as an aid in monitoring and treating HIV infection.

 
http://www.fda.gov/Biologics BloodVaccines/BloodBloodProducts/ApprovedProducts/Substantially Equivalent510kDeviceInformation/ucm246415.htm
 
  •  Kedbumin Albumin (Human) U.S.P. (June 2011)
 
Kedbumin Alubmin (Kedrion Biopharmaceuticals, SpA, Italy) is a plasma-derived albumin with indications for hypoalbuminemia, burns, and hypovolemic shock.
 
http://www.fda.gov/Biologics BloodVaccines/BloodBloodProducts/ApprovedProducts/Licensed ProductsBLAs/FractionatedPlasma Products/ucm 257839.htm
 
  • Bio-Rad GS HIV Ag/Ab Combo EIA (July 2011)
This assay, manufactured by Bio-Rad Laboratories, (Redmond, WA) is designed for use in early diagnosis of HIV infection. This assay can simultaneously detect the HIV-1 p24 antigen and antibodies to HIV-1 groups M and O, and HIV-2 in human serum and plasma. This test may be used as an aid in the diagnosis of infection with HIV-1 and/or HIV-2, including acute or primary infection and as an aid in the diagnosis of HIV-1 and/or HIV-2 infection in pediatric subjects (i.e., children as young as two years of age).
 
http://www.fda.gov/Biologics BloodVaccines/Blood BloodProductsApprovedProducts/PremarketApprovalsPMAs/ucm264723.htm
 
  • Anascorp (Centruroides [Scorpion] Immune F(ab’)2 (Equine) Injection) (August 2011)
 
Anascorp (Bioclon, Mexico) is the first FDA-licensed product specifically intended to treat Centruroides scorpion stings. This is a major public health advancement, as stings by these scorpions can cause severe allergic reactions and even death, in young children and other susceptible individuals.
 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2011/ucm266611.htm
 
  • UltraQual HBV PCR Assay (September 2011)

    This assay (National Genetics Institute, Los Angeles) is the third nucleic acid test approved for hepatitis B virus testing in Source Plasma and will be used in addition to hepatitis B virus surface antigen (HBsAg) tests. It is the first to be approved for testing pools of up to 512 individual plasma samples.
 
http://www.fda.gov/Biologics BloodVaccines/BloodBloodProducts/ApprovedProducts/Licensed Products BLAs/BloodDonorScreening/Infectious Disease/ucm270663.htm
 
Advisory Committee Meetings
 
Transmissible Spongiform Encephalopathies Advisory Committee (October 2010)
 
The committee discussed an updated FDA risk assessment model for potential exposure to variant Creutzfeldt-Jakob (vCJD) in US licensed plasma-derived Factor VIII. In addition, the committee endorsed FDA proposals for revised labeling for plasma derivatives, including plasma-derived albumin and CBER products that contain plasma-derived albumin, to reflect a potential risk of vCJD.
 
http://www.fda.gov/Biologics BloodVaccines/SafetyAvailability/ucm095107.htm
 
http://www.fda.gov/Advisory Committees/Committees MeetingMaterials/Blood VaccinesandOtherBiologics/TransmissibleSpongiform EncephalopathiesAdvisoryCommittee/ ucm225805.htm
 
Blood Products Advisory Committee (BPAC) (December 2010)
 
Based on then-current scientific findings suggesting potential link between XMRV and chronic fatigue syndrome (CSF), BPAC supported asking prospective blood donors about a medical history of chronic fatigue syndrome or CFS diagnosis as a basis for indefinite deferral. The committee also made recommendations on control of dengue virus in the US and addressed the issue of blood donor deferral.
 
http://www.fda.gov/Advisory Committees/CommitteesMeeting Materials/BloodVaccinesandOther Biologics/BloodProductsAdvisory Committee/ucm205013.htm
 
Blood Products Advisory Committee (April 2011)
 
The committee endorsed testing Source Plasma donations for hepatitis B virus nucleic acid testing; recommended establishing manufacturing standards for plasma obtained from Whole Blood donors intended for further manufacture; endorsed using Fresh Frozen Plasma only for further manufacture after its one year expiration date; advised FDA on proposed requirements for providing information to donors regarding the Whole Blood donation process.
 
http://www.fda.gov/Advisory Committees/CommitteesMeeting Materials/BloodVaccinesandOther Biologics/BloodProductsAdvisory Committee/ucm247665.htm
 
Transmissible Spongiform Encephalopathies Advisory Committee (August 1, 2011)
 
The committee voted to defer as donors of blood and blood components, including Source Plasma and other human-derived cells and tissues individuals who spent six months or more cumulatively in Saudi Arabia as US military personnel from the beginning of 1980 through the end of 1996 to reduce the risk of variant Creutzfeldt-Jakob disease; voted to defer blood donors and human cell and tissue donors who had otherwise spent more than 5 years cumulatively in Saudi Arabia between 1980 and 1996.
 
 http://www.fda.gov/Advisory Committees/CommitteesMeeting Materials/BloodVaccinesandOther Biologics/TransmissibleSpongiform EncephalopathiesAdvisoryCommittee/ucm261283.htm
 
Blood Products Advisory Committee (August 2-3, 2011)
 
The committee supported FDA proposal to help alleviate potential blood shortages during a severe emergency by reducing the inter-donation interval for certain eligible blood donors during a severe emergency; supported allowing individuals who previously tested positive for T. cruzi to donate following one negative test result for antibodies to this parasite without further donation.
 
http://www.fda.gov/Advisory Committees/CommitteesMeeting Materials/BloodVaccinesandOther Biologics/BloodProductsAdvisory Committee/ucm247665.htm
 
Efforts by the U.S. Government to prepare for public health emergencies, such as bioterrorism, radiation/nuclear or chemical attacks, as well as emerging infectious diseases comprise a number of essential activities in which CBER plays an integral role. One such activity is the expeditious development and licensing of products to diagnose, treat or prevent disease following exposure to pathogens that have been identified as bioterrorist agents. Staff must guide the products through the regulatory process, including the manufacturing process, pre-clinical testing, clinical trials, and the licensing and approval process. This process is extremely complex; therefore, early involvement in the process by FDA staff is critical to the success of the expedited review process and to the potential availability of a product under an emergency use authorization.
 
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COUNTERING BIOTERRORISM
 
Efforts by the U.S. Government to prepare for public health emergencies, such as bioterrorism, radiation/nuclear or chemical attacks, as well as emerging infectious diseases comprise a number of essential activities in which CBER plays an integral role. One such activity is the expeditious development and licensing of products to diagnose, treat or prevent disease following exposure to pathogens that have been identified as bioterrorist agents. Staff must guide the products through the regulatory process, including the manufacturing process, pre-clinical testing, clinical trials, and the licensing and approval process. This process is extremely complex; therefore, early involvement in the process by FDA staff is critical to the success of the expedited review process and to the potential availability of a product under an emergency use authorization.
 
CBER works with other federal agencies and industry, through the Public Health Emergency Medical Countermeasure Enterprise (PHEMCE) on a broad array of projects aimed at making our nation better prepared to respond to chemical, biological, radiological, and nuclear (CBRN) threats and emerging infectious diseases, through the development of new countermeasures.
 
CBER also monitors the impact of emergencies or outbreaks of disease on the safety and availability of the blood supply. Preparedness for and response to an attack involving biological agents are complicated by the large number of potential agents (most of which are rarely encountered naturally). Pathogens that have been identified as potential biological warfare agents include those that cause anthrax, botulism, plague, smallpox, tularemia, and the hemorrhagic fevers, among others.
 
Finally, CBER also supports the FDA’s Medical Countermeasure initiative through targeted regulatory science research that addresses key gaps in scientific knowledge, tools, or methods that are required to make regulatory assessments of products aimed to diagnose, treat, or prevent CBRN-relevant public health emergencies.
 
For more information on the counterterrorism work being done by CBER see: http://www.fda.gov/Biologics BloodVaccines/SafetyAvailability/ProductSecurity/ucm110311.htm

 

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INTERNATIONAL PROGRAMS
 
CBER carries out a critical part of its regulatory responsibilities through its International Program (IP). CBER regulates many products that address infectious diseases posing threats to both the US and other countries. IP also faces challenges arising from the growing globalization of the discovery, development, production, and distribution of products it regulates. Thus, the IP represents a coordinated and strategic use of CBER resources in meeting these challenges. The international activities at CBER are managed and coordinated by the Senior Advisor for International Affairs (SAIA) and staff on an International Team within the Office of the Director.
 
The functional areas of CBER’s international activities include:
 
  • Regulatory harmonization/convergence: The process by which the interpretation and/or application of technical guidelines can be made uniform or mutually compatible among various countries.
http://www.fda.gov/BiologicsBlood Vaccines/InternationalActivities/ucm 271079.htm
  • Regulatory capacity building: Assisting other countries to establish or strengthen effective agencies tasked with ensuring the safety and effectiveness of biological products

http://www.fda.gov/BiologicsBlood Vaccines/InternationalActivities/ucm 271082.htm

  • Information sharing: Conferring with regulatory counterparts globally to discuss such issues as product safety, scientific challenges, and inspections in order to better inform the center’s own regulatory decision making and provide access to additional scientific resources and regulatory experience.

http://www.fda.gov/BiologicsBlood Vaccines/InternationalActivities/ucm 271098.htm

  • International standards setting and collaborative research: CBER is a Pan American Health Organization (PAHO)/World Health Organization (WHO) Collaborating Center for Biological Standardization.
     
http://www.fda.gov/BiologicsBlood Vaccines/InternationalActivities/ucm 271529.htm
 
 
Major leadership activities

Foreign Regulatory Seminar (Web-Based): CBER’s Regulation of Biologics
In FY 2011, CBER introduced a web-based program on the work at CBER in the oversight of biological products in the United States, generated from a live program held in October 2009. This web-based production, targeting an audience of international regulatory counterparts, reaches those who could not participate in past meetings, or will not be able to participate in future live events held by CBER.
 
http://www.fda.gov/Biologics BloodVaccines/InternationalActivities/ucm272086.htm
 
Collaborative Regulatory Science and Capacity Building to Advance Global Access to Safe Vaccines and Biological Products
 
CBER/WHO Cooperative Agreement
 
CBER awarded a cooperative agreement grant to WHO on September 14, 2011 to support scientific collaboration and enhance regulatory capabilities of national regulatory authorities (NRAs) to advance global access to safe and effective vaccines and other biologicals that meet international standards. This agreement will further enhance technical cooperation between FDA, WHO, and its member states, with a particular focus on strengthening influenza vaccine regulation for grantee countries, which will contribute to global vaccine access and availability.http://www.fda.gov/Biologics BloodVaccines/ScienceResearch/ucm274213.htm
 
Major International Leadership Activities of CBER Offices
 
Office of Cellular, Tissue and Gene Therapy (OCTGT)
 
OCTGT improved global public health through international collaboration, including research and information sharing through the following activities:
 
  • International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
 
 - Initiated discussion of cellular therapy regulatory convergence effort within Regulators Forum (ICH).
 
- Discussed issues related to advanced therapy medicinal products with the European Medicines Agency (EMA).
 
- Worked with EMA to harmonize regulatory advice for evaluating clinical trials for biologics.
 
  • Participated in the Asia Pacific Economic Cooperation Life Sciences Innovations Forum (APEC/LSIF) in support of regulatory convergence of stem cell therapies (Bangkok, Thailand, July 5-7, 2011).
 
  • Consulted with WHO in xenotransplantation issues.
 
  • Participated in several European Commission biovigilance intiatives (EUSTITE, SOHO V&S, and Project NOTIFY) aimed at improving clinician recognition of, and global communication about, serious adverse events and reactions related to clinical use of human organs, tissues, and cells, including assisted reproductive therapies.
 
  • Led FDA participation at the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) aimed at incorporating refinement, reduction, and replacement of animal use in translational research, product development, and safety testing for biologics (vaccines, and cell and gene therapies) (8th World Congress on Alternatives and Animal Use in the Life Sciences, Montreal, Canada, August 21-25, 2011).
 
Office of Vaccines Research and Review (OVRR)

 
OVRR continued its collaborations with WHO and other international organizations to advance vaccine development programs worldwide. Among the collaborations were:
 
  • Contributing to the worldwide efforts to select yearly seasonal influenza vaccine strains as an Essential Regulatory Laboratory in the WHO Global Influenza Surveillance and Response System; also, in collaboration with the Office of Compliance and Biologics Quality, contributing to the worldwide efforts to generate appropriate reference virus strains and reference reagents for influenza vaccine production, both seasonal and pandemic.
 
  • Working with the WHO-coordinated African Vaccine Regulatory Forum (AVAREF) to define the oversight roles of the National Regulatory Authorities (NRAs) of its 19 member nations. OVRR and other experienced NRAs, such as the EMA, shared advice in the regulation of clinical trials of vaccines, interacting with national and local IRBs and ethical committees to strengthen NRA capacity to regulate new medical products. This is key to capacity building, since it helps increase the number of competent NRAs throughout the world.
 
  • Participating in WHO assessments of regulatory systems of global NRAs and capabilities of countries and regions, including China and Egypt, to determine their competency. These assessments were then available for use by the WHO vaccine prequalification program to provide independent guidance and advice to the United Nations (UN) on the quality, safety, and efficacy of vaccines being considered for purchase by UN agencies. This assistance helped to ensure that each vaccine under consideration is suitable for target populations and complies with established standards of quality. In FY 2011, CBER participated in assessments of both China and Egypt.
 
  • Serving as a technical expert to advise WHO in the areas of research, manufacturing, and potency testing of polio vaccines.
 
  • Working with the WHO Developing Countries’ Vaccine Regulators Network (DCVRN), composed of national regulatory authorities (NRAs) from developing and emerging-economy countries. In FY 2011 OVRR, along with WHO and HHS, collaborated with the DCVRN, the Brazilian National Health Surveillance Agency, Pan American Health Organization, Health Canada, EMA, and other key stakeholders to develop international regulatory capacity enhancement for influenza vaccines.
 
Office of Blood Research and Review
 
International Society on Thrombosis and Haemostasis (ISTH) (Kyoto, Japan, July 22-28, 2011)
 
The Office delivered several presentations on topics including regulatory considerations for clinical trials supporting licensure of novel Factor VIII and Factor IX products, the suitability of insect cells for the expression of human coagulation factor VIII, and the association of Factor XIa in intravenous immune globulin products with thrombotic adverse events.
 
EMA-FDA Blood Cluster

 
OBRR continued its participation in the FDA-European Medicines Agency (EMA) information exchange on drugs intended for human and animal use, medical devices, and biologics:

 
http://www.fda.gov/InternationalPrograms/Agreements/Confidentiality Commitments/ucm093989.htm.
 
As part of this collaboration, FDA/OBRR staff hold bimonthly conference calls with their EMA counterparts and have disucssed such issues as product safety and postmarket monitoring.
 
This program facilitated information-sharing about pending applications and post-marketing surveillance activities. To facilitate further collaboration, FDA and EMA have agreed to share information about scientific breakthroughs in certain “clusters of interest” relevant to both the US and European Union, including one relevant to blood products:

 
http://www.fda.gov/InternationalPrograms/FDA Beyond OurBordersForeignOffices/European Union/ucm 114345.htm.
 
The FDA- EMA blood cluster held its first meeting in February 2010. In FY 2011, OBRR discussed such topics as immune globulins.
 
World Health Organization (WHO) activities

 
  • Worked with WHO to develop biological reference preparations for blood products and in vitro diagnostic devices.• Participated in the International Conference for Drug Regulatory Authorities (ICDRA), chairing workshops and providing presentations on blood products and antivenoms.
  • Participated in the Blood Regulators Network and the annual meeting of the Expert Committee on Biological Standardization (ECBS), and discussed FDA’s pre-market requirements for HIV and malaria rapid diagnostics with the Technical Working Group on Product Dossier Assessment for Prequalification of Diagnostics.
  • Discussed with the WHO Blood Regulators Network (BRN) the agency’s approach to regulation of blood and blood products
  • Participated in the annual meeting of WHO’s Expert Committee on Biological Standardization to discuss such topics as blood and in vitro diagnostics product
  • Provided advice to the WHO Technical Working Group on Product Dossier Assessment for Prequalification of Diagnostics on pre-market requirements for HIV and malaria rapid diagnostics.
 
International Society of Blood Transfusion (ISBT)
 
  • Supported efforts by the ISBT Working Party on Transfusion-Transmitted Infectious Diseases to establish a repository for bacteria linked to contamination of platelet products in order to support product validation and testing efforts and improve product safety.
  • Collaborated on the development of the first international standard for alpha-1-antitrypsin products that will be used to help standardize potency for therapeutic products.
  • Presented a draft document prepared by a working party of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (SSC-ISTH) that describes principles for regulators and industry to consider in developing new Factor VIII and Factor IX coagulation products. International acceptance of these principles and eventual incorporation of these ideas into FDA guidance will help to harmonize potency assignments and labeling of these products.
 
Office of Biostatistics and Epidemiology
 
World Health Organization
 
  • Collaborated with WHO to improve global vaccine safety, through an ongoing collaborative international proof-of-concept study on the association between Guillain-Barré syndrome and H1N1 influenza vaccines. OBE initiated a collaborative approach to monitor potential serious vaccine reactions.
  • Resumed transmission of US Vaccine Adverse Events Reporting System (VAERS) reports to the VigiBase database of WHO’s Uppsala Monitoring Centre in support of an exploratory data mining project to assess the additional value of international data sharing to OBE’s safety signal detection process.For more information on the International Program see:
http://www.fda.gov/BiologicsBlood Vaccines/InternationalActivities/default.htm
 
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SAFETY TEAMS
 
CBER responds to product safety issues through its Blood Safety Team, Tissue Safety Team, and Vaccine Safety Team. These teams comprise product scientists, clinicians, epidemiologists, and manufacturing and communications experts. They coordinate investigations with other agencies and regulatory partners, formulate appropriate responses, and communicate with stakeholders.
 
Safety teams meet regularly and during emergencies, help to develop and guide strategic and scientific approaches to enhance safety, and collaborate with other components of FDA and other agencies, particularly the Centers for Disease Control and Prevention.
 
Blood Safety Team
 
The safety of the blood supply and of blood components is critical to the large number of individuals who receive these potentially life-saving therapies each day. Despite the fact that many of the products have been available for many years, systems to detect potential safety signals in large populations of treated individuals have only become available more recently.
 
Based on increased reports of thrombotic events following the administration of intravenous immune globulin, the agency is further investigating testing methods for the thrombotic potential of these products.
 
Laboratory evaluation of thrombotic events related to administration of an intravenous immunoglobulin product suggested an association with elevated levels of coagulation Factor XIa, a natural protein found in blood that helps to trigger clot formation. FDA organized an international public workshop to discuss how to reduce the risk of thrombotic events linked to IGIV products. The agency is working with all IGIV manufacturers to institute testing of these products before they are released to the marketplace, in order to identify lots containing elevated levels of FXIa levels.
 
FDA is also collaborating with the National Institute for Biological Standards and Control (United Kingdom) to develop an international standard for testing immunoglobulin products for their potential to cause clots following administration.
 
Tissue Safety Team
 
Human cells and tissues present unique safety challenges, especially the risk of transmitting communicable diseases from donor to recipient, and the risk of contamination during processing.
 
In FY2011, the Tissue Safety Team (TST) received an average of 9 adverse reaction reports per month involving a communicable disease in tissue recipients; most reports were from cell and tissue manufacturers. Reports of communicable 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.
 
The TST collaborated with CDC in the investigation of reports of potential communicable disease transmission through organ transplantation, where tissues also were recovered from the same donor. The TST did not identify
any significant public health threats requiring further action after thorough review and investigation of reports of potential communicable disease transmission.
 
Vaccine Safety Team
 
In FY 2011, the Vaccine Safety Team (VST) played an important role as a forum for discussing and enhancing cross-center communication on vaccine safety topics. Throughout the year, VST kept key CBER staff informed of important safety surveillance initiatives, communications efforts, and ongoing public health activities throughout the center and other Department of Health and Human Services agencies.
 
In FY 2011, the VST informed and contributed to CBER decisions on:
 
  • Surveillance and detection of safety signals following administration of influenza vaccines
  • Refinement of internal processes to address potential safety signals for vaccines

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OFFICE OF BIOSTATISTICS AND EPIDEMIOLOGY
 
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 Research Team in the Immediate Office of the Director.
 
Major leadership activity
 
OBE has taken the leadership role in the following areas of trial design, safety evaluations, and post-licensure monitoring of vaccines and other biologics regulated by CBER.
 
Review and Evaluation of Regulatory Submissions
 
OBE contributed to all approved applications for FY 2011:
 
http://www.fda.gov/BiologicsBlood Vaccines/DevelopmentApproval Process/BiologicalApprovalsbyYear/ucm242930.htm
 
In particular, the Division of Biostatistics made significant contributions in the areas of statistical analyses, competing risk models, and quantitative evaluation of submissions on cord blood establishment and devices for transplant patients.
 
The Division of Epidemiology made significant contributions in the review and evaluation of post-marketing surveillance studies, 11,000 reports on serious adverse events, and 279 annual or quarterly safety update reports.
 
Bayesian and Adaptive Clinical Trial Designs
 
OBE contributed to the development of innovative clinical trial designs that could shorten the product development process, reduce the cost of clinical trials, and enhance chances of success of the clinical trial using modern statistical methods. In particular OBE investigated Bayesian statistical methods that allow combining information from previous studies or information gathered during an ongoing study to modify the trial according to pre-specified guidelines. The office provided advice to sponsors on the use of adaptive designs at all phases of product development including, e.g., shortening the time of the trial or increasing study size.
 
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidance documents/ucm071072.htm)
 
Statistical Methods in Bioassay, Assay Validation, and CMC
 
OBE provided statistical expertise on the design and analyses of bioassays, validation of bioassays, and assessment of chemistry, manufacturing, and controls (CMC) protocols for manufacturing of vaccines. OBE staff also participated in a US Pharmacopeia Statistics Expert Committee developing guidelines for design, analysis and validation of potency assays, and in a Clinical Assay Working Group of the International Society for Clinical Biostatistics that is preparing a technical paper on clinical assays.
 
Improving Safety Assessments
 
OBE evaluated and re-engineered key internal processes and implemented training procedures in advanced analytical methodologies in data mining to optimize the assessment of safety signals in very large databases. This process improvement, combined with application of new information technology, facilitated systematic surveillance of CBER licensed products. Several FDAAA mandated key surveillance procedures were implemented.
 
In FY 2011, OBE cooperated with product offices to post information about fibrin sealants (Evicel and Tisseel) and graft failure in ophthalmologic and neurosurgical procedures, as well as information about subcutaneous immune globulin (Vivaglobin) and thromobotic events. These postings are available at:
 
http://www.fda.gov/Drugs/Guidance ComplianceRegulatoryInformation/Surveillance/ucm082196.htm
 
In FY2011, OBE posted comprehensive postmarketing safety evaluations for two widely used vaccines, Ixiaro and Hiberix, on the following site:
 
http://www.fda.gov/Drugs/Guidance ComplianceRegulatoryInformation/Surveillance/ucm204091.htm
 
Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program
 
OBE led the integration of the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program into the FDA Mini-Sentinel Project. PRISM is a national claims-based active surveillance system originally developed in 2009 for H1N1 influenza vaccine safety surveillance. PRISM is the largest population-based vaccine safety surveillance system in the United States and continues to be expanded and transformed into a multi-purpose vaccine safety surveillance program within FDA’s Sentinel Initiative. The goal of this program is to create a sustainable active surveillance system to inform regulatory decision making and advance safety science. PRISM is currently evaluating two rotavirus and one human papillomavirus vaccine to help clarify potential safety concerns that have been reported by other surveillance systems and to enable FDA to better assess any potential risk.
 
Blood Safety Continuous Active-surveillance Network (Blood-SCAN)
 
OBE contributed to the initiation of Blood Scan, a second major program in the FDA Mini-Sentinel Project. During the first three years (2011-2014) of the program’s development, Blood-SCAN will identify data resources and analytic techniques for assessing safety concerns regarding blood and blood-derived products, as well as validate administrative code data used for blood products and related outcomes. The Blood-SCAN system will permit ongoing confirmation of safety issues that may impact this group of medical products.
 
Influenza vaccine safety surveillance
 
OBE continued to play a major leadership role in planning, coordinating, and implementing influenza vaccine safety surveillance and research through collaboration with the National Vaccine Program Office (NVPO), Centers for Disease Control and Prevention (CDC), Centers for Medicare and Medicaid Services (CMS), Indian Health Service (IHS), Department of Defense (DoD) and Veterans Administration (VA). During the 2010-2011 northern hemisphere influenza season, OBE reviewers identified a safety signal for febrile seizures in young children after a seasonal influenza vaccine, Fluzone, through statistical data mining of the Vaccine Adverse Event Reporting System (VAERS) database. CDC conducted studies through its Vaccine Safety Datalink that followed more than 200,000 children 6 months through 4 years of age. The analyses showed that febrile seizures following influenza and pneumococcal conjugate (Prevnar13) vaccines did occur, but were rare. These results were reviewed by FDA, CDC, and the CDC’s Advisory Committee on Immunization Practices. This review concluded that the benefits of vaccination in protecting against serious influenza disease in young children outweighed any risk from febrile seizures and recommendations for vaccination with influenza and pneumococcal conjugate vaccine were not changed. In the Centers for Medicare & Medicaid Services database, seasonal influenza vaccine near- real-time surveillance and an end of season analysis for Guillain Barré Syndrome (GBS) was completed for the 2010-2011 northern hemisphere season. Near real-time surveillance for GBS after seasonal influenza vaccine was initiated for the 2011-12 season.
 
Expanding Vaccine Safety Surveillance using large healthcare claims databases
 
OBE staff continued to work with multiple external collaborators on vaccine safety concerns and development of better mathematical and statistical analysis of safety data including testing novel data mining methods.
 
Expanding Blood and Blood Derived Product Safety Surveillance using large healthcare claims databases
 
Staff from OBE and OBRR developed and used statistical techniques to estimate the rate of occurrence of transfusion-related acute lung injury (TRALI), hemolytic transfusion reactions, and immune globulin-related thrombotic events. An important contribution was the detection, using the HealthCore database, of a previously unidentified safety issue regarding thromboembolic events following use of a subcutaneous immunoglobin. In another study, OBE collaborated with OBRR and CMS using Medicare claims data to analyze occurrence of babesiosis among the elderly persons in the U.S.
 
Advance Risk Assessment for Emerging Infectious Diseases for Blood and Blood Products
 
To acquire specific data for risk assessments in support of effective public health decision-making, OBE sponsored a public workshop titled “Data and Data Needs to Advance Risk Assessment for Emerging Infectious Diseases for Blood and Blood Products”. The workshop goal was to develop consensus on rapid data collection for risk assessment in two areas: the donor screening questionnaire and estimates of prevalence for asymptomatic emerging infectious diseases (EID) in donor populations.
 
http://www.fda.gov/Biologics BloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm 272047.htm
 
Supporting and Enhancing the Use of Epidemiologic Tools among Researchers and Reviewers in the US and Globally
 
OBE staff gave many presentations, organized scientific sessions, and taught courses at a variety meetings and conferences organized by industry, academia, and government. OBE also held a series of six seminars in which international experts in the areas of clinical trial designs, biostatistics, and post-marketing safety evaluations provided training workshops to staff members from CBER and other FDA Centers.
 
OBE staff participated in the development of the following guidance documents released by CBER:
 
  1. Draft Guidance for Industry, Clinical Investigators, and Food and Drug Administration Staff – Design Considerations for Pivotal Clinical Investigations for Medical Devices (August 2011, with CDRH)
  2. Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products (January 2011)
 
See “Guidances” section of this report for details.
 
Advisory Committee meetings
 
OBE staff gave presentations at the following Advisory Committee meetings:
 
Cellular, Tissue and Gene Therapies Advisory Committee (September 22-23, 2011)
 
(See advisory committee listing in “Office of Cellular, Tissue and Gene Therapies.”)
 
http://www.fda.gov/Advisory Committees/Calendar/ucm267714.htm
 
Transmissible Spongiform Encephalopathies Advisory Committee (August 1, 2011)
 
(See advisory committee listing in “Office of Blood Research and Review.”)
 
http://www.fda.gov/Advisory Committees/Committees MeetingMaterials/Blood VaccinesandOtherBiologics/TransmissibleSpongiform Encephalopathies Advisory Committee/ucm275567.htm
 
Pediatric Advisory Committee (September 22-23, May 17-18, May 16, and May 11, 2011)
 
Ethics of administering subtherapeutic doses of investigational products to children for the purpose of determining, drug metabolism, disposition, and targeting.
 
http://www.fda.gov/Advisory Committees/CommitteesMeeting Materials/PediatricAdvisoryCommittee /ucm247489.htm
 
Allergenic Products Advisory Committee (May 12, 2011)
 
Discussed statistical aspects of clinical trials of allergenic products.
 
http://www.fda.gov/Advisory Committees/Committees Meeting Materials/BloodVaccinesand Other Biologics/AllergenicProducts Advisory Committee/ucm263446.htm
 
Vaccines and Related Biological Products Advisory Committee (February 25, 2011)
 
(See advisory committee section of Office of Vaccines Research and Review above.)
 
http://www.fda.gov/Advisory Committees/CommitteesMeeting Materials/BloodVaccinesandOther Biologics/VaccinesandRelated BiologicalProductsAdvisory Committee /ucm 246393.htm
 
Pediatric Advisory Committee (December 7, 2010)
 
Discussed pediatric-focused safety reviews, as mandated by the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, for a variety of drugs and vaccines.
 
http://www.fda.gov/Advisory Committees/CommitteesMeeting Materials/PediatricAdvisory Committee/ucm234285.htm
 
http://www.fda.gov/AdvisoryCommittees/Committees MeetingMaterials/PediatricAdvisory Committee/ucm235853.htm
 
Pediatric Advisory Committee (December 6, 2010)
 
Discussed donor and banked human breast milk. FDA convened the meeting to obtain and discuss information and data to provide the Agency with a better understanding of current practices, and potential benefits and risks associated with the donation and banking of human milk.
 
http://www.fda.gov/Advisory Committees/CommitteesMeeting Materials/PediatricAdvisory Committee/ucm201871.htm
 
For a list of publications in 2011 see: http://www.fda.gov/About FDA/CentersOffices/Officeof MedicalProductsandTobacco/CBER/ucm321284.htm
 
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REVIEW MANAGEMENT
 
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 and CBER reviewers follow best internal practices of product review. MPR also efficiently and simultaneously manages the ongoing review of many biological products in various stages of the product lifecycle.
 
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. This year CBER started initial planning for an electronic MRP (eMRP). This will electronically provide information to reviewers and other staff about timelines and regulatory requirements, further facilitating review functions.
 
In FY 2011, RM continued to enhance the robustness of the review process by improving or instituting a variety of projects and collaborations, as listed below.
 
 
Identifying best practices for regulatory review
 
RM staff improved MRP by identifying best practices, developing opportunities to simplify the process, and improving the quality and consistency of the review. This included looking for commonalities among the seven regulatory pathways CBER uses to regulate products. CBER also improved the ability of CBER to keep current with evolving regulatory requirements by instituting internal tool that provides timely, targeted information to the staff.
 
External Standards
 
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 2011, approximately 142 CBER staff participated in 116 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 American Society For Testing and Materials to develop product standards for tissue based products
  • serving as liaison to AABB scientific committees and reviewing standards for blood establishments
  • collaborating with the National Institute For Biological Standards and Control to help set standards for seasonal influenza vaccine reagents
  • 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.
 
Bioinformatics and Information Technology
 
The RM staff continued to support the transition from paper to electronic submissions and records by organizing 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 support development of standard terminologies for drug review and regulation by providing expertise and guidance to the Healthcare Information Technology Standards Panel (HITSP) of the American National Standards Institute (ANSI). 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 also initiated ongoing changes that increased the use of electronic communications for submission and review. Notable FY 2011 accomplishments of RM staff in support of the bioinformatics and information technology include:
 
Study Data Tabulation Model (SDTM)
 
In FY 2011, CBER received 25% of Original and Efficacy BLA submissions in SDTM as the standard for the electronic submission of human clinical trial data. CBER clinical review staff continued to expand the standard to include domains required to meet the needs of biologic product submissions. 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 FY 2011, CBER announced acceptance of ADaM for all regulatory submissions. Review staff continued to assess the standard and identify areas for expansion to meet the needs of biologic regulated products. For more on ADaM see: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/
ElectronicSubmissions/ucm248635.htm
 
RM and CBER review staff participated in the Patient Centered Outcome Research (PCOR) project under ARRA (Recovery Act). The goal of this three-year endeavor, which has four components, is to promote high quality care by providing scientific information that helps clinicians and patients determine the care that best suits their needs. The four components are:
 
1. Janus Repository: Updated the Janus physical database design and automated the validation, loading and management of clinical trials data in a data warehouse to support regulatory review and patient-centered outcome research.
 
2. Legacy Data: Converted legacy data on comparative efficiency from clinical studies to a standard format for storage in the data repository; this helps to answer important scientific questions that bear on public health issues.
 
3. Modern Analytical Tools: Support comparative effectiveness research using the clinical study data repository in conjunction with existing analysis tools as well as pilots of new tools, such as JMP Clinical (software for identifying adverse events in clinical trial data) and Spotfire (data analysis and visualization software).
 
4. PACES (Partnership in Applied Comparative Effectiveness Science): Facilitate development of advanced and robust analyses for detecting clinical trends that identify which interventions are most effective for specific patients under specific circumstances, e.g., innovative clinical trial design and scientific computing strategies
 
Structured Product Labeling
 
Structured Product Labeling (SPL) is a Health Level Seven (HL7) message exchange standard for establishing a robust repository of establishments and products. SPL facilitates storing, accessing, and evaluating product information, such as active ingredients, strengths, dosage forms, and routes of administration.
 
In FY 2011, CBER staff expanded its HL7 SPL implementation by applying additional electronic validation criteria to currently submitted regulatory data and developing standards for other CBER regulated product classes. Per the “Guidance for Industry: Indexing Structured Product Labeling” (June 2008), CBER completed the necessary data elements and structures for indexing pharmacologic class for vaccines and plasma derived products.
 
In addition, CBER began indexing allergenic extracts, a project that should be completed by FY 2012. 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.
 
On June 1, 2009, an electronic establishment registration and listing system went into effect for products regulated by CBER and that are required to be registered and listed under 21 CFR 207 (e.g., vaccines, allergenics, and plasma derivatives). In FY 2011, CBER began gathering business and technical requirements, using the Health Level Seven (HL7) SPL standard and establishment registration and listing system, to include blood/blood components and cell/tissue products. This will replace the current paper registration and listing now used for these products and harmonize all CBER regulated product classes into standard for data exchange and validation. CBER will continue to support stakeholders as they transition from paper to the electronic system.
 
Information Technology System Enhancements
 
In FY 2011, CBER completed the upgrade of IT systems from older client server technology to Web-based technology. This upgrade makes the systems significantly more reliable, reduces their dependency on desktop configurations, and increases their overall security capability and footprint.
 
Other technology upgrades included Oracle, Documentum, and architectural changes to comply with new FDA standards.
 
The CBER Electronic Document Room, an internal collaboration and document sharing tool, was redesigned and released in March 2011, which focused on streamlining the user interface, integrating more seamlessly with related IT systems, providing a location to store review-related documents that had no other storage location, and a records management application (RMA) for document tracking and retention scheduling. The updates to the CBER EDR increased efficiency for more than 1000 users, provided more accurate data from four related systems, provided the Document Control Center (DCC) with an electronic RMA tool, and reduced reviewers’ need for multiple copies of submissions and documents.
 
RM developed a new reporting system for CBER’s adverse event reporting and lot distribution data systems (CBAERS, VAERS, and LDD) to support Office of Biostatistics and Epidemiology requirements for vaccine and therapeutic products safety surveillance, in compliance with Section 915 and 921 of FDAAA. This consolidated DataMart significantly improved data reporting and inquiries.
 
RM also incorporated a PHINMS messaging system into the VAERS systems architecture to ensure secure data exchange between FDA/CBER and CDC. New functionality was also developed to support Data Mining Text features enabling additional surveillance methodologies for standardizing information for a comprehensive review of incoming adverse event reports.
 
FDA Electronic Submission Gateway (ESG) is the central transmission point for sending information electronically to CBER and the FDA, and is managed by CBER for the Agency. Under CBER leadership in calendar year 2011, the FDA ESG processed more than one million electronic submissions (i.e., adverse event reports and regulatory applications/submissions).
 
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OFFICE OF COMPLIANCE AND BIOLOGICS QUALITY
 
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.
 
Significant Regulatory Activities
 
Order to Cease Manufacturing of HCT/Ps Issued to Trent Arsenault

On November 1, 2010, FDA issued an Order to Cease Manufacturing to Trent Arsenault (Fremont, California) following inspection of its facilities for recovering and distributing semen, based on failure of the company to provide adequate protections against the risks of communicable disease transmission via their product.
 
For more information on this action, go to: http://www.fda.gov/Biologics BloodVaccines/SafetyAvailability/TissueSafety/ucm232852.htm
 
Order to Cease Manufacturing of HCT/Ps Issued to Sunrise Medical Laboratories, Inc.

On February 23, 2011, FDA issued an Order to Cease Manufacturing to Sunrise Medical Laboratories, Inc. (Hicksville, New York), which tests donors of reproductive HCT/Ps for relevant communicable disease agents and diseases, for violations that failed to provide adequate protections against the risks of communicable disease transmission. Following compliance with applicable regulations, FDA authorized them to resume operations.
 
For more information on this action, go to: http://www.fda.gov/Biologics BloodVaccines/SafetyAvailability/TissueSafety/ucm244563.htm
 
Warning Letters Issued to Two Reproductive HCT/P Establishments On June 14, 2011, FDA’s Detroit District Office issued a Warning Letter to Advanced Fertility Group, PC, Evansville, Indiana, following an inspection that documented deviations from the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps). The deviations included certain failures in donor screening and specimen testing.
 
To view the full text of the Warning Letter go to: http://www.fda.gov/ICECI/EnforcementActions/Warning Letters/2011/ucm263857.htm
 
FDA issued a Warning Letter on July 15, 2011, to Seattle Sperm Bank, LLC (Seattle, Washington) following documentation of significant deviations from the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps). Among the deviations were failure to determine as ineligible those donors with risk factors for, or clinical evidence of, relevant communicable disease agents or diseases, or whose specimen tests were reactive on a screening test for a communicable agent.
 
To view the full text of the Warning Letter go to: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters /2011/ucm263833.htm
 
 
Warning Letter Issued to Octapharma AB
 
On April 15, 2011 FDA issued a Warning Letter to Octapharma AB (Stockholm, Sweden) following documentation of significant deviations from current good manufacturing practice in the manufacture of Octagam and Octagam intermediates. Among the deviations were failure to ensure that validation of the manufacturing process was conducted properly, inadequate investigations for out-of-specification results for clarity, and failure to ensure Octagam is free from turbidity as determined by visual inspection of final containers.
 
To view the full text of the Warning Letter go to: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters /2011/ucm254485.htm
 
Company Charged and Convicted of Introducing an Unapproved New Drug- Stem Cells- into Interstate Commerce
 
Fredda Branyon, of Scottsdale, Arizona, former owner of Global Laboratories LLC, pleaded guilty and was convicted on August 18, 2011, for introducing an unapproved new drug, stem cells, into interstate commerce for non-research purposes without FDA approval. Branyon admitted that she knew that FDA approval was required to distribute stem cells for non-research related purposes but nonetheless sold the stem cells. According to the factual basis filed with the plea agreement, Branyon sold approximately 183 vials containing stem cells to an individual in Brownsville, Texas, on 27 separate occasions between April 2009 and February 2010, and received approximately $300,000 for the sale of the stem cells.
 
Branyon faces up to three years in prison and a fine of up to $10,000 for the conviction.
For more information, go to: http://www.justice.gov/usao/txs/
 
Physician Charged with Falsifying Clinical Drug Trial
 
CBER issued a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) to clinical investigator Wayne E. Spencer, M.D. (Topeka, Kansas), and by consent agreement he was later disqualified as a clinical investigator.
 
Dr. Spencer was subsequently indicted on charges of falsifying study data in a clinical drug trial he was paid to conduct.
 
Spencer and his clinical research coordinator, Lisa Sharpe, entered guilty pleas on and face a maximum penalty of five years in federal prison and a fine up to $250,000 on the conspiracy charge, a maximum penalty of 20 years, and a fine up to $250,000 on each of the mail fraud charges, and a maximum penalty of three years and a fine up to $10,000 on providing false information to the FDA.
 
For more information, go to: http://www.justice.gov/usao/ks/Press Releases/2011/oct/Oct19a.html 
 
http://www.fda.gov/downloads/RegulatoryInformation/FOI/Electronic ReadingRoom/UCM263782.pdf

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CRITICAL PATH INITIATIVE
 
CBER Research Prepares Reviewers to Evaluate Future Biologic Products
 
The Critical Path Initiative is designed to help FDA foster innovation in the development, regulation, evaluation, and use of medical products:  (http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/default.htm).
 
CBER staff collaborate with FDA’s Office of Critical Path Programs and other stakeholders to contribute to the agency’s objectives for this program.
 
These efforts are important because many new therapies with the potential to change medical care in the 21st Century are complex biological products, such as gene and stem cell therapies. These products are the fruits of breakthroughs in fields such as genomics, proteomics, nanotechnology, and stem cell biology. In order to provide expert and timely regulation of these products, CBER researcher-reviewers must have state-of-the-art knowledge and skills to evaluate their safety, purity, and potency.
CBER research also addresses threats to the safety of the blood supply from existing and emerging infectious diseases that necessitate careful screening of donor blood and plasma and therapeutic substances derived from them. In addition, CBER 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 effectiveness of certain vaccines.
 
Recognizing these challenges, CBER supports and pursues mission-related 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).
 
In 2004, FDA launched CPI in response to the significant decrease in the number of submissions of new products for approval that was occurring despite major advances in medical science. (See “Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products”): http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htm
 
CBER Projects funded through the Critical Path Initiative
 
In FY2011, CBER scientists made further progress that contributed to the development of new testing methods aimed to improve the potency and efficacy of certain vaccines and allergens. In addition, CBER advanced innovative therapies by developing in vivo and in vitro methods to identify measurable characteristics to ensure the safety, quality, and potency of novel biologics. Furthermore, CBER made advances in protecting the blood supply by developing methods to monitor the safety and quality of donated blood and blood products.
 
CBER scientists conducted several of these projects through collaborations with academic institutions and other government institutions, such as the Albert Einstein College of Medicine, Hannover Medical School (Germany), Baylor College, Feinstein Institute for Medical Research, New York University, University of Pittsburgh, University of Virginia, the National Institutes of Health, and the National Institute of Standards and Technology.
 
 The proactive approach CBER takes continues to enhance the development of innovative technologies and novel therapies that will improve public health.
 
Improving Tools and Testing for Vaccine Safety and Potency
 
  1. Using novel technology to evaluate the safety and potency of polysaccharide-based vaccines by assessing their identity, structure, stability, and impurity profiles. CBER aims to reduce or eliminate the need for bioassays, which are highly variable and require lab animals for testing of polysaccharide-based vaccines.
  2. Studying the use of in vitro / ELISA vaccine testing of botulism vaccines prior to animal testing of vaccine lots. The ELISA testing could support any type of botulinum vaccine product, although currently there are no licensed botulism vaccines.
  3. Evaluating the safety, immunogenicity, and protective effectiveness of several promising live, attenuated mycobacterial vaccine strains in animal models.

    Promoting Development of Innovative Therapies

  4. Identifying the characteristics of stem cells that correlate with differentiation, growth, and migration to the appropriate location after transplantation into animal models. Such characteristics will be used to help predict the safety and activity of neural progenitor cells used in clinical trials.
  5. Improving the safety and efficacy of adenovirus gene therapy vectors used to treat a variety of diseases (e.g., cancerous tumors) by identifying barriers(e.g., immune responses) that block or neutralize the vectors, preventing them from reaching their target cells.
  6. Developing a rapid in vitro screening method to detect insertional mutagenesis of integrating vectors (mutations caused by inserting new genes into a cell&chromosome) to facilitate initial safety evaluation of new gene therapies.
  7. Developing preclinical models and identifying reproducible biomarkers of vascular endothelial dysfunction to evaluate the safety of hemoglobin-based
  8. Developing improved animal models and identifying biomarkers for toxicity assessment of blood substitutes.

    Continuing Efforts to Ensure Blood and Blood Product Safety

  9. Developing product quality biomarkers for stored blood cells by identifying measurable characteristics in the nucleic acids of blood cells that can reliably predict the quality of stored blood cells.
  10. Developing an animal model of human platelet transfusions to enable studies of underlying mechanisms of transfusion-related acute lung injury (TRALI) that will help product reviewers evaluate the potential of current and future platelet products to mediate TRALI.
  11. Developing a comprehensive HIV variant viral reference panel for assay standardization and evaluation of approved/investigational HIV assays and lot release testing to ensure that licensed assays detect new circulating strains of HIV.
  12. Developing reagents to evaluate new and existing assays to detect insect-borne viruses that may be threats to the blood supply, such as Dengue virus.
  13. Developing assays and reference panels for blood donor surveillance and virus transmission/infectivity studies for blood safety.
  14. Developing the first DNA-based laboratory test to screen blood donors for the tick and blood-borne parasite, Babesia.

    Ensure Allergen Potency

  15. Developing new methods to assess the quality and potency of German cockroach allergen extracts, and to enhance the standardization of individual allergen content of other complex allergenic extracts.
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OFFICE OF COMMUNICATION, OUTREACH, AND DEVELOPMENT
 
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.
 
Public outreach
 
OCOD plays a significant role in leading and coordinating the Center’s outreach efforts. OCOD works closely with the program offices and the Office of the Director to educate stakeholders about CBER’s regulatory, compliance, policy and research activities: the office evaluates public interest in particular topics and identifies and/or develops informational documents for proactive posting on CBER’s web site. This includes developing such content as frequently asked questions on product approvals, product safety issues, emerging infectious diseases, enforcement actions.
 
OCOD is also responsible for reviewing any such materials for disclosure prior to distribution or web posting.
 
In order to enhance and improve transparency and communication about CBER’s programs and initiatives to our stakeholders, OCOD established a Twitter page in FY 2011. Twitter provides the center an additional communication tool to reach both consumers and industry stakeholders who use social media as one way to get information. 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. OCOD also works with the product 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 with orientation of new employees and extending throughout their careers at CBER.
 
In FY 2011, 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.
 
In addition, CBER met its FY 2011 goal of training 100% of the Center’s supervisors in required competencies. Another focus during FY 2011 was ensuring that CBER’s contracting officer representatives (CORs) maintained their certification by offering specific training courses, as well as developing a new COR Seminar Series to provide a collaborative forum for staff to share their knowledge and expertise.
 

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OFFICE OF MANAGEMENT

 
The mission of the Office of Management (OM) is to provide support for financial management, strategic planning, performance reporting, human resources liaison, facilities issues, advisory committees, and veterinary services.
 
Major activities
 
In August 2011, CBER posted its CBER Strategic Plan (CSP), on the FDA Web site. The CSP provides strategic direction for the next five fiscal years (2012 – 2016) (see link below).
 
The CSP supports the strategic objectives assigned to the biologics program that are contained in the FDA Strategic Priorities document that was issued in April 2011 (see link below).
 
The CSP is based on CBER’s mission and vision, and identifies six strategic goals and related objectives and strategies that include national preparedness, global public health, new biological products, safety of biological products, regulatory science and research, and organizational excellence and accountability.
 
CBER Strategic Plan (Fiscal Years 2012 – 2016):

http://www.fda.gov/downloads/AboutFDA/CentersOffices/Officeof MedicalProductsandTobacco/CBER/UCM266867.pdf.
 
FDA Strategic Priorities (Fiscal Years 2011 – 2015): 

 
http://www.fda.gov/AboutFDA/Reports ManualsForms/Reports/ucm227527.htm
 
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 FDA offices and track progress in key program areas. The objectives of FDA-TRACK are explained through its name: Transparency, Results, Accountability, Credibility, and Knowledge-sharing. Launched in 2010, FDA-TRACK monitors the performance of all CBER offices through data collection using key performance measures that are chosen each year. Following data collection and analysis, the CBER center director and office directors meet quarterly with senior FDA officials to report their progress on these performance measures and key projects.
 
In FY 2011, the center provided timely, accurate, and meaningful quarterly updates of progress in improving efforts that are key aspects of the center’s ability to fulfill its mission. The updates presented at the FDA-Track quarterly briefings included activities related to several efforts, including efforts to:
 
  • Maintain full AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care International) accreditation for the CBER Animal Facility• Continue to meet or exceed user fee performance goals
  • Implement a quality assurance program in the Office of Blood Research and Review to increase the efficiency and consistency of application reviews
  • Plan a workshop to encourage discussions that will support development of a safe and effective vaccine for cytomegalovirus.
  • Conduct a public workshop on cell and gene therapy clinical trials in pediatric populations
 
For additional details on CBER FDA TRACK and its accomplishments see: http://www.fda.gov/AboutFDA/Transparency/track/ucm195008.htm
 
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GUIDANCES OF NOTE
 
Blood and Blood Products
 
1. Guidance for Industry: Availability of FDA’s eSubmitter Program for Regulatory Submissions from Licensed Blood Establishments (August 2011)
 
This guidance announced the availability of FDA’s eSubmitter Program for regulatory submissions from licensed blood establishments. The eSubmitter program facilitates the electronic submission of Biologics License Applications, Biologics License Supplements and annual reports by licensed blood establishments that collect Whole Blood and blood components, including Source Plasma.
 
http://www.fda.gov/BiologicsBlood Vaccines/GuidanceCompliance RegulatoryInformation/Guidances/Blood/ucm266499.htm
 
2. Guidance for Industry: Donors of Blood and Blood Components: Notification of Donor Deferral - Small Entity Compliance Guide (June 2011)
 
This guidance is intended to help blood collection establishments considered small entities better understand and comply with the regulations that require donor notification of deferral based on the results of tests for evidence of infection with a communicable disease agent(s) or other eligibility criteria
 
http://www.fda.gov/BiologicsBlood VaccinesGuidanceCompliance RegulatoryInformation/Guidances/Blood/ucm257559.htm
 
3. Guidance for Industry: “Computer Crossmatch” (Computerized Analysis of the Compatibility between the Donor’s Cell Type and the Recipient’s Serum or Plasma Type) (April 2011)
 
This guidance provides recommendations on how blood establishments should comply with FDA regulations if they use computer cross-match systems to ensure that blood released for transfusion is compatible with the intended recipient.
 
http://www.fda.gov/BiologicsBlood Vaccines/GuidanceCompliance RegulatoryInformation/Guidances/Blood/ucm252829.htm
 
4. Guidance for Industry: Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components Intended for Transfusion (December 2010)
 
This guidance notifies establishments that manufacture Whole Blood and blood components intended for transfusion about FDA approvals of Biologics License Applications (BLAs) for serological donor screening test systems that detect antibodies to the parasite T. cruzi in plasma and serum samples from individual human donors. It also provides recommendations for testing donations of Whole Blood and blood components for evidence of T. cruzi infection, blood donor and product management, labeling and procedures for reporting the implementation of a licensed T. cruzi test.
 
http://www.fda.gov/Biologics Blood Vaccines/GuidanceCompliance RegulatoryInformation/Guidances/Blood/ucm235855.htm
 
5. Guidance for Industry: Recommendations for Blood Establishments: Training of Back-Up Personnel, Assessment of Blood Donor Suitability and Reporting Certain Changes to an Approved Application (November 2010)

This guidance provides recommendations for training back-up personnel, assessing blood donor suitability, and reporting certain changes to an approved application for licensed blood establishments. The recommendations may be helpful to blood establishments in the event of an emergency.
 
http://www.fda.gov/Biologics BloodVaccines/GuidanceCompliance RegulatoryInformation/Guidances/Blood/ucm235785.htm
 
Human Cells, Tissues, and Cellular and Tissue-Based Product Guidances
 
1. Investigational New Drug Applications (INDs) for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications (June 2011)
 
This guidance provides advice to a variety of appropriate sponsors (e.g., cord blood banks, registries, transplant centers, or individual physicians serving as sponsor-investigators), to assist in the submission of an IND for certain hematopoietic progenitor cells, cord (HPC-C)1. The guidance will assist sponsors when such HPC-Cs are not licensed in accordance with federal regulations, and when a suitable human leukocyte antigen (HLA) matched cord blood transplant is needed for treatment of a patient with a serious or life-threatening disease or condition and there is no satisfactory alternative treatment available. This guidance finalizes the draft guidance entitled “Guidance for Industry and FDA Staff: Investigational New Drug Applications (INDs) for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications” dated October 2009.
http://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance ComplianceRegulatoryInformation/Guidances/Blood/UCM266021.pdf
 
2. Potency Tests for Cellular and Gene Therapy Products (January 2011)
 
This guidance provides manufacturers of cellular and gene therapy (CGT) products with recommendations for developing tests to measure potency; it applies only to products reviewed by OCTGT. These recommendations are intended to clarify the potency information that could support an Investigational New Drug Application (IND) or a Biologics License Application (BLA). It is intended to supplement related documents and does not replace or supersede any currently published guidance documents, with the exception that this guidance finalizes the draft guidance entitled “Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products” dated October 2008.
 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance ComplianceRegulatoryInformation/Guidances/ CellularandGeneTherapy/UCM243392.pdf
 
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WHITE OAK PLANNING
 
The Food and Drug Administration (FDA) and the General Services Administration (GSA) are consolidating FDA headquarters at the government-owned White Oak Federal Research Center in Montgomery County, Maryland. The consolidation project is authorized by Public Law 101-635 (FDA Revitalization Act of 1990) and is funded through a GSA appropriation. This initiative directed the secretary of the US Department of Health and Human Services and the GSA administrator to consolidate the agency’s headquarters into modern office and laboratory facilities.
 
The White Oak Planning Team plans and oversees the center relocation project and is responsible for moving all components of CBER to the consolidated White Oak campus. The team comprises employees in the Office of Management who coordinate activities with FDA’s White Oak Consolidation Program, the General Services Administration, and members of the architectural and engineering design teams from Kling-Stubbins, RTKL Associates, Inc., and Louviere, Stratton & Yokel (LSY). The task of the collaboration is to ensure that the design and construction of the facilities in the southeast quadrant of the campus will adequately support the missions of the programs that will locate there.
 
Construction of the Southeast Quadrant, which includes the CBER/CDER labs (Building 52/72), and the CBER/CDER offices (Buildings 71 and 75) is currently scheduled for completion in December 2013.
 
For more information see: http://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/default.htm
 
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