The Center for Biologics Evaluation and Research (CBER) worked diligently during Fiscal Year 2017 to fulfill its core mission: ensuring that safe and effective biologic products and related devices are available to the public.
We are particularly proud to have approved several therapeutic “firsts” that represent significant achievements in fulfilling our mission: Kymriah, the first gene therapy in the US, which is approved for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse; MACI, the first FDA-approved product for repairing knee cartilage defects in adults that is grown from cells on scaffolds using healthy cartilage tissue from the patient’s own knee; Odactra, the first allergenic extract to be administered under the tongue for the treatment of house dust mite-induced nasal inflammation; and Haegarda, the first subcutaneous preventive treatment option for hereditary angioedema (HAE), which enables easier at-home self-injection by the patient or caregiver, to prevent HAE attacks in adolescent and adult patients.
In addition, the Center played an important role in protecting and promoting the public health against emerging infectious diseases, such as Zika and Ebola. During FY 2017, CBER completed expedited reviews of seven Investigational New Drug applications (INDs) for Zika vaccines, and CBER continues to advise the US Department of Health and Human Services (HHS) and international regulatory partners on Zika virus vaccine development. The Center also continued to provide strategic direction to national regulatory authorities addressing safety and efficacy concerns related to Ebola virus vaccines in development. In addition, CBER oversaw the implementation of nationwide blood donor screening for Zika virus using two investigational donor screening nucleic acid tests, and subsequently licensed the cobas Zika test—the first test intended to detect Zika virus in blood donations and living organ donors.
The report below highlights these and other CBER accomplishments of FY 2017. The work performed contributed not only to the core mission of the FDA, but also to national and international public health, and to global preparedness for future public health challenges.
Peter Marks, M.D., Ph.D.,
Center for Biologics Evaluation and Research
Advancing access to safe and effective products
CBER’s notable achievements in FY17 advanced our work on behalf of public health. Specifically, the Center:
- Exceeded the PDUFA performance target by completing 100% of the standard and priority Biologics License Application (BLA) and New Drug Application (NDA) reviews within the specified review timeframes (FY 2017 receipt cohort) by July 31, 2017, two months before the end of the fiscal year.
- Acted on 100% of the standard and priority Efficacy Supplements within the specified timeframes.
- Exceeded the performance target for 510(k) submissions, issuing a MDUFA decision on 100% within 90 days for all 510(k)s received through July 31, 2017.
- Developed and implemented the Device Submissions Tracking System, version 1.0 to improve regulatory tracking of 510(k) device applications and expedite the medical device review process.
- Collaborated with the National Institutes of Health (NIH) to complete a final version of a template for clinical investigators to use when organizing clinical trial protocols. The template includes instructional and sample text for investigators writing phase 2 or phase 3 clinical trial protocols that require investigational new drug (IND) or investigational device exemption (IDE) applications. The aim of the template is to expedite both the writing of high-quality protocols by investigators and the review process at both FDA and NIH.
- Contributed to the passage of the FDA Reauthorization Act of 2017, which reauthorizes four medical product user fee programs.
- Ensured that user fee obligations continued to be met.
- Implemented several initiatives to ensure compliance with provisions in the 21st Century Cures Act, most notably the Regenerative Medicine Advanced Therapy Designation program to foster the development and approval of these novel therapies to aid patients with serious or life-threatening diseases.
Approval of major, innovative, complex biologic products
Office of Vaccines Research and Review
- Odactra: The first sublingual allergen extract for the prevention of house dust mite-induced allergic rhinitis, with or without conjunctivitis in people 18 through 65 years of age.
- Rubber Panel T.R.U.E TEST: An aid in the diagnosis of allergic contact dermatitis in persons 6 years of age and older whose history suggests sensitivity to one or more of the 5 substances included on the Rubber Panel T.R.U.E. TEST
- Efficacy supplement for Gardasil 9: Human Papillomavirus 9-valent Vaccine, Recombinant to include a two-dose regimen for individuals 9 through 14 years of age.
Office of Blood Research and Review
- cobas Zika test: First FDA-approved commercial blood screening test for the detection of Zika virus RNA in donated human plasma, and in organs from living donors.
- cobas® HIV-1: An in vitro nucleic acid amplification test for the quantitation of human immunodeficiency virus type 1 in EDTA plasma of HIV-1- infected individuals, using the automated cobas 6800/8800 specimen processing, amplification, and detection systems.
- cobas® 8800 and 6800 Systems: Support an automated and integrated workflow to run PCR-based Nucleic Acid Testing in blood screening laboratories.
Office of Tissues and Advanced Therapies
- Kymriah: Cell-based immunotherapy composed of genetically-modified autologous T-cells, for relapsed or refractory B-cell acute lymphoblastic leukemia in children and young adults 3-25 years of age. It is the first gene therapy available in the US.
- Haegarda: First C1 Esterase Inhibitor for subcutaneous administration to prevent hereditary angioedema attacks in adolescent and adult patients, which enables easier at-home self-injection by the patient or caregiver.
- MACI: Autologous cellularized scaffold product for repairing single or multiple symptomatic, full-thickness cartilage defects of the knee with or without bone involvement in adults. MACI is the first FDA-approved product that uses tissue engineering to grow cells on scaffolds using healthy cartilage tissue from the patient’s own knee.
- Kedrab:Human rabies immunoglobulin indicated for passive, transient, post-exposure prophylaxis of rabies infection when give immediately after contact with a rapid or possibly rabid animal, and concurrently with a full course of rabies vaccine.
- Rebinyn(Coagulation Factor IX [Recombinant]), GlycoPEGylated: Recombinant DNA-derived coagulation Factor IX concentrate, indicated for use in adults and children with hemophilia B for 1) on-demand treatment and control of bleeding episodes; and 2) perioperative management of bleeding.
Advancing Product Development and Ensuring Product Safety
In addition to determining the safety and effectiveness of medical products, CBER also facilitates the development and availability of important products at both the national and international levels. In addition, the Center conducts post-marketing surveillance of approved products to ensure that unanticipated safety concerns are identified.
Office of Vaccines Research and Review
- Collaborated with the National Institute of Allergy and Infectious Diseases to convene the public workshop “Bacteriophage Therapy: Scientific and Regulatory Issues” to discuss this alternative to antibiotics treatment of infection and facilitate future development of bacteriophage therapy products. (July 10-11, 2017)
- Participated in the Zika Vaccine Development Interagency Working Group, the Zika Medical Countermeasures Leadership group, and the NIAID-WHO sponsored workshop, “Scientific Consultation on Zika Virus Vaccine Development,” to provide advice on clinical development and licensure pathways for Zika vaccine candidates.
- Participated in a workshop sponsored by the Coalition for Epidemic Preparedness Innovations to discuss licensure pathways for Ebola vaccines. (March 2017).
- Convened the Vaccines and Related Biological Products Advisory Committee to discuss considerations for clinical trial evaluation of vaccine candidates to protect against Respiratory Syncytial Virus disease, a leading cause of hospitalizations and health care visits in children under five years of age. (May 2017)
- Convened the Vaccines and Related Biological Products Advisory Committee to discuss the safety of a hepatitis B vaccine formulated with a novel adjuvant (July 2017).
- Facilitated the development of vaccines for Ebola virus:
- Provided scientific and regulatory guidance to sponsors and stakeholders to expedite clinical trials on multiple vaccine candidates.
- Collaborated with federal and global partners, including the National Institute of Allergy and Infectious Diseases, Centers for Disease Control and Prevention, Health Canada, European Medicines Agency, and the World Health Organization, on the scientific and regulatory pathways for the licensure of Ebola vaccines.
- Participated in a continuing monthly meeting of the federal Influenza (Flu) Risk Management Meeting (FRMM) to facilitate ways to improve the annual influenza vaccine virus selection process.
- Developed two new influenza vaccine potency assays as alternatives to the traditional single radial immunodiffusion (SRID) potency assay. Both assays, a monoclonal antibody (mAb) capture ELISA, and a receptor-binding surface plasmon resonance (SPR) based assay, were evaluated in a large international collaborative study sponsored by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA). The study, which included vaccine manufacturers, regulatory agencies, and other public health agencies, demonstrated that both assays can quantify H3 and influenza B antigens in blinded vaccines and distinguish heat-stressed vaccine samples from unstressed vaccine. This suggests they are promising alternatives to the traditional SRID potency assay.
Office of Blood Research and Review
- Made available a panel of human plasma samples to aid in the regulatory evaluation of serological tests to detect recent Zika virus infection.
- Convened two public workshops to strengthen collaboration and information exchange on blood safety:
- “Pre-Clinical Evaluation of Red Blood Cells for Transfusion” in collaboration with NIH/NHLBI, DoD, and HHS/OASH to discuss new methodologies for pre-clinical evaluation of the safety and efficacy of red blood cell transfusion products. (Oct. 6-7, 2016)
- “Emerging Tick-borne Diseases and Blood Safety” in collaboration with NIH/NHLBI, Department of Defense, America’s Blood Centers, and the American Association of Blood Banks, to discuss tick-borne pathogens that are emerging as threats to blood safety, the effectiveness of current and potential mitigation strategies, and the general approach to decision making on blood safety interventions. (Apr. 6, 2017)
- Participated in collaborative studies to establish the 1st WHO International Standards for Zika virus RNA and Chikungunya virus RNA for NAT-based assays developed by the Paul Erlich Institute.
- CBER, as an active member of the AABB Inter-organizational Task Force on Domestic Disasters and Acts of Terrorism, worked with the blood collection industry and device manufacturers to ensure the availability of blood and blood components in areas of the continental U.S., Puerto Rico, and the Virgin Islands impacted by the hurricanes in 2017.
Office of Tissues and Advanced Therapies
- Collaborated with the FDA Office of Scientific and Professional Development and Health Research Alliance to convene the workshop “Gene Editing Workshop: Technologies and Applications on FDA-Regulated Products.” The workshop provided training to FDA scientists and staff on the latest gene editing technologies and their potential applications in biomedical, veterinary, and food industries. (Nov. 1, 2016)
- Convened the 20th U.S.-Japan Cellular and Gene Therapy Conference in collaboration with Japan’s Ministry of Education, Culture, Sports, Science, and Technology under the U.S.-Japan Cooperative Research Program. The focuses of the conference were advances and potential applications of CRISPR/Cas9-based genome editing system and opportunities for collaborations among scientists from the US and Japan. (March 17, 2017)
- Convened two public workshops in FY 2017 to strengthen collaboration and information exchange on human cells, tissues, and cellular and tissue-based products:
- “Identification and Characterization of the Infectious Disease Risks of Human Cells, Tissues, and Cellular and Tissue-based Products,” The purpose of the public workshop was to discuss current methods for identifying and characterizing infectious disease risks associated with human cells, tissues, and cellular and tissue-based products. (Feb. 8-9, 2017
- “Innovative Alternatives to Renal Replacement Therapy: Developing a Roadmap” in collaboration with CDRH, NIH, CMS, and the Kidney Health Initiative. The purpose of the workshop was to discuss scientific, technical, and regulatory challenges that must be met to enable development of bio-artificial or bioengineered alternatives to dialysis. (Mar. 23-24, 2017)
- Met with the Friedreich’s Ataxia Research Alliance (FARA) to discuss potential gene therapies for Friedreich’s Ataxia (FA), and to inform FARA and the research community of areas where more work may be needed to support development of gene therapies for FA. (Jan. 23, 2017)
- Hosted a patient-focused drug development meeting on hereditary angioedema to obtain a better understanding of patients' perspectives on the challenges posed by HAE, the impact of current therapies for this condition, and information and insights from patients and caregivers on the impact of hereditary angioedema on daily life and participation in clinical trials. (Sept. 25, 2017)
Office of Biostatistics and Epidemiology
- Convened the first public workshop on the Sentinel Post-Licensure Rapid Immunization Safety Monitoring (PRISM) Program, in collaboration with Harvard Pilgrim Healthcare. The workshop brought together stakeholders to discuss PRISM’s capabilities, examine vaccine-related adverse events, and outline future directions for expansion and integration of PRISM into the regulatory review process. (Dec. 7, 2016)
- Collaborated with OBRR, the National Heart Lung and Blood Institute and the Department of Health and Human Services’ Office of the Assistant Secretary to launch the Transfusion-Transmissible Infections Monitoring System (TTIMS). This program helps to ensure the continued safety of the US blood supply and monitors the effects of FDA’s policy changes regarding donor deferral. TTIMS contractors monitor over 50 percent of the U.S. blood supply for HIV, hepatitis B virus and hepatitis C virus, and conduct HIV recency testing.
- Contractors for the Transfusion-Transmissible Infections Monitoring System (TTIMS) program completed donor testing for HIV, Hepatitis B, and Hepatitis C viruses for over 50% of the U.S. blood supply. They also conducted HIV recency testing (time elapsed before a measureable amount of antibody to, or genetic material of, the infectious organism is produced) on more than 600 samples collected over a 5-year period, and completed initial analysis of the first 19 months of data, exceeding the stated performance goals.
- Initiated a safety program called Biologics Effectiveness and Safety (BEST) as part of the Sentinel Initiative. BEST will 1) monitor the safety and effectiveness of CBER-regulated biologic products using large claims and electronic medical records databases; 2) develop new Natural Language Processing and data analytics to improve the use of electronic medical records for safety monitoring. This program is part of CBER’s efforts to build a national biovigilance program to detect rare adverse events using innovative technologies and tools.
- The Office was instrumental in the initiation and development of the concept of BioCompute objects: formatted sets of data that include all software elements (e.g. arguments of the executable program, version information, and references to all the inputs). Such software objects assist with the harmonization of high throughput sequence analysis, evaluation and validation of sequential software analyses called “pipelines,” and the construction of novel pipelines through integration of multiple BioCompute objects. The need for BioCompute objects arose out of problems observed with DNA and RNA sequences that were submitted for regulatory analysis. CBER worked with the community to assist with a workshop held March 11th and 12th at NIH. Since then, the bioinformatics community has taken the concepts and further developed them in what may become a community standard.
- Partnered with the FDA Center for Drug Evaluation and Research (CDER) to host a Duke-Margolis workshop on advancing benefit-risk assessment in the FDA regulatory system Sept. 13, 2017). The workshops reviewed the progress in incorporating structured benefit-risk assessment into the review process under PDUFA V and explored opportunities for more formal, quantitative benefit risk assessments to support regulatory decisions in the future.
- Established CBER’s Science of Patient Input Initiative (SPI, pg. 15), which focuses on scientifically valid, qualitative, and quantitative methods for eliciting patient perspective information on benefits and risks of medical products and for incorporating this information into regulatory decision making. The initiative supports the agency’s efforts to more systematically capture patient perspectives and integrate them into regulatory decision making. It also supports fulfilment of FDA requirements under 21st Century Cures Act and commitments under the sixth authorization of the Prescription Drug User Fee Act (PDUFA VI).
In FY 2017, CBER released guidances as part of its effort to inform stakeholders of the Center’s current interpretation of its regulations and ways that regulated industry can remain in compliance. CBER also cooperated with one or more other Centers to produce a joint guidance that provides insights in common issues of interest to stakeholders. A selection these are noted below.
Office of Blood Research and Review
- “Requalification of Donors Previously Deferred for a History of Viral Hepatitis after their 11th Birthday; Guidance for Immediate Implementation
Provides guidance to establishments that collect Whole Blood or blood components intended for transfusion or for further manufacture with recommendations for a requalification method for donors who had been indefinitely deferred for a history of viral hepatitis after the 11th birthday, prior to the elimination of the donor suitability requirement. This guidance also advises licensed manufacturers who choose to implement the recommendations on how to report the manufacturing change to FDA.
- “Recommendations for Assessment of Blood Donor Eligibility, Donor Deferral, and Blood Product Management in Response to Ebola Virus: Final Guidance for Industry” (Jan. 2017)
Informs blood establishments that collect blood and blood components for transfusion or further manufacture, including Source Plasma, that FDA deems Ebola virus to be a transfusion-transmitted infection (TTI). It also provides recommendations for assessing blood donor eligibility, donor deferral and blood product management if an outbreak of Ebola virus disease with widespread transmission occurs in at least one country.
- “Labeling of Red Blood Cell Units with Historical Antigen Typing Results: Draft Guidance for Industry” (Jan. 2017)
Provides establishments that collect blood and blood components for transfusion, with 1) recommendations for labeling Red Blood Cell (RBC) units with non-ABO/Rh(D) antigen typing results obtained from previous donations (historical antigen typing results); 2) recommendations to transfusion services for managing RBC units labeled with historical antigen typing results; 3) instructions to licensed blood collection establishments that choose to implement labeling of RBC units with historical antigen typing results; 4) instructions for reporting the manufacturing and labeling changes under 21 CFR 601.12.
- Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components Intended for Transfusion; Draft Guidance for Industry (Nov. 2016)
Amends the document entitled “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” (Dec. 2010) by 1) expanding the scope of the guidance to include the collection of blood and blood components for use in manufacturing a product, including donations intended as a component of, or used to manufacture, a medical device; 2) removing the recommendation to ask donors about a history of Chagas disease; 3) providing a recommendation for a reentry algorithm for certain donors deferred on the basis of screening test results for antibodies to Trypanosoma cruzi or on the basis of answering “yes” to the Chagas screening question.
Office of Tissues and Advanced Therapies
- Deviation Reporting for Human Cells, Tissues, and Cellular and Tissue-Based Products Regulated Solely Under Section 361 of the Public Health Service Act and 21 CFR Part 1271; Guidance for Industry (Sept. 9, 2017)
Provides guidance to establishments that manufacture non-reproductive human cells, tissues, and cellular and tissue-based products (HCT/Ps) with recommendations and relevant examples to investigate and report HCT/P deviations.
- Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation in Products in Humans(Updated Dec. 2016).
CBER issued the amended final guidance for industry “Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans” to provide sponsors and applicants of xenotransplantation products with updates concerning production, testing, and evaluation during protocol development and preparation of IND and BLA submissions to FDA.
- Revised Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products Who Have Received Human-Derived Clotting Factor Concentrates (Nov. 11, 2016)
Informs establishments that make donor eligibility determinations for donors of human cells, tissues, and cellular and tissue-based products that FDA no longer considers FDA-licensed human-derived clotting factor concentrates (HDCFCs) a risk factor for Human immunodeficiency virus (HIV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV). Therefore, receipt of FDA-licensed HDCFCs, or sex with a person who has received FDA-licensed HDCFCs, should not be considered a risk factor when determining eligibility of a donor of HCT/Ps.
CBER in cooperation with other centers
(CBER/CDER) (Jan. 2017)
Assists sponsors in demonstrating that a proposed therapeutic protein product is interchangeable with a reference product for the purposes of submitting a marketing application or supplement.
- Statistical Approaches to Evaluate Analytical Similarity (CBER/CDER) (Sept. 2017)
Describes the type of information a sponsor of a proposed biosimilar product should obtain about the structural/physicochemical and functional attributes of the reference product, how that information is used in the development of an analytical similarity assessment plan for the proposed biosimilar, and the statistical approaches recommended for evaluating analytical similarity.
- Evaluation and Reporting of Age-, Race-, and Ethnicity-Specific Data in Medical Device Clinical Studies(CBER/CDRH) (Sept. 2017)
Outlines the FDA’s expectations and provides recommendations for the evaluation and reporting of age-, race-, and ethnicity-specific data in medical device clinical studies. The primary intent of these recommendations is to improve the quality, consistency, and transparency of data regarding the performance of medical devices within specific age, racial, and ethnic groups.
- Postmarket Management of Cybersecurity in Medical Devices; Guidance for Industry and Food and Drug Administration Staff (CDRH/CBER) (Dec. 2016)
Recommendations for managing post-market cybersecurity vulnerabilities for marketed and distributed medical devices.
- BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment (CDER/CBER) (Nov. 2016)
Assists sponsors in the clinical development of drugs, including biologics, for the treatment of patients who have bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer.
Mission Related Research
The research laboratories at CBER create new knowledge that is essential to the fulfillment of our mission of ensuring that products we regulate are safe, pure, potent, and effective—and that new products will be available to the public.
- FDA develops a novel biomarker based test that improves ability to identify asymptomatic carriers of malaria
CBER developed a novel blood test that can identify asymptomatic carriers of malaria who might otherwise be missed by even the most sensitive method available today.
- FDA develops rapid and sensitive assay to assess antibody response to Ebola virus vaccine without using the virus
CBER developed an assay that assesses the ability of antibodies to neutralize Ebola virus, using a technique that does not require the use of Ebola virus itself and can be automated for rapid testing of large numbers of samples.
- High-dose influenza vaccine appears better than standard-dose vaccines in preventing deaths from A(H3N2) influenza among older adults
High-dose influenza vaccine was found to be more effective at preventing post-influenza deaths among elderly individuals during the 2012-2013 influenza season than standard-dose vaccines-- when the A(H3N2) influenza viruses were broadly circulating.
- FDA assay predicts ability of mesenchymal stromal cells to suppress immune system activity
CBER scientists developed an assay that can predict the ability of human mesenchymal stromal cells (hMSCs) to suppress immune system activity--an innovative use of morphological features of cells to rapidly predict future cell behavior.
- Genetically engineered protein drugs for hemophilia trigger antibody production by binding HLA class II antigens
Findings from a CBER study clarifies some of the approaches researchers can use to identify small changes introduced into bio-engineered proteins drugs that don’t exist in the natural protein and that might trigger production of anti-drug antibodies.
- Study of antibody responses to an investigative Ebola vaccine may guide development and evaluation of effective countermeasures
CBER demonstrated novel immune system targets on Ebola virus and identified the major type of vaccine-triggered antibodies that neutralize the virus.