This letter is my first annual report to various stakeholders as the director of the Center for Biologics Evaluation and Research (CBER). It summarizes what we have done over the past year, and includes regulatory, research, and administrative accomplishments that demonstrate the extraordinary work of our staff. You will also notice in this letter that, following the CBER restructuring, which occurred in FY 2017, the Office of Cellular, Tissue and Gene Therapies became the Office of Tissues and Advanced Therapies. Therefore, we will use that terminology in this report.
In fiscal year 2016, I am pleased to report that CBER enhanced its operational efficiency, which facilitated getting new treatments to the public. For example, as of September 30, 2016, the Center exceeded its regulatory performance target by completing 100% of standard and priority reviews of Biologics License Applications (BLA) and New Drug Applications (NDA) within specified review timeframes. Similarly, CBER exceeded the performance target for 510(k) submissions and Real Time Supplements, issuing a decision on 100% of Medical Device User Fee Amendments (MDUFA) submissions received during FY 2016 within 90 FDA days.
In addition, our researchers generated critically important new scientific knowledge in support of the development and regulation of safe and effective medical products, examples of which are included in this report. And the Center’s rapid responses to the Ebola and Zika Virus outbreaks demonstrated our ability to quickly and effectively focus regulatory and scientific knowledge and skills on the challenge of emerging international public health crises.
The report below highlights some accomplishments of FY 2016 and demonstrates how our successes contributed to national and international public health, and to preparedness for future public health challenges. In the coming years, we look forward to continued work with all of our stakeholders to promote and protect public health.
Peter Marks, M.D., Ph.D., Director,
Center for Biologics Evaluation and Research
Advancing access to safe and effective products
Ensuring that safe and effective biologics are available to those in need is core to the Center’s mission. During the past year the Center performed admirably in this regard.
- Exceeded 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 2016 receipt cohort) by September 30, 2016.
- Acted on 100% of standard and priority Efficacy Supplements within specified timeframes by September 30, 2016.
- Exceeded the performance target for 510(k) submissions and Real Time Supplements, issuing a MDUFA decision on 100% of submissions received (FY 2016 receipt cohort) within 90 FDA days.
- Convened multiple bilateral and trilateral meetings with the World Health Organization and the European Medicines Agency to review progress on the clinical development of Ebola vaccine candidates, and provided expertise at two WHO-sponsored conferences to discuss reference material preparations for Zika virus vaccine candidates.
- Convened a Vaccines and Related Biological Products Advisory Committee meeting (November 13, 2015) to discuss appropriate clinical study designs to evaluate the safety and effectiveness of vaccines intended for use during pregnancy to prevent disease in the infant.
Innovative, complex biologic products approved by the Center during the past year, listed according to product office:
Office of Vaccines Research and Review
- BioThrax: Anthrax vaccine, approval of efficacy supplement to include post-exposure prophylaxis of disease resulting from suspected or confirmed Bacillus anthracis exposure, when combined with the recommended course of antimicrobial therapy in persons 18 through 65 years of age.
- Fluad: the first adjuvanted seasonal influenza vaccine licensed in the U.S. for the active prevention of seasonal influenza in people 65 years of age and older.
- FluLaval Quadrivalent: approval of efficacy supplement to extend the age range to include children 6 through 35 months of age for the prevention of seasonal influenza. With this approval, there are now two FDA-approved seasonal influenza vaccines for infants as young as six months of age.
- Gardasil 9: Human Papillomavirus 9-valent Vaccine, Recombinant, efficacy supplement that includes males 16 through 26 years of age, for the prevention of anal cancer and genital warts.
- Vaxchora (Cholera Vaccine Live Oral): for the prevention of cholera caused by serogroup O1 in adults 18 through 64 years who travel to cholera-affected areas. Vaxchora was granted fast-track designation by FDA and was a priority review. FDA awarded the manufacturer of Vaxchora a tropical disease priority review voucher, under a provision (Sec. 1102) of the Food and Drug Administration Amendments Act of 2007.
Office of Blood Research and Review
- Idelvion: Coagulation Factor IX (Recombinant), Albumin Fusion Protein, indicated for the treatment and control of bleeding episodes in children and adults with Hemophilia B. Idelvion is the first coagulation factor-albumin fusion protein to be approved in the world and the second Factor IX fusion protein product approved in the U.S.
- Vonvendi: von Willebrand Factor (Recombinant), indicated for the on-demand treatment and control of bleeding episodes in adults 18 years of age and older with von Willebrand disease. Vonvendi is the first FDA-approved recombinant von Willebrand Factor.
- Coagadex: Coagulation Factor X (Human), the first coagulation factor replacement therapy licensed in the U.S. for patients with hereditary Factor X deficiency. Coagadex was granted fast track designation and reviewed under FDA’s Priority Review program.
- Adynovate: Antihemophilic Factor (Recombinant), intended for use in adults and adolescents aged 12 years and older with Hemophilia A (congenital factor VIII deficiency) for on-demand treatment and control of bleeding episodes and routine prevention to reduce the frequency of bleeding episodes. Adynovate is the first PEGylated coagulation factor product licensed in the U.S.
- Afstyla:Antihemophilic Factor (Recombinant), Single Chain intended for use in adults and children with Hemophilia A (congenital factor VIII deficiency) for on-demand treatment and control of bleeding episodes and routine prophylaxis to reduce the frequency of bleeding episodes. Afstyla is the first licensed single chain factor VIII product in the world.
Office of Tissues and Advanced Therapies (formerly, Office of Cellular, Tissue and Gene Therapies)
- Imlygic: (talimogene laherparepvec), the first oncolytic virus therapy for the treatment of melanoma lesions in the skin and lymph nodes. Approval of this novel treatment is a major achievement because it can treat areas of the body where lesions have spread that cannot be completely removed by surgery.
Advancing Product Development and Ensuring Product Safety
Although approving products is a core part of our mission, the Center also engages in activities that facilitate the development and availability of important products, and these activities take place on both a national and international level. In addition, once products are approved, the Center conducts post-marketing surveillance to ensure that unanticipated safety concerns are rapidly identified.
Office of Vaccines Research and Review
- Facilitated the development of vaccines for Ebola virus
- Worked closely with 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.
- Assisted FDA’s scientific and regulatory response to the recent Zika virus (ZIKV) outbreak
- Mobilized resources to expedite IND reviews of vaccine candidates for ZIKV
Office of Blood Research and Review
- Published final guidance revising FDA’s blood donor deferral policy to reduce the risk of HIV transmission
- Assisted blood establishments in implementing the new deferral requirements by working closely with AABB and Plasma Protein Therapeutics Association to review and accept updated donor screening and educational materials consistent with the revised policy
- Established a public docket as a mechanism to obtain stakeholder input and scientific evidence on alternative donor evaluation strategies to reduce the risk of HIV transmission.
- Assisted FDA’s scientific and regulatory response to the recent Zika virus (ZIKV) outbreak
- Led publication of guidance documents to reduce the risk of transmission of ZIKV by whole blood and blood components (See “Guidances” section of this report.)
- Working with stakeholders: 1) collaborated with the Office of the Assistant Secretary for Health to ensure that safe blood was available for transfusions in Puerto Rico and other areas in the United States at risk, before a blood screening test for Zika virus became available; 2) worked with manufacturers to help speed the development of screening tests to detect Zika virus at the earliest point in time after infection; 3) worked with the Biomedical Advanced Research and Development Agency to help facilitate the evaluation of these tests and other measures.
- Released a guidance for reducing transmission of Zika virus in blood, including specific recommendations for testing and pathogen reduction of donations (see “Guidances”).
- Organized and convened “Workshop on the Regulation of HIV Test Systems” (December 14-16, 2015, Arusha, Tanzania). This public workshop, funded by the President’s Emergency Plan for AIDS Relief (PEPFAR), was attended by 59 regulators representing 22 African countries and designed to build in-country capacity and foster regional collaboration in the regulatory review of HIV test kits in sub-Saharan Africa.
- Published “Voice of the Patient” reports for Hemophilia A, Hemophilia B, von Willebrand Disease and other Heritable Bleeding Disorders, and Alpha-1 Antitrypsin Deficiency as part of Agency’s Patient-focused Drug Development Initiative.
Office of Tissues and Advanced Therapies (formerly, Office of Cellular, Tissue, and Gene Therapies)
Achieved regulatory advances in the area of human cell, tissue, and gene therapies
- Commissioned a consensus study by The National Academies of Sciences, Engineering, and Medicine (formerly, The Institute of Medicine) to examine the scientific, medical, and ethical implications of human genome editing technologies in biomedical research.
- Issued 9 guidance documents to advance development and strengthen safety surveillance of HCT/Ps (see “Guidances” section of this letter).
- Assisted FDA’s regulatory response to the recent Zika virus (ZIKV) outbreak
- Led development of guidance to prevent ZIKV transmission through transplantation of human cells and tissue products (HCT/Ps). (See “Guidances” section of this letter.)
- Held Part 15 public hearing (September 12 - 13, 2016) entitled, “Draft Guidances Relating to the Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products” with over 90 presenters and over 400 attending in person or by webcast. Stakeholder groups made presentations on minimal manipulation, homologous use, same surgical procedure exception, and adipose tissue derived from HCT/Ps. Information obtained from the hearing will be used to help clarify and finalize a guidance on these regulatory issues to advance development of HCT/Ps.
- Convened the public workshop “Scientific Evidence in the Development of Human Cells, Tissues, and Cellular and Tissue-Based Products Subject to Premarket Approval” (September 8, 2016.)
Office of Biostatistics and Epidemiology
- The cloud-based data storage and analysis technology High-performance Integrated Virtual Environment (HIVE) continued to provide substantial support to next generation sequencing (NGS) research that will enable timely development and regulatory oversight of NGS-based diagnostic tests, quality control of vaccines, and safe and effective therapies. In turn, this will support the continued development of the Precision Medicine Initiative.
- FDA put HIVE onto GitHub, a public web site that enables people to share software and data with users, developers, and people seeking data that someone has made available. GitHub enables people to work on projects simultaneously rather than sequentially. FDA shares data, code, and information with stakeholders on this site. GitHub users can review the software and offer enhancements that could be incorporated into HIVE, resulting in a tool that’s even more effective in addressing the challenges of NGS studies. Sharing HIVE on GitHub fulfills three directives of the Obama administration:
The Sentinel program, which electronic healthcare data including insurance claims and administrative data to monitor the safety of medical products, continued to support post-licensure safety surveillance of vaccines and other biologics. Among the projects of note were the following:
- The protocol for a study of the feasibility of using inpatient electronic health records to assess the association between transfusion-related acute lung injury (TRALI) after administration of platelets, plasma, and red blood cells was completed and posted to the Sentinel website.
“Transfusion-Related Acute Lung Injury after Red Blood Cell, Plasma and Platelet Administration” 2013-2015” (September 2016)
- The pilot study, “Self-Controlled Tree-Temporal Scan Analysis for Gardasil Vaccine” was completed and the final report was posted to the Sentinel website (September 2016)
- The protocol for a study to examine the association between Prevnar 13 (PCV13) vaccine and Kawasaki Disease was revised and posted to the Sentinel website. Kawasaki Disease and PCV13 Vaccine (August 2016)
- The protocol for a study to examine the association between the administration of the influenza vaccine and febrile seizures in children was posted to the Sentinel website.
“Influenza Vaccines and Febrile Seizures in the 2013-2014 and 2014-2015 Influenza Seasons” (August 2016)
- The development of the infrastructure needed to evaluate statistical alerts from vaccine safety data mining activities in mini-Sentinel project was completed, and its final report was posted to the Sentinel website.
“Infrastructure for Evaluation of Statistical Alerts Arising from Vaccine Safety Data Mining Activities in Mini-Sentinel” (July 2016)
- The study protocol for the evaluation of HPV9 vaccine safety surveillance was completed and posted to the Sentinel website.
“Evaluation of HPV9 (Gardasil9) Vaccine Safety Surveillance Using the TreeScan Data Mining Method Surveillance Protocol” (June 2016)
- The surveillance plan or protocol for the sequential analysis of Gardasil 9 (HPV9) vaccine safety with respect to four health outcomes was completed and posted to the Sentinel website. “Sequential Analysis of Gardasil 9 Safety Surveillance Plan”
- The revised protocol for assessment of the association between influenza vaccination during pregnancy and spontaneous abortion was posted to the Sentinel website.
“Influenza Vaccines and Pregnancy Outcomes Protocol (PRISM) v3.0” (December 2015)
Transfusion Transmissible Infections Monitoring System
- Launched the Transfusion Transmissible Infections Monitoring System (TTIMS) in cooperation with Office of Blood Research and Review and in cooperation with the National Heart, Lung, and Blood Institute. TTIMS is an integrated, comprehensive blood donor and donation monitoring system for transfusion-transmitted infections (TTIs) in the U.S. The first nine months of analyzed testing data was presented to the TTIMS Steering Committee (September 26, 2016).
Science of Patient Input (SPI) Initiative
- Launched the Science of Patient Input (SPI) Initiative. The SPI initiative 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 ongoing efforts to more systematically capture the patient perspective and integrate it into our structured regulatory framework. Notable and ongoing SPI activities include: building review capacity and expertise, establishing processes and policies to support the review and tracking of SPI submissions to CBER, and numerous collaborations with our colleagues in other FDA Centers (CDRH and CDER) to advance SPI.
Post-market Safety and Efficacy Studies using Centers for Medicare and Medicaid Services
- Continued collaboration with Centers for Disease Control and Centers for Medicare and Medicaid Services to study the safety of blood and blood products and vaccine effectiveness using CMS data.
- Conducted annual near real-time safety surveillance for seasonal influenza vaccines using CMS data.
One of the ways that the Center facilitates product development is through the development and articulation of policies that help to explain the Agency’s current interpretation of its regulations and ways that regulated industry can remain in compliance. A number of important guidance documents were published in which CBER was either the lead or a cooperating Center. A selection these are noted below.
Office of Blood Research and Review
Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood and Blood Components; Guidance for Industry
Notifies blood establishments that collect Whole Blood and blood components, that FDA has determined Zika virus (ZIKV) to be a relevant transfusion-transmitted infection (RTTI); provides recommendations to reduce the risk of transmission of ZIKV by Whole Blood and blood components. (This guidance does not apply to the collection of Source Plasma and supersedes guidances issued in February and March 2016.)
Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion; Draft Guidance for Industry
Provides blood collection establishments and transfusion services with recommendations to control the risk of bacterial contamination of room temperature stored platelets through the performance of pathogen reduction technology, or bacterial testing of platelets intended for transfusion. Also provides recommendations for secondary testing of platelets as the basis for extending the dating period of platelets, and recommendations to licensed blood establishments for submitting Biologics License Application supplements to include bacterial testing of platelet components.
Provides blood establishments that collect blood or blood components, including Source Plasma, with FDA’s revised donor deferral recommendations for individuals with increased risk for transmitting human immunodeficiency virus (HIV) infection. The guidance recommends making corresponding revisions to donor educational materials, donor history questionnaires, and accompanying materials. The guidance also provides recommendations on donor requalification and product management procedures.
Recommendations for Assessment of Blood Donor Suitability, Donor Deferral and Blood Product Management in Response to Ebola Virus; Draft Guidance for Industry
Provides blood establishments that collect blood and blood components for transfusion or further manufacture, including Source Plasma, with recommendations for assessing donor suitability, donor deferral, and blood product management in the event that an outbreak of Ebola virus disease (EVD) with widespread transmission is declared in at least one country. The guidance recommends donor deferral for a history of Ebola virus disease, travel to an area with widespread Ebola and close contact with a person who has Ebola virus disease.
Office of Tissues and Advanced Therapies
Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps); Guidance for Industry(This document supersedes the draft guidance of the same title dated December 2015.)
Provides establishments that make donor eligibility (DE) determinations for donors of HCT/Ps, with recommendations for testing living donors for West Nile Virus (WNV) using an FDA-licensed donor screening test. This guidance does not provide information regarding testing of cadaveric HCT/P donors for WNV.
Offers recommendations concerning IND submissions for microbial vectors used for gene therapy in early-phase clinical trials. The guidance focuses on the chemistry, manufacturing, and control information sponsors should submit in such an IND and provides an overview of preclinical and clinical considerations for these products.
Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products; Guidance for Industry
Provides establishments that make donor eligibility determinations for donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps), with recommendations for screening donors for evidence of, and risk factors for, infection with Zika virus (ZIKV). This guidance supplements the recommendations contained in the guidance titled “Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)” dated August 2007.
Homologous Use of Human Cells, Tissue, and Cellular and Tissue-Based Products; Draft guidance for Industry and FDA Staff
Provides human cells, tissues, and cellular and tissue-based product (HCT/P) establishments, health care providers, and FDA staff, with recommendations for applying the Title 21 CFR 1271.10(a)(2) criterion of homologous use. This guidance, when finalized, will improve stakeholders’ understanding of the definition of homologous use in 21 CFR 1271.3(c), and how to apply the regulatory criterion in 21 CFR 1271.10(a)(2) to their HCT/Ps.
CBER in Cooperation with other centers
Intended to clarify how FDA applies the factors set forth in section 505-1 of the Federal Food, Drug, and Cosmetic Act 18 (FD&C Act) (21 U.S.C. 355-1) in determining whether a risk evaluation and mitigation strategy 19 (REMS) is necessary to ensure that the benefits of a drug outweigh its risks.
Patient Preferences Information-Voluntary Submission, Review in Premarket Applications, Humanitarian Device Exemption Applications, and De Novo Requests, and Inclusion in Decision Summaries and Device Labeling
CBER/CDRH August 2016
Provides guidance on patient preference information (PPI) that may be used by FDA staff in decision-making related to PMAs, HDE applications, and de novo requests.
Labeling for Biosimilar Products Guidance for Industry
CDER/CBER, March 2016
Intended to assist applicants develop draft labeling for submission in applications for proposed biosimilar products The recommendations for prescription drug labeling in this guidance pertain only to the prescribing information (package insert), except for recommendations in section V pertaining to FDA-approved patient labeling (e.g., Patient Information, Medication Guide, and Instructions for Use). Specific labeling recommendations for interchangeable biological products are not provided in this guidance
Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans
CBER/CDER, March 2016
The purpose of this guidance is to provide information to sponsors regarding the submission of an initial pediatric study plan (iPSP) and any amendments to the iPSP.
Mission Related Research
Applied scientific research is an integral part of the work done at CBER. The Center engages in both laboratory and non-laboratory based research that has direct relevance for regulated products, and this also enables researcher-reviewers to remain at the cutting edge of science and provide the most appropriate advice to sponsors in order to help them best facilitate the development of their products.
CBER scientists create new knowledge in the fields of hematology, cellular and gene therapy, vaccines, and allergenics. This research supports the agency’s regulatory review of biological products by providing a robust scientific basis for regulatory review.
Indeed, in FY 2016 we offered a vision of how we will approach CBER research so it will accommodate the challenges of 21st Century medicine. We are trying to anticipate how CBER will fulfill its mission of ensuring the safety, purity, potency and effectiveness of biological products.
Below are just some examples of the exciting scientific work being done at the Center.
- Using deep sequencing to monitor the safety and quality of influenza vaccines
Technology for rapidly identifying genetic mutations in viruses can be used in a novel way to monitor the safety and quality of influenza vaccines.
“Proof-of-concept” for a technique that identifies the presence of potentially harmful contaminants in probiotics.
- Tracking genetic changes in West Nile Virus that could affect its spread and the ability of blood donor screening tests, future treatments, and vaccines to work effectively
Important insights into understanding the genetic changes the mosquito-borne West Nile Virus (WNV) acquired since it emerged in the United States in 1999.
- Size and shape of human mesenchymal stem cells may predict future biochemical behavior potentially linked to supporting bone growth
Studying characteristics of human mesenchymal stem cells (MSC) that can correlate with mineralization of MSC--a prerequisite step in bone formation.
Strategic planning of research projects, e.g., supporting development of a vaccine against botulism infection; developing tools and data to support production of more potent allergy shots; understanding critical immune system events that protect against intracellular microbes; ensuring the safety and effectiveness of heparin; developing new methods and technologies for rapid-testing, detection, and characterization of emerging infectious pathogens that threaten the safety of tissue and tissue-based products.
General Accomplishments for Operational Excellence
During the past year the Center continued to strive toward higher levels of operational excellence through improved business process, training, and recruitment and retention of the best diverse talent. Some of the achievements of the past year follow.
- Instituted a new resource allocation model and forum for senior leadership to strengthen the budget allocation process and enhance transparency
- Implemented recommendations of Visioning CBER Research in 2025, an initiative done in collaboration with McKinsey & Company Inc. to strengthen management of the regulatory science program. This initiative included a new time-reporting system to track hours spent on research and user fee-supported work. The recommendations reflect one of the goals noted in the CBER Interim Strategic Plan, FY 2017-2019 (“Goal 5: Advance regulatory science and research,” page 18).
- Conducted the first CBER Science Symposium, a two-and-a half day event aimed at fostering information-sharing and the exchange of ideas regarding the broad spectrum of products regulated by the Center. The Symposium provided an opportunity to further leverage, communicate, and collaborate on scientific issues to advance CBER’s regulatory and public health mission.
- Established the Science Impact Series, a monthly seminar at which CBER researchers present their work to the CBER community. The goal is to improve understanding of CBER's regulatory science program, explain the importance of mission-relevant research, and illustrate how CBER's regulatory science program impacts the Center's regulatory mission and public health.
- Initiated collaborative study with the National Academy of Sciences/Institute of Medicine to examine the clinical, ethical, legal, and social implications of the use of human genome editing technologies in biomedical research and medicine. The final report is expected to be published in early FY 2017.
- Convened the 19th U.S.-Japan Cellular and Gene Therapy Conference (March 2016, FDA, Silver Spring, MD) in collaboration with the Japanese Ministry of Education, Culture, Sports, Science, and Technology under the U.S.-Japan Cooperative Research Program. The conference focus was “3D Modeling and Printing of Tissues and Organs.” Speakers discussed innovations in 3D bio-printing, their potential use in regenerative medicine, and regulatory concerns.
- Co-hosted a workshop with the Expert Council of the European “Open Medicine” project (June 20 - 21, 2016, Silver Spring, MD). The goal of the workshop was to review current progress in implementing ISO standards for the unique identification of medicinal products and e-prescribing.
- Developed and launched the electronic Managed Review Process (eMRP) IT system, to provide information about timelines and regulatory requirements to reviewers and other staff. This will enable more effective and efficient management of Biologics License Applications, greater compliance with regulations and user fee obligations, and more effective allocation of human resources.