FY 2020 Report from the Director

Fiscal Year 2020 started out with tremendous hope for progress in the area of innovative biologics, including work advancing the global harmonization of cell and gene therapy. However, as we moved into Calendar Year 2020, it quickly became apparent that a pandemic was looming. A key focus of the remainder of the fiscal year was our work undertaking a proactive response to SARS-CoV-2, the virus responsible for COVID-19. This response has involved every product office and every support office across the Center. It involved rapidly developing policy, drafting needed guidance documents, and providing advice on and evaluating Investigational New Drug applications for hundreds of medical products targeting treatment or prophylaxis. The Center authorized one Emergency Use Authorization request for COVID-19 Convalescent Plasma during the fiscal year. Additionally, during the period from March through September the Center was deeply involved in expediting the development of vaccines to prevent COVID-19, including issuing two guidance documents to assist product development. This work culminated after the close of Fiscal Year 2020 with the Emergency Use Authorization in December 2020 of different mRNA-based vaccines from Pfizer-BioNTech and ModernaTX just one week apart on December 11, 2020, and December 18, 2020, respectively. This remarkable achievement represented an incredible team effort and exemplified the deep and abiding commitment of the Center’s staff to public health.

Although the pandemic response dominated much of the year, the Center continued work on the remainder of its core mission, despite in large part working remotely, licensing five novel biologic products and three blood grouping reagents. These approvals included Palforzia, the first oral immunotherapy product for the mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut in individuals 4 through 17 years of age and Tecartus, a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma. These approvals are part of the overall success CBER had in FY 2020 in achieving or exceeding expectations of the Prescription Drug User Fee Act VI and Medical Device User Fee Amendments, as noted below.

This report summarizes these and other achievements, which reflect our staff’s continued dedication to CBER’s mission and our ongoing commitment to improve public health globally.

Peter Marks, M.D., Ph.D.
Director
Center for Biologics Evaluation and Research

Approval of major, innovative, complex biologic products

In FY 2020, CBER product approvals reflected the Center’s diverse regulatory and research responsibilities, and these contributed significantly to public health through treatment, prevention, and screening.

Office of Vaccines Research and Review

MenQuadfi (Meningococcal (Groups A, C, Y, W) Conjugate Vaccine): Indicated for active immunization for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W, and Y. Approved for use in individuals 2 years of age and older. (April 23, 2020)
Audenz (Influenza A (H5N1) Monovalent Vaccine, Adjuvanted): Indicated for active immunization for the prevention of disease caused by the influenza A virus H5N1 subtype contained in the vaccine. Approved for use in individuals 6 months of age and older. (January 31, 2020)
Palforzia (Peanut (Arachis hypogaea) Allergen Powder-dnfp): Indicated for the mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut. Approved for use in patients with a confirmed diagnosis of peanut allergy. Initial Dose Escalation may be administered to patients aged 4 through 17 years. Up-Dosing and Maintenance may be continued in patients 4 years of age and older. (January 31, 2020)

Office of Tissues and Advanced Therapies

Tecartus (brexucabtagene autoleucel): A CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL). (July 24, 2020)
Sevenfact (Coagulation Factor VIIa (Recombinant)): Indicated for treatment and control of bleeding episodes occurring in adults and adolescents (12 years of age and older) with hemophilia A or B with inhibitors. (April 1, 2020)

Office of Blood Research and Review

Sentosa SQ Genotyping assay: The first next generation sequencing-based in vitro diagnostic (IVD) test intended for use in detecting HIV-1 genomic mutations as an aid in monitoring and treating HIV-1 infection. (November 5, 2019)
Blood Grouping Reagent, Anti-Lea (Murine Monoclonal) (For Further Manufacturing Use) (FFMU): Indicated for a standard raw material for the manufacture of finished Anti-Lea blood typing diagnostic reagent for in vitro use. This FFMU reacts with the Lea antigen. (June 18, 2020)
Blood Grouping Reagent, Anti-Leb (Murine Monoclonal) (For Further Manufacturing Use) (FFMU): Indicated for a standard raw material for the manufacture of finished Anti-Leb blood typing diagnostic reagent for in vitro use. This FFMU reacts with the Leb antigen. (June 18, 2020)
DG® Gel 8 ABO/Rh (2D) Blood Grouping Reagent, Anti-D (Monoclonal Blend): For the determination of ABO forward and reverse group, and RhD antigen on the surface of red blood cells of human blood samples. (March 30, 2020)
DPP HIV-Syphilis System: A single-use rapid, qualitative, multiplex, immunoassay for the detection of antibodies to Human Immunodeficiency Virus Types 1 and 2 (HIV-1/2), and/or Treponema pallidum bacteria (the causative agent of syphilis) in fingerstick whole blood, potassium-EDTA venous whole blood or potassium-EDTA plasma specimens. (October 1, 2020)

Advancing access to safe and effective products

CBER continued to advance access to safe and effective products while achieving or exceeding expectations in its scientific and regulatory evaluation of new products. This includes the following accomplishments:

Emergency Use Authorization (EUA)

COVID-19 convalescent plasma: For the treatment of hospitalized patients with Coronavirus Disease 2019 (COVID-19) (August 23, 2020)

Addressing COVID-19

FDA created the Coronavirus Treatment Acceleration Program (CTAP) to leverage cross-agency scientific resources and expertise for COVID-19 therapeutic development and review. Clinical, operations, and policy supervisors meet regularly to discuss staffing support, trial design, endpoint selection, and consistency of practice and expectations for COVID-19 submissions.
FDA is working with industry and government partners to accelerate the development and availability of SARS-Cov-2 Immune Globulin (human) for investigation for potential COVID-19 treatments. As a part of this effort, FDA provided technical assistance to help establish the Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) study, that began in October and is conducted by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.
Facilitated a Mayo Clinic-led Expanded Access Program for convalescent plasma from April to August 2020 to fill an urgent need to provide patient access to convalescent plasma . FDA worked collaboratively with industry, academic, and government partners to implement the national expanded access treatment protocol (EAP). The program helped approximately 100,000 patients receive convalescent plasma as a treatment for COVID-19 and generated data regarding outcomes associated with its use.

Prescription Drug User Fee Act VI (PDUFA)
As of September 30, 2020:

CBER received and filed one PDUFA BLA with a Standard review timeline and six PDUFA BLAs with a Priority review designation. One of the BLAs with a Priority review designation has been approved. All others are projected to be within goal.
Of the seven filed PDUFA BLA Original Applications CBER received in FY 2019, two had a Standard review timeline, and both were approved. Five PDUFA BLA Original Applications had a Priority review designation, of which three were approved and two received a Complete Response decision.

Generic Drug User Fee Amendments
As of September 30, 2020:

CBER did not receive any ANDA original applications during FY 2020.

Medical Device User Fee Amendments (MDUFA)
As of September 30, 2020, CBER:

Reached all performance goals for 510(k) submissions, Real-Time PMA Supplements, and the PMA 180 Day Supplements. Those still under review are pending within the MDUFA goals.
Exceeded its performance target for FY 2020 510(k) submissions (95% within 90 FDA days), issuing a MDUFA decision on 100% of submissions received within 90 FDA days
Exceeded its performance target for Real-Time PMA Supplements (95% within 90 FDA days). Those still under review are pending within the MDUFA goals.
Exceeded its performance target for PMA 180 Day Supplements (95% within 180 FDA days). Those still under review are pending within the MDUFA goals.
Achieved or exceeded all MDUFA 510(k) review performance goals for FY 2020. As of September 30, 2020, there were twenty-four 510(k) applications with a MDUFA IV decision; 100% were acted on within goal. These within-goal actions include clearing twenty-four 510(k) applications.
Received and filed zero MDUFA Biologics License Applications (BLAs) in FY 2020.
Approved two of the four filed MDUFA BLA Original Applications received in FY 2019, two of which were approved and two of which received a complete response decision. No MDUFA original BLA applications with a Priority schedule review designation were approved.

21st Century Cures Deliverable

CBER continued to help to manage and support the Complex Innovative Designs (CID) pilot program, working closely with the Center for Drug Evaluation and Research (CDER) to devise and disseminate a process for reviewing complex and innovative clinical trial designs.
FDA renewed five advanced manufacturing grants awarded in FY2018 and awarded a new grant to enhance innovations in the manufacture of Adeno-associated virus vectors to help advance the development of gene therapies for diseases affecting very small populations.
FDA also granted 58 RMAT Designations since program inception in December 2016 with 30 being for rare diseases. (Through FY 2020)

Expanded use of vaccines

Expanded the indication of Gardasil 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) to expand the indication to include the prevention of oropharyngeal and other head and neck cancers caused by HPV (June 12, 2020).
Fluad Quadrivalent (Influenza Vaccine, Adjuvanted) approved for active immunization of persons 65 years of age and older against influenza disease caused by seasonal influenza virus subtypes A and types B contained in the vaccine (February 21, 2020).

Increasing efficiency of influenza reference reagent production

Increased the efficiency of influenza reference reagent production by: 1) improving the quality of candidate vaccine viruses; 2) accelerating production of sheep antiserum; 3) providing data to support use of alternative sera; 4) improving the product circular; 5) establishing a process for customer feedback.
Completed an international collaborative study comparing several alternative potency methods and alternative reference reagents. This study assessed whether an alternative reference standard can more accurately assess potency. Additional follow-up studies are being planned for FY 2021 that will continue to evaluate and compare alternative potency methods.

Advancing Product Development & Ensuring Product Safety and Effectiveness

Advancing Product Development

FDA uses existing programs to expedite the development and evaluation of innovative products to treat or prevent serious conditions, when appropriate. As of FY 2020, since the inception of the Breakthrough Therapy Designation process in July 2012, CBER granted 58 Breakthrough Therapy designations, with 30 of the products being for rare diseases (Orphan designated).

As part of its effort to facilitate the development and approval of safe and effective products, CBER works to identify stakeholder priorities and incorporate improved approaches to both research and regulatory science.

Established the CBER Advanced Technologies Team (CATT) to address the need for a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality biologics. CATT aims to achieve this vision by promoting dialogue, education, and input among CBER staff and between CBER and prospective innovators and developers of advanced manufacturing technology intended to be implemented in CBER-regulated products. The goal of this program is to promote a more robust manufacturing process with fewer interruptions in production, fewer product failures, and greater assurance that the biologic products will meet clinical performance expectations. CBER awarded several grants to support research projects to study and recommend improvements for the advanced manufacturing of biological products.
The CBER Advanced Technologies Program continued to promote the development and adoption of advanced manufacturing technologies for biologics. These efforts were coordinated through the following activities:
- The CATT received 18 requests for feedback and meetings with CBER staff. The CATT facilitates discussion of, and responses to, inquiries or meeting requests from prospective innovators and developers of advanced manufacturing technologies intended to be implemented in the manufacture of CBER-regulated products.
- CBER continued to support extramural research projects to study and recommend improvements for the advanced manufacturing of biological products. The center awarded one contract (through the Broad Agency Announcement mechanism) to identify critical quality attributes of cell and gene therapies using a multi-omics approach. CBER also awarded two grants to advance the development of gene therapies for diseases affecting very small populations, potentially even single individuals, by enhancing innovations in the manufacture of adeno-associated virus (AAV) vectors.
- In September of 2020, CBER and the International Symposium on the Continuous Manufacturing of Pharmaceutical (ISCMP) co-hosted a webinar, Integrated and Continuous Biologics Pharmaceutical Manufacturing, with the objective to communicate how Integrated and Continuous Bioprocessing is a comprehensive approach to assure quality, reduce cost, enhance speed to patients and maximize flexibility in addressing national needs and discuss barriers to implementation and strategies to address them.
Contributed to agency efforts to enable patients to engage with FDA through various initiatives, including those organized by the Patient Affairs Staff (PAS) (now called the Office of Patient Affairs) in the Office of the Commissioner:
- Attended more than a dozen patient-focused drug development meetings including those for rare diseases including Krabbe Disease and Pompe Disease.
- Attended FDA/National Organization for Rare Disorders (NORD) patient-led rare disease listening sessions requested by patient groups and organized by the Patient Affairs Staff (PAS). Worked with PAS and NORD to lead several patient listening sessions to better understand patient and caregivers’ perspectives on disease burden, treatment preferences, and clinical trial design.
- Attended Patient Engagement Collaborative (PEC) meetings and worked closely with other FDA Centers and the Office of the Commissioner on cross-cutting patient engagement efforts, including contributing input through the Patient Engagement Council on priority topics.
- Participated in meetings with EMA/FDA patient engagement and rare disease clusters.
- Presented at patient education webinar series on gene therapy sponsored by the American Society of Gene and Cell Therapy (ASGCT) and NORD.
- Participated in planning and presenting at FDA Public Workshop on Patient-Focused Drug Development: Guidance 4 – Incorporating Clinical Outcome Assessments into Endpoints for Regulatory Decision Making on December 6, 2019.

Ensuring product safety: Regulatory actions

FDA works with manufacturers to ensure the availability of CBER-regulated products including those related to public health emergencies such as COVID-19.
To address the COVID-19 Public Health emergency, FDA:
- Issued five Warning Letters for unapproved COVID-19 products, including a vaccine, exosome, adipose, and umbilical cord products, four of which were issued jointly with the United States Federal Trade Commission.
- Issued four Untitled Letters for unapproved COVID-19 products, including exosome, adipose, and umbilical cord products.
- Issued a Safety Alert pertaining to SARS-CoV-2 and COVID-19 for Fecal Microbiota for Transplantation (FMT), as SARS-CoV-2 may be transmitted by FMT (March 2020).
FDA has been exercising enforcement discretion in order to give developers time to come into compliance for certain products that do not raise reported or potential safety concerns, and extended the period of enforcement discretion in the “Regulatory Considerations for Human Cells, Tissues and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use” guidance (July 2020). FDA’s temporary program to help manufacturers of HCT/Ps come into compliance, the Tissue Reference Group Rapid Inquiry Program (TRIP), has also been extended through March 2021.
- In FY 2020, FDA sent 204 letters to manufacturers, clinics or health care providers across the country who may be offering unapproved regenerative medicine products, reiterating FDA’s compliance and enforcement policy. Compliance actions on HCT/P taken by FDA include:
- Issued four Warning Letters for unapproved and/or adulterated regenerative medicine products, including umbilical cord blood, umbilical cord, amniotic membrane, amniotic fluid, and exosome products.
- Issued 9 Untitled Letters for marketing of unapproved regenerative medicine products for numerous diseases or conditions, including some that are serious or life threatening.

Advancing Product Development and Ensuring Product Safety and Effectiveness Public meetings

Office of Vaccines Research and Review

Convened the Vaccines and Related Biological Products Advisory Committee (Oct. 9, 2019) to review the research programs in the Laboratory of Hepatitis Viruses and the Laboratory of Vector-Borne Viral Diseases in the Division of Viral Products, Office of Vaccines Research and Review. The committee also met in open session to discuss and make recommendations on the selection of strains to be included in influenza virus vaccines for the 2020 Southern hemisphere influenza season.
Convened a public hearing entitled, “Use of Fecal Microbiota for Transplantation (FMT) to Treat Clostridium difficile Infection Not Responsive to Standard Therapies” (Nov. 4, 2019) to obtain public input on the state of the science regarding FMT to treat C. difficile infection not responsive to standards therapies, including the available clinical evidence for safety and effectiveness of FMT for this use and to better understand the impact of FDA’s enforcement policy on product development.
The Vaccines and Related Biological Products Advisory Committee met in open session to discuss and make recommendations on the development of chikungunya vaccines (Nov. 8, 2019).
Convened the Vaccines and Related Biological Products Advisory Committee to select the influenza viruses for the composition of the influenza vaccine for the 2020-2021 U.S. influenza season. The viruses are selected based on the committee’s review and evaluation of influenza surveillance data collected from around the world. (March 4, 2020)
Participated in eight meetings sponsored by the World Health Organization that advised developing country national regulatory authorities on vaccine evaluation. This included participation in an Expert Committee on Biological Standardization (ECBS) and Global Advisory Committee on Vaccine Safety (GACVS) meetings.
Initiated two new virus spiking studies in collaboration with industry and 14 other laboratories to evaluate the sensitivity of virus detection using different next generation sequencing (NGS) platforms. One study will use the five reference virus stocks developed in CBER’s Office of Vaccines, Research and Review for standardization of NGS, which represents potential safety concerns in vaccines.
Participated in eight of the federal Influenza Risk Management Meetings (FRMM) to improve the annual seasonal influenza vaccine virus selection process.
Convened the workshop, Considerations for the Use of Real-World Evidence to Assess the Effectiveness of Preventive Vaccines (Sept. 17-18, 2020) Exchanged information with stakeholders from industry, academia, and government about the scientific, clinical, and regulatory challenges and opportunities in using real world evidence to assess the effectiveness of preventive vaccines.
Co-chaired two global regulators meetings held in March and June 2020, convened under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA) in an effort to reach global alignment regarding COVID-19 vaccine development and data required for regulatory decision-making, including pre-clinical data required to support proceeding to first-in-human clinical trials with COVID-19 vaccines, the need to address the theoretical risk that vaccines against COVID-19 enhance the disease, as well as the specific data requirements that will allow a candidate vaccine to proceed to Phase 3 clinical trials, and considerations for Phase 3 trial design.
Chaired the World Health Organization (WHO) Research and Development Blueprint COVID-19 vaccines working group, which provided external advice to WHO on how to coordinate the international COVID-19 response. This facilitated international exchange of data regarding animal models and assays and supported expert science-based consensus on approaches to clinical development of COVID-19 vaccines.

Office of Tissues and Advanced Therapies

The Cellular, Tissue and Gene Therapies Advisory Committee met in open session to hear an overview ad updates of research programs in the Tumor Vaccines and Biotechnology Branch and Cellular and Tissue Therapy Branch in the Division of Cellular and Gene Therapies. (May 8, 2020).
CBER held a workshop, “Facilitating End-to-End Development of Individualized Therapeutics,” to foster the development of individualized therapeutic products for the treatment of one individual or a very small number of patients, based on engineering a product aimed at the specific molecular mechanism underlying a patient’s (or small group of patients’) illness. (March 3, 2020)

Office of Blood Research and Review

Organized a public workshop, Perspectives on In Vitro Diagnostic Devices Regulated by the Office of Blood Research and Review, to provide an overview of key elements of regulatory submission for these devices and to facilitate education and communication between manufacturers and sponsors of these devices and the divisions in CBER that regulate them. (July 15-16, 2019)
Convened the Blood Products Advisory Committee to discuss scientific considerations for cold stored platelet products intended for transfusion, including product characterization, during storage and clinical indications for use. (Nov. 22, 2019)

Office of Biostatistics and Epidemiology

OBE enhanced the Biologics Effectiveness and Safety (BEST) post-market surveillance infrastructure, which formerly consisted of mostly administrative claims data, restrictive pre-configured analytical tools, and a data lag of at least nine months. The newly enhanced system, which is part of the Sentinel initiative, comprises large-scale claims data, electronic health records (EHR), and linked claims-EHR databases with a data lag of approximately three months. Flexible analytic capabilities expedite both simple queries and complex observational studies of many biologic products. The system enables queries and surveillance studies of vaccines, blood-derived products, and blood components in multiple data sources. The linked claims-EHR database supports complex outcomes validation, such as pregnancy outcomes.
OBE conducted a vaccine study as a test case through the BEST System (see above). This study aimed to replicate a previous study by the Vaccine Safety Datalink (VSD) (Klein et al. Pediatrics 2010) that examined the databases and analytic capabilities of the new system. The objectives of this study included: 1) characterizing the capabilities of the newly commenced BEST Initiative; 2) becoming familiar with the operational components of the new system; 3) determining the new system’s ability to reproduce existing evidence for the increased risk of febrile seizures in children receiving the first dose of measles-mumps-rubella-varicella (MMRV) vaccine, compared to that of MMR and varicella vaccines separately but on the same day. The results of the OBE study fulfilled the objectives and demonstrated the ability of the BEST Initiative data network to run a complex study protocol at multiple sites using a distributed data network and the Observational Medical Outcomes Partnership Common Data Model (organizing disparate data sources into the same database design using a common format).
The Transfusion-Transmitted Infections Monitoring System (TTIMS) collected and validated data for over 23 million donations at participating blood establishments as of December 31, 2018. Data analyses were approved for the following:
- Donor and donation prevalence for HIV, HBV, and HCV.
- Classical incidence analysis among repeat donors for the TTIMS study period for HIV, HBV and HCV (September 2015 - December 2018).
- Incidence modeling for first time TTIMS donors for HIV, based on 1) evaluation of donor HIV antibodies, using LAg avidity assays that characterize “recent” HIV infection; 2) viral load testing.
OBE and the Centers for Medicare and Medicaid Services (CMS) developed capabilities for routine and time-sensitive assessments of the safety of vaccines for people 65 years of age and older. OBE, CMS, and the Centers for Disease Control and Prevention conducted near real-time surveillance and self-controlled, end-of-the-season analyses for the risk of Guillain-Barré syndrome (GBS) after influenza vaccination, which demonstrated the capability to rapidly assess safety signals generated by other data sources. A Rapid Cycle Analysis in the Vaccine Safety Datalink, led by the CDC found safety signals in the 2018-2019 influenza season for an increased risk of GBS following high-dose influenza vaccinations and Shingrix vaccinations. CBER, CDC, and CMS formed working groups in February 2019 to refine these safety signals in CMS data.

Mission-Related Research

CBER research is essential for supporting development of safe and effective new products and to the fulfillment of our mission of ensuring that products we regulate are safe, pure, potent, and effective. An important example is a collaboration between the Center for Devices and Radiological Health (CDRH) and the Center for Biologics Evaluation and Research (CBER), the FDA established a Reference Panel composed of standardized material, suitable for the determination and direct comparison of analytical sensitivity and cross-reactivity of nucleic acid-based SARS-CoV-2 assays. This allowed more precise comparison of performance of NAAT SARS-CoV-2 assays.

The additional examples that follow represent the broad scope of our research and illustrates the extraordinary expertise of our scientists.

Blood 2020 Sep 10;136(11):1359-67
HIV incidence in US first-time blood donors and transfusion risk with a 12-month deferral for men who have sex with men.
Grebe E, Busch MP, Notari EP, Bruhn R, Quiner CA, Hindes DA, Stone M, Bakkour S, Yang H, Williamson PC, Kessler D, Reik RF, Stramer SL, Glynn SA, Anderson SA, Williams AE, Custer B, Transfusion-Transmissible Infections Monitoring System (TTIMS)

The authors assessed whether human immunodeficiency virus (HIV) incidence or associated transfusion risk was increased in first-time blood donors following the FDA revised guidance published in 2015 that recommended a change in blood donor deferral of men who have sex with men (MSM) from an indefinite to a 12-month deferral since last sex. No increase in HIV incidence or HIV transfusion transmission risk after implementation of a 12-month MSM deferral policy was observed.

Sci Rep 2020 Sep 24;10(1):15643
Sequence analysis of SARS-CoV-2 genome reveals features important for vaccine design.
Kames J, Holcomb DD, Kimchi O, DiCuccio M, Hamasaki-Katagiri N, Wang T, Komar AA, Alexaki A, Kimchi-Sarfaty C

These collaborators performed a comprehensive in silico analyses of several features of SARS-CoV-2 genomic sequence (e.g., codon usage, codon pair usage, dinucleotide/junction dinucleotide usage, RNA structure around the frameshift region) in comparison with other members of the coronaviridae family of viruses, the overall human genome, and the transcriptome of specific human tissues such as lung, which are primarily targeted by the virus. Their analysis identified the spike (S) and nucleocapsid (N) proteins as promising targets for deoptimization and suggests a roadmap for SARS-CoV-2 vaccine development, which can be generalizable to other viruses.

J Infect Dis 2020 Jul 15;222(2):278-87
Relative effectiveness of influenza vaccines among the U.S. elderly, 2018-19.
Izurieta HS, Chillarige Y, Kelman J, Wei Y, Lu Y, Xu W, Lu M, Pratt D, Wernecke M, MaCurdy T, Forshee R

The researchers did not find major effectiveness differences between licensed vaccines used among the elderly during the 2018-2019 season. Consistent with prior research, they did find that the egg-based adjuvanted and high dose vaccines were slightly more effective than the egg-based quadrivalent vaccines.

Nat Commun 2020 Jul 10;11(1):3461
A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing.
Zhang WW, Karmakar S, Gannavaram S, Dey R, Lypaczewski P, Ismail N, Siddiqui A, Simonyan V, Oliveira F, Coutinho-Abreu IV, DeSouza-Vieira T, Meneses C, Oristian J, Serafim TD, Musa A, Nakamura R, Saljoughian N, Volpedo G, Satoskar M, Satoskar S, Dagur PK, McCoy JP, Kamhawi S, Valenzuela JG, Hamano S, Satoskar AR, Matlashewski G, Nakhasi HL

Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa transmitted by infected sand flies. LmCen−/− is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. The authors found that Mice immunized with LmCen−/− have no visible lesions following challenge with L. major-infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen−/− immunization resulted in protection and an immune response comparable to leishmanization. The authors conclude that LmCen−/− is safe since it is unable to cause disease in immunocompromised mice, induces robust host protection against vector sand fly challenge and because it is marker free, can be advanced to human vaccine trials.

Res Pract Thromb Haemost 2020 Jun 12;4(5):944-5
Effect of pH on thrombin activity measured by calibrated automated thrombinography.
Jackson JW, Surov SS, Liang Y, Parunov LA, Ovanesov MV

The authors of this letter note that many conflicting considerations should be taken when performing calibrated automated thrombogram (CAT) analysis on samples that have a pH change, highlighting the possibility that simple solutions to the issue are not possible.

Vaccines 2020 Jul 12;8(3):E382
Neutralizing antibodies targeting the conserved stem region of influenza hemagglutinin.
Nath Neerukonda S, Vassell R, Weiss CD

Influenza continues to be a public health threat despite the availability of annual vaccines. This article comprehensively reviews the current knowledge about stem-directed broadly neutralizing antibodies and the structural features contributing to virus neutralization.

J Mol Biol 2020 May 15;432(11):3369-78
TissueCoCoPUTs: novel human tissue-specific codon and codon-pair usage tables based on differential tissue gene expression.
Kames J, Alexaki A, Holcomb DD, Santana-Quintero LV, Athey JC, Hamasaki-Katagiri N, Katneni U, Golikov A, Ibla JC, Bar H, Kimchi-Sarfaty C

Protein expression in multicellular organisms varies widely across tissues. Codon usage in the transcriptome of each tissue is derived from genomic codon usage and the relative expression level of each gene. The researchers created a comprehensive computational resource that houses tissue-specific codon, codon-pair, and dinucleotide usage data for 51 Homo sapiens tissues using transcriptome data from the Broad Institute Genotype-Tissue Expression (GTEx) portal. This novel resource may be useful in unraveling the relationship between codon usage and tRNA abundance, which could be critical in determining translation kinetics and efficiency across tissues.

FEBS Lett 2019 Dec;593(24):3449-60
Interaction of adenovirus with antibodies, complement and coagulation factors.
Allen RJ, Byrnes AP

Adenovirus (AdV) is one of the most widely-used vectors for gene therapy and vaccine studies due to its excellent transduction efficiency, capacity for large transgenes and high levels of gene expression. This review summarizes the plasma proteins that interact with AdV, including antibodies, complement and vitamin K-dependent coagulation factors. The authors also review the complex interactions of these plasma proteins with each other and with cellular proteins, as well as strategies for developing better AdV vectors that evade or manipulate plasma proteins.

J Mol Diagn 2019 Nov;21(6):1025-33
A Zika reference panel for molecular-based diagnostic devices as a US Food and Drug Administration response tool to a public health emergency.
Garcia M, Fares-Gusmao R, Sapsford K, Chancey C, Grinev A, Lovell S, Scherf U, Rios M

In 2015, Zika virus (ZIKV) appeared as an emerging pathogen, generating a global and urgent need for accurate diagnostic devices. Reference panels are a fundamental tool for performance assessment of molecular tests. These scientists developed a reference panel for ZIKV. The panel is composed of five vials: two different heat-inactivated ZIKV strains (PRVABC59 and FSS13025) in concentrated stocks and three blinded concentrations prepared from those strains.

Nat Commun 2019 Nov 25;10(1):5353
Targeting specificity of APOBEC-based cytosine base editor in human iPSCs determined by whole genome sequencing.
McGrath E, Shin H, Zhang L, Phue JN, Wu WW, Shen RF, Jang YY, Revollo J, Ye Z

DNA base editors have enabled genome editing without generating DNA double strand breaks. The authors investigated the fidelity of cytidine deaminase-mediated base editing in human induced pluripotent stem cells (iPSCs) by whole genome sequencing after sustained or transient base editor expression. These results demonstrate that cytosine base editor-mediated editing may result in unintended genetic modifications with distinct patterns from that of the conventional CRISPR-Cas nucleases.

CBER Guidance for Industry

CBER produces Guidance documents to inform stakeholders of the center’s current interpretation of its regulations and ways that regulated industry can remain in compliance. The center also collaborates with other FDA centers on joint guidances that cover issues with intra-agency regulatory implications.

Office of Blood Research and Review
Further Testing of Donations that are Reactive on a Licensed Donor Screening Test for Antibodies to Hepatitis C Virus; Guidance for Industry
CBER, October 2019

Considerations for the Development of Dried Plasma Products Intended for Transfusion; Guidance for Industry
CBER, December 2019

Use of Serological Tests to Reduce the Risk of Transfusion-Transmitted Human T-Lymphotropic Virus Types I and II (HTLV-I/II); Guidance for Industry
CBER, February 2020

Alternative Procedures for Blood and Blood Components During the COVID-19 Public Health Emergency; Guidance for Industry
CBER, April 2020

Revised Recommendations to Reduce the Risk of Transfusion-Transmitted Malaria; Guidance for Industry
CBER, April 2020

Implementation of Acceptable Full-Length and Abbreviated Donor History Questionnaires and Accompanying Materials for Use in Screening Donors of Blood and Blood Components; Guidance for Industry
CBER, May 2020

Implementation of Acceptable Full-Length and Abbreviated Donor History Questionnaires and Accompanying Materials for Use in Screening Donors of Source Plasma; Guidance for Industry
CBER, May 2020

Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components; Guidance for Industry
CBER, August 2020 (updated from April 2020)

Recommendations for Reducing the Risk of Human Immunodeficiency Virus Transmission by Blood and Blood Products; Guidance for Industry
CBER, August 2020 (updated from April 2020)

Investigational COVID-19 Convalescent Plasma; Guidance for Industry
CBER, January 2021 (originally published April 2020; updated May, September and November 2020)

Office of Tissues and Advanced Therapies

Human Gene Therapy for Retinal Disorders; Guidance for Industry
CBER, January 2020