The United States Food and Drug Administration (FDA) is hosting its annual conference, Regulatory Education for Industry (REdI), virtually next week from July 19-23. Register for this free conference to learn directly from senior leadership at FDA. Continuing education credits for several professional organizations are available, and this conference can also be used toward GxP training now required by the eighth edition FACT-JACIE Hematopoietic Cellular Therapy Standards.
For the first time, this conference will have tracks for three medical products: drugs, devices, and biologics. The biologics track will focus on different aspects of product development of advanced therapies regulated by the Center for Biologics Evaluation and Research (CBER). Topics include regulation of tissue products under 21 CFR part 1271; development and regulation of cellular, gene, and plasma-derived therapies, and expedited programs for advanced therapies.
The U.S. Food and Drug Administration (FDA) continues to provide updates regarding donor eligibility determination amid the COVID-19 pandemic. In January, it posted an announcement with information about considerations for donor eligibility and vaccines.
The FDA does not recommend testing asymptomatic donors of human cells, tissues, and cell and tissue based products (HCT/Ps), but does offer considerations for donor screening based on information known at this time. HCT/P establishments may wish to consider whether the donor in the 28 days prior to collection:
- cared for, lived with, or otherwise had close contact with individuals diagnosed with or suspected of having COVID-19 infection; or
- had been diagnosed with or suspected of having COVID-19 infection; or
- had a positive diagnostic test (e.g., nasopharyngeal swab) for SARS-CoV-2 but never developed symptoms.
The FDA also states that, based on information available at this time, donors who have received non-replicating, inactivated, or RNA-based COVID-19 vaccines are not precluded from donating HCT/Ps.
The Food and Drug Administration (FDA) announced on April 8, 2020 the issuance of final guidance regarding the administration and study of convalescent plasma collected from individuals who have recovered from COVID-19. The use of COVID-19 convalescent plasma is regulated by the FDA as an investigational product, and health care providers wishing to use this therapy as an option must therefore participate in investigational pathways. The guidance provides information on this and a variety of topics as listed below:
- pathways for use of investigational COVID-19 convalescent plasma,
- patient eligibility,
- collection of COVID-19 convalescent plasma, including donor eligibility and donor qualifications,
- labeling, and
The United States Food and Drug Administration (FDA) published Important Information for Human Cell, Tissue, or Cellular or Tissue-based Product (HCT/P) Establishments Regarding the 2019 Novel Coronavirus Outbreak on February 14, 2020. This announcement notes that the FDA has been working closely with the Center for Disease Control (CDC) and other federal and international agencies to monitor the outbreak of coronavirus (COVID-19).
The FDA stated that respiratory viruses are not generally known to be transmitted by HCT/Ps, potential for coronavirus transmission via these products is unknown. Although routine screening measures for infections are already in use, some programs may wish to use additional donor screening in response to this outbreak. Based on limited information available, the FDA says programs may wish to consider the donor history in the 28 days prior to cell collection for potential donors who have:
- traveled to areas with COVID-19 outbreaks, as defined by CDC
- lived with individuals diagnosed with or suspected of having COVID-19 infection; or
- been diagnosed with or suspected of having COVID-19 infection.
The following are additional details provided by FDA:
In 2018, the United States FDA released six draft guidance documents regarding gene therapy, and the final versions of these documents were released in January 2020. More details can be found in the Just the FACTs newsletter article, FDA Releases Six Draft Guidance Documents for Gene Therapy (2018).
The final documents can be accessed online:
- Chemistry, Manufacturing, and Control Information for Human Gene Therapy Investigational New Drug Applications; Guidance for Industry
- Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up; Guidance for Industry
- Long Term Follow-Up After Administration of Human Gene Therapy Products; Guidance for Industry
- Human Gene Therapy for Retinal Disorders; Guidance for Industry
- Human Gene Therapy for Rare Diseases; Guidance for Industry
- Human Gene Therapy for Hemophilia; Guidance for Industry
The United States Food and Drug Administration (FDA) announced a public workshop titled, “Facilitating End-to-End Development of Individualized Therapeutics,” focusing on development of individualized therapeutic products for one or a small number of patients. This workshop will be on March 3, 2020 from 8:30 am to 5:00 pm ET, and can be attended in person or via webcast. Registration is required.
Per the FDA announcement, the objectives of the workshop are:
- “To discuss scientific challenges to development of individualized therapeutics, and ongoing efforts to adapt products manufactured based on a technology platform to treat diseases affecting one individual or a very small number of patients; explore lessons learned, logistical challenges, failures, and successes.
- To examine challenges under the current U.S. regulatory framework that need to be addressed to have a clear pathway for access to individualized therapeutics, including licensed manufacture and consistent delivery of safe and effective products.
- To explore challenges from the patient perspective that limit development and access to individualized therapeutics; consider research and development, ethical, and product availability and access issues.
- To identify new models of collaboration or synergies that may facilitate aspects of development, including manufacturing, preclinical testing, clinical development, and continuing evaluation for consistent production, availability, and delivery of individualized therapeutic products.”
For more details and to register, see the FDA announcement.
Variability in Cell Collection for IEC Products Discussed with FDA during 2019 Cell Therapy Liaison Meeting
The Food and Drug Administration Cell Therapy Liaison Meeting (FDA CTLM) took place on March 5, 2019 and a summary of the meeting is now online. This meeting was made possible by 13 organizations serving the planning committee, led by Olive Sturtevant and the ISCT North America Legal and Regulatory Affairs Committee. Ms. Sturtevant is also a member of the FACT-JACIE Standards Steering Committee.
Four topics were presented to the FDA, including regulation of biobanking material for future products, collection of mononuclear cells (MNCs) for immune effector cell (IEC) products, minimum characterization criteria for clinical grade induced pluripotent stem cell (iPSC) products, and early interaction mechanisms for tool/device developers.
The presentation and discussion regarding the collection of MNCs for IEC products is particularly timely for many FACT-accredited apheresis facilities. The summary outlines the challenges Dr. Jay Raval presented on behalf of the American Society of Apheresis (ASFA) and the discussion with the FDA afterwards.
This summary may be useful to discussions between apheresis facilities and the commercial manufacturers they work with. It also provides ideas that the field could pursue to reduce variability to a meaningful level that will ensure quality IEC products without limiting the ability of experienced apheresis facilities to care for their patients.
This meeting is just one event regarding this issue in which FACT participated. We will continue to provide updates via the Just the FACTs newsletter as appropriate. In the meantime, we have appreciated the spirit of collaboration that has been demonstrated by commercial manufacturers, healthcare providers, related organizations, and many others.
The United States Centers for Medicare & Medicaid Services (CMS) finalized its National Coverage Determination (NCD) for CAR T-cell Therapy for Cancers on August 7, 2019. Among other changes, the decision no longer requires Coverage with Evidence Development (CED) and now allows coverage for indications on FDA-approved indications and uses recommended by a citation in CMS-approved compendia. FACT appreciates CMS’s consideration of our comments and of those submitted by several of our stakeholders. Many of the changes will promote patient access to CAR T-cell therapy.
The American Society for Transplantation and Cellular Therapy (ASTCT), one of FACT’s parent organizations, indicated that it is also pleased with many of the changes from the proposed decision memo and responded with a comment letter about suggestions for continuing to improve reimbursement for this therapy.
We believe in the utility of FACT Standards to promote safety and efficacy of CAR T-cell therapies; increase harmonization across requirements of regulators, payers, and manufacturers; and reduce burden on hospitals. We will continue to work with all of these stakeholders to do our part to promote patient access.
The Cellular Therapy Community Corner provides a forum for the cell therapy community that includes educational opportunities, recent publications, and upcoming events.
ASGCT Debuts Patient Education Program
The American Society of Gene & Cell Therapy (ASGCT) announced the first release of the Society’s Patient Education program, a new initiative for 2019. Designed by ASGCT committee volunteers in coordination with patient advocacy groups, the new patient-centered portal is designed to educate and inform patients, families, and the public on the status and promise of gene and cell therapies.
The following Sessions are now live on ASGCT.org:
Gene Therapy 101, which includes the following information:
Disease Treatments, which includes the following information:
- Spinal Muscular Atrophy
- X-Linked Myotubular Myopathy
- Leukodystrophy (coming February 15)
- Blood Disorders (coming February 22)
- Inherited Retinal Disorders (coming February 28)
All topics ultimately provide patients and patient advocates with video, text, and infographic resources to share with various stakeholders. ASGCT encourages people to share these resources with their friends and family.
FDA Outlines Planned Policies to Advance Development of Safe and Effective Cell and Gene Therapies
Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research
On January 15, 2019, FDA announced its plans to provide policy guidance and advance its drug development network over the coming year in response to increases in cell and gene therapy investigational new drug (IND) applications. The FDA anticipates receiving more than 200 INDs per year by 2020 and approving 10 to 20 cell and gene products a year by 2025.
The full statement outlines FDA’s policy agenda as it relates to these technologies.
Find a clinical trial through the Jason Carter Clinical Trials Program Offered by The National Marrow Donor Program®/Be The Match®
The National Marrow Donor Program®/Be The Match® is offering a new program, The Jason Carter Clinical Trials Program, designed to help patients with blood cancers or blood disorders and their families find and join clinical trials. Funding was provided by the Carter family, in memory of their son and brother, Jason Carter. This free program offers:
- One-on-one telephone support and information from a clinical trial nurse to help patients and families navigate their clinical trial search.
- Easy-to-use, web-based search tool to find relevant clinical trials: JasonCarterClinicalTrialsProgram.org
- Easy-to-understand educational resources for patients and families to learn about cancer treatment options and clinical trials.
On the JCCTP.org website, there are patient-friendly clinical trial descriptions related to leukemia, lymphoma, MDS, aplastic anemia, and more. Treatments in some of these clinical trials include blood or marrow transplant, but many others trials include the latest cell therapies such as CAR T and immunotherapies.
Patients can also apply for financial assistance from the Drs. Jeffrey and Isabel Chell Clinical Trials Travel Grant. This grant works to offset the cost of travel related to clinical trial participation. Grant eligibility information and application are available on JasonCarterClinicalTrialsProgram.org.
The United States Food and Drug Administration (FDA) released six draft guidance documents related to gene therapy. Three of the guidance documents are disease-specific, and three are related to manufacturing. According to Scott Gottlieb, MD, FDA Commissioner, these documents are the building blocks of the FDA’s framework for advancing gene therapy while requiring safety and effectiveness. The guidance is part of the FDA’s efforts to provide clear recommendations to sponsors and researchers.
The FDA highlights the importance of establishing standardized procedures for cell collection and handling across all collection sites for multi-center clinical trials to assure the quality and safety of the final product as well as ensuring control of the manufacturing process. A list of collection sites, the FDA Establishment Identifier, and accreditations for compliance with established standards (e.g., Foundation for the Accreditation of Cellular Therapy) should be included in the IND.
Additional Manufacturing Draft Guidance Documents
Disease-Specific Draft Guidance Documents
FACT-accredited organizations are regulated by several governmental agencies around the world in relation to quality and safety of cellular therapy products and reimbursement. When draft regulations or guidance documents are released, FACT committees review the information and submit comments as applicable to the scope of FACT accreditation. In the past decade, comments have been submitted to agencies in the United States, Australia, and Europe. The FACT Global Affairs Committee also supports cellular therapy leaders in developing countries to encourage use of FACT Standards.
So far this year, FACT has submitted comments on three topics to two agencies in the United States:
- Docket No. FDA-2017-D-6154 for “Evaluation of Devices Used with Regenerative Medicine Advanced Therapies; Draft Guidance for Industry”; submitted to the Food and Drug Administration (FDA) on February 9, 2018.
- Docket No. FDA-2017-D-6159 for “Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; Draft Guidance for Industry”; submitted to the Food and Drug Administration (FDA) on February 9, 2018.
- National Coverage Analysis for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers; submitted to the Centers for Medicare & Medicaid Services on June 15, 2018.
FACT also plans to review the recently published FDA draft guidance documents for gene therapies. These comments are due by October 10, 2018. If you have input you would like FACT to consider for inclusion, submit those to Kara Wacker at email@example.com by August 31, 2018.
FACT Standards require reporting of adverse events related to cellular therapy product administration. FACT does not dictate the process or timing of such reporting, but requires that the reporting meets the requirements of applicable laws and regulations. We have fielded many questions via workshops, emails, and telephone calls regarding the reporting of adverse events related to commercial cellular therapy products (e.g., Kymriah, Yescarta).
Many stakeholders in the field are working on initiatives to make data reporting, including adverse event reporting, a more streamlined process. In the meantime, the FACT Immune Effector Cell Task Force recommends that programs define a reporting process and document it in a Standard Operating Procedure (SOP). The following are some tips for creating the process:
- Know, understand, and comply with the reporting requirements outlined in the Risk Evaluation and Mitigation Strategies (REMS) for the specific product(s) you administer. List these requirements in the SOP.
- For remaining gaps in the process, define your program’s reporting elements and frequency of reporting, including:
- The types of adverse events that your program will report immediately (e.g., all events, specific grades of cytokine release syndrome) and to what source (e.g., MedWatch, manufacturer).
- The types of adverse events that your program will collate for future reporting, the frequency of reporting such adverse events, and to whom the information will be reported.
- Maintain documentation of all adverse events and reporting records.
- Develop an audit plan and schedule for monitoring compliance with REMS requirements and the program-defined process.
- Regularly check in with your manufacturer contacts for any updates to their adverse event reporting requirements.
For additional information regarding adverse event reporting, visit the REMS websites of Kymriah and Yescarta, review FDA requirements for manufacturer reporting in 21 CFR 600.80 Postmarketing reporting of adverse experiences, and Standard B4.10 and its substandards in the FACT-JACIE HCT Standards and the FACT IEC Standards.
Requirements for Qualifying Third-Party Manufacturers of Cellular Therapy Products Regulated Under U.S. INDs or BLAs
In light of the recent licensing of immune effector cell (IEC) products in the United States, this is an opportune time to continue education regarding third-party manufacturers in general. The manufacturing process for many novel cellular therapy products, including research and licensed cellular therapy products, involves multiple entities: holders of Investigational New Drug (IND) applications for research or Biological License Applications (BLA) for licensure, collection facilities, and processing facilities. Clinical units may be involved with one or more of these facilities.
There are three main responsibilities when third-parties are involved in the manufacture of a research or licensed product: verify regulatory oversight, qualify the vendor or service provider, and define responsibilities.
Though many questions from organizations regarding these requirements are specific to IEC processes, the information below can also be used as guidelines for other types of cellular therapy products.
Verify Regulatory Oversight
- The participating manufacturer (e.g., collection or processing facility) is responsible for verifying that the contracting entity for whom it performs services possesses an approved IND or BLA.
- The Clinical Program is responsible for verifying the manufacturer responsible for the entire manufacturing process (e.g., a commercial manufacturer) possesses an approved IND or BLA.
Qualify the Third-Party Manufacturer
- The IND or BLA holder is responsible for verifying that any facility performing a step of manufacturing complies with GMP and GTP requirements as applicable (see 21 CFR 1271.150(c)(1)(iii)).
- If the IND or BLA is held internally by a FACT-accredited facility, then the facility must perform this qualification and provide documentation to FACT inspectors.
- If the IND or BLA is external, i.e., held by a third-party investigator or manufacturer, this qualification is outside the scope of FACT accreditation and the FACT-accredited facility is not required to provide documentation of this type of qualification to FACT inspectors.
The participating manufacturer must participate in site visits from the IND or BLA holder and provide the level of service required of that entity, including compliance with GMP and GTP requirements as applicable. FACT-accredited facilities that participate in manufacturing for external IND or BLA holders must provide FACT inspectors evidence of complying with these requirements as required by applicable laws and regulations.
- The Clinical Program must perform vendor qualification of the IND or BLA holder. It is the FDA that monitors regulatory compliance, and the Clinical Program only needs to perform vendor qualification. Programs must verify the IND or BLA holder meets its needs in regards to many areas of cellular therapy, including labeling processes (label content applied by whom and how), level of service (turnaround times, customer inquiries), and other metrics defined by the program. Documentation of this qualification must be provided to the FACT inspection team.
- It is acceptable to delegate this activity to the Processing Facility so long as there is robust communication between the program and facility, which should be obvious in documentation.
- The level of participation of the clinical service in manufacturing an immune effector cell product varies. Regardless of where the product is collected or manufactured, responsibilities must be clearly defined.
- If a Clinical Program is responsible for collecting cells or preparing the IEC product for administration, or if independently FACT-accredited cell collection and processing facilities contract with a manufacturer, FACT Standards for collection and processing apply to the steps performed.
- If products are received directly by the Clinical Program or intermediary facility (e.g., blood bank, pharmacy) from a third-party manufacturer, the following responsibilities must be defined at a minimum: chain of custody, product storage, verification of product identity, and management of adverse events. Additional responsibilities will be included in the new edition of FACT Standards to be published in March 2018.
FACT Standard D11.1.2* and its substandards require cellular therapy products to meet pre-determined release criteria prior to distribution from the Processing Facility. When products do not meet release criteria, the Processing Facility Director or Medical Director, as appropriate, must give specific authorization for release.
In the case of investigational products regulated by the Food and Drug Administration (FDA) under Investigational New Drug (IND) applications, the FDA expects that products will not be administered if they fail to meet the release criteria listed in the IND. The FDA recognizes that there are situations when administration of a failed lot may be in the best interest of the patient, but the FDA must be involved in the decision to administer the product. To comply with the FACT Standards, both D11.1.2 and the regulatory requirements of the FDA must be met.
*In the FACT-JACIE Hematopoietic Cell Therapy Standards, the FACT Immune Effector Cell Standards, and the FACT Common Standards.
In November 2017, the FDA released a comprehensive policy framework for the development and oversight of regenerative medicine products, including novel cellular therapies, through the publication of four guidance documents. Two of these documents were finalized, and two are open for public comment.
Draft documents that were open for public comment until February 14, 2018 include:
- Evaluation of Devices Used with Regenerative Medicine Advanced Therapies
- Expedited Programs for Regenerative Medicine Therapies for Serious Conditions
Related documents published in final form include:
- Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception
- Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use
FACT supports the FDA’s efforts to clarify and streamline its regulation of regenerative medicine therapies, and submitted comments organized into two sections: 1) the role of FACT accreditation in advancing cellular therapy for regenerative medicine and 2) specific comments about the guidance documents themselves.
The Food and Drug Administration (FDA) announced the availability of a final document entitled, “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.”
The guidance document provides certain establishments that manufacture non-reproductive human cells, tissues, and cellular and tissue-based products (HCT/Ps), regulated solely under the Public Health Service Act (PHS Act) and under FDA regulations, with recommendations and relevant examples for complying with the requirements to report HCT/P deviations.