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Management of patients undergoing CAR T-cell therapy
and quality of life; (xi) cardiovascular status, including echocardiographic assessments and risk factors for cardio- vascular disease, such as ‘metabolic syndrome’; (xii) respi- ratory status; and (xiii) gastrointestinal and hepatic status.
The role of vaccination following CAR T-cell therapy remains unclear. Until further evidence is available, no specific recommendation can be made. This is, in particu- lar, a problem with small children who might not yet have completed their basic immunization schedule and who therefore need close follow-up.
In view of long-term B-cell depletion, the advisability of vaccination and adherence to the standard recommended national schedules needs to be evaluated for each individ- ual based on the history of infections and laboratory assessments of cellular and humoral immunity.75 If vac- cines are given, specific antibody responses should be assessed.
Post-authorization safety surveillance
As tisagenlecleucel (KymriahTM) and axicabta- geneciloleucel (YescartaTM) are the first agents in a novel class of therapies based on the genetic modification of autologous T cells using viral vectors, the EMA and the FDA have made marketing approval conditional on 15- year post-authorization safety surveillance (PASS). At an EMA-sponsored stakeholder workshop on how to best capture the long-term side effects of different CAR T-cell products over the next 15 years, it was felt that the report- ing of CAR T-cell safety and efficacy in one European reg- istry would avoid the creation of data silos and would allow for the risks and benefits of the different agents to be transparently compared on a common platform. Such a registry would also set an excellent example as to how public registries can not only improve patient care but also help to support affordable health care.76 In March 2019, the EBMT received a qualification opinion from the EMA which found the cellular therapy module of the EBMT registry to be fit-for-purpose for the regulatory overseeing of pharmaco-epidemiological studies concerning CAR T- cell therapy.77
A modified version of the MED-A cell therapy form will be used for CAR T cells and other academic- or industry- manufactured cell therapies. The data submission time points are day 0, day +100, 6 months, and annually there- after. This module has already proven to be effective in capturing basic data sets on academic and commercial CAR T-cell infusions, although the EMA has requested additional safeguards during data capture for regulatory purposes. However, the current minimal data set request- ed by the EMA for commercial products does not require detailed product information such as CD4 and CD8 ratios or transduction efficiencies, as companies consider these to be sensitive proprietary information. Agreed access to a more detailed data set regarding products being evaluated in clinical trials might benefit all those working in the CAR T-cell research field.
In the USA, the FDA has implemented product-specific Risk Evaluation and Mitigation Strategy (REMS) pro- grams. In parallel, the National Cancer Institute-funded Moonshot Initiative program called Cellular Immunotherapy Data Resource, awarded to the CIBMTR in October 2018, will allow for the collection of real-world data. In recent years, the EBMT has worked with the
CIBMTR to develop common data collection policies so the prospect of robust global datasets on the efficacy and safety of CAR T-cell therapies is on the horizon.
It is expected that patients receiving CAR T-cell thera- pies in both investigator-led and pharma-sponsored trials might also have their follow-up data collected in the EBMT registry. In order to address concerns that pharma- ceutical companies may have about the confidentiality of commercially sensitive clinical data, trial data reported to the EBMT registry can be embargoed until investigating centers decide to make such data accessible to the public. Early data collection might also create a virtuous circle whereby knowledge of increased activity might help those lobbying for an improved infrastructure for CAR T- cell therapies across Europe in terms of funding opportu- nities, regulatory frameworks, and, ultimately, commer- cial drug approval. EMA approval for the use of the EBMT registry also places certain responsibilities on the EBMT. As a formal data controller, the EBMT will need to guar- antee a fair and transparent mode of data sharing in order to improve the assessment of the many different agents and ultimately to improve our knowledge on how best to use CAR T-cell therapies.
JACIE and regulatory issues
FACT-JACIE standards were initially developed for the accreditation of HCT programs.78,79 The current 7th edition of the standards also covers immune effector cells (IEC) to accommodate the rapidly evolving field of cellular thera- py, mainly, although not exclusively, genetically modified cells, such as CAR T cells. FACT-JACIE standards do not cover the manufacturing of CAR T cells but do include the supply chain and handover of responsibilities when the product is provided by a third party. Specific clauses in the standards detail the following requirements, among oth- ers: the need for the appropriate recognition of side effects related to the infusion of IEC, a policy for the rapid esca- lation of care in critically ill patients, the availability of specific drugs for CRS and other complications and a labeling system to guarantee both the identification and traceability of the product from the collection to the man- ufacturer and back to the clinical unit. In all involved areas, there is the need for evidence of adequate staffing and training, satisfactory levels of competency, validated pro- cedures and efficient communication. Documentation is available at www.jacie.org.
During the introductory phase of developing CAR T cells, some centers received ‘focused’ site visits for IEC. However, now that the 7th edition of the standards is well established, inspection of IEC standards should be routinely incorporated within standard JACIE site visits, particularly as there is much dependency on the wider accreditation requirements of the HCT program i.e., clinical, apheresis, pharmacy and processing laboratory service, along with quality management system requirements. In fact, in the current 7th edition, only 2% and 6% of items are specifically related to either IEC or HCT, respectively, and 92% of the items are common to all forms of cellular therapy.
In addition to JACIE, the complexity of the clinical management of patients receiving CAR T-cell therapy has led to competent authorities and other regulatory bodies in some European countries requiring the administration of CAR T cells and other IEC within the context of an
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