RESUMO
Sessions included an overview of past cell therapy (CT) conferences sponsored by the International Alliance for Biological Standardization (IABS). The sessions highlighted challenges in the field of human pluripotent stem cells (hPSCs) and also addressed specific points on manufacturing, bioanalytics and comparability, tumorigenicity testing, storage, and shipping. Panel discussions complemented the presentations. The conference concluded that a range of new standardization groups is emerging that could help the field, but ways must be found to ensure that these efforts are coordinated. In addition, there are opportunities for regulatory convergence starting with a gap analysis of existing guidelines to determine what might be missing and what issues might be creating divergence. More specific global regulatory guidance, preferably from WHO, would be welcome. IABS and the California Institute for Regenerative Medicine (CIRM) will explore with stakeholders the development of a practical and innovative road map to support early CT product (CTP) developers.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Células-Tronco Pluripotentes , Testes de Carcinogenicidade , Guias como Assunto , Humanos , Controle de Qualidade , Medicina RegenerativaRESUMO
Cell therapy involves the administration of a viable somatic cell preparation to a patient for the treatment of a disease or traumatic damage. Because cell therapies are complex and very different from traditional biological products, they present significant challenges for regulatory authorities, manufacturers, developers, health care providers, and patients involved in their application. Like other emerging areas of biomedical research and development, there are many issues where regulatory views and decisions among countries and regions may differ due to minimal scientific evidence to support safety and efficacy, and lack of experience with these novel treatments. A brief overview of the current regulatory landscape for cell-based therapies is presented, and the need for a global effort to develop a set of common principles that may serve to facilitate the regulatory evaluation and market availability of these products is identified. In addition, a number of elements that could form a core consensus package of requirements for evaluating human cell therapy products is presented in the supplemental material which should be read in conjunction with the manuscript.
Assuntos
Pesquisa Biomédica/métodos , Técnicas de Cultura de Células/métodos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Engenharia Tecidual/métodos , Pesquisa Biomédica/normas , Pesquisa Biomédica/tendências , Terapia Baseada em Transplante de Células e Tecidos/normas , Terapia Baseada em Transplante de Células e Tecidos/tendências , Guias como Assunto , Humanos , Controle de Qualidade , Organização Mundial da SaúdeRESUMO
A polyvalent therapeutic cancer cell vaccine containing three viable, irradiated, replication-incompetent melanoma cell lines (Canvaxin) was administered to over 2500 patients in various clinical studies. This study examines the fate of Canvaxin cells in 16 patients with Stage II, III or IV melanoma, with special attention on assessing the capacity of the vaccine cells to replicate. The survival time and the potential proliferative capacity of irradiated Canvaxin cells in humans was studied by histologic examination of biopsies of injection sites over a two-week period. The overall results show that the vaccine cell mitotic index in skin biopsies (0.12%) was approximately 6 times lower than the control value (0.71%). Similarly, there was an overall trend toward a decrease in mitotic figures during the two week observation periods. Also, there was a trend towards a decrease in the number of vaccine cells and mitotic figures with increasing cycles. The data indicate that Canvaxin cells do not proliferate after intra-dermal injection, and that cells typically associated with an immune response are present at the inoculation sites.
Assuntos
Vacinas Anticâncer/administração & dosagem , Ciclo Celular/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Feminino , Humanos , Masculino , Melanoma/patologia , Neoplasias Cutâneas/patologiaRESUMO
The regulation of human cell therapy products is a key factor in their development and use to treat human diseases. In that regard, there is a recognized need for a global effort to develop a set of common principles that may serve to facilitate a convergence of regulatory approaches to ensure the smooth and efficient evaluation of products. This conference, with experts from regulatory agencies, industry, and academia, contributed to the process of developing such a document. Elements that could form a minimum consensus package of requirements for evaluating human cell therapy products were the overall focus of the conference. The important regulatory considerations that are unique to human cell therapy products were highlighted. Sessions addressed specific points that are different from those of traditional biological/biotechnological protein products. Panel discussions complemented the presentations. The conference concluded that most of the current regulatory framework is appropriate for cell therapy, but there are some areas where the application of the requirements for traditional biologicals is inappropriate. In addition, it was agreed that there is a need for international consensus on core regulatory elements, and that one of the major international organizations should take the lead in formulating such a consensus document.
Assuntos
Biotecnologia/legislação & jurisprudência , Terapia Baseada em Transplante de Células e Tecidos , Produtos Biológicos , HumanosRESUMO
Since the earliest days of biological product manufacture, there have been a number of instances where laboratory studies provided evidence for the presence of adventitious agents in a marketed product. Lessons learned from such events can be used to strengthen regulatory preparedness for the future. We have therefore selected four instances where an adventitious agent, or a signal suggesting the presence of an agent, was found in a viral vaccine, and have developed a case study for each. The four cases are: a) SV40 in polio vaccines; b) bacteriophage in measles and polio vaccines; c) reverse transcriptase in measles and mumps vaccines; and d) porcine circovirus and porcine circovirus DNA sequences in rotavirus vaccines. The lessons learned from each event are discussed. Based in part on those experiences, certain scientific principles have been identified by WHO that should be considered in regulatory risk evaluation if an adventitious agent is found in a marketed vaccine in the future.
Assuntos
Contaminação de Medicamentos , Vacinas Virais/efeitos adversos , Vacinas Virais/normas , Animais , Bacteriófagos/isolamento & purificação , Produtos Biológicos/efeitos adversos , Produtos Biológicos/normas , Circovirus/genética , Circovirus/isolamento & purificação , DNA Viral/genética , DNA Viral/isolamento & purificação , Contaminação de Medicamentos/prevenção & controle , Humanos , Vacina contra Sarampo-Caxumba-Rubéola/efeitos adversos , Vacina contra Caxumba/efeitos adversos , Vacinas contra Poliovirus/efeitos adversos , Saúde Pública , DNA Polimerase Dirigida por RNA/isolamento & purificação , Vacinas contra Rotavirus/efeitos adversos , Vírus 40 dos Símios/isolamento & purificação , Vacinas Virais/isolamento & purificação , Organização Mundial da SaúdeRESUMO
The issue of which cells to use as substrates for the production of biological products, and especially vaccines, has been with us in one form or another ever since the development of cell cultures in the 1950s. The major cell substrate events that occurred over the past 50 years are reviewed briefly. Although numerous conferences were held during that period, incomplete resolution of some cell substrate issues has remained. Specifically, the potential oncogenicity of cellular DNA derived from continuous cell lines, and the tests that are used to rule out the presence of adventitious agents have been recognized as areas that could benefit greatly from studies using state-of-the-art techniques. A collaborative effort involving WHO, NIAID, and IABS resulted from consensus recommendations of a 2004 conference, and the prospects for revised guidance in the near future on the characterization and use of animal cell substrates are bright.
Assuntos
Produtos Biológicos/normas , Técnicas de Cultura de Células/métodos , Meios de Cultura/normas , Animais , Produtos Biológicos/síntese química , Técnicas de Cultura de Células/normas , Linhagem Celular , Células Cultivadas , Células HeLa , Humanos , Mamíferos , FenótipoRESUMO
Therapeutic cancer vaccines are under development with the goal of enhancing the body's immune response to cancer cells sufficient to arrest cancer cell growth. Among the various approaches being used are those based on whole tumor cells. Developing a suitable measure of the potency of such vaccines presents a significant challenge because neither cellular associated markers nor in vivo biological responses that are correlated with efficacy have been identified; nevertheless, manufacturers and regulatory agencies will need to develop methods to evaluate these products. At this moment, the challenge for manufacturers who are developing whole cell vaccines is to demonstrate batch-to-batch consistency for the vaccine used in clinical studies and to show that comparable vaccine batches have the same capacity to achieve an acceptable level of biological activity that may be related to efficacy. This is particularly challenging in that animal models to test that activity do not exist and direct serological or immunological correlates of clinical protection are not available because protection has not yet been established in clinical trials. In the absence of well-defined biological markers and tests for manufacturing consistency, manufacturers and regulators will need to rely heavily on a highly reproducible manufacturing process--the consistency of the process therefore becomes critical. In developing regulatory approaches to whole cell cancer vaccines, the experience from the field of infectious disease vaccines should be examined for general guidance. A framework that draws heavily on the field of infectious disease vaccines is presented and suggests that at this point in the development of this new class of products, it is reasonable to develop data on quantitative antigen expression as a measure of potency with the expectation that when clinical efficacy has been established it will confirm the appropriateness of this approach. But because this will not be known until the end of a pivotal trial, a bioassay should be considered and run in parallel. Several examples of bioassays are presented along with their advantages and disadvantages. The final selection of a potency assay for use in lot release of a commercializable therapeutic whole cell vaccine ultimately will depend on the totality of the data available at the time of approval by regulatory agencies. Based on information currently available, it is likely that quantitative antigen expression or a bioassay could be used to measure potency. If both are determined to be acceptable, the use of quantitative antigen expression could be considered for routine lot release, while the bioassay could be reserved for use as one of the elements in establishing comparability when manufacturing changes are being considered after approval.