Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. Special Article: Advanced therapy medicinal products in Brazil: regulatory panorama

Silva Junior, João Batista; Silva, Antonio Alfredo Rodrigues e; Melo, Francielli Cristine Cunha; Kumoto, Melina Cossote; Parca, Renata Miranda

doi:10.1016/j.htct.2021.09.010

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Brasil

Hematology, Transfusion and Cell Therapy

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Special article • Hematol., Transfus. Cell Ther. 43 (suppl 2) • 2021 • https://doi.org/10.1016/j.htct.2021.09.010 copy

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. Special Article: Advanced therapy medicinal products in Brazil: regulatory panorama

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Advanced therapy medicinal products, considered special medications, requires Anvisa approval for use and commercialization in Brazil. They include the advanced cellular therapy products, tissue engineering products and gene therapy products, which due to their complexity involve innovation and risks, optimized regulatory channels for their development and life cycle monitoring. The scientific elements and the compliance with applicable regulatory aspects are fundamental pillars for the advancement of clinical trials, the positive evidence of the benefit-risk profile and the definition of the critical quality attributes, from the perspective of making safe, effective and high-quality products available to the population. The approval models of these products in Brazil adapt to the specificities and characteristics of the technology and the patient target population, with accelerated regulatory analyses, use in emergency situations by risk controls and specific monitoring mechanisms, principally those related to rare diseases without other therapeutic alternatives. The opportune access to the advance therapy product with safety, efficacy and quality involves innovative normative elements that include the long-term follow-up of the safety and efficacy and of the adaptive pharmacovigilance requisites, as well as the traceability mechanisms for the start-off materials, products and patients.

Keywords:
Gene therapy; Advanced therapy medicinal product; Anvisa; Clinical trials; Regulatory approval

Term	Concept
Advanced Therapy Medicinal Products (ATMPs)	Special category of new medications encompassing the advanced cell therapy product, the tissue engineering product and the gene therapy product.
Advanced Cellular Therapy Product (ACTP)	Biological product constituted by human cells or their derivatives not chemically defined, with the finality of obtaining therapeutic properties, preventive or diagnostic, by means of a mode of action which is principally metabolic, pharmacologic and/or immunologic, for autologous or allogenic use in humans, (a) having been submitted to extensive manipulation and/or (b) that it develops in the receptor the distinct function performed in the donor.
Tissue Engineering Product (TEP)	Biological product constituted by organized human cells in tissues or organs which present properties permitting the regeneration, reconstruction or substitution of a tissue or human organ, in the presence or not of structural support constituted by biological or biocompatible material, being that it (a) has been submitted to extensive manipulation and/or (b) develops in the receptor the distinct function performed in the donor.
Gene Therapy Product ( GTP)	Biological product whose active component contains, or consists of, recombinant nucleic acid, having the objective of regulating, repairing, substituting, adding or deleting a genetic sequence and/or modifying the gene expression, aiming at a therapeutic, preventive or diagnostic result.
Minimal manipulation	Processing of cells or tissues that does not significantly alter the biological characteristics. The actions considered being minimally manipulation are cutting, separating, centrifuging, submerging or preserving in antibiotic solutions, concentrating, purifying, filtering, lyophilizing, irradiating, freezing, cryopreserving or vitrifying, among others.
Extensive Manipulation	Cell and tissue processing that alters any of their biological characteristics, among which are differentiation and activation state, proliferation potential and metabolic activity. It is any cell and tissue processing which does not configure minimal manipulation. Any type of cell culture is considered extensive manipulation.
Class I advanced therapy product	Advanced cellular therapy submitted to minimal manipulation that performs a function distinct from that performed on the donor.
Class II advanced therapy product	Advanced cellular therapy product submitted to extensive manipulation, tissue engineering product and gene therapy product

Type of access	Description
Compassionate Use	Use of a promising new product, yet without register at Anvisa, but is in any phase of clinical development, destined to a specific patient with a grave debilitating disease and/or which threatens his or her life, in the absence of a satisfactory therapeutic alternative.
Expanded Access	Use of a new promising product, yet without register at Anvisa, or registered, but not commercially available in the country, which is in a phase III study in development or concluded, destined to a group of patients with grave debilitating diseases or in imminent risk of death and without a satisfactory therapeutic alternative.
Post-study use	Gratuitous use of the developed product, applicable in cases of study termination or when the patient participation in the study has been finalized.

	Documental groups	General topics to be discussed
Advanced Theapy Medicinal Product Register Dossier	Non-clinical studies report	Proof of the intended therapeutic effect (proof of concept), of the safe and effective dose, of the route and administration frequency safety, of the interaction with tissues (potential secondary effects), of the viability, lifespan, distribution, persistence, metabolism, excretion, toxicity (product, impurity and excipients), immunogenicity, tumorigenic potential, criteria used in selecting in vitro and in vivo species and relevant animal models and others.
	Report on clinical studies	Studies on clinical safety, biodistribution and grafting, lifespan, ectopic graft, oncogenetic transformation, cellular lineage stability, additional studies on excretion and genomic sequencing alteration, clinical efficacy for the proposed indication, administration and intended dosage scheme, detected adverse events and statistical support data.
	Quality report	Starting materials, raw materials and excipients used, necessary materials for the production of vectors and genetic manipulation of cells, genetic sequencing analysis, virulence attenuation and description of tropisms, information on the selection and collection of human material, information on the active component and final product, employed analytical methodologies, description and flows of the production stages, reports on the validation of critical stages, validation reports on analytical methods, traceability mechanisms, transportation validation, stability studies and storage care.
	Report on the approval analysis issued by the competent authorities, when applicable.
	GMP certification for the manufacturer of the active component and the final product
	Proposals for use orientations to health professionals and patients (product information)
	Models of primary and secondary packaging
	Risk Management Plan for populational use of the product and, among others
	Strategies for long-term monitoring
	Mechanisms for distribution, logistics and export/import, when applicable

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH) R. Dr. Diogo de Faria, 775 cj 133, 04037-002, São Paulo / SP - Brasil - São Paulo - SP - Brazil
E-mail: htct@abhh.org.br

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[1] * Corresponding author at: Gerência de Sangue, Tecidos, Células e Órgãos - GSTCO. Agência Nacional de Vigilância Sanitária (Anvisa), Brasília, DF, Brazil. E-mail address: batista.junior@anvisa.gov.br (J.B. Silva Junior).