Medicamentos Biologicos y Biosimilares. Reglamentacion

Notas del editor

1. Recently a number of countries issued final guidance addressing the regulation of biosimilars and the content of biosimilar applications. The World Health Organisation (WHO) has also issued guidelines for local regulatory authorities that are seeking to develop national standards. The following table describes features of biosimilars guidance adopted by the WHO, Canada and Japan. Japan issued its final guidance in March 2009, followed by the WHO in October 2009 and Canada in March 2010.
2. MEDICATIONS THAT CAUSE HYPOGAMMAGLOBULINEMIA
3. Biotherapeutic products (biotherapeutics) have a successful record in treating many lifethreatening and chronic diseases. However, their cost has often been high, thereby limiting their access to patients, particularly in developing countries. Recently, the expiration of patents and/or data protection for the first major group of originator’s biotherapeutics has ushered in an era of products that are designed to be ‘similar’ to a licensed originator product. These products rely, in part, for their licensing on prior information regarding safety and efficacy obtained with the originator products. The clinical experience and established safety profile of the originator products should contribute to the development of similar biotherapeutic products (SBPs). An increasingly wide range of ‘SBPs1’ are under development or are already licensed in many countries and a need for guidelines for their evaluation and overall regulation was formally recognized by the WHO in 2007 4. This document is intended to provide guidance for the development and evaluation of such biotherapeutics.
4. On the basis of proven similarity, the licensing of a SBP will rely, in part, on non-clinical and clinical data generated with an already licensed reference biotherapeutic product (RBP). This guideline can be adopted as a whole, or partially, by NRAs worldwide or used as a basis for establishing national regulatory frameworks for licensure of these products. Comparability exercise The comparability exercise for a SBP is designed to show that the SBP has highly similar quality attributes when compared to the RBP. However, it also includes the non-clinical and clinical studies to provide an integrated set of comparative data. The comparability data at the level of quality can be considered to be an additional set of data over that which is normally required for an originator product developed as a new and independent product. This is the basis for reducing the non-clinical and clinical data requirements. Although the quality comparisons are undertaken at various points throughout the quality application/dossier, a distinction should be made between usual quality data requirements and those presented as part of the comparability exercises. It may be useful to present these as a separate section in the quality module.
5. In addition, SBPs are manufactured and controlled according to their own development since the manufacturer of a SBP normally does not have access to all the necessary manufacturing information on the originator product. However, even minor differences in the manufacturing process may affect the pharmacokinetics, pharmacodynamics, efficacy and/or safety of biotherapeutic products. As a result, it has been agreed that the normal method for licensing generic medicines through bioequivalence studies alone is not scientifically appropriate for SBPs.
6. Decision making regarding the licensing of SBPs should be based on scientific evidence. The onus is on a manufacturer of a SBP to provide the necessary evidence to support all aspects of an application for licensing. As with any drug development program, the development of a SBP involves a stepwise approach starting with characterization and evaluation of quality attributes of the product and followed by non-clinical and clinical studies. Comprehensive characterization and comparison at the quality level are the basis for possible data reduction in the non-clinical and clinical development. If differences between the SBP and the RBP are found at any step, the underlying reasons for the differences should be investigated. Differences should always be explained and justified and may lead to the requirement of additional data (e.g. safety data). BLA/MAA” shall mean a Biologics License Application (“BLA”) submitted to the FDA or a Market Authorization Application (“MAA”
7. As a general rule, the product should be expressed and produced in the same host cell type as the RBP (e.g. E.coli, CHO cells, etc.) in order to minimize the potential for important changes to critical quality attributes of the protein and to avoid introduction of certain types of processrelated impurities (e.g. host cell proteins, endotoxins, yeast mannans) that could impact clinical outcomes and immunogenicity. The host cell type for manufacture of the SBP should only be changed if the manufacturer can demonstrate convincingly that the structure of the molecule is not affected or that the clinical profile of the product will not change. A complete description and data package should be provided that delineates the manufacturing process, starting with development of expression vectors and cell banks, cell culture/ fermentation, harvest, purification and modification reactions, filling into bulk or final containers, and storage. The development studies conducted to establish and validate the dosage form, formulation, and container closure system (including integrity to prevent microbial contamination) and usage instructions should be also documented (see relevant guidelines such as ICH).
8. ESTABILIDAD TOO. Diferencias en degradacion. Bajo condiciones de estres. Biological activity is the specific ability or capacity of the product to achieve a defined biological effect. It serves multiple purposes in the assessment of product quality and is required for characterization, and batch analysis. Ideally, the biological assay will reflect the understood mechanism of action of the protein and will thus serve as a link to clinical activity. A biological assay is a quality measure of the ‘function’ of the protein product and can be used to determine whether a product variant has the appropriate level of activity (i.e. a product-related substance) or is inactive (and is therefore defined as an impurity). The biological assay also complements the physicochemical analyses by confirming the correct higher order structure of the molecule
9. Decision making regarding the licensing of SBPs should be based on scientific evidence. The onus is on a manufacturer of a SBP to provide the necessary evidence to support all aspects of an application for licensing. As with any drug development program, the development of a SBP involves a stepwise approach starting with characterization and evaluation of quality attributes of the product and followed by non-clinical and clinical studies. Comprehensive characterization and comparison at the quality level are the basis for possible data reduction in the non-clinical and clinical development. If differences between the SBP and the RBP are found at any step, the underlying reasons for the differences should be investigated. Differences should always be explained and justified and may lead to the requirement of additional data (e.g. safety data). BLA/MAA” shall mean a Biologics License Application (“BLA”) submitted to the FDA or a Market Authorization Application (“MAA”
10. ESTABILIDAD TOO. Diferencias en degradacion. Bajo condiciones de estres. Biological activity is the specific ability or capacity of the product to achieve a defined biological effect. It serves multiple purposes in the assessment of product quality and is required for characterization, and batch analysis. Ideally, the biological assay will reflect the understood mechanism of action of the protein and will thus serve as a link to clinical activity. A biological assay is a quality measure of the ‘function’ of the protein product and can be used to determine whether a product variant has the appropriate level of activity (i.e. a product-related substance) or is inactive (and is therefore defined as an impurity). The biological assay also complements the physicochemical analyses by confirming the correct higher order structure of the molecule
11. In vitro studies: Assays like receptor-binding studies or cell-based assays (e.g. cell-proliferation or cytotoxicity assays) should normally be undertaken in order to establish comparability of the biological/ Pharmacodynamic activity of the SBP and RBP. Such data are usually already available from the biological assays described in the quality part of the dossier (see chapter 8.2.2). Reference to these studies can be made in the non-clinical part of the dossier. In vivo studies: Animal studies should be designed to maximize the information obtained. Such studies should be comparative in nature (see above), should be performed in (a) species known to be relevant (i.e. a species in which the RBP has been shown to possess pharmacodynamic and/or toxicological activity) and employ state-of-the-art technology. Where the model allows, consideration should be given to monitoring a number of endpoints such as: - Biological/ pharmacodynamic activity relevant to the clinical application. These data should usually be available from biological assays described in the quality part of the dossier (see chapter 8.2.2) and reference to these studies can be made in the non-clinical part of the dossier. If feasible, biological activity may be evaluated as part of the non-clinical repeat dose toxicity study (described below). In vivo evaluation of biological/ pharmacodynamic activity may be dispensable if in vitro assays are available, which have been validated to reliably reflect the clinically relevant pharmacodynamic activity of the RBP. - Non-clinical toxicity as determined in at least one repeat dose toxicity study in a relevant species and including toxicokinetic measurements. These measurements should include determination and characterization of antibody responses, including anti-product antibody titres, cross reactivity with homologous endogenous proteins, and product neutralizing capacity. The duration of the studies should be sufficiently long to allow detection of potential differences in toxicity and antibody responses between the SBP and RBP.
12. Decision making regarding the licensing of SBPs should be based on scientific evidence. The onus is on a manufacturer of a SBP to provide the necessary evidence to support all aspects of an application for licensing. As with any drug development program, the development of a SBP involves a stepwise approach starting with characterization and evaluation of quality attributes of the product and followed by non-clinical and clinical studies. Comprehensive characterization and comparison at the quality level are the basis for possible data reduction in the non-clinical and clinical development. If differences between the SBP and the RBP are found at any step, the underlying reasons for the differences should be investigated. Differences should always be explained and justified and may lead to the requirement of additional data (e.g. safety data). BLA/MAA” shall mean a Biologics License Application (“BLA”) submitted to the FDA or a Market Authorization Application (“MAA”
13. As for most biological medicines, data from pre-authorization clinical studies are usually too limited to identify all potential unwanted effects of a SBP. In particular, rare adverse events are unlikely to be encountered in the limited clinical trial populations being tested with the SBP. Therefore, further close monitoring of the clinical safety of these products in all approved indications and a continued benefit-risk assessment is necessary in the post-marketing phase. *** Any specific safety monitoring imposed on the RBP or product class should be incorporated into the pharmacovigilance plan for the SBP, unless a compelling justification can be provided to show that this is not necessary. Moreover, potential additional risks identified during the review of the data obtained with the SBP should be subject to further safety monitoring (e.g. increased immunogenicity that might result from a difference in the glycosylation profile).
14. This is particularly important for posology and safety-related information, including contraindications, warnings and adverse events. International Nonproprietary Names (INN)
15. *to set up appropriate regulatory oversight for the licensing and post-marketing surveillance of SBPs that are developed and/or authorized for use * The experience and expertise of NRA in evaluating biotherapeutic products is a key prerequisite for appropriate regulatory oversight of these products. The NRA is responsible for determining a suitable regulatory framework for licensing SBPs. The NRA may choose to utilize or amend existing pathways or develop a new pathway for this purpose. * Como desarrollo de productos bioterapéuticos es una zona de rápida evolución , la revisión regular de la ANR para su licencia, la adecuación de la normativa para ejercer la supervisión y el procesos y políticas que constituyen el marco normativo es un componente esencial de un buen funcionamiento y la supervisión actualizada regulatoria para fármacos.
16. Si no hay un parametro PD confiable, poco sensible o dificil de medir la similitud debe basarse en los parametros PK. Si se cumplen los datos PK y PD se denomina biosimilaridad ortogonal!!!!!!-
17. Bio ensayos, binding assas, enzyme kinetics Fingerprint Like biosimilarity
18. Ej: difernecias en la glicosilacion (puede ser afectada por procesos de manufactura)
19. Ej: difernecias en la glicosilacion (puede ser afectada por procesos de manufactura)
20. Ensayo LG/Rc: Es la mas común forma de medir productos biológicos circulantes. Basado en interacciones con macromoleculas como anticuerpos,
21. Ensayo LG/Rc: Es la mas común forma de medir productos biológicos circulantes. Basado en interacciones con macromoleculas como anticuerpos,
22. Inmunogenicidad se refiere a la respuesta uinmune al biologico que puede desencadenar una toxicidad mediada inmune, o una disminucion de la efectividad de este.
23. Inmunogenicidad se refiere a la respuesta uinmune al biologico que puede desencadenar una toxicidad mediada inmune, o una disminucion de la efectividad de este.
24. Crossover: Vm corta <5 dias, Es considerado el mas sensible para evaluacion de similitud PK. da los resultados mas confiables con el menor numero de participantes. Debe considerarse la inmunogenicidad y el periodo de washout. Paralelo : la mayoria de biologicos tienen vida media larga y respuestas inmune.
25. Demographic Group: Clinical pharmacology studies should be conducted in the subject or 415 patient demographic group most likely to provide a sensitive measure of differences between the 416 proposed biosimilar product and the reference product. The patrocinador should provide justification 417 for why the subject or patient group chosen for clinical pharmacology studies will provide the 418 most sensitive measure of difference between the proposed biosimilar and reference products. 419 The total number of subjects should provide adequate power for similarity assessment. Analysis 420 of the data from all subjects as one group represents the primary study endpoint, and a statistical 421 analysis of the data from the subgroups would be exploratory only.
26. Se debe obtener todas las medicines PK para el biosimilar y el producto de referencia. La exposición total se calcula como la concentración en tiempo a infinito. Multiples dosis -> AUC De tiempo Zero a tau como endpoint primario; C valle y max en el estado estable, y son endpoints secundarios.
27. Area under the effect curve.
28. Fda recomienda convertir todos las grafiacas en log. El patrocinador puede justificar el uso del intervalo que emplee.
29. Fda recomienda convertir todos las grafiacas en log. El patrocinador puede justificar el uso del intervalo que emplee.
30. Inmunogenicidad: capacidad que tiene el sistema inmune de reaccionar frente a un estímulo bioquímico de naturaleza generalmente proteica.
31. Creada por el Decreto NO 1490/92. autoridad reguladora de medicamentos, y está facultada para otorgar su registro sanitario, de acuerdo a los requisitos y procedimientos establecidos en cada caso. Transferir el poder de un gobierno central hacia autoridades que no están jerárquicamente sometidas.
32. Definiciones. Acreditar en forma fehaciente su calidad, eficacia y seguridad.
33. Excepto vacunas  Disposición ANMAT NO 705/05
34. Respuesta a los 180 días hábiles desde que se envió la solicitud
35. Resumen de características del producto
36. Resumen de características del producto
37. Capítulo II es resumen del capítulo III
38. Controles del proceso de producción (control de calidad). Demostrar la ausencia de agentes extraños/externos o la capacidad de ser eliminados o reducidos durante el proceso de fabricación. Resultados de los ensayos en un mínimo de tres lotes
39. Controles del proceso de producción
40. En ciertos tasas la elección de una especie será suficiente (cuando se encuentre una sola especie relevante o en estudios a largo plazo). De no hallarse al menos una especie relevante, se podrá considerar el uso de animales transgénicos que expresen el receptor humano o el uso de proteínas homólogas.
41. Determinar reacciones de antigenicidad: anticuerpos antiproducto
42. Propiedades farmacológicas del producto y su relación con la indicación terapéutica. Eficacia farmacológica: ecuación beneficio/riesgo, para las indicaciones clínicas que se postulen, sea favorable para el paciente.
43. respaldar la farmacocinética, farmacodinamia, seguridad y eficacia del producto. Los mismos deberán ser realizados de acuerdo a la normativa vigente.
44. Fase I: tolerabilidad y perfil farmacocinético en humanos. Fase II: se demuestre actividad terapéutica, así como la aparición y magnitud (incidencia y gravedad) de los efectos adversos. Fase III: eficacia terapéutica comparada (ensayo clínico controlado), en un número de pacientes significativo, con información adecuada en cuanto a calidad y cantidad de los efectos adversos observados.
45. A partir de la experiencia reportada en forma espontánea y/o a través de estudios clínicos. implementación de un sistema integral de captación de reportes, análisis epidemiológico, evaluación y manejo de riesgos y procedimientos de reporte e información detallados, que permitan al laboratorio elaborador o importador de un producto biológico o biotecnológico un control del perfil de eficacia y seguridad del mismo a lo largo de su ciclo de vida.
46. Agente biológico que ha demostrado ser similar o comparable a la medicación original en términos de eficacia, seguridad y calidad del producto. Esta similitud se demuestra por medio de ejercicios comparativos rigurosos. Un biosimilar nunca puede ser idéntico a la medicación biológica original, pero sí puede ser considerado similar luego de haber cumplido con los citados ejercicios de comparacion rigurosa.
47. Artículo 1- autorizada y comercializada ampliamente en otro país o grupo de países cuyas funciones regulatorias, fiscalizadoras y marco normativo resulten acordes a nuestra legislación.
48. Información fisicoquímica, farmacéutica y biológica (Disposición 7075/2011). Los estudios deben ser realizados en iguales condiciones con respecto al comparador. Demostrar atributos de calidad muy similares al medicamento de referencia
49. Cumplimiento de una serie de criterios predeterminados. Para cada indicación deberá disponerse de los datos científicos que sustenten cada una de ellas. Técnicas apropiadas para la determinación de las propiedades físico-químicas, actividad biológica, inmunoquímica (de corresponder) e impurezas.
50. Si, evaluado todo el conjunto de datos ampliados pertenecientes a los estudios de calidad, pre-clínicos y clínicos se observaran aún diferencias significativas, podrá denegarse la autorización de registro del medicamento bajo el amparo de la presente norma.