CARRERA DE ESPECIALIZACION EN …biotecnologiaindustrial.fcen.uba.ar/wp-content/uploads/2010/04/... · CARRERA DE ESPECIALIZACION EN BIOTECNOLOGIA INDUSTRIALBIOTECNOLOGIA INDUSTRIAL

CARRERA DE ESPECIALIZACION EN CARRERA DE ESPECIALIZACION EN BIOTECNOLOGIA INDUSTRIALBIOTECNOLOGIA INDUSTRIALBIOTECNOLOGIA INDUSTRIALBIOTECNOLOGIA INDUSTRIAL

FCEyNFCEyN--INTIINTIMateria de Articulación CEBI E6Materia de Articulación CEBI_E6

ASUNTOS REGULATORIOS PRODUCTOS BIOTECNOLOGICOSBIOTECNOLOGICOS

Docente a cargo: Mario Malaspina

CEBI_E6_2 : Registro de Medicamentos de Origen Biotecnológico. Regulatoria en Nuestro

P í P t lII M I t i lPaís. Parte lII: Marco Internacional

CUAL ES EL CONFLICTO EN ESTE MOMENTO… ?

Aparición del borrador de la guía:EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATIONGeneva, 19 to 23 October 2009Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs)

This document has been prepared for the purpose of inviting comments and suggestions on the proposals contained therein, which will then be considered by the Expert Committee on Biological Standardization (ECBS). The text in its

t f d t il t d f l ti f thpresent form does not necessarily represent an agreed formulation of the Expert Committee. Comments proposing modifications to this text MUST be received by 9 October 2009 and should be addressed to the World Health Organization, g ,

Y PORQUE ES EL CONFLICTO…??LA PROXIMA….CLASE. Parte IIIMARCO INTERNACIONAL

EEUU: FOOD AND DRUG ADMINISTRATIONhttp://www.fda.gov/

FDA: UN POCO DE HISTORIA O “EN TODAS PARTES SE CUECEN HABAS I”

1927 — La "Oficina de Química" es reorganizada en dos entidades. Las funciones regulatorias se en la "Food, Drug and Insecticide Administration" (Administración de Alimentos, Drogas e Insecticidas) y las no regulatorias en la "Bureau of Chemistry and Soils" (Oficina de Química y Desechos). 1930 — El nombre "Food Drug and Insecticide Administration" es1930 — El nombre Food, Drug and Insecticide Administration es recortado a "Food and Drug Administration" (FDA) 1938 — Más de 100 personas mueren después de haber consumido un sulfa-elixir con sabor a frambuesa, el cual había sido introducido al mercado por la S.E. Massengill Company sin las pruebas correspondientes. Alrededor del 70% del elixir era dietilenglicol, producto altamente tóxico. Como consecuencia del escándalo y protesta públicos se promulgó el "Acta Federal de Alimentos, Drogas y Cosméticos"se promulgó el Acta Federal de Alimentos, Drogas y Cosméticos (Federal Food, Drug, and Cosmetic Act) de 1938, la cual daba poder a la FDA de pre-aprobar todas los nuevos medicamentos introducidos en el mercado interestatal.

CBER: Vacunas, Hemoderivados y Biológicos

http://www.fda.gov/BiologicsBloodVaccines/default.htm

Aspectos Regulatorios

• En USA, las proteínas y los péptidos son aprobados por la FDA como NDA ( New Drugaprobados por la FDA como NDA ( New Drug Application, section 505) o como BLA (Biological Licence Application, section 351 PHA Public Health Service Act).

• Sin embargo, se les “escaparon” un para como ANDA Abreviated New Drug ApplicationANDA – Abreviated New Drug Application –antes de que se generara la “gran discusión”.

Comparability

“The current FDA use of the term “comparability” generally refers to the comparison of a biological product before and after ato the comparison of a biological product before and after a manufacturing change by the manufacturer. A sponsor may be able to demonstrate that a product made after a manufacturing change is comparable to a product made before implementation of the

h Thi b d t t d th h diff t t fchange. This may be demonstrated through different types of analytical and functional testing and might not require additional clinical studies. The Agency may determine that the two products are comparable if the results of the comparability testing p p y gdemonstrate that the manufacturing change does not affect safety, identity, purity, or potency. (It is important to note, however, that this has generally been applied in cases where the manufacturer and Agency have full access to the manufacturer’s dataand Agency have full access to the manufacturer’s data –something that may not be the case for follow-on products.) See April 1996 FDA Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic p y g g pBiotechnology-Derived Products”.

However a number of important issues related to development ofHowever, a number of important issues related to development of such follow-on products also have been identified. First, there is general recognition that the idea of sameness, as the term is used in the generic drug approval process under the Federal Food, Drug, and Cosmetic (FDC) Act and applied to small molecules, will not usually be appropriate for more structurally complex molecules of the type generally licensed as biological products under the Public Health Service (PHS) ActService (PHS) Act

Traditionally, some natural source proteins have been regulated as drugs under the FDC Act, including insulin, hyaluronidase, menotropins, and h th h hil th t l t i hhuman growth hormones, while other natural source proteins, such as blood factors, are regulated as biological products under the PHS Act.

Proteínas recombinantesProteínas recombinantes

F i l ( l i i d l ó l)• Fortical: (calcitonina de salmón, spray nasal): la FDA consideró que en base a una completa caracterización fisicoquímica estructuracaracterización fisicoquímica, estructura primaria, secundaria y terciaria, Fortical era indistinguible de Miacalcin NS. Los estudios d st gu b e de aca c S os estud osfarmacocinéticos y farmacodinámicos y de inmunogenicidad en animales demostraron comparabilidad entre ambos productos

Proteínas recombinantes

• Omnitrope (somatropin): fue la primer hormona de crecimiento humana recombinante en ser aprobada como ANDA FDA 505(b)(2) tomando como ( )( )producto de referencia o similar a “Genotropin” rh-GH, aprobado por FDA p , p ppara la misma indicación .

Producto Droga Aprobación MW (Da)

Proteínas no glicosiladasProteínas no glicosiladas

Forteo Teriparatide NDA 4.118Byetta Exenatide NDA 4.187Lantus Insulina Glargina NDA 6.063Betaseron Interferon ß -1b BLA 18.500Genotropin Somatotropin NDA 22.500

P t í Gli il dProteínas Glicosiladas

Rebif Interferon ß -1a BLA 22.500Epogen/Procrit Epoetin α BLA 30.500Enbrel Etanercept BLA 150 000Enbrel Etanercept BLA 150.000

Proteínas PEGiladas

PegIntron PegInterferon α-2b BLA 31.000Neulasta Pegfilgrastim BLA 39.000

Anticuerpos Monoclonales

Rituxan Rituximab BLA 145 000Rituxan Rituximab BLA 145.000Avastin Bevacisumab BLA 149.000Erbitux Cetuximab BLA 152.000

EMEA: COMUNIDAD ECONOMICA EUROPEAhttp://www.emea.europa.eu/home.htmp p

EUDRALEX: LEGISLACION DE EMEAhttp://ec.europa.eu/enterprise/pharmaceuticals/

d l / d l hteudralex/eudralex_en.htm

Guidelineshttp://www.emea.europa.eu/htms/human/humanguidelines/biologicals.htm

GUIDELINE ONSIMILAR BIOLOGICAL MEDICINAL

PRODUCTS

For the Marketing Authorisation Applications (MAAs) based on the demonstration of the similar nature of the two biological medicinalproducts Comparability studies are needed to generate evidenceproducts. Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy, of the new similar biological medicinal product and the chosen reference medicinal product authorised in the Community.

GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS CONTAINING BIOTECHNOLOGY-

Similar biological medicinal products are manufactured and controlled according to their

DERIVED PROTEINS AS ACTIVE SUBSTANCE: NON-CLINICAL AND CLINICAL ISSUES

Similar biological medicinal products are manufactured and controlled according to their own development. An appropriate comparability exercise `will be required to demonstrate that the similar biological and reference medicinal products have similar profiles in terms of quality, safety and efficacy. The quality issues relevant for demonstration of comparability for similar biological medicinal products containing recombinant DNA-derived proteins are addressed in the ”guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: quality issues” (EMEA/CHMP/49348/05). The Marketing Authorisation (MA) application dossier of a biological medicinal product claimedThe Marketing Authorisation (MA) application dossier of a biological medicinal product claimed to be similar to a reference medicinal product already authorised shall provide a full quality dossier. Comparable clinical efficacy and safety has to be demonstrated. The principles for this exercise are laid down in this guideline. Product class specific annexes will supplement this guideline

h d h b ill b id tifi dwhere a need has been or will be identified. The same reference medicinal product should be used for all three parts of the dossier (i.e. quality. safety and efficacy aspects). In case the originally authorised medicinal product has more than one indication, the efficacy and safety of the medicinal product claimed to be similar has to be justified or, if necessary, y p j , y,demonstrated separately for each of the claimed indications.

EMEA Marco Regulatoriog

• Cada producto biosimilar es analizado a través de Guías específicas para Biosimilares “caso por caso”

• Guidelines on “Similar Biological Medicinal• Guidelines on Similar Biological Medicinal Products”

• Guidelines on SBMP containing biotechnological-derived proteins as Active Substance– Quality issues

N Cli i l d Cli i l i– Non-Clinical and Clinical issues• Annex to guideline on SBMP• Adopción de ICH-Q5E como Guía deAdopción de ICH-Q5E como Guía de

Comparabilidad

ICH: COMITÉ INTERNACIONAL DE ARMONIZACION

http://www.ich.org/cache/compo/276-254-1.html

S6: Preclinical Safety Evaluation of Biotechnology-Derived PharmaceuticalsQ6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological ProductQ5E: Comparability of Biotechnological/Biological Products subject to

h i th i f t ichanges in their manufacturingQ5D: Quality of Biotechnological/Biological Prod.: Derivation and Characterisation of Cell SubstrateQ5C Q lit f Bi t h l i l P d t St bilit T ti fQ5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological ProductsQ5B: Analysis of the Expression Construct in Cells Used for Production of r DNA (Biotechnological)r-DNA (Biotechnological)Q5A(R1): Viral Safety Evaluation of Biotechnology Products

PIC/s: ESQUEMA COOPERATIVO DE INSPECCIÓNhtt // i h /http://www.picscheme.org/

WHO: ORGANIZACIÓN MUNDIAL DE LA SALUD (OMS)http://www who int/es/index htmlhttp://www.who.int/es/index.html

OPS: ORGANIZACIÓN PANAMERICANA DE LA SALUDhttp://new paho org/hq/index php?lang=eshttp://new.paho.org/hq/index.php?lang=es

ARGENTINA Y LA OMS

PORQUE LA OMS NOS “COMPROMETE”?

PETENECER A LA RED PANAMERICANA PARA LA ARMONIZACIÓN DE LA REGULACIÓN FARMACÉUTICA (RED PARF)

2002 Disposición Nº 2309/02

Aprueba el documento “Buenas Prácticas deFabricación y Control de Medicamentos OMS2309/02 92”, (Resolución GMC Nº 61/00) BO.- 21/06/02

1995 Disposición N° 1930/95 Cumplimiento de BPFyC, OMS 1975.-

PHARMACOPOEIAS: FARMACOPEASPHARMACOPOEIAS: FARMACOPEAS

1.- BRITISH PHARMACOPOEIA: Capítulos particulares por activos

2 UNITED STATES PHARMACOPOEIA: capítulo general de biológicos2.- UNITED STATES PHARMACOPOEIA: capítulo general de biológicos

3.- EUROPEAN PHARMACOPOEIAS: Capítulos particulares por activos.

4.- FARMACOPEA ARGENTINA VII: Capítulos generales.

Ninguna codifica Productos terminados

Hay que tener en cuenta los “FORUM”

MERCOSUR: MERCADO COMUN DEL SURhttp://www.mercosur.gov.ar/

XXIX REUNIÓN ORDINARIA DEL SGT Nº 11 “SALUD” / COMISIÓN DE PRODUCTOS PARA LA SALUD

La Delegación de Brasil, en consonancia con lo acordado en la XXVIII ReuniónOrdinaria, recordó que la información a remitir por los países incluye:

• la comparación entre las recomendaciones de OPS y lo efectivamente la comparación entre las recomendaciones de OPS y lo efectivamenteaplicado y no aplicado por cada Estado Parte expresadas en forma de cuadroa fin de facilitar su consolidación• la visión global de cada país, desde el punto de vista estratégico, sobre susf t l d bilid d l tfortalezas y debilidades en el tema.• El cuadro incluye iniciativas previstas por OMS e ICH y aspectosrelacionados con la biotecnología, además de los previstos por la OPS.• En el área de estudios clínicos y estabilidad se siguen las• En el área de estudios clínicos y estabilidad, se siguen las recomendaciones de OMS e ICH.

ENTONCES:CUAL ES EL CONFLICTOCUAL ES EL CONFLICTO EN ESTE MOMENTO… ?

Aparición del borrador de la guía:EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATIONEXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATIONGeneva, 19 to 23 October 2009Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs)This document has been prepared for the purpose of inviting comments and suggestions on the proposals contained therein, which will then be considered by the Expert Committee on Biological Standardization (ECBS). The text in its present form does not necessarily represent an agreed formulation of the Expert Committee. Comments proposing modifications to this text MUSTExpert Committee. Comments proposing modifications to this text MUST be received by 9 October 2009 and should be addressed to the World Health Organization,

COMENTARIOS AL DOCUMENTO DE OMS

“ Recently, the expiration of patents and/or data protection for the first major group


y, p p p j g pof originator’s biotherapeutics has ushered in an era of products that are designed to be ‘similar’ to a licensed originator product.”El documento para fundamentar las acciones que habría que realizar para aprobar un biosimilar se centra exclusivamente en la experiencia de los países centrales y desconoce p p yabsolutamente lo sucedido con biosimilares en países como Argentina. Esto queda plasmado en forma prístina en el primer párrafo de la introducción, líneas 67 y 68 que dicen


Considerations for choice of reference biotherapeutic productp pen donde dice “The choice of RBP should not infringe on patents or intellectual property in the jurisdiction it is registered nor bypass those of the jurisdiction in which the SBP will be marketed”jurisdiction in which the SBP will be marketedy se vuelve a remarcar en el apartado Roles and responsibilities of NRAsdonde dice:“The licensing of SBPs should be consistent with the laws and regulations for patents, intellectual property, and data protection (where they exist)” (líneas 1053 a 1055)1.- Antepone intereses económicos a intereses de salud pública.2 - Desconoce las experiencias hechas en países como Argentina2. Desconoce las experiencias hechas en países como Argentina 3.- Coloca a las industrias locales y porque no también a las autoridades sanitarias nacionales en una situación de Compromiso.


“Based on current understanding and limited experience with SBPs, t ti b tit ti f i i t d t ith SBP t th


automatic substitution of an originator product with a SBP at the pharmacy level is not recommended at this time. Decisions regarding automatic substitution of SBPs should be made by health authorities in each country taking into account the pharmacovigilance system in y g p g yplace, patient safety and other relevant factors.” (Líneas 277 a 281)¿A que limitado conocimiento y experiencia se refiere el documento en este párrafo? En Argentina si tomamos como ejemplo la EPO deberíamos plantear lo opuesto ya que las unidades comercializadas de los biosimilares sonlo opuesto ya que las unidades comercializadas de los biosimilares son mucho mayores que la de los originales


“However, even minor differences in the manufacturing process may affect the pharmacokinetics pharmacod namics efficac and/or safet


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”y pp pEsta afirmación es el caballito de batalla argumental de las empresas que desarrollaron los medicamentos biotecnológicos originales, que de tanto repetirla en diferentes ámbitos pareciera que pasó a ser una verdad

Y ENTONCES “VOLVEMOS”…PORQUE ES EL CONFLICTO…??PORQUE ES EL CONFLICTO…??LA PROXIMA….CLASE. Parte IVENSAYOS CLINICOS Y DOSSIER FORMATO CTDENSAYOS CLINICOS Y DOSSIER FORMATO CTD

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CARRERA DE ESPECIALIZACION EN …biotecnologiaindustrial.fcen.uba.ar/wp-content/uploads/2010/04/... · CARRERA DE ESPECIALIZACION EN BIOTECNOLOGIA INDUSTRIALBIOTECNOLOGIA INDUSTRIAL