GOOD REGULATORY PRACTICE (GRP): Ensuring Quality Throughout the Regulatory Process

Transcripción

1 GOOD REGULATORY PRACTICE (GRP): Ensuring Quality Throughout the Regulatory Process DRUG INFORMATION ASSOCIATION 2nd Latin American Regulatory Conference

2 Mexican Pharmaceutical Market USD millons and % MS.. Mexican Pharmaceutical Market = 14,000 drug products 46,000 medical devices Marketed drug products: Patent, Generics (with/ without BE) Audited 8,573 (69.7% ) Generics 700 ( 9.0%) Total Market 76.7% 12, % Goverment 2,091 (17%) Public Hospitals (6.3%) Source: IMS

3 Mexican Regulatory Actors Health Secretariat COFEPRIS COFEMER IMSS / ISSSTE / IMPI EC / IRB CCAYAC Pharmacovigilance Center Mexican Pharmacopeia Law Regulatory documents Codes (Reglamento) Official Guidance

4 The Mexican Ministry of Health COFEPRIS Challenges DRUG PRODUCTS: QUALITY, SAFETY, EFFICACY ORGANIZATION, INFRASTRUCTURE AND CAPABILITIES 40 Agency rewiers NDA, ANDA, IND, RENEWAL HARMONIZATION PARADIGMS

5 Dealing with COFEPRIS timeframes COFEPRIS Timeframes (days) 200 New Drug Application (NDA) timeframes ( ) UCL=622.7 _ X=426.9 LCL= /03/ /04/ /06/ /08/ /08/ /09/ /10/ /10/ /11/2007 submission date

6 EC/IRB Timeframes 120 EC TIMEFRAMES 95% CI for the Mean 100 EC TIMEFRAMES YEAR

7 Documents delivery timeframes 30 EC APPROVAL TO DOCUMENTS READY AT PHARMA 95% CI for the Mean Days YEAR

8 Documents review to RA Submission 10 DOCUMENTS REVIEW TO RA SUBMISSION 95% CI for the Mean 8 DAYS YEAR

9 RA submission to Agency submission (filing preparation) 7 RA Submission to Agency submission 95% CI for the Mean Days YEAR

10 Mexican Agency timeframes Mexican Agency timeframes 95% CI for the Mean Days YEAR days + 7 days

11 Hi Level Process Country: Mexico * (this information is based on calendar dates) Total CSA 247 days Documents ready PA translation Protocol Customization CTA Submission PI (site) EC Approval Doc review Filing prep Agency approval Site Ready FPS LPO Inconsistent standards Lack of process ownership Deficient process management

12 Ensuring Regulatory Process Throughout Quality Clinical Data Quality

13 Is there any relationship between CRA Capabilities and data Quality? Sigma Level Site Quality Levels (Sigma values) distributon * MONITOR ALATORRE ARRIAGA BRIONES CARDENAS CASTILLO CERVANTES CORONA CRAVIOTO CUEVAS ECHARTEA GUERRA HERNANDEZ LOPEZ MOSQUEDA PAREDES PONTONES REYES 1.5 Ene-04 May-04 Sep-04 Ene-05 Date May-05 Sep-05 Ene-06

14 Quality Tools and DMAIC Mapping Nombre del Proyecto: Reducción de Verificación de documentos fuente Versión: 13-Ene.2006 Nivel de Importancia para el cliente CTQ Sitio aprobado Monitor a cargo Sitio entrenado Reporte de Monitoreo Datos monitoreados DNF (papel, sistema) Evidencia científica (documentos fuente/crf) Total Ranking Proceso Variables (KPIV) KPIV Modo de falla Efecto Calificación Verificación de Calificación del sitio especificaciones inadecuada del sitio Falta de Calificación experiencia en los inadecuada verificadores de la del sitio calificación (Falso positivo) Entrenamiento en Calificación preestudio inadecuada deficiente del sitio (Falso positivo) Número de Revisión Falta o datos discrecional al 25% exceso de revisados de los Dif. módulos revisión de los CRF (desperdicio) Evaluación de la Falta de productividad por planeación y monitor con base sobrecarga al número de datos de trabajo revisados (SDV) FMEA S E V O C Causa potencial U R Falta de especificacione 7 s claras Falta de entrenamiento 1 No existe un programa de entrenamiento 10 que certifique la calificación de sitios Falta de herrramienta basada en un análisis estadístico o de tendencias 10 No existe un método confiable para la evaluación de la productividad de los 10 monitores co base a SDV D R Acciones Controles actuales E P Resp. recomendadas T N Existe un listado de 1) Normalizar la Karin Mauer verificación que no ha 1 operación mediante 49 sido validado la elaboración de un SOP Ninguno 1) Entrenamiento en 1) Karin el SOP. Mauer 2) Verificación del 2) Sandra Mtz 7 56 nivel de acuerdo intra e inter verificador Existe un programa 1) Diseño de un 1) Laura Ruy general de Programa de 2) Jorge Cruz entrenamiento a los entrenamiento en el 1 80 sitios, mismo que dan trabajo basado en los monitores que no el expertise actual han sido calificados. de los monitores Ninguno 1) Elaboración de 1) Sandra Mtz una herramienta basada en Control estadístico y en AQL que permita 1 50 determinar la cantdad de datos a revisar en cada visita basado en un nivel de aceptación de calidad Existe una base de 1) Diseño de una 1) Julio datos denominada herramienta que Cárdenas GTMS que pretende permita visualizar la calcular el número de carga e trabajo del horas que los monitores monitor con base al dedican a la actividad de 1 80 SDV SDV, sin embargo esa base no refleja la cantidad de datos que revisa cada monitor 2,5,13 Instalaciones del sitio adecuadas ,5 Equipo calibrado ,5, 7, 12 Competencia del Inv ,5,7,12 Competencia del equipo de investigación del sitio ,6 Carga alta de trabajo del monitor ,4,6 Competencia del monitor Número de datos revisados Diseño del entrenamiento Calificación del sitio ,13 Tiempo de envío de datos ,13 Velocidad de transmisión ,13 Tiempo de captura Diseño de queries para identificar desviaciones Competencia del coordinador para identificar desviaciones % Pareto chart 80%

15 Variables KPIV (Independent Variables Site Qualification Source document verification (Data Points) CRA Competences/ Expertise CRA Work-load Quality Measurement System CTQ (Dependent VARIABLE) Y = Data Quality Expressed as number defects per million opportunities

16 Relationship between data quality and study complexity Percent Residual Plots for ADJUSTED SIGMA LEVELS Normal Probability Plot of the Residuals Residual Residual Residuals Versus the Fitted Values Fitted Value 20 Histogram of the Residuals Residuals Versus the Order of the Data Frequency Residual Ho: Study complexity is not associated with Quality level Ha: Study complexity is associated with Quality level Residual Observation Order

17 Site Qualification Tool Staff Data Acquisition and Management Clinical & La Supplies management Regulatory aspects Quality assurance Facilities/ Infraestructure Equipment Site Management Site Performance Communication with sponsor Total

18 DMAIC Site Certification Probability Plot of RESI6 Normal Mean StDev N 43 AD P-Value Percent RESI Percent Residual Plots for ADJUSTED SIGMA LEVELS Normal Probability Plot of the Residuals Residual Residual Residuals Versus the Fitted Values Fitted Value Frequency Histogram of the Residuals Residual Residual Residuals Versus the Order of the Data Observation Order

19 CRA Certification Kappa Analysis

20 How can predict a process using a biased measurement system? Protocol review Basic Questionnaire Four standard sections: Design, Inclusion and exclusion criteria, procedures, efficacy and safety measurements New protocol for overall personnel. Complexity: High. Participants: CRA First Exercise: March 16, 2006 Agreement inter-cra Second exercise: May 25, 2006 Agreement intra-cra Type of analysis: Kappa by attributes

21 Interpretation % Kappa value Interpretation -100 to 59 Random agreement Marginal. Improvement is required Good Excellent

22 Accuracy results by CRA Each CRA vs Standard

23 Inter-agreement and overall accuracy results BASIC QUESTIONNAIRE Overall acuracy Overall acuracy Inter agreement Inter agreement

24 Accuracy results between CRA All appraisers vs Standard Exc/Incl Design Efficay & Safety Procedures

25 Conclusions Inter agreement analysis for CRA was performed Kappa analysis reveled a random agreement between CRA Agreement results must be improved On the job program training need to be developed Intra-agreement analysis should be performed Kappa analysis will be a key tool for site s qualification

26 Site Qualification Tool Staff Data Acquisition and Management Clinical & La Supplies management Regulatory aspects Quality assurance Facilities/ Infraestructure Equipment Site Management Site Performance Communication with sponsor Total

27 GOOD REGULATORY PRACTICE (GRP): Ensuring Quality Throughout the Regulatory Process DRUG INFORMATION ASSOCIATION 2nd Latin American Regulatory Conference