Enrico Invernizzi Alessandra Grande

Transcription

1 Con il contributo educazione di Enrico Invernizzi Alessandra Grande Roma, venerdì 1 marzo 2013 Merck Serono - RBM, Colleretto Giacosa, Italy

2 Outline Regulatory enviroment Biomarkers: What and why Which quality systems for exploratory biomarker investigations? Conclusions

3 Outline Regulatory enviroment Biomarkers: What and why Which quality systems for exploratory biomarker investigations? Conclusions

4 Background Need to analyze Human Samples in compliance with a specific and defined Quality Standard (see ICH E6 GCP requirements) Many similarities between GCLP and GLP exist, however, compliance with GLP will not automatically ensure compliance with GCP EMA Reflection paper

5 Recent developments BARQA RQA Booklets on Good Clinical Laboratory Practice 2003 / 2008/2012 EFGCP Guideline for Auditing Clinical Laboratories 2005 DAIDS Good Clinical Laboratory Practice Standards 2008 WHO Good Clinical laboratory Practice (GCLP) 2009 MHRA Guidance on the maintenance of regulatory compliance in laboratories that Perform the analysis or evaluation of clinical trial samples 2009 Numerous initiatives to standardize/harmonize clinical trial sample testing

6 What is GCLP? Taken from Dan Ozaki SQA Webinar October 26, 2012 GCLP, or Good Clinical Laboratory Practice, is a set of guidelines that strives to promote the quality and validity of research conducted with clinical trial specimens.

7 Sound familiar? What is GCLP? Taken from Dan Ozaki SQA Webinar October 26, 2012 GCLP = GCP + GLP In its simplest form, Good Clinical Laboratory Practice is a combination of Good Clinical Practice and Good Laboratory Practice.

8 Main points GCLP Provides a bridge between GCP and GLP Why not GLP: because the clinical samples are out of the scope Why not GCP: because the laboratory issue is not covered Standard promulgated by the WHO and the UK-MHRA: recognised quality standard Standard implementable within MerckSerono and accepted/implemented by CROs

9 Benefits of GCLP compliant studies GCLP ensures that results are: Reliable Repeatable Auditable Taken from Dan Ozaki SQA Webinar October 26, 2012 Assured to be of the highest quality and can be compared to those of other GCLP-compliant studies.

10 Major changes / additional topics Focus on patient safety Training of staff on GCP Informed consent Confidentiality of patient data Contracts / communication / Serious breaches Sample integrity / sample management and tracking Blinding / unblinding

11 Good Clinical Laboratory Practice (GCLP) GCLP applies to those principles established under GLP for data generation used in regulatory submissions relevant to the analyses of samples from a clinical trial. At the same time it ensures that the objectives of the GCP principles are carried out. This ensure the reliability and integrity of data generated by analytical laboratories. GCLP is intended to provide a unified framework for sample analysis to lend credibility to the data generated and facilitate the acceptance of clinical data by regulatory authorities from around the world. GCLP applies equally to analysis of blood samples for routine screening of patients (haema/bioch) as to pharmacokinetics.

12 Good Clinical Laboratory Practice Main Rules Taken from Dan Ozaki SQA Webinar October 26, 2012 Organization and Personnel Equipment SOPs Facility Test and Control Articles and Reagents Sample Shipment/ Storage Data Generation/H andling/stora ge/archival I.T. and Data Security Organizational Chart and Master Schedule Current CVs and Job Descriptions Current records of Safety/Institutio nal Training Assay/Equipme nt Training SOP Training Competency Assessments SOP Installation/Perf ormance Verification Records Calibration Records Preventative Maintenance Records Malfunction Reports/Correct ive Action Temperature Monitoring (if applicable) SOPs cover all processes key to the conduct of the study SOPs are located in areas where work is conducted SOPs have standard format and approval from management SOPs have review cycle and are current SOP Document Control SOP Change Control Process Space is adequate to conduct the studies Space is segregated to prevent test mix-up or contaminations Facility SOP outlining access and maintenance Facility is maintained as clean and procedures exist Disaster recovery plan exists Vital information is captured (i.e. concentration, lot/batch, expiration date, open date, who opened) Adequate separation exists to prevent contaminations Maintenance of articles at appropriate temperatures/con ditions Use of reagent log with reagents dates of use Procedure for Parallel/Bridging Testing of Reagents exists Trending of control values Appropriately trained personnel exist for specimen shipment/receiving Sample receipt area is maintained separately from sample processing Sample storage conditions are monitored and recorded Access to samples is limited to ensure sample integrity Chain of custody Data recording follows ALCOA Errors in Data Entry are corrected with a single line, initials, date, and reason for change Raw data is promptly recorded in laboratory notebooks or worksheets Handling/security procedures exist to preserve data integrity Outdated materials are stored in an archive Archive has limited access and material is able to be retrieved in a timely manner Computer systems are accessed via individual usernames and passwords Physical access to data servers is limited Changes in computerized systems are controlled and analyzed Computer hardware and software maintenance activities are documented Data servers are backed up to an appropriate medium on a regular basis Disaster Recovery Plan exists Electronic Archive Plan exists

13 Regulatory requirement 28 February EMA/INS/GCP/532137/ GCP Inspectors Working Group Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples 2. Introduction In the absence of any comprehensive guidance, from regulatory and monitoring authorities, for laboratories that perform the analysis or evaluation of clinical trial samples, some clinical laboratories have applied the principles of Good Laboratory Practice (GLP). There are some aspects of GLP that will be applicable to clinical sample analysis. However, it should be noted that the scope of GLP is designed for non clinical studies and consequently does not take into account issues that may impact on the safety and rights of clinical trial subjects.

14 GLP and GCLP In Europe when biomarker measurement are performed on samples collected from subjects entered in a clinical trials of new investigational agents, laboratories conducting these analyses are subjected to the clinical trials regulations Despite this, clinical trial regulations make few specific references to laboratories and are somewhat vague in terms of what is expected, although it is clear that Quality Assurance is a requirement As a response to the clear lack of direction in this field, a quality system termed GCLP (Good Clinical Laboratory Practice) has been created in UK In essence GCLP is very closely related to GLP but takes into account the context and terminology employed in clinical trials While there appears to be no requirement for laboratories conducting biomarkers analyses to comply to a full QA system like GCLP in United States, several key publications have recommended adopting patient sample tracking, SOPs, analytical plans, facilities, study reports, compliance with FDA regulations on electronic record and signature, etc

15 Outline Regulatory enviroment Biomarkers: What and why Which quality systems for exploratory biomarker investigations? Conclusions

16 Definitions Biomarkers: a characteristic that is objectively measured and evaluated as an indicator of normal biologic or pathogenic processes or pharmacological response to a therapeutic intervention Clinical endpoint: a characteristic or variable that reflects how a patient feels or functions, or how long a patients survives. Surrogate endpoint: A biomarker that is intended to substitute for a clinical endpoint. It is expected to predict clinical benefit, harm, or lack of benefit or harm.

17 Examples of biomarkers Therapeutic class Biomarkers Clinical endpoint Antihypertensive drugs Blood pressure Stroke Drugs for glaucoma Intraocular pressure Preservation of vision Drugs for osteoporosis Bone density Fracture rate Antiarhythmic drug Arrhythmias Survival Antiretroviral drugs Viral RNA CD4 Survival Antidiabetic drugs Blood glucose Morbidity Lipid-lowering drugs Cholesterol Coronary disease Drugs for prostate cancer PSA Tumor response

18 Biomarkers: Why? To support early selection of new lead compounds with proved efficacy (early go/no go) and to minimize risk of failure in late-phase development To characterize safety profile and to evaluate exposure-response relationships To reduce the size, costs and time taken for clinical trials. 40% of all new medicines fails due to the lack of efficacy ( 30%) or safety ( 10%) To rationally drive the drug development process, accelerate the early clinical development of candidates, and tackle the high attrition rate in late clinical development To improve the understanding of drug MoA in patients and enhance the decision-making processes To support the selection of clinical indications and of the target patient population and support the treatment schedule optimization

19 From exploratory biomarker to its validation RISK Exploratory biomarker In vitro test differs compared with intact organism Animal models not identical to human disease Test must be done in human beings Drug discovery Preclinical Phase Phase 1 Phase 2 Phase 3 Biomarker ID Biomarker demonstration Biomarker validation COST If preclinical biomarker not available, identification/verification entirely based on human samples

20 Use of biomarkers Stage of Biomarker Value to Company Regulatory Value Surrogate Can substitute for clinical endpoints Shortens development time Can be used for registration Validated Known and established biomarker Aids decision making Supports dose finding and Secondary/tertiary claims Demonstration Probable or emerging biomarker Can aid decision making Can support rationale for development Exploratory Research tool Little prior information Low

21 Biomarkers in Merck Serono-RBM What we do to support biomarkers investigations in our Labs: Select, validate and measure disease, PD, efficacy and toxicity biomarkers in human samples from Phase I to Phase IV Select and validate in vivo biomarkers in toxicology studies Manage biomarker activities to ensure translation from preclinical into clinical studies Develop, adapt and validate analytical methods for measurement of the identified biomarkers in clinical studies through genomics, proteomics Contribute to the development of biomarker plans, clinical protocols and lab manuals for clinical trials and participate to project teams and clinical teams. As different types of biomarkers require the availability of different technologies, implement and qualify techniques / assays e.g. Luminex, FACS, Affymetrix, ELISA, PCR and pyrosequencing, cell-based assays Assure determination of biomarkers in clinical studies Select and monitor CROs for outsourced biomarker determinations Foster patient selection and stratification, personalized medicine.

22 What we do in our labs Define the technical objective/analytical method Demonstrate method feasibility Experimentally demonstrate the method s ability to achieve the objectives Define acceptance criteria for key validation parameters Qualify and characterize key reagents and disposables Determine stability of prepared samples and standards Document the method Formal write-up as an analytical test method Define validation parameters needed Cite specific experiments required to demonstrate the validity of the method List acceptance criteria for relevant validation parameters Define number of replicates, reporting format Validate the analytical Method performance - perform experiments outlined in protocol Final report

23 Outline Regulatory enviroment Biomarkers: What and why Which quality systems for biomarker investigations? Conclusions

24 Analytical considerations within biomarker scientific community It is not generally possible to validate biomarkers analytical methods according to strict GLPs. GLP-like validation according the spirit of bioanalytical guidelines GLP-like validation can be useful to ensure to get valid information about biomarkers providing reliable data for critical decision making It is not practical or necessary to perform full validation during the exploratory phase of a drug development program. Assay should be reliable for its intended application The goal of assay development and validation is to develop a valid assay rather than to validate a developed method that is that the biomarker assay shoud be demonstrably fit for purpose

25 Outline of the quality system in place for biomarker investigations All instruments qualified: maintenance and validation programs in place Standard operating procedures/working instructions available and applied Personnel is trained and trainings recorded and documented Dedicated and separated lab areas depending on the tech used Biological samples management and storage Study protocols and reports with study directors issued and approved Activities recorded and documented directly, promptly, legibly accurately and in a durable form in Research Record Book Quality controls of experimental data Studies, activities, documentations QA audited Study materials managed and stored properly Raw data stored in defined and controlled place Check if analysis that are going to be performed are covered by informed consensus

26 Our needs Give a name to activities that are already in place (and routinely conducted) but that live in a grey quality standard (no pure QMS, no pure GCP, no pure GLP) Clearly defined quality standard to be requested to a CRO that performs human sample analysis Clearly identify these kind of studies in the MSS Cover those GCP/ethical aspects that are required when analyzing human samples. To be in line with EMA requirements for clinical samples analysis that, even if doesn t quote GCLP, clearly refers to it

27 Our different steps from BMT lab set up GLP like QMS GCLP initiative MS GCLP Ispezione GLP GCP asses. GCLP asses. Quality committ ment Double work QMS+GLP Self evaluation Gap analysis GLP for preclinical validation refinement New quality statement Guidelines reviewed and Global Document (=MS interpretation) issued GCP training Gap Analysis performed in order to verify the status of the RBM BMT pilot lab vs MS interpretation GCP assessment of BMT and DMPK labs Head of GCP QA (May) GCLP training (September) GCP training (December) GCLP assessment of BMT and DMPK labs by Tim Stiles Qualogy (September)

28 GCLP Assessment Objective The objective of the review was to assess the current level of compliance of the Biomarker and Bioanalytics laboratories with the requirements of Good Clinical Laboratory Practice (GCLP) and to identify any areas that could preclude the facility attaining full compliance with GCLP. In addition the review was intended to provide any help, assistance and guidance the laboratory might require in order to understand and implement GCLP. Audit scope The primary scope of the review was to focus on those parts of the laboratory which undertook the analytical laboratory work in support of the clinical trials performed.

29 Quality system for biomarker investigations in MS It is not possible to run exploratory biomarker investigations under full GLP. To ensure the highest standard for our studies and upon internal assessment of the most suitable quality system, it was agreed that All our activities are carried out according to the applicable principles of GLP. The human samples generated as part of the clinical trial were analyzed in accordance with the applicable principles of GLP regulations. No formal claim of compliance with GLP is made. As part of a clinical trial, the work was conducted in accordance with the GCP: Consolidated Guideline ICH Topic E6, adopted by CPMP, July 1996 issued as CPMP/ICH/135/95.

30 Outline Regulatory enviroment Biomarkers: What and why Which quality systems for exploratory biomarker investigations? Conclusions

31 Conclusions From pre-clinical to clinical studies, biomarkers will help to successfully progress products that improve human life This means: De-risk product development by identifying the best lead candidate with the optimal balance of potency, safety and positive drug-like attributes Rapid generation of critical information to sustain or kill, hence reducing the overall cost of drug development Support clinical indications High study quality is MANDATORY

32 Acknowledgements - Mauro D Antonio - Clinical Biomarkers Director - Merck Serono RBM - Colleretto Giacosa, Italy