Specific Presentations and Discussion Topics for The 1 st CRO Closed Forum (Montreal, Sept. 14 th 2010)

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1 Specific Presentations and Discussion Topics for The 1 st CRO Closed Forum (Montreal, Sept. 14 th 2010) Advion Interfacing with the FDA on issued 483 s an Opportunity to Discuss Science and Address Misunderstandings? A little long-winded for a title but getting to the point that CROs spend a lot of time wrestling with internal processes once we hear that a 483 has been issued for X, Y or Z. We often do this with half the story (i.e. only what s in the public domain) and inevitably run around like headless chickens adding to the confusion as we panic ourselves and many of our clients. There has to be a better way. An Update about the Global Bioanalytical Consortium (GBC) and harmonization of bioanalytical guideline. Algorithme Pharma Inc. Effect of counter-ion anticoagulants: different agencies approach; is it real or just a matrix effect when we analyze multiple plasma lots? Understanding the importance, usefulness and long term goal of the Global CRO Council (GCC). History and ideas. What s the degree of commitment of the members? What are the main benefits? How often do we meet? When and where do we meet? Membership common Mission & Vision? Our Structure (meetings and working groups). Use of surveys to consult ourselves on important topics. Importance to work together to overcome scientific and regulatory issues of common interest. Publications. Alturas Analytics, Inc. Would a CRO Governing and Auditing Body Benefit Our Industry? Analytical Bio-Chemistry (ABC) Laboratories, Inc. Quality Management System (QMS). The US FDA nor EMEA regulation nor ICH harmonized guidelines address bioanalysis in support of clinical trials (with only a hint of conducting the preclinical bioanalytical work under GLP s). A quality standard addressing the bioanalytical testing of preclinical and clinical trial samples would ensure consistency in the way industry and contract organizations conduct this work. Everyone has responsibility for quality and compliance to the quality management the Quality Assurance unit does have the responsibility of developing the QMS and implementing it. Harmonization of bioanalytical discussions should include the implementation of a sound quality management system lessons to be learnt from our colleagues in the GMP world and the application of aspects of ICH Q7A and Q10 to bioanalysis.

2 Anapharm The importance of applying sound scientific principles throughout the bioanalytical activities which are performed in the different phases of the drug discovery and development process. Anapharm Europe BASI The following topics will be discussed: (1) Define and establish the importance of the variability of the internal standard in analytical methods based on LC/MS/MS. (2) Discuss reinjection vs. reanalysis vs. non-reportable values. The need of harmonizing the inspections performed by different authorities make this event useful and necessary. It is important to discuss and reach a consensus regarding the criteria in which the audits are based. Since the CRO concentrate the majority of experts in bioanalysis, our contribution is valuable and necessary and should be taken into account. Regarding findings during agency inspection being somewhat inspector dependant. We have always been told that science should drive the decision making process. However, in an FDA inspection last year, the inspector gave us a finding not because we did not have scientific justification for the decision (There were several note book pages detailing the scientific reasoning behind the changes that were made.), but because we changed our minds and reversed the original decision. Is it necessary to use fresh QCs for stability assessments (not just calibrators)? One of our sponsors recently got a 483 finding for this. This is not addressed in the guidance. If fresh calibrators and QCs are needed, where does it stop? Do you need fresh weighings of reference material too? Seems to defeat the purpose of generating stabilities. It gets even more complicated with multi analyte methods. LTS with co administered drugs. Also not addressed in the guidance. In fact the white paper that came out in the last year or two allows for frozen validation samples for validation stability assessments. The co-dosed issue could potentially cost a lot of money to remediate and where do you stop? For example, oncology studies have a notoriously large mixture of drugs co administered. Only for products that are marketed as a co-administered product perhaps? Abnormal IS. Especially for stable label methods. Should there be a standard set of criteria that defines what is abnormal? Is abnormal IS criteria applied automatically to every batch of samples or is it a judgment call left up to the project manager? Whole blood stability evaluation may be another topic. What implication does it have when the concentration result of whole blood QCs is significantly different than nominal concentration (e.g drug bound to protein or red blood cells, or other cell component)? Sample injection volume evaluation to assess the range of injection volume that can be used (implications to acceptable changes to the mobile phase, flow rate, column temperature). Are we heading in the direction of our GMP colleagues who have very little leeway in making modifications to chromatographic settings for validated methods?

3 Cedra Discussion on an excellent example of a chiral LC-MS/MS assay in which the determination of both metabolite enantiomers is impacted by hemolysis but parent drug is not. Details on the investigation and its impact will be presented. This topic is under discussion within both the clinical chemistry and regulated bioanalytical communities and is moving into global guidance. This presentation should stimulate discussion on making assays insensitive to hemolysis and/or when we should assign samples as Not Reportable. Celerion CRO Challenges in a Diverse Regulatory Environment Frontage Laboratories, Inc. Successful Partnership with Pharmas - Partnership vs. Contracting. This topic is related to the specific challenges we are under (as an outsource provider lab) when trying to meet regulatory expectations. Sharing our experiences with other CRO leaders. Selectivity test related to the sources of blank matrix for std/qc preparation: For global multicenter studies, do we need to use blank matrices from different countries to assess the assay selectivity? For BE studies where pilot and pivotal studies are conducted in different countries, do we need to assess the assay selectivity? The challenge of import/export biological samples for getting blank matrices from other countries. Interference of common OTC drugs in selectivity test: list of the OTC drugs could be very different in the blank matrices from different countries Cross-validation to support global studies: How do we do cross-validation if the same assay is used in several countries? What would be the acceptance criteria? KCAS Laboratories ICON Stability issues in bioanalytical methods validation and the definition of "fresh. "An Organizational and Operational Framework" for the Global CRO Council Intertek USA dba Alta Analytical Laboratory Biosimilar and Bioequivalence: FDA regulatory expectations Validation considerations for dried blood spot analysis methods ISR investigations and closeout SNBL USA, Ltd. Method qualification vs. validation for nonclinical biomarker analyses. Especially matrix stability assessments based on %Initial, not %Nominal

4 Use of surrogate matrix (buffer or diluent) for calibration and QC sample preparation in test article formulation analysis for nonclinical studies. Parexel PPD A huge gap has started to form between regulatory guidelines and practical application in the industry. So much attention is given to certain "less important" issues that essential science is being neglected, actually causing a drop in standards. Furthermore guidelines are resulting in huge price increases causing problems for CRO's and Industry. How to create consistency amongst inspectors. No two auditors interpret the guidelines the same way - hugely frustrating. Can the CRO council help? We need harmonization around requirements for assay transfer. For many CROs, many of our assays are initially developed elsewhere. What level of validation is necessary for an assay transfer? If certain experiments are not repeated (i.e. long term stability testing), what is the expectation regarding documentation the CRO must have to support data generated elsewhere? Is the data alone adequate or does the CRO also need all the supporting documentation around the creation of the data (copies of notebooks, raw data, validation of assay used, maintenance/calibration records, training records, etc.)? The industry often learns of FDA "current thinking" through the 483 process and private and public discussions that follow. As a CRO council, we may be able to improve the process through a liaison between us and the agency to question findings and legitimacy of their scientific and regulatory basis. Certainly, we will not all want to share every 483 finding, but some that are novel and introduce new expectations should have a forum for review and discussion with the agency. PRA International We will present our recent experience with FDA inspection in Netherland, we will share our approach setting up a lab in USA and how to harmonize it with the lab in Netherland. Tandem Labs There are some validation topics for which no consensus has been reached in the past, therefore, leading to different interpretation of the guidance between the FDA inspectors. This forum should bring these topics up with the agency for clear directions and, hopefully, reach an agreement based on scientific reasons. Some examples: o QCs storage: is it enough to store a set of QCs with the study samples (to be used for LTS or in case of freezer failure), or all the analytical QCs used in the daily runs must be stored with the samples as well? o Are the same temperature freezers (e.g. -20C) considered equivalent? o Internal standard criteria?

5 o o o FT, BT, LTS- need 6 aliquots from 6 separate tubes which were taken through the test conditions or can 6 aliquots be made from the same tube? Extract stability, is it really needed? The guidance is just a guidance, we are told to use scientific judgment when conducting a study, but if there are no clear rules, the interpretation can be very different.