1. Life Sciences Product Development Weaving People, Processes, and Procedures Together for SuccessLarry K. Wray, PhD Presented at BIO2DEVICE GROUP March 2, 2010 2010 Larry K. Wray 1

2. To Set the Stage Focus will be on development of in vitro diagnostic (IVD) tests, but aspects also apply to reagents and life science tools, and devices Weave together the people, process, and procedural elements of development, along with pitfalls and things to look out for or anticipate, for a successful outcome These elements feed into two structural frameworks Business strategy and management (e.g. stage gate reviews) Compliance and regulatory requirements (e.g. design control) 2010 Larry K. Wray2 3. Goal and Outcome Cover main elements of product development process, But, main goal and focus will be on success elements from best practices and lessons learned from mistakes Resulting in reduced time to market and cost, with improved quality and margins and in full compliance with QSR and ISO Finish with trends which will change the nature of the business 2010 Larry K. Wray 3 4. What is an in vitro diagnostic product (IVD)? Definition: In vitro diagnostic products are those reagents, instruments, and systems intended for use in diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. [21 CFR 809.3] 2010 Larry K. Wray4 5. IVDs are a type of device Regulatory Authority: IVDs are medical devices as defined in section 210(h) of the Federal Food, Drug, and Cosmetic Act, and may also be biological products subject to section 351 of the Public Health Service Act. Like other medical devices, IVDs are subject to premarket and postmarket controls. IVDs are also subject to the Clinical Laboratory Improvement Amendments (CLIA '88) of 1988. 2010 Larry K. Wray 5 6. LDTs (Laboratory Developed Tests) LDTs are tests that are developed by a single clinical laboratory for use only in that laboratory (aka home brews) FDA generally exercised enforcement discretion over standard LDTs Regulated under Clinical Laboratory ImprovementAmendments (CLIA) by Centers for Medicare andMedicaid Services (CMS) Being reconsidered for tests employing complexalgorithms to generate patient results (In VitroDiagnostic Multivariate Index Assays, IVDMIAs) 2010 Larry K. Wray 6 7. Types of Products Immunoassays Molecular Diagnostics Arrays Sequencing Laboratory instruments or Point of Care (POC) Cancer, cardiac, drugs of abuse/ toxicology, genetics, fertility/pregnancy, infectious disease, metabolic, therapeutic drugs, transplant 2010 Larry K. Wray 7 8. FDA Waterfall Design Process for Design ControlDesign Control Guidance for Medical Device Manufacturers, FDA CDRH, 1997 2010 Larry K. Wray 8 9. Stage Gate Process Standard Used by Most Companies Pietzsch, J.B. et. al. Stage-Gate Process for the Development 2010 Larry K. Wray of Medical Devices, J. Mol. Devices, vol. 3, 20114, 20099 10. PACE- Product and Cycle-Time Excellence One example of a conceptual and practical background behind the Stage Gate Process 2010 Larry K. Wray10 11. Picking the right technology and platform Performance, e.g. sensitivity, reproducibility, throughput, etc. Laboratory workflow (instrument footprint) Cost of instrument and reagents Breadth of applications- allows for menu expansion Multiplex capability Instrument registration- easier to go IVD route if not RUO Minimize number of new parts/ proven technology if meets requirements 2010 Larry K. Wray11 12. Defining the project scope Define intended use early- defines studies required and regulatory path If ASRs (Analyte Specific Reagents), consider whether a test to be developed later ASRs are the active ingredients (e.g. antibodies, nucleic acid sequences, etc.) of tests Follow design control to make it easier to develop a test and obtain approval 2010 Larry K. Wray 12 13. Project scope continued Decide on CLIA vs. IVD route- parallel IVD route if CLIA to keep options open CLIA requirements less stringent than FDA CLIA restricted to single lab, cant distribute FDA considering regulating IVDMIAs in CLIA labs Common strategy is to launch initially in CLIA lab and follow with FDA submission 2010 Larry K. Wray 13 14. Getting Started Assumes the business case has been made and basic product design decided Form project team Start team meetings Put together project plan Start executing on deliverables 2010 Larry K. Wray14 15. The Project Team and Leader Include essential participants who need to contribute to projects success Keep it small, with one member with decision making authority form each functional area Typically R&D, manufacturing, marketing, quality, regulatory Extended team can include areas such as finance and customer support Minimize turnover Decide on rules and norms at the first meeting. Make sure responsibilities are clear and understood. Hold regularly scheduled meetings and issue meeting minutes with action item (project leader) 2010 Larry K. Wray 15 16. Planning- Focusing the Fuzzy Front End Moving from the fuzziness of discovery to the focus of a developmentIn preparing for battle I have always found that plansare useless, but planning is indispensable.Dwight David Eisenhower 2010 Larry K. Wray16 17. From Research to Development Companies commonly have Research (also called Discovery) structured separately from Development These can be two very different cultures and mind sets Research is more free wheeling, whereas Development is a more disciplined process, which is appropriate for each role In recruiting Development staff the particular requirements for this process must be kept in mind It is important for the R and D groups to work together as a team to transfer technology to the development process- a relay race, not a toss over the wall! 2010 Larry K. Wray17 18. The Development Phase Begins Limited, but critical set, of performance characteristics evaluated and found acceptable to determine feasibility of the approach prior to formally proceeding to Development. Development is not discovery and should be more like building a bridge, where the materials and plans are available and a cost and timeframe can be reasonably estimated OK to proceed to Development with some risk, but this needs to be evaluated as part of feasibility determination Includes both the product design and manufacturing and testing processes needed to support the product 2010 Larry K. Wray18 19. Developing the product First step is to typically optimize the product, e.g. component concentrations, run times, etc. Software packages are commonly used for various experimental designs and data display and interpretation Used both to optimize the procedures and also for specification setting Guard Bands are also typically run, bracketing acceptable ranges, e.g. component concentrations Evaluate with some real patient samples, not just artificial matrixes! Start this at feasibility or have a unwelcome surprise! 2010 Larry K. Wray 19 20. Design of Experiments (DOE)- A Standard Approach to Assay Optimization www.jmp.com SAS Institute 2010 Larry K. Wray 20 21. DOE- Response Surface Designs are Used for Finding Optimal Conditions www.jmp.com SAS Institute 2010 Larry K. Wray 21 22. Other things to incorporate in developing the product Multiple lots of components (internally produced and incoming from vendors) are evaluated for consistency and meeting specifications Evaluate performance on multiple instrument platforms to take into account variability Do the same with multiple operators Start accelerated stability studies on key components 2010 Larry K. Wray 22 23. Process development for design transfer to operations In parallel with product development, manufacturing processes and quality control (QC) tests are developed and documents drafted Specifications are developed for in-process and final release testing and incoming materials Important to develop using equipment of same type used in operations! Take into account the work flow and requirements in operations, which could be different from R&D Involve manufacturing and QC personnel early in developing procedures for transfer Bottom line- this needs to be an effective design transfer to operations so things work independently in their hands! 2010 Larry K. Wray 23 24. Process and Test Method Validation After manufacturing process and QC test methods are developed they have to be validated Drafting is typically initiated by Development or a Design Transfer function, but the actual runs should be carried out by operations personnel in the setting that production and testing is to be performed Data from DOE studies can be used to characterize the process parameters and the actual validation runs should challenge the process at extremes of the ranges Typically three manufacturing runs are conducted for process validation, but this number depends upon the individual process(es) itself 2010 Larry K. Wray24 25. Process Validation: establishing by objective evidence that a process consistently produces a result or product meeting its predetermined requirementsProcess Validation Guidance, Global Harmonization Task Force (GHFT), 2004 2010 Larry K. Wray25 26. Test Method Validation: Demonstrates that the method is suitable for its intended purpose (e.g. product acceptance testing Type of analytical IDENTIFICATIONTESTING FOR IMPURITIES ASSAY procedure - dissolution (measurement only) characteristics - content/potencyquantitat. limitAccuracy -+ - +Precision Repeatability-+ - + Interm.Precision -+ - +Specificity++ + +Detection Limit-- + -Quantitation Limit -+--Linearity-+-+Range-+-+Validation of Analytical Procedures: Text and Methodology Q2(R1), InternationalConference on Harmonisation (ICH), 2005 2010 Larry K. Wray26 27. The product and processes are optimized and ready for Design Verification The product design is complete when Performance requirements are achieved Formulation of reagents and assay protocol locked Manufacturing and QC procedures developed Vendors for incoming materials identified and qualified (at least preliminarily) Risks identified and mitigation procedures developed Bottom line- this is the final product configuration (or close to it) 2010 Larry K. Wray 27 28. Design Verification and Validation Verification- we built it right. Accomplished though internal testing Validation- we built the right thing Usually in conjunction with external clinical studies. Both on final protocol, reagents, etc. 2010 Larry K. Wray 28 29. Design Verification Preapproved protocols with acceptance criteria to assess product performance Per Design Control, Customer Requirements are translated into Product Requirements Product Requirements determine acceptance criteria Performance characteristics such as specificity, accuracy, precision, linear range, and reproducibility are assessed Studies are typically done in house Evaluation of more than one performance characteristic can be combined in a given study Protocols can be used as templates for other products, saving time and promoting consistency of approach 2010 Larry K. Wray29 30. Clinical Laboratory Standards Institute (CLSI) (formerly NCCLS) is a Source of Standards and Guidelines Recognized by FDA EP05-A2 Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline-Second Edition EP06-A Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline EP07-A2 Interference Testing in Clinical Chemistry; Approved Guideline- Second Edition EP14-A2 Evaluation of Matrix Effects; Approved Guideline-Second Edition EP17-A Protocols for Determination of Limits of Detection and Limits of Quantitation; Approved Guideline EP21-A Estimation of Total Analytical Error for Clinical Laboratory Methods; Approved Guideline EP25-A Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guidelinewww.clsi.org 2010 Larry K. Wray 30 31. Design Validation Commonly the same as clinical studies Clinical studies an FDA requirement, at least for PMAs Not required under CLIA Usually 3-4 sites 3 for reproducibility 1 for analytical performance Purpose is evaluation in customer hands, although important to assure proper set-up at sites, e.g. instruments in calibration Sometimes advisable to go to FDA for pre-IDE (pre-submission) meeting to review approach prior to initiation of studies Documentation is critical, particularly for traceability, additional analysis of data, or repeat sample runs 2010 Larry K. Wray 31 32. Regulatory Submission Data is a combination of internal (analytical) and external (clinical) studies Development typically prepares the technical part of the package, with Regulatory Affairs being responsible for the submission per se, along with follow-up and ongoing coordination with FDA and international agencies Repeat: for a new technology or novel intended use, best to meet with FDA prior to clinical studies for pre-IDE Approvals typically in about 90 days for 510ks and a year for PMAs, but clock can stop during review, delaying approvals CE Marking for EU, which can either be self-certified or require a Notified Body 2010 Larry K. Wray32 33. Projects that ran into problems and lessons learned- Transferring New Technology A project plan for a new molecular diagnostic product line was developed and communicated without taking into account new technology transfer A new DNA amplication technology was licensed and transferwas underway. Timelines were committed to prior todemonstration of feasibility. The technology was not asstraightforward to incorporate into a product, as originallyanticipated. As could be expected, the project slipped and theentire program was impacted. Lesson: New technology might not be directly adaptable for anew application, without optimization or modification. Accountfor this as part of project and business planning. 2010 Larry K. Wray33 34. Problems and lessons- Moving from a Tool to an IVD A 510k was submitted for a molecular diagnostic with an instrument platform that had not been cleared A product was developed using a Research Use Only (RUO) instrument and associated reagents, with the assumption that this would be acceptable to FDA, based on previous experience and assumptions. The agency would not accept this, resulting in much time and expense retrofitting the instrument, along with developing specifications for reagents and consumables. Lesson: If you plan to ultimately submit for FDA approval, develop the product under design control on a cleared platform or plan on submitting the platform for approval. 2010 Larry K. Wray34 35. Problems and lessons- Incorporating New Processes A new process was introduced into a major component of a product under development A new labeling process was introduced for a probe in an In SituHybridization (ISH) product. The process was not reproducible,resulting in the project being be put on hold. Loss of credibility tothe team and at least a year delay on the project resulted. Lesson: Dont try to parallel a new, untested, major processchange while trying to develop a product in which it will be amajor component. If this is desired, allow the time and have amore feasibility based timeline. New processes need to gothrough process development! 2010 Larry K. Wray35 36. Problems and lessons- Maintaining Good Laboratory Practices An Analyte Specific Reagent (ASR) was later decided to be submitted as a 510k ASRs are components of products, which are not required to bedeveloped under Design Control. This ASR was not even done under Good Laboratory Practices(GLP), with a lack of documentation, for example. The project was delayed significantly and much of the work hadto be repeated. Lesson: Think ahead. Employ at least GLP in developing anycomponent, but better to at least follow the main elements ofDesign Control. Its OK to add more later, not to have to repeatwork! 2010 Larry K. Wray36 37. Problems and lessons- Design Transfer to Operations Failures occurred frequently in QC on the same product which passed routinely in Development A sequencing based product was transferred to operations which previously had no problems in Development. No one could seem to make in in Ops, but when it came back to Development, no problem. Additional training (this was a somewhat technique dependent protocol) and review of specifications was required. Lesson: Involve operations early in transferring a new process or QC procedure and develop procedures and specifications that take into account people, process, equipment, and facilities in operations. Its not transferred if they cant make it! 2010 Larry K. Wray 37 38. Problems and lessons- Setting Specifications for Incoming Materials A molecular diagnostic, which had been on the market for several years, suddenly stopped working Upon investigation, the vendor introduced a new process formaking a key component. The material still met incoming specs!Ultimately the issue was resolved by refining the specificationsand negotiating a modification in the process with the vendor. Lesson: Understand attributes of a component that critical andset specifications accordingly. Dont just incorporate off the selfspecs that might have been set for a different application. Also,use vendors whose processes are under control and are ISOcertified, if at all possible. If possible, write into supplyagreements requirements for vendors to inform you of processchanges to materials. 2010 Larry K. Wray 38 39. Problems and lessons- Communicating with the FDA Additional studies supporting submission of a major product for an established manufacturer had to be done after the submission went to FDA (and after several months of review). Samples were not always available, along with resources, to conduct the studies. This resulted in a significant delay in approval (well over a year), increased cost, lost sales and market share, and considerable trauma to the organization. Lesson: Communicate early with FDA (e.g. pre-IDE) and make sure the communication is understood both ways. Dont make assumptions, e.g. they wont require this or they havent asked for this before. Document samples and studies well. Read Decision Summaries of comparable products. 2010 Larry K. Wray 39 40. Emerging Trends for IVDs Personalized Medicine Detailed information from the Human Genome Project isrevolutionizing IVDs Differentiate disease susceptibility, drug reactions and response Moving from single markers to multiplex assays which incorporate algorithms for data interpretation (IVDMIAs) More extensive studies can be required to demonstrate clinical utility Companion diagnostics- challenges in coordinating drug- diagnostic development and with regulatory path 2010 Larry K. Wray40 41. Emerging Trends (2) Technology is developing rapidly Next generation sequencing (NGS) Approaching the $1000 personalized sequence Arrays- DNA printed on plastic, glass, or silicon chips Allows investigation of 1000s of sequences (e.g. SNPs, Single Nucleotide Polymorphisms) Microfluidics Lab on a Chip- Point of Care (POC) testing Much of this will and is migrating from tools to diagnosticsspace with product development and regulatoryimplications 2010 Larry K. Wray 41 42. Lab-on-a-Chip (LOC)Agilent Technologies www.agilent.com 2010 Larry K. Wray 42 43. Emerging Trends (3) With the new FDA administration, the regulatory climate is changing More restrictive use of 510ks- tightening definition of predicate devices More oversight over LDTs, e.g. IVDMIAs 2010 Larry K. Wray 43 44. Emerging Trends (4) Healthcare costs, legislation, and taxes Questions to ask of a proposed new product How will this impact healthcare decisions? What impact will this have on cost? Who will pay for it? Impactof potential legislation unclear What will the impact of any changes to tax code be on innovation? 2010 Larry K. Wray 44 45. Emerging Trends (5) Emerging economies Growing new markets, e.g. China Understanding new markets and regulatory climate New technology shift overseas New technology will increasingly come from outside U.S. Product development and clinical trials are also shifting overseas All of this calls for a less U.S. centric view 2010 Larry K. Wray 45 46. Some Take Homes The right team and team dynamics is critical Early planning is important Define intended use and strategy Anticipate obstacles and formulate alternative paths Understand the technology and processes thoroughly, optimize, and set appropriate specifications Maintain good documentation, follow GLP, QSR/ISO Design and develop to customer requirements (both external and internal) Communicate with FDA early and understand expectations 2010 Larry K. Wray46 47. Some Resources Food and Drug Administration www.fda.gov FDA Office of In Vitro Diagnostics (OIVD) http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagn ostics/default.htm European Commission (Medical Devices) http://ec.europa.eu/enterprise/sectors/medical-devices/index_en.htm European Diagnostics Manufacturers Association www.edma-ivd.be Global Harmonization Task Force (GHTF) www.ghtf.org International Conference on Harmonization (ICH) www.ich.org Clinical and Laboratory Standards Institute (CLSI) www.clsi.org IVD Technology www.devicelink.com/ivdt American Association for Clinical Chemistry www.aacc.org 2010 Larry K. Wray 47 48. Contact InformationLarry K. Wray, PhD (925) 596-4344 lkwray@msn.com 2010 Larry K. Wray 48