Total pathway to method validation

The role of the medical laboratory scientist (MLS) in method evaluation development and implementation extends well beyond the customary bench practices of validation and verification towards involvement with the total process from conception to commission. There is a temporal sequence of activities requiring more than just analytical skills. This is in keeping with the changing expectancies of the modern clinical laboratory [1] and the advancing role of MLSs within them. The current IFCC and EFLM education and training syllabus, reflects this [2, 3]. Here, we aim to create a roadmap for the total pathway to method validation to demonstrate the level of input required of MLSs to successfully validate their proposed method. The collective experience of the authors has shown that development pathways logically break into three interactive but independent activities namely predevelopment, development and post-development. Each of these phases comprises inputs and outputs variously from pathologists, scientists, clinicians, published literature, guidelines and administration (Table 1). The pre-development phase starts with clinical assessment in terms of purpose and likely demand. Definition of the project and the purpose of the assay are paramount in advance of commencement. There must be a clear statement of intent which should be embodied within a formal protocol. Projects may falter at this point unless there is an assignment of responsibilities and a conviction by the group to proceed. Engagement with the relevant specialists ismandatory at this point and the dialoguemust be bidirectional so that both perspectives are clearly defined. The drive forward can come from the specialties or from the laboratory itself, but afterwards the initiatives and momentum comes from MLS who are necessarily required to do the bulk of the work hereafter. After the decision to proceed has been made the MLS needs to engage in an exhaustive literature review which mostly targets existing methodologies and the technical options. Part of this search will include a survey of other clinical laboratories that may be already active with the test. This helps to assure there is regional or global interest in the test as well as to provide potential collaborative support. Accessibility to an external quality assurance program is sought if one exists. At this point, the MLS has assumed responsibility for either continuance or cessation of the project. This becomes dependent on a feasibility study to assess selection and suitability of available equipment. In essence, theMLS assesses the analytical requirements and determines whether the laboratory is capable of proceeding in terms of resources, instruments and anticipated development time. If the project is feasible continuation now requires a business case which covers, clinical need, technical matters in terms of reagents and instruments and various financial elements surrounding these. The intention is to convince administration of the worth of the project, assign resources, seek the various authorities and align with strategic planning and other priorities. The business case is not merely an accountancy exercise because final test cost is usually not the key determinant at this time and is calculated later. *Corresponding author: Dr. Gerald Woollard, Members RCPAQAPAACB Advisory Committees, St Leonards, NSW, Australia; and Department of Pathology and Laboratory Medicine, Auckland City Hospital, New Zealand, Phone: +64 9 3074949 Ext 22053#, E-mail: GeraldW@adhb.govt.nz Brett McWhinney: Member RCPAQAP-AACB Advisory Committees, St Leonards, NSW, Australia; Analytical Chemistry Unit, Department of Chemical Pathology, RBWH, Herston, QLD, Australia Ronda F. Greaves: Member RCPAQAP-AACB Advisory Committees, St Leonards, NSW, Australia; Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia; and Executive, Emerging Technologies Division, International Federation of Clinical Chemistry and Laboratory Medicine, Milan, Italy. https://orcid.org/0000-00017823-8797 Wilson Punyalack: Member RCPAQAP-AACB Advisory Committees, St Leonards, NSW, Australia; The Royal College of Pathologists of Australasia Quality Assurance Programs (RCPAQAP), St Leonards, NSW, Australia Clin Chem Lab Med 2020; 58(11): e257–e261

To the Editor, The role of the medical laboratory scientist (MLS) in method evaluation development and implementation extends well beyond the customary bench practices of validation and verification towards involvement with the total process from conception to commission.There is a temporal sequence of activities requiring more than just analytical skills.This is in keeping with the changing expectancies of the modern clinical laboratory [1] and the advancing role of MLSs within them.The current IFCC and EFLM education and training syllabus, reflects this [2,3].
Here, we aim to create a roadmap for the total pathway to method validation to demonstrate the level of input required of MLSs to successfully validate their proposed method.The collective experience of the authors has shown that development pathways logically break into three interactive but independent activities namely pre-development, development and post-development.Each of these phases comprises inputs and outputs variously from pathologists, scientists, clinicians, published literature, guidelines and administration (Table 1).
The pre-development phase starts with clinical assessment in terms of purpose and likely demand.Definition of the project and the purpose of the assay are paramount in advance of commencement.There must be a clear statement of intent which should be embodied within a formal protocol.Projects may falter at this point unless there is an assignment of responsibilities and a conviction by the group to proceed.Engagement with the relevant specialists is mandatory at this point and the dialogue must be bidirectional so that both perspectives are clearly defined.The drive forward can come from the specialties or from the laboratory itself, but afterwards the initiatives and momentum comes from MLS who are necessarily required to do the bulk of the work hereafter.
After the decision to proceed has been made the MLS needs to engage in an exhaustive literature review which mostly targets existing methodologies and the technical options.Part of this search will include a survey of other clinical laboratories that may be already active with the test.This helps to assure there is regional or global interest in the test as well as to provide potential collaborative support.Accessibility to an external quality assurance program is sought if one exists.
At this point, the MLS has assumed responsibility for either continuance or cessation of the project.This becomes dependent on a feasibility study to assess selection and suitability of available equipment.In essence, the MLS assesses the analytical requirements and determines whether the laboratory is capable of proceeding in terms of resources, instruments and anticipated development time.If the project is feasible continuation now requires a business case which covers, clinical need, technical matters in terms of reagents and instruments and various financial elements surrounding these.The intention is to convince administration of the worth of the project, assign resources, seek the various authorities and align with strategic planning and other priorities.The business case is not merely an accountancy exercise because final test cost is usually not the key determinant at this time and is calculated later.Prior to the development phase, the decision to proceed has already been made in terms of starting point and likely success.The feasibility phase would have made the choice for a commercial product (if one existed) or to commit to development in-house.Dependent on this, verification or a full validation will be needed.Verification is always less demanding.Validation is required if a new method is to be designed from ground up based on scientific principles and technological skill.The validation process is the sole responsibility of the MLS.The analytical difficulty may vary between projects as well as the analytical skill invested.However, the net outcome must be a rigorous and exacting investigation that adheres to the strict criteria detailed in international guidelines [4,5].Usually, these will be from organizations such as Food and Drug Administration (FDA), Clinical and Laboratory Standards Institute (CLSI) or Committee for Medicinal Products for Human Use (CHMP) of European Medicines Agency.
After completion of the verification or validation, a full report needs to be issued by the MLS.This must detail everything that has been done with accompanying data.The report must be circulated to a formally appointed quality group consisting of scientists and pathologists who can gauge the quality of the analysis and the suitability of the test for service inclusion.This quality group must understand the analytical, technical and clinical principles of the test and have a vested interest in outcome.
After successful verification/validation, the MLS must pursue several other activities prior to submitting the test for service.Foremost is the implementation of control mechanisms consisting of internal QC charts, an external quality assurance programme, acceptance/rejection criteria, uncertainty principles, commutability, instrument operational records and a maintenance programme.If other regional labs are also offering the same test then attempts should be made to harmonize the results.If there are differences then requesters should be alerted to them.The MLS is required to calculate the cost which includes all reagents and consumables (calibrators, internal/external controls) staff time per batch, expected batch sizes, instrument devaluation and repair.These costs need to be known to allow billing.Lab-wide costs such as occupancy and power, administrative overlay, mark-ups and contingency are usually calculated outside of the actual test cost and applied by administration.The MLS must also arrange for inventory and procurement (suppliers, delivery times and instrument maintenance schedules) to prevent service interruption subsequent to test inclusion.This requires forward estimates of the likely demand.Documentation describing collection requirements, sample handling, storage conditions and instability needs to go to specimen services.The MLS must write the bench method in a suitable format for staff to follow.The method document must then be stored in the laboratory documentation system for retrieval and future updates.Training of staff ensues with traceable competency assignments.An entry is written for the laboratory handbook to alert and advise potential requestors.It must contain all relevant material regarding patient preparation, test requirements, interpretation and reference intervals/decision limits (usually generated during validation).Hereafter, the MLS usually relinquishes some of the responsibilities to other relevant staff.All electronic online test lists and applications must be updated to reflect the changes.New test codes may need to be created within the Laboratory Information System (LIS).Page layout, report design, fixed and reflex comments, reference limits and units must be designed usually by the development group who best understand the test and its implications.The MLS will oversee a post-launch audit to monitor and record batch failures/causes, analytical/instrument problems, test robustness (ability to withstand variations from the SOP), turnaround time, request rates, abnormal result rates, utilization and enquiries/commentaries.If the method is substantively novel the MLS should endeavour to publish the work.Any interesting clinical findings and unique cases should also be reported in various formats such as colloquia, special interest groups and related journals.
In summary, it is not sufficient for the MLS to be solely adept at analysis.They need to have a thorough understanding of all facets of the process from conception to completion and this requires a much wider scope of involvement.The manifesto of laboratory medicine professionals clearly alludes to this [6].The labscape is projecting further from just bench practice into stewardship and the provision of an entire diagnostic service.The generation of a numeric output is insufficient in itself.MLSs must be conversant with all the tests from their facility and especially those for which they are responsible or have designed themselves.Furthermore, MLSs need to be aware of their changing roles and of emerging technologies when selecting and optimizing their preferred methods or planning for future ones [7].
Finally, this total pathway requires the MLS to be proficient in their ability to conceive and direct validation processes starting with the opening strategy to gain clinical and administrative support before embarking on the test method itself.The methodology can be designed from ground up using scientific principles or implemented from commercial or published methods.It must be technically robust enough to be transferred into the routine environment and survive scrutiny from rigorous quality and

Table  :
Total pathway to method validation.
Feasibility studyProcess to examine all the available test methods Essential prior to test commencement or development An in-depth assessment of the lab capability or otherwise -Literature review of published applications -Determine availability of commercial test products -Decision for in-house vs commercial test methods -Consideration of equipment and reagents required