Uncommon Cents

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Whether its buildings or relationships, the best approach to any task is to invest in a solid foundation at the outset. Business dealings occur because people are able to realize unfulfilled needs through products and services offered by service providers. However, in the case of clinical research, one must build a business relationship that will not only survive, but flourish for many years.
The purpose of this article is to provide some guidance in evaluating the quality of existing contractor relationships, identifying the optimal path to changing service providers, and establishing some rules and concepts that will support the business relationship for existing and future clinical research programs.

Define Your Needs
Working with contractors who are able to adapt to your processes is key to your clinical projects’ success. Occasionally, there may be a need to specify certain ground rules for all potential suppliers, who should be able to provide details as to how they will respond to your specific requirements.
Ask all newly identified service providers to complete a standard Request for Information, which should be regularly updated. Contractor responses should be scrutinized, a brief written vendor evaluation noted, and the information made centrally available. At this point, a short list of suitable, multi-disciplined vendors should be
prepared. Those vendors who are not included in the list should be contacted and asked to clarify their positions on specific issues. If you feel that their responses merit further consideration, add them to your short list as alternates.
Once suitable contractors are identified, their capabilities and capacity specific to your project must be determined. A two- to three-page summary of the draft protocol must be provided. This document should contain specific information regarding study timelines and visit schedules, site locations, patients to be screened and enrolment goals, testing requirements, reporting requirements, data transfer frequency and format, as well as specific governance requirements such as conference calls during and following site initiation, specific reports (DSMB, data queries, etc.), extranet access to data, and so on.
Eliminating as many potential sources of inefficiency as possible is a key consideration in a clinical project. Failure to do so at this stage could lead to increases in pass-through costs or additional charges due to changed orders.
Ideally, discussions should begin early in the process. The central lab will often be able to assist you with design logistics, identifying errors or omissions in the concept, and will be able to offer testing and service options that may produce cost and/or time efficiencies. It is very important that you discuss the study’s objectives, as well as goals specifically regarding the primary and secondary objectives, especially if they are based upon lab determinations. You do not want to use an assay that has large intra-assay variability if you are looking for a small shift in the analyte concentration. These are the kinds of discussions you don’t want to have at 50 per cent enrolment.

Level the Field
Once Request for Proposals have been received, it is important to schedule a one-hour bid defence with each potential supplier. This can be done by telephone, or through services such as WebEx™ or Microsoft’s Live Meeting. These tools are, in many ways, better than a face-to-face meeting because they allow additional resources to be incorporated into the discussion at a moment’s notice, including whiteboards, documents and spreadsheets. Additionally, presentations and discussions can be played back in real time. This provides the opportunity to identify the proposal’s specific strengths and weaknesses, as well as get a sense for the vendor’s capability to deliver. The logistical aspects of the proposal should be very clear to the vendor, as should their responses to your specific questions.
If you have asked the central lab to provide pricing for pharmacokinetic and/or biomarker analysis, it is important have a discussion regarding sample stability, required processing times and data reporting. It is crucial that everyone’s expectations are clear from the outset.
A new type of laboratory testing is available that permits the simultaneous analysis of multiple analytes. Multiplexed assays are extremely cost-effective when considering analyte profiles, for example cytokines and chemokines. If you are planning on using these assays to analyze 20 different cytokines, 30 specimens could be analyzed in two hours of run time and two hours of prep time from a single aliquot. If you were to perform this using ELISA technology, the same amount of testing would require at least 40 hours of run time and 40 to 80 hours of prep time, and would require seven to 10 separate aliquots. While multiplexed assay materials are more expensive, you save time and associated costs, such as sample storage and archiving.

Pass-through Charges
Transportation pass-through charges can account for as much as 50 per cent of the central lab proposal. However, understanding the invoicing mechanism for pass-through charges will ensure that you are able to effectively monitor these transactions. The central lab’s responsibility is to manage the transportation logistics and courier service providers. The courier is responsible for the timely and efficient transportation of biological samples worldwide. Your central lab will work with local, national or international courier service providers and understand how they operate. The business relationship with the couriers will facilitate real-time tracking of shipments, ensuring the fastest and most secure routings, emergency services, brokerage services and customs clearance assistance to guarantee that your study samples arrive on time. Review with your vendors the details regarding estimated costs, such as the date of courier quotation, opportunities for cost-savings, and included services that may have inflated the costs. A more recent quotation may reflect charge increases that are not considered in another bid, even though both vendors plan on working with the same courier. Also, your vendor may have provided a worst-case scenario whereby each subject visit requires a separate shipment, when this may not be the case. A little co-ordination between the study manager, the site monitors and the central lab could significantly reduce transportation costs.

Auditing
Throughout this process you have identified your first and second choices for your preferred central lab supplier. At this point, you should schedule lab audits for both potential suppliers. A well-organized central lab will be able to demonstrate documented SOPs, process-control checkpoints, error-trapping processes, as well as physical layout, facilities and capabilities, security, information systems and provide you with an opportunity to meet the key vendor contacts and obtain copies of current certifications and CVs. It is important to nurture the relationship because, although you will only be selecting one central lab for this study, other opportunities may exist in the future where the non-
contracted central lab may be the best choice.
The audit report should be completed and shared with the central lab, which should respond within a reasonable timeframe. This information should be included with centrally filed vendor information for use by other departments.

Establishing the Working Plan
Once you have selected your central lab, good business practice dictates that you notify the other bidders that you are continuing your discussions with a potential vendor and that they will be notified shortly as to their status. At this point, a suitable Master Services Agreement, which stipulates the legal mechanisms, should be exchanged. If you require services from your preferred vendor immediately, a Letter of Agreement can be quickly established to define a fixed fee for a fixed service, pending the execution of the Master Services Agreement.
The project’s working plan starts with the work order — the refined proposal that identifies the scope of services, areas of responsibility, and applicable fees following analysis and discussion. It is important to consider whether additional testing may be required in the future, as with novel biomarker assays. For example, a reserve 2-ml EDTA plasma aliquot and 2-ml serum aliquot from each subject visit can be collected and preserved at -80 C both during and for a fixed period of time following the study. The costs are minimal for this service, which offers additional flexibility.
The logistical plan begins with the list of investigators and their contact information. During the initiation phase, the central lab will validate the site information and provide details regarding specimen collection and transportation procedures, collection-kit designs, and the correct manner in which to complete the supplied documentation and reference ranges for the tests to be performed. This information will constitute the study’s laboratory manual. It is good business practice to ask for this document in “track changes” mode, so that you can sign-off on each change, and ensure that nothing identified for change was overlooked.
It is important that time be set aside to thoroughly review these documents. Ask for samples of the required specimen-collection kits and review the necessary procedures with your CRA co-ordinator to ensure that anyone who is in contact with the sites is able to correctly explain the procedures required throughout the study.
Your central lab should provide toll-free access and 24-7 support to sites throughout the course of the study. It is critical that lab questions be addressed quickly, since they usually arise at the time of sample collection or shipment.
You should also consider asking the central lab to participate at the investigator meetings. Your central lab project manager will be able to present all relevant information to the central lab and provide guidance to the sites regarding their role and responsibilities. It is important to remember that the central lab is a critical part of your study team, and that the project manager will be the first person to identify and help resolve site problems.

In the Real World
There are many ways in which problems can arise in a clinical trial that often cannot be foreseen: changes to the protocol, material malfunctions, changes introduced due to subject recruitment or responses to treatment, changes to transportation or import/export regulations, etc. For all changes that affect the scope of work and costs associated with the central lab, it is advisable to establish a change order. The change order can take the form of either a restated work order or a separate document identifying a new activity.
The effect of contractual changes upon the study operational plan should be considered and changes must be communicated to all affected parties. If the sites will be affected, it is advisable to ensure that such changes are well documented and that revised, version-controlled documents are submitted to the sites. Notifications and memos should be retained by the sites and be easily retrievable for future reference.
It is important to put cost considerations in perspective. Not taking such action could lead to erroneous procedures that may not be immediately evident, resulting in increased costs associated with the testing of low-quality samples, reporting of erroneous results, additional queries, and additional time required by data managers, as well as the potential impact upon the data safety monitoring boards.
By keeping these points in mind, your next central lab outsourcing venture should be a positive and rewarding experience.

Peter Colbourne is the past director, central laboratory and current director, business development for CIRION Clinical Trial Services Inc. (Montreal, QC). He can be reached at colbournep@cirion.com