The work is called many things at different companies – Drug Safety, Preclinical R&D, Drug Disposition, Drug Evaluation, DMPK, Experimental Toxicology – but it all falls under the preclinical umbrella of drug development. It’s a crucial component for both IND and NDA filings, yet most pharmaceutical companies, being asked to do more with less, cannot handle every required study in house. Outsourcing has become a key element in getting the work done. In fact many pharmaceutical companies have virtual drug safety or toxicology groups and outsource everything.

We are used to hearing about the strategic alliances and partnerships formed on the clinical side of drug development, but very little is discussed about these arrangements from the preclinical arena. In all the seminars, articles and discussions on outsourcing, preclinical outsourcing seems to have been overlooked. Although the dollar figures are not as big as those of the clinical industry, they are still significant. According to Patricia Gow, director of business development with MDS Pharma Services (MDSPS), her company’s market research indicates that, of the $50 billion spent annually on global R&D, $5 billion is in the preclinical arena (excluding discovery research). “That’s a lot of money to manage,” said Ms. Gow. She added that overall pharmaceutical outsourcing is increasing to approximately 15% of the global expenditure in the next three to five years.

Preclinical services are also provided by most CROs, though they are typically thought of as clinical providers. They wouldn’t provide these services if there weren’t compelling business reasons to do so. Although preclinical services comprise little of Quintiles’ total sales, Joan Bristol, the company’s director of business development and project planning, said, “It’s obviously important for Quintiles to provide these services to our clients, important enough for us to acquire a preclinical facility in Kansas City.”

In Covance’s 1999 annual report, that company segmented its services into two areas, Early Development and Late Stage Development. Early Development, including preclinical and Phase I services, earned out approximately 33% of Covance’s 1999 net revenues. The 1999 report also indicated that the company devotes more than one million square feet of preclinical laboratory space in four locations. Preclinical development services are certainly considered a core competency by Covance. At MDSPS, Ms. Gow indicated that more than 15% of business is preclinical, making it a significant service to provide.

When we talk about preclinical work, what is typically included? At The R.W. Johnson Pharmaceutical Research Institute (RWJPRI) preclinical development includes toxicology, pathology (including clinical pathology), clinical and preclinical drug metabolism (in vitro and in vivo), pharmacokinetics (PK), and bioanalytical support for all samples from preclinical studies through Phase III studies. Preclinical studies can be long and labor intensive and the scientists at RWJPRI had plenty to keep them busy with in-house studies. To ask these scientists to also create an outsourcing strategy, negotiate contracts with vendors, assure confidentiality agreements were in place, etc. was adding to already-full plates. But the directors devised a plan in which they would establish a separate, dedicated support group within Preclinical Development to help define the outsourcing strategy and facilitate all outsourcing programs.

Adding SPMs
When setting up a preclinical outsourcing group, the first points to consider are the organization of the group’s support and the specific roles and responsibilities of the group. At RWJPRI the first question was whether to align the group along their functional area of expertise or along specific projects. Although it meant moving people out of their comfort zone, we have found that aligning along projects is more effective. Most pharmaceutical companies outsource compartmentally, i.e., general toxicology, drug metabolism, genetic toxicology, while other groups are contracting studies on a one-off basis with little or no internal discussion or communication across the functional groups. Yet, at the same time these companies are setting up teams for specific compounds or therapeutic areas. In order to be strategic, we must have a good overview of all the studies required for each compound, break down the compartments and present a seamless view to our suppliers.

We designated the sourcing group staff as Sourcing Project Managers (SPM), which was a good description of their role, and assigned each about 4-6 projects or compounds. These projects range from late discovery through full development and each SPM has projects covering every phase. The concept was to be involved with the compound as early as possible in order to have the best historical perspective and be able to identify opportunities for more strategic outsourcing. This was not easy on the newly minted SPMs, who now had to learn about aspects of preclinical development beyond their experience in a specific functional area.

Our SPMs don’t need to be experts in everything, but they must know enough about each area to ask the right questions both internally and of the contract laboratories. We cross-trained within the group and also invited key members of our preclinical development customer base to provide information and training to the group. Additionally, we asked our providers for assistance. Most providers relish the opportunity to come talk about what they do for current or potential customers. Since contract facilities get information and feedback from their entire customer base, they are also an invaluable source of information. We learned early not to be afraid to use them.

When setting up a preclinical sourcing group, identifying the roles and responsibilities of the members is the most important and probably most difficult task. Our group brainstormed ideas and got feedback from our internal customers to get a handle on what assistance they needed and expected from such a group. It was a tough balance and we had to establish some ground rules. First and foremost, we knew our role was to serve as facilitators. While the SPM may try to influence where a study might be placed, the ultimate outsourcing decision will always remain with the functional team or team leader. The science cannot be compromised. It’s important to let the scientific staff know this so they don’t feel that they have lost control of their study. Once this is communicated, we can clarify the other roles of the SPM team to everyone.

At RWJPRI the SPMs are valuable members of each project team to which they are assigned. They need to be involved from the beginning. At the point that an outsourced study is discussed, the SPM swings into action, capturing study design information and timelines in order to prepare a thorough Request for Quotation (RFQ). This takes time but it is time well spent, especially early in the program, to insure that we have a clear picture of expected costs and when they will be incurred. This is crucial for any team working within a strict budget. Once a decision has been made on where to place the study, the SPM insures proper legal agreements are in place, and that the contract facility is approved by the Laboratory Animal Medicine and Quality Assurance groups as appropriate.

While this is going on, the SPM also facilitates the protocol and any other statements of work that are necessary to clearly define each party’s tasks. The protocol must be reviewed and approved by all necessary parties. While the technical work is being done, there is also internal financial paperwork that can be initiated and finalized with the appropriate people. It obviously requires a lot of coordination and communication to make sure all this happens prior to initiation of a study. The use of a checklist is extremely useful to keep track of all the components before, during and after a study.

It is key that the SPMs have a preclinical background. This establishes credibility both with the internal customers and external contract facilities. Since most outsourced studies are performed under GLP guidelines, a good working knowledge of GLPs is also important. One of the decisions that needs to be made regards monitoring the outsourced studies. Monitoring can mean many things to many people but the main reason for monitoring is to insure the study is running under control, according to both the protocol and to GLPs (if applicable), and will be completed as anticipated, with no surprises. It is really a matter of managing both the study and the contract facility. Monitoring visits can range from several hours to several days, and the number of visits to a contract facility will vary with the duration of the study.

Previously, all monitoring of studies was performed by a scientist on the project team, which took them away from other responsibilities at work. Monitoring is an area that is somewhat unique to the preclinical world and an area where a sourcing group can be extremely helpful, as long as there is a clear understanding of the responsibility and limitation of that role. At RWJPRI, when a study is going to be outsourced, the SPM and the customer get together to map out a plan for monitoring and managing the study. For the most part, the SPM can handle all monitoring functions, but there may be portions of the study that other members of the project team wish to observe; they would handle the monitoring at that time.

While the preclinical development directors at RWJPRI recognize the benefit of having an SPM handle monitoring, they also require their staff to visit the contract facility at least once during the course of a long-term study. Sometimes the knowledge of a particularly complex technique or skill resides with the principal scientist and that person must be the one to observe the same technique at the contract facility.

Strategic Planning
Successful outsourcing is accomplished by strategically planning which studies or portions of studies will be outsourced. The decision to outsource any study resides with the project team or functional department and is typically based on resource and technology issues. If there are limited in-house resources, the company must determine what they choose to keep in-house. Often this is based on what the company considers core competencies and what is considered extremely proprietary. There is no need to share information before one is ready. This is why most discovery work is kept in-house at big pharma.

Preclinical departments and project teams should take stock of what they are currently doing in-house and why, and look for trends. They should also look at the skills of their staff and where they are best utilized. In addition, they should begin looking at outsourcing on a study-by-study basis, but then broaden the picture. Where can studies be bundled? What types of studies typically follow each other or are done simultaneously? This may lead to different directions for outsourcing support. The sourcing group must remain involved since, as facilitators, they play an integral role in locating appropriate contract facilities for a particular study or studies. Typically the choice of the appropriate provider is based on three main factors:

– Scientific Evaluation: “Do they have the scientific capability to meet our needs?”

– GLP Compliance: “Are the quality and GLP practices acceptable?”

– Business Assessment: “Do they have the financial stability we need to feel comfortable?”

When evaluating potential providers, a sourcing group can act as the advance scouting team. We’ve heard the stories of a large number of key people traveling a great distance to visit/audit a lab, only to get to the site and find out it really can’t provide the specific services needed for the study. Using an SPM with good preclinical knowledge to prequalify a contract facility can be a real timesaver. The SPM should get an overall feel of the three items above and report back to the team on whether a full visit is warranted. In addition to the actual visit, information on FDA audits can be obtained from FOI and financial information from sources such as D&B can be useful tools. If the provider looks good from all perspectives, it’s time to get the project team (including QA) involved for a more thorough inspection and discussion. This way, when the RFQ is sent out, each facility being considered has a good understanding of your expectations and requirements.

The Big Picture
Every outsourced study has both technical and administrative issues. One must make sure to identify the primary person for each area at both the contract facility and the sponsor company. One of the best ways a dedicated sourcing project manager can help is to facilitate the study kick-off meetings. These are invaluable; they insure that all parties know what is going on and whom they need to know. The sponsor should pull together all appropriate staff from both company and provider to review the background, protocol and deadlines of the particular study. Also, both sides should review terms and make sure everyone is using the same definition for terms like “monitor,” “batch,” “audited” and “draft.” The sponsor should use clear language; if something must be done on November 5th, one shouldn’t say “early November.” If data is needed before the end of the day, one must make sure the deadline provides a clear time, such as “Data tables are due via fax [and provide the fax number] no later than 4:30 pm EST.” It seems silly at times, but it avoids unhappiness later.

These meetings are best done in person, but videoconferences or teleconferences can also work. This is not a time to be stingy with information. At this point, confidentiality agreements are signed, so open discussion can take place. When they outsource, most pharmaceutical companies want the contract facility to act as an extension of their in-house lab. The only way to do this is to make sure they know as much as the sponsor does about the program. When time is taken to provide background on the compound or other work done to date to the staff at the contract facility, they feel much more ownership of the study.

When holding kick-off meetings, one must be sure to include all appropriate parties that may be outside the specific preclinical area, but which have a vested interest in the success of the study. If dose formulation or analysis is part of the outsourced package, the sponsor should include members from the Formulations or Analytical Groups in the meetings. If there are complex requirements for shipping samples or tissues, the sponsor should include members Shipping/Receiving or Archiving as appropriate. Effective outsourcing means no surprises to your colleagues.

Lastly, it is important that the sourcing group be the primary point of contact if there are any problems. If something does go wrong, it is best to let the sourcing group handle it. Let the scientific staff stick with science. The sourcing group knows more about the big picture for both the project and the provider. Typically the scientific staff is uncomfortable dealing with problems and is happy to have support. The use of a post-study evaluation survey can be helpful to capture the scientific staff’s impression of how well the study was handled by the contract facility. The sourcing group should facilitate gathering this information.

The future of preclinical outsourcing is strong and a dedicated sourcing support group can be beneficial. As FDA requirements change, in-house scientists can focus on emerging technologies while the sourcing group facilitates ongoing projects. Efficiencies will be gained when the decision process about when to outsource and where to outsource is streamlined.