Outsourcing is becoming a trend in preclinical development and is projected to increase from the current 20-25% to 30-50% of R&D expenditures in the next few years.

1. Benefits Of Outsourcing
2. Plan For The Investigational New Drug (IND) Application
3. Technical Points To Consider
4. Planning And Designing Individual Studies
5. Technical and Administrative Issues
6. Selecting A Contract Research Organization (CRO)
7. Questions To Ask The Contract Research Organization
8. Legal Agreements
9. Sponsor’s Internal Financial Paperwork
10. Monitoring Plan

Benefits Of Outsourcing

There are many requirements that are needed for preclinical development that require a great deal of time and capital expenditure. Setting up and running an accredited vivarium takes many resources. In order for these tests to qualify for regulatory submission, the tests must be conducted per GLP which also takes additional resources.

In addition to not having to invest in the expensive infrastructure associated with preclinical toxicological studies, companies using outsourcing to support their discovery and development process save in the following ways:

• Increased available capital
• Preserved R&D focus
• Wider range of available expertise
• Increased flexibility

To take advantage of savings opportunities available in the preclinical phase through outsourcing, the entire project must be well thought out and carefully planned. Begin with your goal in mind, and then work backwards. Otherwise, you risk missing toxicity problems that could have been detected before clinical trials. Consider the following points when designing your plan:

• What is the goal?
• What is a simple statement of the objectives?
• What is the preclinical need identified by internal customers, project teams, and management?
  • increased resources
  • range of expertise
  • flexibility
  • preserve the R&D focus of the client company or group
• What is the design of the clinical trials?
• What is the design of the preclinical testing?
• What is the study design?
• What are the timelines?
• What is the budget?
• What is the long-term marketing strategy and plans? (These will affect clinical trial design, which in turn affects preclinical testing.)

Plan For The Investigational New Drug (IND) Application

• Which FDA center will be reviewing the study—CDER or CBER?
• Which division? What are that division’s particular concerns?
• Which reviewer? What are that reviewer’s particular concerns?
• What will FDA be looking for in clinical trials. Plan preclinical testing accordingly.
• Which international agency(s) will be reviewing the study? What are their concerns and requirements?
• What is the planned timing for the IND application? Assume Phase II quickly ramping up after Phase I.
• What are the IND application submission requirements?
  • Lot Number
  • Integrated summary
  • Report summary
  • Tables
  • Report copy
• From the company’s perspective
  • Which studies can be bundled?
  • Which studies typically follow each other?
  • Which studies are typically done simultaneously?
• Good Laboratory Practice (GLP) – probably required, at least for critical studies

Technical Points To Consider

• Formulations
• Known toxicity problems
• Route of administration
• API formulation (analytical characterization preferred)
  • Stability
  • API Assay
  • Impurities
  • Diluents, inert ingredients
• Side effects
• Dosage
• Bioanalytical support
• Dose solution analysis
  • Homogeneity
  • API level all dose groups

Planning And Designing Individual Studies

When planning and designing the individual studies to be outsourced, consider the applicable ICH guideline, as well as the following points:

• Planning the protocol
• Species
• Doses
  • Low—lowest efficacious dose
  • High—highest anticipated exposure (+safety margin, if possible)
  • 1x, 5x, 10x mg/kg
  • Rationale
• Data and report format
• Report deadline
• Route of administration—consider the clinical phase
• Regimen—consider the clinical phase
• Duration—consider the clinical phase

Technical and Administrative Issues

• Identify primary administrative and technical contacts in both the sponsor company and contract facility.
• Specify responsibilities—consider GLP requirements

Selecting A Contract Research Organization (CRO)

When a sponsor has decided to outsource, it must select a contract research organization (CRO). That process might typically include the following steps:

• A project manager is identified for the specific outsourced project. Ideally, the project manager will have experience with preclinical testing. The project manager should:
  • Identify suitable CROs
  • Issue RFQs (Request for Quotation)
  • Facilitate and monitor outsourced study
  • Conduct post-study evaluation
  • Assemble a project team to handle different aspects of a project, especially if it is large or complex, and ensuring that the general composition of the outsourcing project team is representative of the commercial, technical, and compliance areas.
• Project manager prequalifies the CRO by:
  • Visiting the CRO facility
  • Coordinating a QA audit of the facility
  • Obtaining FDA audit and history information
  • Obtaining references and/or financial information
• Project manager and needed team members visit the CRO (if necessary)
  Request for quotation (RFQ)

Questions To Ask The Contract Research Organization

• Scientific evaluation – “Do they have the scientific capability to meet our needs?” Some points to consider:
  • Experienced with route of administration
  • Experienced with type of molecule
  • Experienced with all species for study
  • Protocols, including SOP references
  • Example or report formats
  • Training records for technical staff
  • Complete and thorough SOPs
  • Clinical pathology capabilities
  • Timing of results
  • In-house QA
  • Veterinarian on staff
  • AAALAC accredited
  • Board-certified pathologist to oversee necropsy
• What is the turn-around time for both draft and final pathology reports?
• Regulatory compliance—”Are the quality and GLP and cGMP practices acceptable?”
  • What is the CRO’s FDA history?
  • What is the CRO’s GLP experience?
  • What is the CRO’s cGMP experience?
  • Is the CRO an approved contract facility, in terms of both laboratory animal medicine and quality assurance?
  • What are the GLP and cGMP report requirements?
• Business assessment—”Do they have the financial stability that we need to feel comfortable?”
• How committed is the CRO management?
• Customer Service
  • Does the CRO have good customer service?
  • How are they at communication?
  • Is it easy to locate the right person to answer a particular question?
  • Are their responses timely? Are their answers complete and helpful?
  • Do they have a reputation for quality?
  • Are they respected in the scientific community?

Legal Agreements

Good, clear, well-defined legal agreements, created with the help of the sponsor’s contract analyst and attorney, enable a positive business relationship. Consider including the following in the agreements:

• Brief statement of objectives
• Contract points
• List of the Bio/Pharm materials and applicable regulatory requirements to be provided to the CRO by the client
• Communication
  • Who is the primary contact person in the client’s and CRO’s organization?
  • What are the schedules of client/CRO communication?
  • Frequency and type of meetings
  • Formal report schedules
  • Informal report schedules
  • Written communication—What formats are desired?
  • Oral communication—Guidelines
  • How will problems be resolved?
  • What are the payment schedules?
  • Glossary of terms

Sponsor’s Internal Financial Paperwork

• Make sure the finance department has budgeted for the study.
• Make sure the accounts payable department has planned to process and pay the invoices.

Monitoring Plan

A good monitoring plan for the project can include the following:

• Sponsor design a plan for monitoring and managing study
• Sponsor visits, audits, interim data review

Download printable version of our booklet Preclinical Toxicology – Points to Consider in Program Design (PDF).