Designing an effective oversight management plan to maintain GCP throughout your trial appears a simple, straightforward strategy for a successful clinical trial. Yet, its implementation can be challenging. My perspective is based upon my years in virtual and semi-virtual small biotech companies (<20 people, currently at Lakewood Amedex, www.lakewoodamedex.com), as a consultant to a CRO (ARIANNE Corporation, www.ariannecorp.com), and as an Instructor at Northeastern University College of Professional Studies Regulatory Degree. With clinical trials becoming more global and only ~50 percent conducted in US (according to Monitor 2011), outsourcing to a CRO is required by small companies to insure the best chance of success. I ask my students, “what is your criteria for selecting a CRO?”. Cost, ontime delivery, report quality, communication with the company, qualityof staff, recommendation from a colleague or reputation in the industry. The responses vary, but no student ever mentions communication with the company. After they have discussed their rationale, I provide my opinion and explain why communication is critical. It starts with defining responsibilities between sponsor and service provider from the beginning to avoid the blame game. Prior to selecting a CRO, an internal company meeting is required to outline responsibility for:
- Project Management (CRO selection,Project management plan, Medical Monitoring plan, Clinical monitoring plan)
- Study Startup (Protocol development, ICF development, Regulatory submissions, PI/Site selection, Site initiation, IRB submissions, Laboratory selection, Laboratory manuals/kits, Study reference manual, Trial master file, Investigator meetings)
- Data Management (Source data forms, CRF development, CRF filling instructions, Data transfers, Discrepancy reconciliation, Data management plan, Statistical analysis plan)
- Study Execution (Drug shipment, Clinical monitoring, SAE handling, Sample shipments, CRF transmission)
- Study Closeout (Close out visit, Database lock. TLFs, Clinical Study Report, Master File reconciliation)
Following internal discussions, the first interaction with a CRO or site should be the exchange of a Confidentiality Disclosure Agreement (CDA). This standard industry practice can become an initial signal of the type of organization that will become your partner. As a Sponsor, upon submitting a CDA to a CRO or site, I have received redacted responses “that would in the old days use all the ink in a red pen”. For small biotechs that do not have the luxury of in-house counsel, there are excellent firms, such as TriUnity Law Group (http://triunitylaw.com) that supply and customize templates for often-used contracts. Edits can become so severe and argumentative that not only does it get the process off to a bad start, it actually can eliminate the vendor or site altogether. A CDA exchange and execution should meet your organization’s expectations because this will ultimately foreshadow the communication with your vendor or site.
A Statement of Services should clearly define the responsibilities for the Sponsor and Vendor. Key items should include:
- Project Setup Activities - Clinical Project Setup/Preparation, Case Report Form (CRF) Design, Review CRF, Prepare CRF Completion Guidelines, Set up Master Action Plan, Database Design/Review/Build, Data Management Plan, Data Validation Plan, Monitoring Plan, Clinical Trial Management System Setup and maintenance, Investigator Meeting Preparation, Presentation and Attendance
- Regulatory Aspects - IND Maintenance (amendments, the reports, and annual reports), IP shipment, IRB Submissions, IB update, eCTD publishing and submission
- Project Management & Team Meetings - Project Management, Vendor Management, Face-to-Face Client Meetings, Internal Team Meetings, and Ongoing Training
- Site Setup - Feasibility and Site Identification, Pre-Selection Visits, Informed Consent Form, Essential Document Management, Regulatory Compliance Review of Essential Documents for Test Article Release, Site Contract Management, Investigator Payment Management, and Site Initiation Visits
- Clinical Aspects - Medical Resolution of Inclusion/Exclusion Queries, Site and Team Support, Physician Review of AE/Medical History and Con-meds Coding, Physician Review of Safety Listings, and Statistical Analysis Plan (SAP)
- Ongoing Clinical Operations - Interim Monitoring Visits, Site Management, Drug Supply Management, Investigator Payment Administration, Investigator Files Setup and Maintenance, Trial Master Files Set-up and Maintenance, Clinical Data Listing and Patient Profiles, Site Audits, IND Safety Report Distribution, Management of Non-Drug Trial Supplies, Newsletters Development and Distribution, Query Resolution, and Site Closeout Visits
- Test Article Management
- Database Management - Database Maintenance, Data Entry and Verification, Data Cleaning, Listing Review, Medical Terminology Coding, SAE Reconciliation, External Data Transfers, Critical Variable Review, Final Database QC, and Archival
- Pharmacovigilance - Medical Monitor, Safety Database –Setup& Maintenance, SAE Processing – Receipt & Follow-up, Medical Review of SAEs, Preparation of SAE Narrative and Reports, Notify Expedited SAE Reports to Regulatory Authorities / ECs / PIs as needed, Set up and Manage a Data Safety Monitoring Board
- Biostatistics - Produce Statistical Analysis Plan (SAP), Produce Table, Listing and Figure Shells, Produce and Validate Tables, Listings and Figures, Final Statistical Analysis
- Medical Writing - Clinical Study Reportand SAE Narratives
- Quality Assurance
- Central Lab - Identify, Select and Negotiate Contracts, and Management
With a signed statement of services, the first plan that should be prepared and established is the communication plan between the CRO and Sponsor. The plan should outline and clearly define the methods and flow of communication. It is applicable to the Sponsor/CRO, CRO/Investigational Sites, CRO/Vendors (Central and local labs, drug depot, etc.), and the CRO internal. Additionally, theplan should also include a detailed project team contact list for key staff members and is updated regularly. A communication flow diagram (Figure 1) should be included to easily establish the line of communication.
Figure 1. Example of Communication Flow Diagram
Communication with the CRO Project Management, CRO Safety (clinical operations), Data management and central labs should be direct to the Sponsor. Another key communication is between the CRAs through a Lead CRA (LCRA). Weekly meetings/teleconferences should be scheduled between the Sponsor and CRO. An agenda and minutes from the previous meeting should be prepared by the Sponsor and distributed to the participants allowing enough time for a review prior to the call. For written status communications, the CRO should provide the following status reports each week to the Sponsor:
- Regulatory Documents provided by Project Coordinator
- Monitoring Visit Schedule
Alternatively, the Sponsor should provide the following status reports each week to the CRO:
- API shipment and availability for each site
Both the CRO and Sponsor should have CRF completion and data entry status reports through an electronic data capture system. Emails with pertinent study information should be printed and placed in the Trial Master File. Monitoring visit reports should be prepared and submitted to the Sponsor according to the Monitoring Plan.
The Sponsor should insure CRA-Site communication in which the assigned CRAs contact each site regularly to discuss study status, issues, and scheduling of visits as well as Project Coordinator-Site Communication in which the assigned Project Coordinators contact study sites as needed to obtain regulatory documents. Finally the CRO should conduct weekly teleconferences with the Vendors (central labs, etc). Obviously, ad hoc communication on critical issues (safety, regulatory, IP) are necessary and should not wait until scheduled weekly calls.
To conclude, one should be more realistic than optimistic and be prepared to have backup plans. Stick to the weekly schedule and keep the call to one hour regardless of the agenda. Be respectful of everyone’s time. If topics need further discussion, take them offline. If calls do not require the allotted time, be brief and let the team continue with running the trial. Educate yourself or surround yourself with people that understand and work “fluently” with you. Adapt and be flexible with your counterparts, and last but not least, share the successes with your extended team/family.