A 6-Month Process for Planning Multinational Clinical Trials

Choosing the optimal study design in a drug development plan requires a high level of experience in the relevant indications, the medical environment, and regulatory requirements. It is also vital for the researchers ethical responsibility and the commercial success of a drug. But expertise in project and logistics management is just as important to the success of a clinical trialand it is often taken for granted. Multicenter trials, and those that are also multinational, especially require extensive planning and management.

Planning is a process that requires management. The reason that most projects fail to meet their timelines is that planning is not managed thoroughly enough. The planning process deserves attention and monitoring in parallel with the other components of clinical research.

Once the need and objectives for a trial are defined, proper planning over a period of at least six months is vital to ensure a successful study management. Planning should equally emphasize ideal scenarios, contingency plans, and risk management at all key steps in the form of what if analyses.Decisions on consequences and solutions for different potential outcomes should be planned up front, not made at the last minute or in crisis situations.

Although perceived as minutious and cumbersome, planning can be organized and structured in a clear, simplified mode. Planning can also be understood as an investment with quantified and specific returns.

The following approach can help optimize the preparation of a multinational multicenter trial. For each month leading up to the enrollment of the first subject, we suggest the key activities outlined in the accompanying checklist for day-to-day use of 100 Points to Consider for Effective Study Preparation.

6 months ahead: Study design
Study planning is only one component of an overall successful drug development plan. Whenever possible, key elements of the respective study designs should preexist and be kept current in a master development plan.

Not all elements can be or need to be finalized at that time, but they all need to be under control for content and timelines, with assigned accountabilities within the core project team.

Thorough evaluation of expert opinions, current literature, and the availability of sufficient pharmacology, toxicology, and clinical data help to achieve consensus among all relevant parties involved regarding study objective, rationale, and scientific methodology. This should include evaluation of expert opinions; current literature; and availability of sufficient pharmacology, toxicology, and clinical data.

Completing this first step should in turn trigger operational planning timelines for targeted final evaluations; availability of study drugs, comparators, and placebo; and selection of countries of interest for study execution.

To prevent delays and cost increases at later stages, the following key risks need to be assessed and options for solutions need to be worked out:

• Document management (that is, need for investigator brochure and/or local regulatorydocumentation)
• Detailed project plan with key event dates
• Selection of technologies to be used (for example, IVRS, remote data entry, e-CRF)
• Functional resource planning with geographical deployment.

5 months ahead: Feasibility
Although design and strategies are essential, the success of a clinical trial depends on the ability to plan. This includes validation of availability of subjects, and also availability of investigators and study management resources (for example, vendors and geographic deployment of internal resources).

The project team should be identified for all core functions involved.

Key aspects of drug supply management such as labeling and importation requirements, manufacturing, and packaging and distribution plans should be defined and initiated at this stage.

Risks can be reduced by ensuring:

• a back-up strategy for countries and site selection.
• a contingency plan for packaging and shipment delays.
• subject recruitment initiatives, as legally possible.
• user requirements for vendor management (insourcing and outsourcing).

4 months ahead: Vendors and logistics
This plan proposal assumes that generic toolsmaster agreements and contract templatesare already in place for core standard terms for vendors, investigators, and grant management. It is further assumed that a contract research organization (CRO) is not intended to participate in the early study planning phase.

Based on the results of the feasibility study, sites should be selected, the study discussed with investigators, and the terms and conditions negotiated with prequalified sites. A series of operational documents should be prepared: operational sections of protocol, standard informed consent, case report form (CRF), updated investigator brochure, and information and advertisement materials.

An investigator meeting(s) and all related aspects should also be prepared. The importance of a well-thought-through overall communication plan, which defines in detail the structure of the project team, including vendors, and the lines and ways of communication within the project team and with investigators, ethics committees, and regulatory authorities, is often overlooked and should be designed and deployed. This communication plan is critical to success.

At this stage, vendor management should be proceeding well, the budgetary options are ready in case recruitment issues arise, and local standards should be known and in place for study initiation.

3 months ahead: Local applications
Local readiness now needs to be achieved, including:

• submission to local independent ethics committees and health authorities.
• assessment of drug labeling and importation requirements.
• collection of appropriate essential documents from investigational sites.
• definition of process flow for safety handling and all other identified needs (for example, specific personnel and budget needs).
• selection of sites confirmed by prestudy visits.

In parallel, specific plans for data management and quality assurance need to be prepared.At this time in the planning process, resources must be reliably assigned in all operational locations, ensuring a timely study start as well as continuous and updated knowledge of local requirements. Ideally, letters of intent with vendors should be agreed upon.

2 months ahead: CRF and monitoring
Monitoring and data management conventions should be checked for consistency and integrated into training packages and the statistical plan.

The CRF design should be finalized and action taken to work out printing order and logistics for shipment.

Database design, including safety rules, should be put in place and validated.

A quality control check of processes, procedures, and resources should now be conducted so that alterations or corrections can be made before the study starts.

1 month ahead: Training and site management
The project team, vendors, investigators, and study site personnel need an extensive introduction to, and training in, the study details. Suitable tools for accomplishing that include investigators meetings with all parties involved, study initiation visits, project team kickoff meetings, and the use of media tools as appropriate.

After a final check of the availability of all required study prerequisites, subject recruitment can start.

Points to remember
Although everyone seems able to find the time and money to redo, finding the time and budget to plan properly seems very rare. Planning, however, is a key function, not just an intuitive process that scientific professionals can handle spontaneously.

Constant evaluation of operational feasibility and adaptation to project reality is critical. Use of standards that are already in place simplifies work and shortens timelines.

Regularly controlled and proactively managed quality ensures cost containment of projects. Although this concept is routinely used in manufacturing and other industrial sectors, clinical research still has room for improvement.

Finally, communication is key and is too often overlooked.

SIDEBAR: 100 Points to Consider for Effective Study Preparation6 months ahead

• Define the study objective and rationale.
  
• Review literature and discuss with experts.
  
• Decide on the study design.
  
• Calculate sample sizes and prepare the statistical plan.
  
• Ensure availability of suitable preclinical and Phase 1 information.
  
• Plan rough timelines for the study course.
  
• Prepare the project plan.
  
• Check availability of study medication in principal terms.
  
• Decide on test drug(s) and comparator drug(s).
  
• Prepare a contingency plan for unavailability of comparator drugs in some countries.
  
• Decide on detailed timelines for study preparation, performance, and evaluation, including critical time points.
  
• Decide on the countries of interest.
  
• Develop table of contents of the investigator brochure.
  
• Identify and decide on study management technologies.
  
  5 months ahead
• Design the feasibility study plan.
  
• Identify investigators for the feasibility study.
  
• Perform the feasibility study.
  
• Decide on countries involved, number of sites, and number of subjects per site.
  
• Decide on final list of potential investigators.
  
• Prepare a contingency plan for nonactive investigators.
  
• Start preparation of the investigator brochure.
  
• Order study medication.
  
• Prepare a contingency plan for delayed availability of study medication.
  
• Identify labeling and importation requirements for the study medication.
  
• Decide on packaging and shipment strategy.
  
• Prepare a contingency plan for packaging and shipping delays.
  
• Find out about subject recruitment opportunities.
  
• Plan the project team structure.
  
• Identify project team members and their roles and responsibilities.
  
• Prepare detailed resource plan for the overall study.
  
• Decide on a resource contingency plan.
  
• Implement study management technologies and train project team.
  
• Find vendors for outsourced study activities and technologies.
  
• Prepare vendors briefing documents.
  
  4 months ahead
• Decide on vendors.
  
• Finalize vendors budgets.
  
• Plan and manage the audit of vendors.
  
• Prepare and sign contracts for vendors.
  
• Prepare, organize, review, and finalize communication plan with project team, vendors, and investigators.
  
• Order packaging of study medication.
  
• Decide on subject recruitment activities.
  
• Prepare a contingency plan for slow recruitment.
  
• Decide on the strategy for investigators meeting(s).
  
• Identify, negotiate budget, and sign contract with the organizer of investigator meeting(s).
  
• Decide on venue(s) and date(s) and prepare investigators meeting(s).
  
• Prepare a template for investigator contracts.
  
• Plan and organize prestudy visits.
  
• Negotiate terms and conditions of contract with investigators.
  
• Decide on final list of investigators.
  
• Prepare study budget and seek approval.
  
• Prepare a contingency plan for delays in budget negotiations and approval.
  
• Prepare a study approval and ethics committee submission plan.
  
• Prepare a contingency plan for ethics committee and study approval delays and/or problems.
  
• Prepare draft protocol and plan and manage the review process.
  
• Organize QA review of protocol.
  
• Prepare final protocol.
  
• Finalize contracts with investigators.
  
• Prepare standard consent document.
  
• Define and organize translation requirements for consent document.
  
• Plan and manage review process for consent process in different countries.
  
• Prepare standard consent documents per country.
  
• Prepare advertisement plus other subject- and/or investigator-related information material.
  
• Plan and manage review process for advertisement and additional information material in the different countries.
  
• Finalize advertisement and additional information material.
  
• Prepare, organize review, and finalize case report form (CRF).
  
• Prepare, organize review, and finalize investigators brochure.
  
• Organize translations of study material according to local requirements.
  
• Plan the individual submissions to ethics committees.
  
• Prepare, organize review, and finalize the ethics committee submission packages for all investigators.
  
• Prepare, organize review, and finalize study approval submission package in countries with parallel submission.
  
  3 months ahead
• Submit to ethics committees (and regulatory authorities in countries with parallel submission).
  
• Prepare, manage review, and finalize audit plan.
  
• Prepare drug labels.
  
• Confirm site selection and budgetary-specific needs, including resources.
  
• Collect all legally required information from investigators (that is, essential regulatory documents and contracts).
  
• Collect information on national serious adverse event (SAE) and adverse event (AE) handling requirements.
  
• Prepare, organize review, and finalize data management plan.
  
  2 months ahead
• Submit regulatory study approval documents to respective authorities, if possible.
  
• Plan and organize printing of the CRF (including enough reserve).
  
• Prepare, manage review, and finalize the CRF convention manual.
  
• Prepare, organize review, and finalize the monitoring convention manual.
  
• Prepare training material for the project team.
  
• Prepare, organize review, and finalize the SAE and AE handling plan.
  
• Prepare, organize review, and finalize the safety database.
  
• Verify roles and responsibilities for key processes, such as safety.
  
• Prepare, organize review, and finalize database.
  
• Finalize statistical plan.
  
  1 month ahead
• Train the project team.
  
• Hold investigators meeting(s).
  
• Hold kickoff meeting with project team and vendors.
  
• Ensure study approval and drug importation licenses.
  
• Release study medication.
  
• Manage study medication and material shipment to sites.
  
• Plan and set up the investigator fees payment process.
  
• Prepare site master files.
  
• Organize study initiation visits, as required.
  
• Ensure all study drugs and material arrived at sites.
  
• Perform study initiation visits at sites with control of ethics and study approval, arrived medication, and other study material.
  
• Train study coordinators and other involved site staff.
  
• Initiate subject recruitment activities.