Jennifer Goldfarb, CCRP
Senior Director, Clinical Research Support Office
Children’s Hospital of Philadelphia
Grace Wentzel, CCRP
Director, Clinical Research Services
The Research Institute at Nationwide Children’s Hospital
Abstract: The study start-up process sets a study up for success or failure. This article provides an overview of study start-up, the players on the study team, and the infrastructure required for successful study start-up. Tools for the study feasibility assessment for dissecting and implementing the protocol and for ensuring compliance are described. Challenges to study start-up and solutions to those challenges are provided.
Introduction
Study start-up is everything that must take place from the first point of contact with the sponsor to the moment that the study team is ready to screen and enroll subjects. Study start-up can be compared to the gestation period in pregnancy. The baby, in this case the study, must be nurtured and developed in a way that will produce a healthy, desired outcome; a successfully executed study.
Many things must happen before a study can be started:
- Conversations with the study team , key stakeholders, ancillary departments, CRO, and sponsor (to name a few)
- Planning for all components of the protocol
- Requests for information
- Development of study processes to ensure protocol adherence and to identify gaps
- Regulatory submission and approval
- Confidentiality Disclosure Agreements (CDAs) and Clinical Trial Agreements (CTAs)
- Staffing: planning, reallocating, hiring
- Site visits
- Budgeting
- Creation of the informed consent form and other study documents
- Training
- Development of collaborations and any needed process development with ancillary departments
Even though study start-up tasks are challenging, it is very satisfying when study start-up is done right. Making an informed choice to take on or decline a study can lead to satisfaction as well. The study team does not have to conduct every study that is offered and should have established criteria to guide them in their study selection. One approach may be to select the studies that offer the greatest benefit to the populations that they serve, have a high chance of enrolling an adequate number of subjects, and perform according to the protocol without logistical issues at that institution.
The Players on the Study Team
At any institution, the players on the study team include:
- Principal investigator
- Sub-investigators
- Study nurse or study coordinator
- Regulatory coordinator
- Ancillary resources
These key players are essential to the success of any study; therefore, the plan for team communication should be established early and continued throughout the lifecycle. Effective ongoing communication among the study team is essential to the success of a study. Without regular team meetings, for example, issues with study enrollment may go unnoticed for extended periods of time, leading to the ultimate failure of the site to enroll the necessary number of participants.
The approach to the study start-up process has been undergoing a culture shift in recent years. While progress has been made, study teams still need to slow down and be more methodical about study start-up. All of the key players must inform study start-up, as no single team member has all of the answers. The investigator, for example, may consider the study’s science but not its logistical feasibility. The study nurse/coordinator may find the science interesting but is usually more concerned with study operations.
Other players may be present at some institutions, including:
- Feasibility coordinator
- Study intake team
- Site assessment visit
- Budget analysis
- Sponsored projects office or contract manager
- Training/compliance coordinator
Nationwide Children’s Hospital has an institution-wide mandatory feasibility assessment process that includes a feasibility coordinator team and a training/compliance coordinator, which has significantly improved the feasibility process.
It takes a village to successfully conduct a study. If the right people are not involved, the study will not be conducted efficiently and effectively. The study team must think broadly about everything that could possibly be needed by the study and must also plan for costs. Study teams often take on studies that they are not equipped to conduct due to limited resources.
Feasibility Evaluation
Sometimes, study coordinators get into a rut of reinventing the wheel every time that they work on a study because each study is unique. While studies are complex and multi-factorial, a standardized process for feasibility evaluation can be developed. The issue always boils down to whether the clinical research site has the resources necessary to conduct the study. The necessary resources are time, space, access to protocol-required tests and procedures, research participants, and staff.
Questions about resources must be answered fairly quickly because the timeline is running. Study coordinators often feel an enormous pressure to move fast and may not stop to think about the questions that must be answered before proceeding. Sometimes, study coordinators may feel external and/or internal pressure to conduct a study.
Feasibility assessment needs to be a priority during the study start-up process. Once the CDA is in place and the study team can see the protocol and a draft of the sponsor’s budget, the team must move quickly into the feasibility review of the different aspects of the study in order to make an informed decision about whether to participate. A good review ensures that only feasible studies move forward, protecting the precious institutional resources of staffing related to coordination, contracting, budgeting, institutional review board (IRB) review, and other institutional resources.
A feasibility assessment is an established standard process to objectively review every study. External biases can color the way that studies are evaluated. Having a standardized process for evaluating studies will minimize bias and facilitate objective study assessment.
Feasibility can be conducted at the level of the investigator, the department, and/or the institution. At some institutions, the investigator is the sole decision-maker in selecting new studies. However, there is now more interest in developing processes whereby new study feasibility is assessed in a more formal manner with the involvement of key personnel early in the process in order to fully evaluate studies and to best position studies for success.
The interest in conducting a study should ideally be aligned with the overall goals of the investigator, the department, and the institution. This requires answering difficult questions such as:
- Who defines the goals and what are they?
- What happens when goals conflict?
There are many reasons for clinical research sites to assess feasibility (Table 1). Saving time and money is one reason, although this can be tough for some teams to process since it requires a shift in effort with more up-front work. Study teams may not think that they have the time to assess feasibility and may not know how to measure cost savings. Ultimately, conducting a thorough feasibility assessment can allow sites to focus their time on studies that are both desired by the investigator and feasible.
Proactively identifying and addressing competing priorities are other added benefits of a formal feasibility assessment. When multiple investigators are working on similar studies, the study team may not know that they are “competing” for patients. Assessing feasibility enables study teams to fully understand the requirements of the study, allowing the team the opportunity to be fully committed and knowledgeable in the conduct of the study, potentially reducing errors and improving efficiencies.
In determining feasibility, timelines matters. No matter how feasible the study seems, if the timeline does not work, the study is not feasible. Knowing when the sponsor will close enrollment, the number of study participants that the clinical research site can enroll, and the amount of time that is likely required for IRB review, for budget negotiations, and for contract execution will all make a huge difference in the feasibility of a study.
The study start-up timeline can range from eight weeks to more than six months. One factor that influences the study start-up timeline is the ease of budget and contract negotiation and finalization. If there is a sticking point, the study may never move forward. Understanding the status of contract negotiations is really important, because if there is a deal breaker, it may make sense to stop assessing feasibility.
The complexity of the protocol and the investigator and sponsor responsiveness will influence the study start-up timeline. At Children’s Hospital of Philadelphia, the Clinical Research Support Office knows that with certain sponsors, study start-up that would normally take 8 to 12 weeks could take about 6 months because of anticipated sponsor delays.
Committee review and competing workloads also impact timelines. Multiple committees may review each study, and this takes time. Competing workloads of the study coordinator and the principal investigator are also a concern. Investigators often over-extend themselves.
The feasibility process should have steps that assess workflow at the clinical research site and clearly-define responsibilities for various tasks. It is ideal to begin the feasibility process as early as possible in order to avoid wasted efforts on a study that will not work. An approval process must be in place, whether this is done at the level of the investigator, the department, or the institution.
The protocol feasibility tool available for use at Children’s Hospital of Philadelphia starts with first-line questions (Table 2). These questions enable study teams to conserve the time investment in a new study by quickly determining if a study is feasible on a grand scale. Study teams only move forward when answers to the first-line questions indicate that a study may be feasible.
The first question, for example, asks when enrollment is scheduled to end. Children’s Hospital of Philadelphia has received requests from sponsors to initiate new studies where enrollment ends within a month. It is not possible for Children’s Hospital of Philadelphia to complete study start-up and opening enrollment within a month. Thus, the feasibility of a study is quickly determined.
Best practice in assessing study feasibility at Children’s Hospital of Philadelphia includes developing a written tool to objectively review study feasibility for the required study population, time, resources, finances, staff, space, and so forth. Conducting feasibility meetings about new studies with key personnel and investigators is another best practice. Study teams at Children’s Hospital of Philadelphia are not required to conduct feasibility meetings; however, these meetings are encouraged. If a study team says that they do not have time for a feasibility meeting, it may be an indication that the team is not ready to take on a new study.
Developing a defined feasibility assessment and approval process with steps to resolve conflicts is another best practice. There may be times when the investigator insists on conducting a study; however, the administration determines that the study will not work for one reason or another. There must be a way to mitigate and resolve conflicts.
Dissecting the Protocol
At Nationwide Children’s Hospital, every study with procedures that are being done outside of the standard of care or that are paid on a per-subject per-procedure basis is required to go through the mandatory feasibility process managed by Clinical Research Services. This was put in place after the institution had a deficit because some investigators had taken on studies that were under-performing or had accepted budgets that were inadequately paying for study procedures. Nationwide Children’s Hospital has a mandatory study feasibility process focused on ensuring that procedures being done for research purposes are clearly defined, the study budget covers the cost of conducting the study, and the study can operationally be conducted at NCH. The investigators are responsible for determining the scientific adequacy of the study.
One of the first steps after the feasibility process is to ensure that the study team understands the protocol. This is also part of feasibility. However, it is necessary to dissect the protocol to ensure that the budget is sound and the study can be operationalized in an effective way (Table 3).
The study team must know:
- Where the subjects will be recruited and enrolled
- Where the subjects will be seen for their study visits
- Whether study visits will be combined with standard of care visits.
It is also necessary to know whether the clinical research team has prior experience and contacts in the area. If so, knowing how other study(ies) performed will help the study team understand the necessary resources for the study being evaluated. All of this information is also required for the development of adequate budgets.
The study team must know which procedures will be done during a study and when they will be done. This part of the evaluation includes determining whether additional staffing/resources will be necessary to conduct a study. For example, one study at Nationwide Children’s Hospital has bi-weekly infusions and requires the clinical research nurse to be in the pediatric intensive care unit for the entire eight-hour infusion. When evaluating studies, it is important to review all the information in the schedule of events, which can be missed.
Another key question is whether the clinical research site has, or the sponsor will supply, the right equipment for the study. In another study at Nationwide Children’s Hospital, weekly infusions were given to five children. The supplies, which were not part of the budget, cost $55 for every infusion.
Determining which ancillary service providers will be needed for a study is another consideration in dissecting the protocol. The study team must know this and have the buy-in of ancillary service providers. This requires discussing the study with staff in ancillary departments during the protocol dissection process, not after IRB approval.
The study team must also consider how the procedures required by the study will impact the number of potential enrollees. At Nationwide Children’s Hospital, if the science is worth it, Clinical Research Services will find a way to make the study work. It is crucial, however, to identify potential barriers and ways to manage them early, not after the study has started. IRB submission and budget and contract approval may occur simultaneously, or each process may be dependent upon other processes being completed, depending on institutional procedures.
Nationwide Children’s Hospital has established a study start-up team and has developed tools to lead clinical research nurses and study coordinators through the protocol implementation process and facilitate protocol compliance. These tools are very helpful to clinical research nurses and study coordinators who are working on other protocols and seeing subjects for study visits who tend to delay study start-up activities.
In 2015, Nationwide Children’s Hospital created a study start-up team comprised of three people in Clinical Research Services who are highly organized, very processed-oriented, and very technology-savvy. The team members are also non-confrontational, so when they work with clinical research nurses and study coordinators, it is clear that they are there to assist them through this process. They are not seen as threatening when they check in on what is happening with a study to ensure that timelines are met. A member of the study start-up team is assigned to each study.
Study start-up tools are a protocol implementation checklist, a study start-up timeline, and a study start-up calendar. The protocol implementation checklist is useful in both investigator-initiated studies and industry-sponsored studies, but it may be more helpful for investigator-initiated projects. When turning a grant application into a protocol, many things are missed. The checklist helps the study team identify what questions must be answered in order to operationalize a study. Even for industry-sponsored studies, the checklist helps the study team identify questions to ask the sponsor or contract research organization. The checklist covers:
- Type of study
- Responsibilities:
- Study-specific procedures
- Ancillary departments
- Source documents, including whether the sponsor is providing them or the clinical research site needs to develop them
- Laboratory kits and processing requirements
Using the checklist enables the study team to determine what study start-up will involve, how long it will take, and whether additional staff will be needed to conduct a study.
The study start-up timeline starts with the date when Nationwide Children’s Hospital receives the study, followed by the date when a study start-up team member is assigned to the study. Next, the date for completion of the protocol dissection is added, and a meeting with the study team lead is scheduled if there are questions about the protocol. Identifying how the inclusion/exclusion criteria will be reported and documented is the next step in the timeline. Nationwide Children’s Hospital recruits many subjects who live in other countries and states, which requires obtaining medical records from those places.
Clinical Research Services offers a la carte services. Principal investigators can use some or all available services. Multiple meetings are held with the principal investigator so that staff members in Clinical Research Services understand which services the principal investigator plans to use for a study. Any meetings with the sponsor that might be required are also on the timeline.
The study start-up calendar works backwards from the target enrollment date. It includes activities that must occur each week and is used to track completion of those activities.
Compliance Checks
Clinical research tends to be reactive. Every time that a study process went wrong at Nationwide Children’s Hospital, processes were changed to ensure that the problem would not repeat. Challenges with protocol adherence exist at every site. Quality improvement and quality assurance processes can be implemented before the first subject is enrolled in order to reduce risks during study implementation and conduct (Table 4).
The study start-up team member assigned to a study also does a final comparison of the source documents, the protocol, the case report forms, and the informed consent form. Launch meetings will uncover issues about 50% of the time. By reviewing and comparing the study documents ahead of time, mistakes can be corrected, compliance can be achieved, and all of the study documents will be as clear and concise as possible.
The inclusion/exclusion criteria source document is designed to prove that the subject meets the criteria for a study. This document contains a line for every calculation that is required and a checkbox for every document that requires back-up documentation. It also includes the start and stop dates for medications when necessary as per the protocol.
The research chart includes a print out of all of the withdrawal and stopping criteria. The study coordinator and the principal investigator can refer to this at each visit. This ensures that they do not miss the withdrawal and stopping criteria or have to refer to the protocol to find that criteria during a visit.
At least one week prior to the start date for enrollment, a mock visit is conducted and the launch meeting is held. The launch meeting helps identify the financial and operational aspects of the study and tries to clear up any issues before the first subject is enrolled.
Conclusion
The study start-up process sets a study up for ultimate success or failure, and there are key components that have the ability to make the conduct of the study more efficient and effective. Feasibility assessment is a best practice for all clinical research sites in order to fully evaluate the desirability and feasibility of new studies. Evaluating the feasibility of new studies to ensure accepting the “right” studies for the investigator and the institution allows for the success of not only that particular study, but potentially all studies being conducted at the institution. Other best practices include establishing a communication plan, dissecting the protocol as a team, creation and use of study start-up tools and checklists, and methods to evaluate any potential issues with protocol adherence.
TABLE 1
Reasons to Assess Feasibility
- Saves time and money
- Proactively identifies and addresses competing priorities
- Avoids surprises and overpromising
- Promotes better relationships between sponsors and clinical research sites
- Makes the best use of staff time and possibly creates efficiencies
- Enables staff to conduct the study effectively and compliantly
TABLE 2
First-line Study Feasibility Questions at Children’s Hospital of Philadelphia
- When is enrollment scheduled to end?
- How much time will it take to:
- Obtain IRB approval?
- Finalize the contract?
- Be ready to enroll subjects?
- What is the anticipated date of enrollment of the first subject?
- How much time will be available for enrollment?
- How many study subjects are needed (contracted number)?
- How many potential study subjects who meet eligibility criteria does the clinical research site have access to, if known?
- Are enough study staff members currently available to fully staff the study? Will it be necessary to hire new staff or transition staff from other studies?
TABLE 3
Dissecting the Protocol at Nationwide Children’s Hospital
- Where will subjects be recruited and enrolled?
- Where will they be seen for their study visits?
- Are study visits combined with standard of care visits?
- Will marketing tools be needed?
- Does the study team have prior experience and other contacts in the area?
- Which procedures will be done and when?
- Does the site have the right equipment?
- Does the site need additional staffing/resources?
- Is the equipment being supplied? Does it meet the institution’s standards?
- Does the team need additional training?
- What ancillary service providers will be needed?
- Will the procedures impact the number of potential enrollees?
TABLE 4
Compliance Checks at Nationwide Children’s Hospital
- Study start-up team
- Comparison of documents:
- Source documents
- Protocol
- Case report forms
- Informed consent form
- Inclusion/exclusion source document designed to prove that the
subject meets the criteria:
- Lines for calculations to be made
- Start/stop dates for medications
- Identification of when back-up documentation should be printed
- Source document in the research chart with withdrawal/stopping
criteria:
- Reviewed at each visit
- Mock visit at least 1 week prior to start date
- Launch meeting