Protocol Feasibility to Promote Trial Efficiency
Scientific abstracts and articles have reported that 20-50% of studies do not accrue subjects at the site level (1-6). This contributes to a significant amount of waste in clinical research, particularly in the forms of staff time and monetary resources. Such waste can be reduced through the careful selection of clinical trials to activate early in the process, before investing a lot of resources. The protocol feasibility review process achieves this by providing a method to review the logistical aspects of a clinical trial prior to starting the activation process.
The concept of an early-phase review for feasibility is not new. Stage-gate framework from industrial-organization psychology suggests ending projects with a low likelihood to succeed early on will result in an increased likelihood of success of those projects moving through the process (8). It embodies the business decision, which predicts whether this project has the capability to achieve the required objectives. The primary purpose of this theory is to ensure that projects approved for development are allocated proper and needed resources. The secondary purpose is to provide a mechanism and parameters to abandon development of a project which is unlikely to succeed before too many resources are dedicated to its execution. This process is suggested for use when there are many competing projects vying for limited resources in a constrained time period. Sounds like a familiar situation, doesn’t it? This framework has been validated in the research and development (R&D) field to show, while more projects were never started, the ones that were started saw greater success (8).
The initial reaction to such a process may be that the trial activation process does not need yet another review; however, this administrative review is not intended to duplicate other reviews, such as the scientific review performed by a protocol review and monitoring committee (PRMC) or the ethical review of an IRB. Instead, this review should take place before the PRMC or IRB reviews and should review logistical feasibility, financial feasibility and accrual feasibility to determine if the study will meet requirements in the timeframe requested.
While you can learn a lot on-the-job, you shouldn’t “fake it ‘til you make it” when it comes to clinical research. A thorough evaluation of the protocol and associated documents should be done to determine if your organization has the ability to complete the procedures and data collection required from the protocol. Questions to ask during this review include:
- Do you have the staff resources to dedicate to the study?
- Do the staff have the proper training to complete the procedures required?
- Does your investigator have the knowledge to run the study properly?
- Do you have the staff bandwidth to take on the intensity of the study?
- Do you have access to the needed facilities to complete the study?
- Do you have the equipment (or will the equipment be provided)?
- Do you have access to staff who are properly trained/licensed/certified to use necessary equipment and/or perform specialized procedures?
- What additional departments and/or ancillary services are needed to complete the study requirements and is it feasible to utilize those resources?
- If you have to sub-contract, does the sub-contract guarantee to meet required timelines for services rendered?
Other factors, such as the number of participant enrollments requested, the timeframe for enrollment, and the frequency of procedures, need consideration. For example, having one research nurse may be fine for most studies that see participants for a blood draw and questionnaire on a weekly basis for eight weeks, but that one resource is likely not adequate for a PK study with eight blood draws and questionnaires over a 48-hour period, even though the same number and type of procedures are required.
You would never buy a house if you couldn’t make the monthly payments, so why should you open a trial if you do not have the means to cover the costs? Regardless of the sponsor type for the study (for-profit company, institutional study, federal grant, etc.), complete a financial analysis of the study to look at what the sponsor will reimburse and what the institution will need to commit for completion. Highlighting “big ticket” items helps with future negotiations, if it is decided to activate the study, as well as knowing whether to secure additional funding, ensuring study costs can be met. It is important to not only think about procedure costs, but also an approximation of staff cost and other study maintenance costs (such as committee approvals). Not meant to be a thorough Medicare coverage analysis or budget draft, a financial feasibility should look at the draft budget and ask the following questions:
- Who is paying for what?
- What procedures/items are “big ticket” costs?
- If there is a negotiation and it falls short, where will the necessary funds come from?
- Is the organization willing to activate this study if there are insufficient funds (i.e., cover the costs that aren’t made up externally)? If so, where do those funds come from?
If you can’t accrue the necessary number of participants to a study, then the scientific aims of the study are not met and you either exact more costs for the sponsor of the study, or fail to answer the scientific question and waste effort and time of your organization and participants with the project. Ethical implications aside, it is important to determine whether you can meet the necessary or requested accrual goal in the time allotted by looking at past performance data. When considering whether it is likely that the needed number of subjects can be accrued, consider:
- The principal investigator’s (PI’s) study completion record. If the PI hasn’t met the accrual goal on the last five studies, will they likely meet it on this study? Perhaps the accrual goal is too lofty for the site.
- Current competing studies. If multiple sites vie for the same participant population, it will be harder to accrue participants to another protocol. Perhaps this is not the time to activate a new study, but it could be revisited when another study wraps up.
- Similar, closed studies performed. Can your organization accrue to the disease type? How does your site perform on studies of a similar phase? What is your performance with studies with the sponsor?
Also look at the pool of participants to draw from. There is a lot of literature on factors affecting the ability to accrue participants to research. Ensuring you have the knowledge needed to maximize your ability to identify and reach out to potential participants, consider where your participants will come from and how many potential participants there are. Look at past screen fail rates; if only one in 10 people consent, you will need to reach out to 200 people in order to consent 20. If you do not have a large enough participant pool at your organization, is it possible to get referrals or advertise? And, importantly, make a realistic assessment of whether you can get the requested number of participants in the timeframe the sponsor is asking for. About 90% of late phase clinical trials have to extend their recruitment timelines (4). This delays the ability to continue the drug approval process and increasing drug development costs.
Putting It All Together
A protocol feasibility review takes these elements and puts them into a formalized process. It is important to define the mission and scope of the committee to keep the purpose clear of improving the activation process, and ultimately, the successful completion of clinical trials. Ensure that there is no duplication of review or effort by this process. Also, have an administrator present to keep the review on track. This will help the committee process items thoroughly during the meeting and allow for dissemination of committee decisions after the meeting.
As this committee reviews logistics, finances and performance data, make sure there is expertise in these areas. We recommend ensuring there is someone knowledgeable of the available staffing resources, someone knowledgeable of clinical trial finances, and someone who understands clinical trial recruitment. Some of these areas of expertise may be covered by the same person. At the same time, keep the committee efficient, considering how often the committee needs to meet and whether the committee needs to meet in person. Determine who needs to review in order to pass or deny a study and the committee’s decision power. If the committee determines a study is not feasible, what happens? Can the decision be appealed? To whom do you communicate the decision? These are all important factors to consider in order to have a successful process.
A protocol feasibility process can increase the probability of a successful clinical trial by ensuring the necessary infrastructure is present to complete the aims of the study in the required timeframe. While it is another step in an already lengthy activation process, it can help improve timelines by removing protocols from activation processes having little or no chance of succeeding.
- Dilts DM, Cheng SK, Crites JS, Sandler AB, Doroshow JH. Phase III Clinical Trial Development: A Process of Chutes and Ladders. Clin Cancer Res. 2010;16(22):5381-89.
- Durivage HJ, Bridges KD. Clinical trial metrics: Protocol performance and resource utilization from 14 cancer centers. J Clin Oncol. 2009;27(15s):S6557.
- Dilts DM, Sandler AB, Cheng S, Crites L, Ferranti A, Bookman MA, Thomas JP, Ostroff J. Accrual to clinical trials at selected comprehensive cancer centers. J Clin Oncol. 2008;26(suppl):abstract 6543.
- IOM (Institute of Medicine). 2010. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Washington, DC: The National Academies Press.
- Tate WR, Cranmer LD. Developing a predictive model for cancer clinical trial accrual. J Clin Oncol. 2014;32(15S):6557.
- Tate WR, Abraham I, Cranmer LD. Center-Specific Modeling Predicts Cancer Trial Accrual More Accurately Than Investigators and Random Effects Modeling at 16 Cancer Centers. JCO Clin Can Inform. 2019;3:1-12.
- Stage-Gate International. Overview of the Stage-Gate Innovation Performance Framework.
- Griffith TL, Sawyer JE. Research Team Design and Management for Centralized R&D. IEEE T Eng Manage. 2010;57(2):211-24.