Clinical Researcher—April 2018 (Volume 32, Issue 4)
Julie Agriesti, CCRC; Paula Smailes, RN, MSN, CCRC, CCRP
Few clinical trials are lucky enough to experience no start-up obstacles at an academic medical center (AMC). More often than not, these sites have a multitude of issues to overcome getting a study off the ground; however, sponsors are paying more attention to how long it takes sites to navigate the process from site feasibility and qualification to budget/contract execution and first patient enrolled.
Site staff must take note of what kinds of obstacles they face. Knowing how these obstacles can be addressed and their associated processes improved will put sites in a position of being more appealing to sponsors when they are recruiting potential sites for new studies. For this reason, it is advantageous for site leaders to be proactive on what may be an issue at start-up, in an effort to streamline the process for future studies.
It is common for sponsors to send out feasibility questionnaires to determine if various sites might be qualified to conduct one of their studies. These assessments may elicit data from a site, such as metrics of their patient population or whether or not sites have the designated staffing or equipment.
When it comes to site data, it may be challenging to get patient metrics in the time allotted to return the feasibility form. In an effort to be proactive, site staff should get updates on patient population metrics on a quarterly basis, so that the information is easily accessible when feasibility questionnaires arrive. Sites may also develop a website or brochure with this information to be easily accessible to sponsors.
The bottom line is to make your site look ready and marketable for the next study.
Checklists for Quality
Once a feasibility questionnaire has been received, a study start-up checklist may be created in the eventuality the site is accepted for the study (see Table 1); this can help to keep the start-up process on track. A checklist would need to be adapted to the events in site start-up and serve as a guide to ensure all documents have been appropriately processed, equipment and supplies received, contract negotiated, and training completed.
Checklists may also need some adaptation based on site workflows, and can be used as a quality instrument in clinical research. In fact, healthcare safety activists have looked to checklists to solve a plethora of problems with their well-known utilization in the aviation industry.1 Checklist compliance is increasingly utilized in healthcare organizations to improve quality, which can be translated to clinical research study start-up.
Site staff can construct their checklist to decide which start-up activities may be done in sequence and which items can be done simultaneously. Utilizing checklists at the beginning of the study is a means to keep staff on target with what remains outstanding and delaying study start.
A common problem in clinical research trials is difficulty enrolling patients. In fact, in an average clinical trial, 20% percent of principal investigators (PIs) fail to enroll any patients and 30% enroll more slowly than expected.2 This is a very real obstacle that needs to be considered when starting a new trial.
A careful review of the eligibility criteria is necessary to determine if the site has access to the size and/or kind of patient population necessary to support the study. Eligibility criteria should be realistic for the disease under study, and broad enough to allow enrollment of a sufficient number of subjects.3 If the criteria are stringent, site staff may be challenged to recruit and retain the contracted number of subjects.
As the old saying goes, “Those who fail to plan, plan to fail.” The recruitment plan should be finalized prior to the initial institutional review board (IRB) submission. This is why it is essential to have a well thought-out recruitment plan at study start-up, because implementation of any outreach method added after approval will be delayed until IRB review.
If achieving success cannot be accomplished from recruitment exclusively through the site’s existing patient population, community outreach may be a necessary form of recruitment. This is especially true if the intervention is a novel therapy. For sites that are parts of large organizations or research networks, utilizing electronic medical records and data mining may be useful in finding the select population.
If there are concerns with study eligibility and recruitment prior to study start, be sure to engage the monitor or study sponsor. Concerns and foreseen issues may not be unique to your site, but the reality across many sites.
If enough sites bring up potential difficulties, the sponsor may consider amending the criteria to make it easier for recruitment goals. For this reason, it is not just beneficial to your site to raise concerns, it may also be advantageous for the overall success of the study. The recruitment plan will need to be completed before IRB submission, so attention to this step should begin when considering feasibility and completed as soon as the site has been notified of acceptance.
Regulatory affairs is another area that can be fraught with long wait times. Once the site has the IRB submission ready, it may sit in a long queue of studies waiting to be reviewed.
In the earliest stages of site feasibility, sponsors want to know how long it will take for IRB approval, and benchmarking may be used to compare the time frame to other sites. IRB approval times may vary based on whether the site uses a local or central IRB, or a combination of both.
Unpredictable timelines for institutional IRB and ethics committee deliberations may create significant delays for study start-up, and some organizations reported more efficiency and speed with the use of central IRBs.4 This reality becomes clear when the time frames of local IRBs and the size of the institution are factored into the equation. For example, the large number of clinical trials being reviewed at AMCs may delay timely protocol review and explain why approval takes longer at these institutions.
Overcoming the long wait times from submission to approval can be difficult goal to achieve. The solutions for site staff include ensuring documents are complete in the initial IRB application and proactively address any key issues the IRB may identify. Having a contact at the IRB may help speed along the submission and provide updates on its progress, which can be relayed to the sponsor. For more active sites, it may be cost effective to have a full- or part-time regulatory specialist to handle this aspect of study management.
Budgets and Contracts
The budget and contract are usually the first must-handle start-up items the site will encounter after being chosen, but the amount of time it takes for them to be fully executed can be onerous. Many reasons account for this, but one of the biggest comes from complex budget negotiation strategies and practices that are understood by few—and mastered by even fewer—research professionals.5
Before a site can begin to negotiate, an internal cost calculation needs to be completed. Depending on the complexity of the study, requesting rates for different services may be a time-consuming venture. Add to it, the back-and-forth nature of the process, and several weeks can go by.
Further, in some instances, the financial staff may have limited experience with budgets and negotiation. To overcome this obstacle, it is crucial to be prepared; study success or failure can rest on this.5 Preparing means knowing the protocol and required procedures, understanding the cost of running the study, and identifying problem areas. This can help make sure the process runs in a smooth and timely manner.
Data Management—What’s the Plan?
Out of the many obstacles that can delay study start-up, data management can often be overlooked since the IRB, budget, and contract usually take precedence. That could be a mistake, because the site could end up having multiple issues in relation to the electronic data capture (EDC) system that could prolong study initiation.
Site staff should check the sponsor’s EDC system requirements against capabilities at the site as soon as the information is available. Potential problems can include not having the right system requirements for the EDC system, not being able to submit data through tight firewalls, and not having fast enough Internet speed. Resolution of these issues may require support from the information technology department to upgrade web browsers or operating systems.
In addition, using EDC requires study personnel to have access to the system. Before that access can be granted, the study staff need to undergo training. Sites can inquire about training and access requirements for the EDC system, in order to alert personnel to the amount of time it will take to complete training; this may take several hours per individual, and any delays in having all of the necessary staff trained may impact access for everyone. Weekly reminders may be helpful to keep staff on task and avoid training procrastination.
It is important to consider billable items for research and establishing the appropriate research billing accounts before the study begins. The logistics will take time to establish; first up, a coverage analysis should be done to identify charges that may be covered by third-party payors, including Medicare. This may help to inform the study budget and may be considered with that process, too, in order to ensure compliant processing.
The goal is to correctly bill study items to the study and items covered by insurance to the patient. The necessity of this lies in the avoidance of fraud. Timeliness in the reconciliation of study and patient accounts when the study is ongoing will further support billing compliance.
Unfortunately, there are documented cases of sites that have not been successful at this process. Emory University agreed to a $1.5 million settlement for falsely billing Medicare and Medicaid for clinical trial services that were not permitted by the Medicare and Medicaid rules in a whistleblower case, while what is now known as USC Norris Comprehensive Cancer Center settled for $1.9 million after admitting to overbilling with oncology trials.6
Knowing your contract well at the start of the study can be a proactive measure that avoids downstream effects of study billing errors. It is typical for billing accounts to be established once the study is IRB approved, making this one of the final steps in the study start-up process.
Conducting clinical trials is a test of one’s skills in project management and the associated logistics that come with it. To get a study off the ground, many tasks need to be performed in order to maintain regulatory compliance and contractual obligations.
Knowing what the obstacles may be is the first step to devising a plan to overcome them. The second step is organization through the creation of a checklist to improve site quality by tracking completion of start-up tasks. Furthermore, centralized versus decentralized organizations may have additional variables that may further impact the flow of study start-up.
The ultimate goal is to eliminate the tendency to be reactive when things go wrong, and instead capitalize on proactive measures that lead to beautiful beginnings.
- Clay-Williams R, Colligan L. 2015. Back to basics: checklists in aviation and healthcare. BMJ Quality Safety 24(7). http://qualitysafety.bmj.com/content/24/7/428
- Youngquist L. 2012. Site driven metrics. Appl Clin Trials 21(3). appliedclinicaltrialsonline.com/site-driven-metrics?pageID=2
- Liu MB, Davis K. 2010. A Clinical Trials Manual from the Duke Clinical Research Institute: Lessons from a Horse Named Jim (2nd ed.). West Sussex, UK: Wiley-Blackwell.
- Lamberti MJ, Chakravarthy R, Getz KA. 2016. New benchmarks for trial initiation activities. Appl Clin Trials 25(12). appliedclinicaltrialsonline.com/new-benchmarks-trial-initiation-activities
- Parke J. 2013. Negotiating effective clinical trial agreements and study budgets with research sites. Appl Clin Trials 22(4). appliedclinicaltrialsonline.com/negotiating-effective-clinical-trial-agreements-and-study-budgets-research-sites?id=&sk=&date=&pageID=2
- Association of Clinical Research Professionals. 2016. Clinical trial billing errors generate multi-million dollar fines. ACRP Blog. https://acrpnet.org/2016/03/04/clinical-trial-billing-errors-generate-multi-million-dollar-fines/
|Julie Agriesti, CCRC, (firstname.lastname@example.org) is a research site manager at The Ohio State University Wexner Medical Center.|
|Paula Smailes, RN, MSN, CCRC, CCRP, (email@example.com) is a member of the ACRP Editorial Advisory Board, a senior training and optimization analyst for clinical research at The Ohio State University Wexner Medical Center, and a visiting professor with Chamberlain College of Nursing.|
Table 1: Study Start-Up Checklist
|Confidential Disclosure Agreement signed by PI and submitted|
|Feasibility confirmed by team and submitted|
|Notice of sponsor selection received|
|Notify organization of new study, if applicable: Request contract and budget|
|Receipt of regulatory packet or access to investigator portal online|
|Recruitment plan developed|
|Informed consent form versions approved by sponsor|
|Prepare IRB submission packet:
|Protocol submitted to IRB|
|Regulatory packet to sponsor:
|Establish accounts with Research Billing Office|
|Internal budget finalized for sponsor|
|IRB approval received and sent to sponsor|
|Sponsor site initiation visit set up|
|Medicare analysis form submitted and lab accounts established|
|Sponsor’s training completed|
|Regulatory binders received|
|Study drug received|
|Study supplies received|
|If laptops, ECG machines, or other pieces of equipment are provided by the sponsor, these need to be checked by clinical engineering|
|Dry ice agreements|
|Site initiation complete|
|Recruitment plan enacted|