Site Visits 101: Visits Before, Without, And After Trial Participants

By Susan Swonger, clinical research consultant and senior clinical research coordinator, and Daniel Fox, MPH, Ph.D., founder/CEO, Clinical Research Payment Network, Land of Lincoln Clinical Research, and DiversiTrials

SSV, SIV, IMV, COV… the acronyms encompassing the types of clinical trial site visits are both numerous and nebulous. From the initial communication and introductions to the final closeout, every trial comprises a series of fundamental visit types, targeted objectives, and anticipated outcomes that progress study milestones through the clinical trial life cycle.

Trial enrollment and data collection are primary objectives of clinical trial performance; however, sites must perform a methodical series of administrative, regulatory, and quality assurance visits before, without, and after trial participants are stakeholders in the process.

Here, discover the primary visit types that occur at a clinical research site before, without, and after the presence of clinical trial participants.

Site Selection Visit (SSV)

OBJECTIVE: Following a successful feasibility questionnaire, interested sponsors and/or CROs will contact a potential site to perform a pre-study site visit (PSSV), also known as a pre-study visit (PSV) or site selection visit (SSV).

Regardless of the acronym, the objective remains the same: Either in-person or virtually, it is to evaluate a site’s experience, expertise, interest, staff, facilities, and potential patient populations that are available for a specific clinical trial.

CRAs may also discuss additional topics with your site, such as the performance of competing trials, trial performance processes (informed consent, disaster recovery, decentralized elements, etc.), experiences with certain IRBs, and start-up timelines.

OUTCOME(s): Sites will either be considered or not considered for a clinical trial following an SSV. If selected, they may be notified about the next steps within weeks to months. Sites are often not notified of non-selection; however, many considerate CRAs take the time to let them know. In rare events, CRAs may inform sites why they were not selected for a trial.

BEST PRACTICES: Prepare for SSVs as you might for a job interview.

1. Have a strong “resume”: CRAs will ask sites about their past trial performance. They also will request copies of core SOPs, such as those dedicated to PI oversight, informed consent, disaster recovery, sample transport (as needed), or DCTs. This is like a resume, and it is not best practice to provide CRAs with your site’s entire SOP manual. However, you can offer the table of contents and select SOPs upon request.
2. Dress to impress: Staff will give the CRAs a tour of your site and its operational facilities. Make sure facilities are clean, organized, and likely to provide positive impressions.
3. Answer questions with confidence: CRAs will often ask site staff, including the PI, about their experience in research and how they would accomplish certain aspects of a trial. For example, a CRA may ask coordinators how they would process informed consent, answer data queries, or receive IP. They may also ask PIs about their clinical trial track records or how they managed trial challenges, such as serious adverse events (SAEs), sponsor audits, or IRB queries.
4. Ask questions: SSVs are not just interviews from a sponsor to a site. They are also the site’s opportunities to ask relevant questions about the trial to determine if it is a good fit. Read the protocol (if available) to an extent of understanding and ask the relative questions.
   
   ​The more in-depth and specific a site’s questions are, the more a CRA knows the site is not only prepared to host the SSV but also highly interested in being awarded the trial.

Site Initiation Visit (SIV)

Fast forward two to five months: The site is awarded the trial, it negotiates and executes a reasonable CTA and budget, the IRB approves the submission, supplies start to arrive, and it is time to schedule the site initiation visit (SIV).

OBJECTIVE: To assure sponsors that everything is in place to begin enrolling patients at a site.

CRAs will often present a slide deck and documents, such as the protocol, investigator brochure, and lab manuals, to relevant site staff, including the PI. The combined study team (CRA and site staff) will confirm that all supplies are received, regulatory documentation is complete, and the site has the necessary access to and training on the clinical trial’s technology platforms.

OUTCOME(s): The primary outcome of an SIV is the “green light” — a sponsor authorizes a site to begin enrolling patients. Oftentimes, sites receive the green light while the CRA is still on-site. They may also be notified of the green light a few days later after the CRA has filed the necessary documentation. Rarely, but on occasion, sites may host an SIV and receive a delayed green light, such as during IP shortages when, even if a site had trial candidates ready for enrollment, they would have to wait for IP and supply replenishment to proceed.

BEST PRACTICES: Before an SIV, double and triple check the following for a seamless and successful experience:

1. One of the greatest challenges during SIVs is time and facility allocation. An average SIV may take from 2 to 6 hours, which can be costly to sites and their PIs. Communicate the availability of the site staff to the CRA. PIs are generally not available to carve hours from their clinical practice to attend an SIV. Therefore, plan investigator time efficiently with the CRA to optimize PI and sub-investigator time.
2. Make sure the meeting room space has the necessary accommodations (projector, computer, etc.) and adequate seating. The last thing anyone wants to do is to have 10 site professionals crowding around a CRA’s laptop in a broom closet for 3 hours.
3. By now, a CRA should have a clear understanding of site performance. The SIV is the last chance to ask final questions before a trial goes live. It is also the last chance for a site to change its targeted enrollment goal.
4. Depending on how the CTA was negotiated, SIVs may trigger site start-up costs. Be sure to contact the finance department or responsible administrator accordingly.

Routine Checks: Interim Monitoring Visit (IMV)

OBJECTIVE: A designated CRA will remotely review data or travel to the site to review source documents routinely throughout the trial to validate data capture, identify potential errors, which will eventually become queries for site staff to address, and review study records for variables such as adherence to GCP, ALCOA-C+, and PI oversight. The primary objective is to review and validate all study data sources for compliance, completeness, and verification according to current industry guidelines and regulations.

OUTCOME(s): After reviewing study records for compliance with the study protocol and regulations, CRAs will present queries and questions first in a discussion format and then as a formal monitoring report. The monitoring report will outline an IMV’s processes, highlight findings, and make requests of the site to resolve or address any findings that require attention to maintain compliant study performance. Monitoring findings may be addressed and fixed at the time of the monitoring visit. Others may require additional time and are established as requests with due dates, such as the time of the next monitoring visit. Although rare, monitoring visits have the potential to halt a trial at a site if findings are of critical concern to a trial’s integrity.

BEST PRACTICES: IMVs may be managed for success with the following best practices:

1. Be proactive: When in doubt, ask the CRA. A site has visibility into its own processes whereas a CRA has visibility into the processes of all sites in the study. If sites make errors from the beginning that are not addressed, they artificially generate more queries compared to discovering, identifying, and addressing a problem before future work is performed. Ask the CRA to review source documents before participant enrollment and contact them during challenging situations. The more a CRA knows about a site’s performance, the fewer surprises are likely to be identified during IMVs.
2. Establish internal QA processes: Many sites adopt an internal “pre-monitoring” protocol to ensure all source documentation is reviewed, re-reviewed, and ready for the CRA. Whether it’s a buddy system with fellow coordinators or an entire QA department, establishing internal quality systems often encourages routinely successful and efficient monitoring visits.
3. Prepare: IMVs are integral quality moments in a trial that demonstrate a site’s capacity to perform services and generate satisfactory results. Prepare for the visit, communicate with CRAs on expectations and agenda, and make sure that all staff, including the PI, are available to meet and discuss the trial’s performance.

Audits

OBJECTIVE: “Congratulations on being one of the study’s highest-enrolling sites!” or “We’ve identified some pretty concerning findings from reports and monitoring visits” can both lead to the same follow-up statement: “We need to schedule an audit of your site.” Whether it’s the sponsor or the FDA contacting the site or showing up without notice, audits host a myriad of purposes in the industry. Primarily, they are a formal assessment of local and federal compliance with safety and protocol processes of all study data at a site.

OUTCOME(s): Sponsors and regulatory authorities, such as the FDA, will audit the site and generate an audit report. Audit report outcomes may range from “no findings” to some findings with follow-up and further to 483 warning letters, study closure, or even site closure in severe cases. If the FDA issues a 483 to a site, it is officially a public record and is often reportable on future study feasibilities and questionnaires.

BEST PRACTICES: Some of the industry’s best practices to manage and address audits include:

1. Make it an SOP: Audit readiness and audit response SOPs are almost standard among sponsors; however, they are only now beginning to emerge among many small clinical research sites. How should staff react in the event of a surprise audit? What are the procedures for contacting sponsors? Where is the “war room”? What is the communication plan? The workflow? Each of these logistics must be planned, not reacted to, and many high-quality sites make these reactions a significant component of their SOP manuals and staff training matrices.
2. Be honest and concise: It's critical to answer the questions of an auditor with honesty and integrity. It is also critical, however, to answer the questions and only the questions from an auditor. Similar to any form of auditing experience in every industry, organizations will train staff to answer questions but at the same time not to volunteer unnecessary information. Some sites may require special training to manage and interact with auditors, whereas all other staff will be instructed to refer questions to appropriately trained and experienced individuals.
3. Stay prepared. “Quality is doing the right thing even when nobody is looking.”
   ​If a site has strong processes in place, routinely reviews with internal quality systems, and importantly stays persistent about constant data review and quality, it has pro-actively enhanced the results of an audit. Quality processes take time and energy; however, they are by far one of the most important systems that a site can invest in for compliant research performance and an exceptionally positive reputation in the industry.

Database Lock Visit

OBJECTIVE: The trial participants have completed their visits, data has been monitored, and the trial is ready to close. To complete the process and extract data for final formatting to the FDA, sponsors may perform a database lock. Once complete, the data can no longer be changed without extensive authorization. Thus, a database lock visit at a site performs one final quality check of all data and then organizes it for final data lock and query resolution.

OUTCOME(s): Upon completion, site data will be locked for editing, prepared for data transfer, and transferred to the sponsor for final analysis.

BEST PRACTICES: Similar to audits, a site that is prepared and persistent about actively monitoring the quality of its data will optimize the database lock experience.

Site Closeout Visit

OBJECTIVE: Database lock visits are not always equivalent to site closeout visits (COVs). Oftentimes, sponsors may host database locks as sites complete participant enrollment and then close out all study sites when every patient has completed. Thus, a COV is necessary to ensure the final reconciliation of data, resources, and study services.

OUTCOME(s): COVs are the complement of an SIV. They are the final planned and agreed-upon service interaction between the site and the sponsor/CRO. Trial obligations are wrapped up, bills are paid or in transit, and the majority of the study’s communication will cease. In essence, the COV is the last goodbye between sponsors/CROs and sites.

BEST PRACTICES: Consider the following best practices before and during a COV:

1. Get paid first: Although it is not ideal, sites often must resort to waiting to schedule a closeout visit until sponsors/CROs are financially compliant in payments. Trial CTAs often agree to pay withholding or holdback following a close-out visit, comprising 5%-15% of a study’s overall revenue. Many studies, however, are far beyond noncompliance in payments beyond withholding limits. Thus, as COVs are the last promise to keep as a site, many sites establish policies that require all payments to be made prior to scheduling closeout visits.
2. Debrief: Sites, sponsors, and CROs often conclude COVs without adequately discussing the benefits and challenges of the study performance. As a result, they will only make the same mistakes during the next trial because they did not take the time to communicate the pros and cons of the trial. To combat recurring inefficiencies, sites should schedule time during the COV to review trial performance and logistics for potential improvements.
3. Stay in touch: COVs may be the end of a study; however, they do not have to be the end of the relationship. Many sites use COVs as the next step of their business development pipeline by highlighting their accomplishments and expressing interest in future trials. At the very least, they establish protocols to collect and document contacts for long-term document storage and future trial opportunities.

Let’s Revisit

Site visits are challenging, customized to every protocol, and risk absolute chaos if they are not managed appropriately. There are, however, routine best practices that are adopted among some of the most successful sites. Stay prepared and organized throughout the clinical trial process. Accurately record data and observations and be sure to communicate with industry stakeholders, especially the trial participants. Finally, remember why we perform research, beginning with protecting the safety and well-being of our trial participants with confidential trial performance, secure data, and successfully reported results that will advance future medicines from the clinical trials we perform to generations of healthier communities.

In part two of this 101 series on site visits, learn about the visits that include clinical trial participants.

About the Authors:

Susan Swonger is a clinical research consultant with over 20 years of experience as a clinical research coordinator, rater, and e-TMF specialist. She started her research career as a psychometrician doing Alzheimer’s trials. She is a member of ACRP and supports Save Our Sites as well as diversity in clinical trials.

 

 

Daniel Fox, Ph.D., is the founder and executive of the Clinical Research Payment Network, Land of Lincoln Clinical Research, Save Our Sites Conference and Alliance, and DiversiTrials. He has worked in the translational sciences, from bacteria and animals to pharmaceutical manufacturing, quality control, and clinical site administration, for over 15 years and strives to be a servant community leader to ensure open access to clinical trials for everyone regardless of where they live, what they look like, or how much money they have. Fox specializes in legal and financial translational sciences with a focus on ensuring clinical research stakeholders (sponsors, PIs, site staff, and, importantly, patients) have everything they need, from payments and SOPs to protocols, equipment, and networks, to perform successful quality research and advance healthcare technology as quickly, efficiently, and safely as possible.