Characterizing the Protocol-Guided Source Preparation Process at Investigative Sites

Optimizing the study start-up process (SSU) is an area of keen interest to clinical research stakeholders. More than a decade of qualitative and quantitative research has been conducted benchmarking site activation timelines.^1,2 Recent studies have also shown that start-up timelines are increasing despite the promise of new practices and technologies aimed at accelerating this instrumental activity. A 2025 white paper published by ICON suggested that the process is becoming more protracted due to operational advances that have not been able to completely reverse the effects of rising protocol execution demands and complexities.³ A 2023 study by Advarra reinforced a similar trend.⁴

Another recent study suggests that study start-up efficiency may be predictive of overall enrollment performance.⁵ The study reported that clinical trials achieving or surpassing the 70 % accrual threshold typically exhibited a median activation time of 140.5 days compared to a median activation time of 187 days for studies that failed to achieve this accrual threshold.

Challenges and bottlenecks in the study startup process have been well characterized, including protracted contracting and budget negotiations, a lengthy and inefficient site qualification process, the growing complexity of protocols and executional models supporting them, and the difficulty of finding patients under ever-stricter eligibility criteria. Sites face growing technology and training burdens, along with resource and capacity issues which are compounded by a lack of standardization in the activation steps and documentation requirements across various sponsors and CROs. Sponsors and CROs have attempted to tackle these barriers with a variety of initiatives from use of central IRBs, implementing unified study start-up platforms, adopting standardized contracting language, and fostering stronger site relationships all in an effort to find a more efficient process.⁶ Sites are also evaluating ways to streamline their internal processes and eliminate the “white space” by systematically mapping out their process and establishing parallel vs. sequential site activation practices.^3,7

One area that could greatly reduce study start-up cycle times, but that until now, has never been explored, is the process and associated inefficiencies that sites face when interpreting protocols and translating source document templates into their own data collection tools and systems. Successfully navigating the protocol-guided source preparation process may hold the key to unlocking even more efficiency in the study start-up process. Because these activities are not well understood, the Tufts Center for the Study of Drug Development (CSDD) collaborated with CRIO—a clinical trial technology company providing a variety of software solutions to support site operations—to conduct a study to characterize this process.

Study background

Tufts CSDD launched the global, on-line survey among investigative sites between September and December 2025. The survey was developed following a series of six in-depth interviews that the Tufts CSDD team conducted with site representatives across various site types in the US, Europe, and Latin America.

The interviews were first used to gain consensus on the overall workflow of the protocol-guided source preparation process. Figure 1 provides a high-level overview of a typical protocol-guided source preparation process and when and how it factors into the overall site activation timeline. Items in orange represent the sponsor’s process while items in blue reflect the site’s process. While the workflow varies by the type of investigative site, the illustration is representative of the overall steps and associated inputs that sites require in order to prepare their source documents.

The interviews uncovered key processes and pain points associated with this operational data collection workflow and systems used to capture source data. The findings from the interviews helped to shape the content and focus of the survey which covered a variety of topics including:

• Documents and inputs required to create source documents
• Roles and work effort involved in the process of creating source documents
• Utilization and impact of sponsor/CRO-provided source document templates
• Systems used for data capture
• Evaluation of source preparation process sophistication

To better understand overall site operations, the survey also explored the various systems that sites use to manage their clinical trials such as regulatory start-up systems, CTMS, IRB/ethics, financial systems, and others but this report focuses exclusively on the findings related to the source preparation process.

Invitations were emailed to approximately 60,000 site representatives from various lists including clinical trials.gov, Tufts CSDD site lists and contacts provided by CRIO. Data cleaning and analysis were performed in RStudio. Tufts CSDD conducted descriptive statistics and subgroup analyses. Responses from a total of 209 investigative site professionals were analyzed.

Responses were obtained from a broad mix of site types and roles across different geographic regions although the majority of responses were from site representatives in the US and Canada (Table 1).

On average, respondents conducted 10 industry-sponsored Phase II and III clinical trials in 2025 although a wide range was reported (minimum of 1 up to 1138 trials).The sites conducting the most trials (1138 with the next highest reported volume of 400) were at academic medical centers based in North America. Respondents conducted studies across all therapeutic areas with no therapeutic area dominating the mix.

The protocol-guided source preparation process—inputs, timelines and process sophistication

Final versions of five documents were identified by sites as the topmost critical documents needed in order to create their source documents (Table 2).

For the majority of sites, the timely receipt of these documents is essential for an efficient study activation process. In other words, lack of receipt of these documents is a rate limiter to their internal activation process. On average sites reported that it takes approximately 6 weeks (5.84 weeks) to receive all the required information needed to support the protocol-guided source preparation process but that it can take up to 20 weeks to obtain this information. Most of the sites receive the final protocol and ICF template in a relatively timely manner which is not surprising given that these must be submitted to the IRB/Ethics Committee as part of the study approval process. However, more than half the sites reported that the final CRF template, pharmacy, and lab manuals are received in a timely manner less than 60% of the time, thus contributing to delays in the activation process. It should be noted that the survey did not define a specific timeline of document receipt relative to the overall study start-up process, so timeliness was left to respondents to interpret based on when they start their protocol-guided source preparation process.

Many sponsors and CROs provide source document templates to facilitate the source preparation process; either full/comprehensive templates or partial templates. In terms of comprehensive templates, one-third (33%) of the sites reported these are essential to their process with nearly half the sites (46%) reporting these templates are helpful but not essential to their process. 6% of the respondents indicated they rely entirely on these templates while 15% indicated they have no bearing on the creation of the source documents. No significant differences were noted between full/comprehensive and partial source document templates in terms of their contribution to the creation of the site’s own source documents. Similar to the top five most critical documents noted above, sites report that they don’t always receive these in a timely manner. In particular, 26% of the sites who indicate these templates are essential to their process receive these in a timely manner less than 60% of the time.

Respondents were asked to characterize their source preparation process overall. The majority of sites (80%) reported that their process is highly or somewhat structured and uniform with 20% indicating the source preparation process is somewhat or very informal and ad hoc. Research-only sites report that their process is the most highly structured and uniform compared to other site types. Higher volume sites report somewhat more structured process compared to lower volume sites, but the difference is not statistically significant.

The protocol-guided source preparation process—roles and workload considerations

Lead CRCs/Study Coordinators are the top drivers (57%) and significant contributors (31%) to the process. CRCs with experience in the indication are also major drivers (32%) or top contributors to the process (43%), with PIs playing an important role (27-30%). Support departments are minimally involved. Nursing (55%), laboratory (49%), and pharmacy (43%) representatives are most often reported as not involved in the process.

The majority of respondents (77%) indicated that the skills and training needed to interpret the protocol (and associated documents) and translate these into the data collection requirements are a significant or somewhat constraining factor for their organization. No significant differences were noted across different site types or by region although a somewhat higher proportion of research-only sites (85%) noted these were constraining factors compared to community-based sites (80%) and academic/healthcare system/federally funded sites (68%). More sites in North America (79%) indicated these were a significant or somewhat constraining factor relative to sites in the rest of the world where only 60% noted these as substantial limitations.

From a workload perspective, the results revealed a strong relationship between trial complexity and the work effort required to complete the process. Sites were asked to estimate the work effort required to prepare the source documents across these four options:

• 1-10 hours
• 11-20 hours
• 21-40 hours
• >40 hours

Across all trial types, work effort increases as protocol complexity rises with high-complexity studies frequently requiring more than 21 hours to complete the process (Table 3).

High complexity trials across all trial types were reported by 80% or more of the sites as requiring >21 hours to complete the process. More sites indicated that oncology trials require >40 hours relative to the other trial types.

There were some differences noted across different site types (although these were not statistically significant):

• A higher proportion of academic/health system/federally funded sites reported greater work effort was required for oncology studies compared to the other site types.
• A higher proportion of Community-based sites reported that rare disease and pediatric trials require the greatest amount of time relative to other site segments.

The protocol-guided source preparation process—source document locations

Paper-based systems are still the predominant place where sites capture study information (Table 4). Within electronic systems, the location varies based on the type of information used with some information being captured in the EMR/EHR vs. research-specific eSource systems.

While all sites reported using both paper and electronic systems to differing degrees, some differences were noted by site segments.Relative to their counterparts:

• Academic/health system/federally funded sites capture more information in the EMR/EHR
• Community-based sites capture more information in paper-based systems
• Research-only sites capture more information in research-specific eSource systems

Again, these differences were not statistically significant.

Opportunities for improvement

Sites identified several key opportunities to enhance the protocol-guided source preparation process and accelerate study activation times. For sponsors, sites recommended the following:

• Ensure consistency across all relevant documents.
• Ensure footnotes/notes section of schedule of assessments is detailed with operational expectations.
• Provide final documents in a timely manner.
• Provide red-line version of amended documents.

Multiple verbatim comments reinforced the importance of the cross-document inconsistency issue noting that protocol complexity is a less significant risk to study conduct than the lack of clarity. As one respondent noted:

“We often are receiving protocols, lab manuals, IB, pharmacy manuals, ICF—that are not in agreement with each other or have glaring mistakes that are not corrected. Study procedure timelines don't match the lab processing for those study procedures, or data collection guides don't match the visit schedule. We often see inclusion and exclusion criteria that contradict each other. All of this adds confusion, unavoidable PDs (protocol deviations), missing data, out of window study visits, but most importantly it can impact patient safety and data quality.”

Sites recommend the following for technology service providers:

• Allow sites to perform EDC entry for a "dummy patient" early on in the process to verify comprehensive data collection.
• Explore opportunities to further integrate systems into the site'sworkflow (CTMS, financials, lab).

Finally, sites had the following recommendation for their peers:

• Involve someone with clinical background as part of the protocol-guided source preparation process.
• Conduct cross-checks between source, EDC, and labs/imaging reports to ensure alignment.
• When evaluating eSource systems, consider how well they integrate into your workflow to support a more structured and uniform protocol-guided source preparation process.

Closing thoughts

This study aimed to characterize a critical aspect of site operations that has received little attention and may not be well understood by many sponsors and CROs.Sponsors/CROs may not fully appreciate the extent to which this process influences the site activation timelines or the role they play in accelerating study start-up. While most sites appreciate having sponsor/CRO-provided source document templates, respondents strongly advocate for greater time and effort spent on the part of sponsors to ensure cross-document consistency and document clarity. Moreover, there is a need for sponsors to recognize that final versions of key documents are required as necessary inputs to source preparation, and that timely receipt of these documents is critical to an efficient start-up process. Additionally, sites emphasized that amendments to any of these critical documents triggers a re-work of the entire source preparation process. Having red-lined versions of the document changes, however, greatly facilitates the review and revision of the source documents.

From a site perspective, the results of this survey confirmed that the protocol-guided source preparation process is:

• Generally structured and systematic across most sites.
• Often driven by lead CRCs/CRCs with experience in the indication and PIs.
• Dependent on specific skill sets which most sites note are a constraining factor.
• Time-consuming; requiring upwards of 20-40 hours for complex protocols.

The results also highlight the fact that while electronic systems are being used across all site types, most sites still rely on paper-based source documents as a key place to capture source information. With approximately half the sites reporting they still capture much of their source data in paper systems, the industry can anticipate that full scale EHR-to-EDC integration will continue to progress slowly. Further, these results suggest there is continued room to explore how to leverage eSource and fully integrate this into site operations. At a minimum, this study provides a solid benchmark for evaluating adoption rates of electronic systems in the future.

In the site interviews and free-text comments in the survey, respondents also emphasized that while the redundancy of transcribing data from source into EDC is a pain point, the bigger barriers come from:

• Capturing source data outside of the health system (i.e., tracking down information if a patient has an AE and sees a provider who is not within the health system).
• Capturing all of the detailsrequired for SAE reports.
• Chasing down clinicians to clarify missing or unclear information.
• Extensive lab data entry particularly for oncology and inpatient trials.

Some of these challenges may not be easily overcome, but sites appreciate a recognition of the burdens these activities place on site staff above and beyond inefficiencies associated with data transcription.

As with all site-related activities in clinical research, one-size does not fit all.The protocol-guided source preparation process, workflow, resources, and systems vary by different site segments. What is universal however, is how serious sites take their obligation to ensure accurate and high-quality data generation by employing a systematic and robust approach to source preparation.

Authors

Beth Harper, MBA*

Ruby Madison Ford, MPH

Roula Krayem, MS

Raymond Nomizu, JD

Jonathan Andrus, MS

Kenneth Getz, MBA

*Corresponding Author ([email protected])

Tufts Center for the Study of Development, Tufts University School of Medicine

CRIO, Inc.

Acknowledgments

The authors would like to acknowledge the site representatives who participated in the in-depth interviews and who completed the survey.

References

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