The clinical trial start up phase is a vital yet time-consuming stage of any clinical research study. With multiple stakeholders and many contracts and formalities involved, the start up phase is particularly prone to delays. While delays are often inevitable in clinical trials, in this article we present 5 tips for optimizing the study start up phase and minimizing setbacks and their associated costs.

The clinical trial startup phase: What is study start-up?

Study start up (SSU) is the initial phase of a clinical trial which includes all the administrative, design, and preparatory tasks that must be completed before the trial begins. Study start up involves significant documentation, negotiation and formalization of agreements, planning and organization, budgeting, and communication between numerous parties – the sponsor, a CRO (if applicable), sites, legal and financial teams, vendors, and IRB(s).

Clinical trial start up activities

Study start up covers a wide range of operations, and is considered to be finished when the research team starts screening and enrolling participants. However, certain activities involved in start up may also continue during the study.

Broadly speaking, study startup activities include the following:

• Discussions between key stakeholders (sponsor, CROs, sites, ancillary departments, etc.)
• Developing comprehensive protocols for all clinical trial processes
• Developing informed consent forms (ICF) and other study forms
• Submitting requests for information
• Developing plans for services such as laboratory analyses, diagnostic imaging, and telemedicine
• Budgeting and creating feasibility reports
• Compiling and submitting IRB application and documentation for approval
• Identifying and contacting potential trial sites
• Executing Confidentiality Disclosure Agreements (CDAs) with trial sites
• Pre-visiting potential trial sites
• Executing and negotiating Clinical Trial Agreements (CTAs) with sites
• Visiting sites for trial initiation
• Planning, allocating, and hiring staff
• Training clinical trial staff

Clinical trial start up timelines and delays

While there is no prescriptive template for study start up timelines as each study is unique, the main activities do tend to follow a similar general timeline. There may be overlap between the various start up, although there are certain steps such as submitting regulatory applications which must occur before or after other specific tasks are initiated or completed.

Surveys have suggested that start up cycle times have increased and that the majority of sponsors and CROs are somewhat or completely unsatisfied with their study start up processes.[²] There are numerous potential sources of delay in the clinical trial start up phase, particularly in negotiating CTAs with sites and submitting various documents for regulatory approval (with the FDA and IRBs). Errors or missing information in regulatory submissions are common reasons for setbacks which can be avoided through proper review of documentation. Negotiations with sites can be streamlined by focusing on clarity and transparency in communications.

The timeframe for site initiation visits (SIVs) can vary widely as it depends on the completion of prior tasks and involves monitors/other actors visiting sites to train staff on the trial protocol and ensuring that various actors have a complete understanding of the protocol and their responsibilities. Clinical trial design plays a significant role here, with more complex trials generally involving more time-consuming SIVs.

Finally, the time necessary to wrap up SSU is also difficult to gauge because it depends on the eventual enrollment; if insufficient participants are recruited, startup activities continue. Unfortunately, recruitment setbacks are a common problem faced by nearly 80% of clinical trials.[³],[⁴]

Being aware of potential setbacks and understanding why they occur puts sponsors and researchers in a better position to plan their clinical trials effectively and mitigate the risk of SSU delays and/or their resultant consequences. Let’s take a look at some specific methods for optimizing SSU processes and streamlining clinical trial start up.

Accelerate the clinical trial start up timeline with these 5 study start up tips

1. Design the study and protocol with the startup timeline in mind

Conventional clinical trial design often focuses on operations from recruitment onward. Specific guidelines for study start up activities are generally left out because these tasks are deemed to be dependent on the study protocol. However, it is for this very reason that SSU considerations should be included in study design, as overly complex study designs and protocols can be the cause of delays in the start up phase. Being mindful of the significant time and costs involved in the start up phase and assessing how each aspect of study design will affect start up activities can result in streamlined start up.

This may require reevaluating certain aspects of the study such as eligibility criteria, recruitment targets, informed consent forms, and reporting procedures, to name just a few examples. By aiming to minimize unnecessary complexities in the protocol, the study startup can be optimized before the activities even start.

Moreover, by reusing or building upon previously successful trial designs and past agreements (i.e., past contracts with high-performing sites), less time will be required for negotiating with entirely new players and creating documentation from scratch.

2. Establish a clear study budget and select vendors accordingly

Establishing a comprehensive study budget is the basis for selecting and negotiating contracts with sites and vendors. A clear budget can help in determining the cost-benefit ratio of potential outsourcing agreements or the adoption of software-based solutions for specific tasks, guiding vendor selection.

For example, for a sponsor conducting a decentralized trial who has never worked with wearable monitoring devices for remote health endpoint data collection, it may be ideal to partner with a device manufacturer who also manages data servers and can provide technical troubleshooting and maintenance, rather than purchasing the wearable devices and assuming those functions internally. Such an arrangement would avoid the need for training internal staff on the devices; budget and resource availability will be major guiding factors in such decisions.

A well-designed budget will help sponsors and researchers allocate resources wisely, outsourcing those tasks that would be more costly to assume internally. Not only does this strategy accelerate the startup timeline by minimizing internal training and integration of new systems, but it will also keep costs down if managed effectively.

3. Screen sites thoroughly and efficiently with site feasibility questionnaires and reuse high-performing sites

Working with high-performing sites is key to ensuring enrollment is completed within the expected timeline. Establishing a standardized workflow will help in managing ongoing communications with various sites and clarifying which metrics are to be used to determine site capacity to execute the trial.

First, clear and coherent trial documentation that clearly lays out trial requirements should be distributed to potential sites, which will reduce the need for redundant discussions to clarify details. This enables the trial site to accurately assess their capability to conduct the trial. Depending on the contents of these documents, CDAs may be required.

Establish an internal standard, such as comprehensive site feasibility questionnaires (SFQs), which will be used to quantitatively assess potential sites. Ideally, these would be scalable to allow for equivalent assessment of sites with different capacities (of internal staff or patient access, or both). Define a workflow to assist with tracking documentation and assessment progress across multiple sites. Allocate a dedicated staff member to oversee this process and be available to quickly respond to sites, minimizing delays in clarifications and negotiations.

Furthermore, building an internal database of high-performing sites used in prior trials can reduce site identification activities significantly. Include as much detail as possible in this database to enable rapid assessment of a site’s fit for each new trial with its unique requirements.

When new sites or an increased number of sites are needed, sponsors can also consider contracting CROs to leverage their site networks and familiarity with the sites to decrease activation timelines. However, when working with new sites, conducting pre-study site screening visits is essential to validate the site’s claims and responses to the SFQ to ensure firsthand that they have the capabilities, patient population, and resources required to undertake the study.

4. Prepare thoroughly for IRB submissions

IRB submissions can be stressful, but sponsors and investigators are more likely to miss critical pieces if the process is rushed. Adopt a systematic approach, predict potential setbacks, and prepare thoroughly for all IRB submissions. Create multiple variations of promotional material to have different versions on hand to update outreach campaigns without having to re-submit for IRB approval. Thoroughly revise all communications, protocols, and drug and participant information contained in the documentation for errors before submitting. Modern solutions such as CTMS, CDMS, or eTMF systems can help with the organization, tracking, and data validation of such documentation.

Furthermore, give consideration to the selection of an IRB as they may have different approval turnaround timelines. For multi-center studies, it has been suggested that central IRBs could be faster than local IRBs.[⁵]

5. Optimize management of essential regulatory documentation

The “essential documents” in clinical trials refer to the regulatory documents needed for a research study to be approved to move forward. It is grouped into three categories:

• Federal Regulatory documentation (i.e., the FDA in the US)
• Institutional Review Board (IRB) or Independent Ethics Committee (IEC) submissions
• Standard Operating Procedure (SOP) requirements

It can be challenging to manage these documents because of the sheer amount of forms and copies generated throughout the study startup phase. Poor project management here is likely to lead to delays further down the line as it will be harder to track down documents and provide a clear audit trail.

These essential documents deserve dedicated attention for their collection, organization, management, and tracking. Focus on the completeness and accuracy of information, because even simple typos or mismatched addresses between source documents can lead to regulatory rejections or setbacks due to finding and correcting errors. Then, develop a method to ensure consistency between entries of the same information across different documents or submission packages. Consider investing in digital solutions such as eTMF or CTMS/CDMS, or partnering with a clinical documentation specialist to track these documents and ensure consistency, with modifications updated across various documents, and everything neatly organized and easy to access.

Beyond the benefits of streamlined document processing and faster study start up, proper document management, especially in the context of increasingly complex and decentralized trials, is also vital for ensuring patient safety and being able to provide an audit trail to demonstrate compliance with protocol, regulations, and ethics standards.

Conclusions

Amidst the increased complexity of regulatory landscapes and clinical trial protocols/designs, bottlenecks and delays have become commonplace in clinical trials. That’s why it’s also increasingly important for sponsors to think and plan strategically, proactively, and early to minimize these setbacks and the resultant consequences of wasted time and money. Optimizing trial design to streamline study start up activities sets the clinical trial off on the right foot and can reduce headaches while also eventually bringing the new treatment faster to the patients who need it.