Study start-up encompasses a series of activities aimed at preparing a clinical trial for execution. These activities include but are not limited to protocol development, regulatory submissions, site selection, and contracting. Each step is crucial in laying the groundwork for a successful trial, as delays or errors during start-up can cascade into significant setbacks later in the trial timeline.
Every country approaches clinical trials and study start-up a little differently. The European Union (EU), in a bid to harmonize clinical trial regulations across member states, implemented the European Clinical Trials Regulation (commonly referred to as CTR or EU CTR). This change to the regulatory framework for the conduct of clinical trials in Europe presents new challenges for sponsors and CROs in terms of study start-up and site activation, as it forces clients and CROs to strategize more than ever.
To successfully navigate this new landscape, strategic decision-making and expertise in complex start-up processes are more crucial than ever. Precision For Medicine, with its extensive experience and holistic approach, is well-equipped to guide sponsors through the intricacies of site activation under EU CTR.
The EU CTR submission process
One of the most significant changes introduced by EU CTR is that a submission for one study can be done for multiple countries simultaneously. Each submission is divided into two parts.
- Part I is like the previous Competent Authority submission and is focused on assessment of the scientific and medicinal product documentation, namely the trial protocol, Investigators Brochure (IB), Investigational Medicinal Product Dossier (IMPD), Good Manufacturing Practice (GMP) evidence and investigational product labelling. In case of a submission to multiple EU countries, one country must be selected as the Reporting Member State (RMS) and will coordinate with other concerned member states to gather feedback and reach a consensus decision.
- Part II, on the other hand, is similar to the previous Ethics Committee (EC) submission and deals with the ethical aspects of the trial, such as site and investigator suitability, trial compensation and patient-facing materials, and is assessed on a national level by each participating country.
Mapping the submission process
Under the EU CTR, all EU member states involved in a clinical trial must come to a unanimous agreement on the scientific and medicinal product documentation. This requirement adds complexity to the regulatory process, as any objections or feedback from one country can delay approval for all participating countries. Therefore, sponsors and CROs must strategize meticulously to ensure alignment among regulatory authorities and minimize delays in trial initiation.
EU clinical trial regulation submission timeline
Sponsors have the option to submit Part I and Part II in parallel or sequentially. Parallel submission offers the shortest timeline, as both parts are reviewed concurrently. However, there may be instances where a sequential submission is more appropriate, such as when a sponsor wants to obtain feedback on the protocol before proceeding with the ethical submission. Deciding between parallel and sequential submission requires careful consideration of the study's specific requirements and goals. At Precision, our operational teams work closely together to assess each study's unique needs and determine the most effective submission strategy.
The role of regulatory in site activation
Navigating site activation under the EU CTR requires careful planning, proactive management, and strategic decision-making. By optimizing site selection, contracting and regulatory compliance strategies, sponsors and CROs can expedite trial initiation, mitigate risks and ensure successful execution of clinical trials in the European region. As the regulatory landscape continues to evolve, collaboration between sponsors, CROs and regulatory authorities will be essential to navigate the complexities of site activation effectively.
When planning a clinical trial under CTR, sponsors face several critical decisions that can significantly impact the study's timeline and success. At Precision, our strategic and operational experts work collaboratively with sponsors to ensure the most expedient pathway is adopted.
Submitting one site at a time or waiting until all sites in a country are ready for submission
Submitting one site allows for a faster start, but it may lead to delays if issues arise that delay the submission of subsequent sites as part of a substantial amendment. On the other hand, waiting for all sites to provide their regulatory documents ensures a more cohesive submission but may prolong the time to first site activation. start-up
Submitting one site at a time or waiting until all sites in a country are ready for submission
Submitting one site in each EU country allows for a faster start, but it may lead to delays if issues arise that delay the submission of subsequent sites as part of a substantial modification. On the other hand, waiting for all sites to provide their regulatory documents ensures a more cohesive submission but may prolong the time to initial submission and consequently first site activation.
Proactive management of regulatory feedback
Timely management of Requests for Further Information (RFIs) is paramount under the EU CTR to prevent trial rejection or delays. RFIs, or queries to Part I and/or Part II, must be addressed promptly and accurately to maintain trial momentum.
Proactive approaches, such as daily monitoring of regulatory portals and collaboration with translation agencies, can facilitate timely responses to RFIs and ensure compliance with regulatory timelines. Moreover, sponsors and CROs should anticipate potential RFIs and develop contingency plans to swiftly address them.
Coordination of protocol versions across different regions
Sponsors must decide whether to align their EU submission with other regions, such as the United States or Asia, or proceed with different protocol versions for each region. While having a single global protocol can streamline the trial, it may also lead to delays if changes are required to accommodate regional requirements.
Choosing the right lead country or RMS
Some countries may be more conservative in their assessments, while others are known for their efficiency. However, even the most favorable RMS cannot ignore the concerns raised by other member states. Precision's regulatory experts can provide valuable feedback on recent experience with different RMS.
Precision's approach to site selection and submission
At Precision, we understand that start-up is not a siloed activity. Effective site activation requires close collaboration between medical, feasibility, clinical study startup and regulatory teams. Our operational knowledge informs our regulatory strategies, ensuring that submission plans are not only compliant but also operationally feasible.
Below are some examples of important questions to ask when pulling a strategy together:
- How important is it to meet FPI by a certain date? When is that date, what country to target?
- Where to find the patient population? What is the timeline for this country?
- Do you want to tier the countries based on timelines or based on patient population?
- How important is to meet FPI by a certain date? When is that date, what country to target?
- Where to find the patient population? What is the timeline for this country?
- Do you want to tier the countries, based on timelines or based on patient population?
- What is the risk mitigation? Chose only CTR countries and submit in waves? Or select additional countries in EU outside of CTR?
- Medical considerations? Different protocols in different regions?
- Phase I dose escalation study? First in Human for a couple of patients only? Potentially followed by an expansion at more sites?
- Large Phase III study?
By integrating regulatory expertise into our start-up process, we can proactively address potential challenges and develop solutions that optimize both compliance and operational efficiency. This holistic approach sets Precision apart and enables us to deliver seamless start-up services to our clients.
- Feasibility: Our feasibility team works closely with the operational teams to identify the most suitable sites based on the study's specific needs. We consider factors such as site experience, patient availability, site contract and regulatory timelines to ensure optimal site selection, while our extensive network of sites across Europe allows us to quickly identify and engage the best-fitting sites for each study.
- Regulatory: Precision's regulatory experts play a crucial role in guiding sponsors through the submission process. They provide insights on country-specific requirements, help coordinate responses to regulatory queries and ensure that all submissions are compliant and completed within the required timelines. By leveraging our regulatory expertise, we can anticipate and mitigate potential hurdles, minimizing delays and ensuring a smooth submission process.
- Site Activation: We recognize that the ultimate goal of the submission process is to achieve site activation. Therefore, our regulatory strategies are designed with operational considerations in mind. Our regulatory team works together with our site start-up team to ensure that all necessary documents and approvals are in place to enable swift site activation once the submission is approved.
Navigating study start-up under EU CTR
Finding the best strategy for your study start-up under EU CTR is highly nuanced. For studies with a narrow patient population or urgent timelines, we may recommend a targeted approach, focusing on a single country or a select group of sites. This allows for faster submission and quicker site activation. In contrast, for larger Phase 3 studies, a wave approach may be more appropriate, where sites are submitted in batches to balance speed and risk mitigation. However, this is just a generalization. The best approach to site selection and submission is the one that considers the nuances of that specific trial—and that takes experience.
Discover the difference true expertise makes in start-up phase. From navigating EU CTR to managing the requirements of different countries outside the EU, Precision for Medicine is your partner for taking your clinical trial further, farther, and faster.
