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The CTA Process Under Regulation (EU) 536/2014: Why Flexible Writing Solutions Are Needed

European Commission, Regulation (EU) No. 536/2014 is challenging the status quo when it comes to clinical trial writing solutions. In addition to the requirement of additional clinical trial documents (lay summaries), the Clinical Trial Application (CTA process) has also been updated under these new regulations, putting an emphasis on the Sponsor’s (and the Sponsor’s writing team’s) ability to move quickly, thoroughly, and flexibly in order to keep the study startup timelines on track.


The CTA evaluation process generally takes up to 60 days and includes 3 main phases: Validation, Assessment, and Decision (summarized in Figure 1). The assessment phase is further categorized into Part I and Part II, which can occur simultaneously. Part I consists of a joint assessment by Member States Concerned (MSC) led by the Reporting Member State (RMS) and Part II is an opportunity for each individual MSC to assess the CTA and submit an individual conclusion. Throughout the evaluation process, the MSCs may issue requests for information (RFIs), potentially resulting in an extension of the 60-day timeline. Multiple RFIs can be issued during the different phases of the evaluation process; however, when multiple RFIs are issued during the Assessment phase, the overall timeline will only be extended once. Each RFI will have its own due date and failure to meet the due date results in lapse of the application.


Figure 1 Summary of Initial CTA Evaluation Process


The complexity of and effort required to complete an RFI response can vary. In some cases, an RFI may include questions that result in nothing more than providing additional already-completed documents, providing additional context to support the study design, and/or providing publications referenced in the CTA. But sometimes, an RFI can include requests that require updates to already-approved documents, such as the protocol, lay protocol summary, informed consent forms, and/or other documents. In these cases, timelines are typically condensed compared to industry standard timelines (document development outside of the CTA evaluation process). Example timelines showing the comparison of standard timelines and timelines within the context of an RFI response are shown in Table 1, based on recent GLOBAL experience.


Table 1 Example Timelines: Standard Compared to Timelines for Document Updates in an RFI Setting

Document

Standard Timeline

Average Timelines from Recent GLOBAL Managed Projects

Protocol Amendment

2 — 4 weeks

5 days

Informed Consent Form(s)

3 — 5 days

1 day

Protocol Lay Summary

3 — 5 days

1 day

Investigational Medicinal Product Dossier

2 — 4 weeks

5 days

Typical steps in the writing process include draft development, cross-functional team review, comment adjudication meetings, quality control, approval, and sign-off. To achieve these condensed timelines and prevent lapse of a submitted CTA, Sponsors must prepare for and implement creative writing solutions without skipping important steps and compromising quality.


One strategy to ensure success is to working with a writing team (internal, external, or a combination thereof) that has the expertise, flexibility, and experience to effectively adapt the writing process within the required RFI response timelines. This must include same-day review of the RFI and immediate identification of impact to components of the CTA to determine if any document updates are required. From there, attributes of the writing team that directly relate to success include the following:


  • Experience: Experienced writers who have years of regulatory writing under their belt carry knowledge of the specific elements required for regulatory documents. An experienced writer can hit the ground running with little to no delays necessary for onboarding when it comes to understanding what needs to be done.

  • Empower: Empowered writers are able to have direct and meaningful interactions with contributing subject matter experts, initiate document changes, escalate gaps within the project team, and push for resolutions without being slowed down by extensive bureaucratic processes. Writers who are bogged down with rigid Standard Operating Procedures that may require seeking approval from internal or external stakeholders for document updates, delivery, or even project start can slow the process down. This can mean the difference between a successful RFI response keeping study timeline on track or a lapsed CTA resulting in costly timeline delays. Empowering writers takes a degree of trust that can be built through relationship continuity (discussed below).

  • Continuity: Engaging a team that has a degree of consistency and continuity is helpful when work towards challenging timelines. A history of work and existing productive relationships allows the writing team to move faster due to already having program/study document familiarity and familiarity with contributing subject matter experts.

  • Flexibility: Flexible strategies are needed in order to fit the entire writing process in shorter durations. This can include rolling review cycles, taking advantage of time zones to gain additional work hours, rolling quality control review, and collaborative authoring practices. Flexible strategies may also include overlapping activities that wouldn’t necessarily overlap in standard practice. For example, the summary of changes for a protocol amendment may need to be initiated during the development of the amendment, thereby reducing time to complete once the protocol amendment is final. The ability to adapt workflows to achieve regulatory mandated timeline goals is crucial to success.

Working with a team or organization that prioritizes writing services as a crucial drug development activity is paramount to success in challenging settings, such as aggressive timelines or responding to less than favorable feedback from regulatory authorities. Boutique writing organizations, like GLOBAL, typically have the following characteristics that create goal alignment between the Sponsor and writing team:


  • Infrastructure that allows for flexible project strategies: A boutique writing organization tends to be smaller and flatter. This often means less rigid Standard Operating Procedures, allowing for customized solutions versus a one-size-fits all approach. Boutique organizations generally have fewer levels between writers and executive leadership, resulting in greater employee empowerment and often stronger relationships with Sponsors.

  • Higher quality resources: A boutique organization that focuses solely on writing activity is more likely to offer experienced writers, as hiring practices prioritize quality over quantity of resources. Additionally, such organizations typically have better turnover rates, which allows for offering of consistent personnel to Sponsors, contributing to efficiency (crucial in the CTA evaluation setting).

  • No conflicts of interest: A writing-focused boutique organization is solely dependent on the quality and success of the writing services rendered. There is no revenue generated from services such as study management, data management, or monitoring. Therefore, the success of the writing projects is crucial to the organization’s success.


GLOBAL takes a bespoke and boutique approach to expert drug and device consulting, regulatory submission support, and strategic writing. We strongly believe (and have the client testimonials to back it up!) that we can offer our Sponsors an unmatched level of expertise, attention, and quality. Each product deserves undivided attention when it comes to the writing expertise necessary to ensure forward program momentum and ultimately get innovative therapies into the hands of the people who need them.

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