Broad principles

EU-PEARL developed five templates for sponsors developing their own platform trials: a Master Protocol Template (MPT), an Intervention Specific Appendix (ISA) or sub-protocol template, a template for the statistical analysis plan (SAP), a data monitoring committee (DMC) charter template adjusted for the purpose of conducting a platform trial, and a guidance for supplementary information to the CTR Cover Letter. A spreadsheet which is intended to be a Platform Trials Best Practices tool that can be used to assist in the operational planning of a collaborative platform trial is also provided.

EU-PEARL templates are provided as a PDF in a user manual (Additional files 1, 2, 3, and 4). The separate Platform Trials Best Practices tool is provided in Excel format to support its utility in a user manual (Additional file 5).

EU-PEARL templates present content suggestions and best practices that add value for creating ICH-compliant protocols and SAPs, but these come with the caveat that they may not work in all situations. IRP authors should use their judgment and, above all, make sensible structuring choices based on their specific IRP.

In addition, the goal was for EU-PEARL to be globally relevant, and the publication includes links to relevant regional guidances and other useful resources where possible, with explanation, to maximize utility of the resource. Consultation with the relevant regulatory health authority is highly recommended in cases where there is doubt.

The EC, EMA, and CTFG have jointly issued in 2022 “Complex Clinical Trials—Questions and Answers” document for which “Recommendation Paper on the Initiation and Conduct of Complex Clinical Trials” issued in 2019 by the former Clinical Trials Coordination Group (CTCG) has served as a basis. This document provides clarification or additional information and lays out certain considerations regarding scientific aspects, planning and set-up, submission for obtaining CT authorization (CTA), conduct, reporting and transparency, analysis, and interpretation of Complex Clinical Trials (CCTs) under the EU Clinical Trials Regulation 536/2014 (CTR) and EU In Vitro Diagnostic Medical Devices Regulation 2017/746 (IVDR) [11], as well as their use in submissions for marketing authorization.

In March 2022, The Food and Drug Administration (FDA or agency) announced the availability of a final guidance for the industry entitled “Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics.” Master protocols use a single infrastructure, trial design, and protocol to simultaneously evaluate multiple drugs and/or disease populations in multiple sub-studies, allowing for efficient and accelerated drug development.

The EU-PEARL templates are written in Microsoft Word and start with reader instruction. Different font colors are used to explain the intended use: instructional text, common and suggested text, variable text, example text, and highlighted yellow text. The yellow highlighted text in the EU-PEARL templates shows modifications that were made to the TransCelerate CPT V8 to make the template suitable for the master protocol approach. Deletions from the CPT are not shown. Instructional and example text are integrated into the templates through discrete color-coded fonts. These should help authors make informed choices as they navigate the evolving and complex area of IRPs.

Platform Trials Best Practices tool is an Excel spreadsheet divided over several tabs, each tab applicable to a particular clinical operations sub-team involved in the planning of a platform trial. This tool may not be all-inclusive due to the variety and complexity of platform trials, different organizational procedures, and national/local requirements. Therefore, reference to the appropriate governance committee’s guidance on relevant standard operating procedures (SOPs), company/organizational work instructions, etc. for applicable related procedures/requirements is recommended.

Generic templates

The use of templates to develop regulatory documents is a standard practice and is well accepted by health authorities, industry, and academia. For clinical studies, the use of a protocol template provides a common structure that might benefit sponsors, investigators, sites, vendors, and regulators. It supports consistency, clarity, and ease of use and offers further efficiencies. Platform trials often have a structure of a master protocol and associated ISAs or sub-protocols.

EU-PEARL developed five templates for sponsors developing their own platform trials: a Master Protocol Template (MPT) and an Intervention Specific Appendix (ISA) or sub-protocol template (Fig. 2), a template for the statistical analysis plan (SAP), a data monitoring committee (DMC) Charter template adjusted for the purpose of conducting a platform trial, and a guidance for supplementary information to the CTR Cover Letter.

Fig. 2

Outline of the master protocol and ISA or sub-protocol

The core of the study setup is determined by the master protocol. The ISA is the appendix to the related master protocol which describes: the specific features of the intervention and treatment of participants assigned to that specific intervention or the control group to which it is compared, as well as intervention-specific assessments and procedures (e.g., administration of study medication when there are different dosing frequencies and routes of administration, and any special laboratory evaluations/biomarkers, endpoints, and risks that are intervention-specific). The ISA is a simplification of the concept of a domain-specific appendix which could be used to support platform trials like REMAP-CAP [12].

The templates allow the users to focus on the science and strategic development of the integrated research platforms without having to be concerned about the flow of content within the protocol that they are developing. In addition, the structure of the master protocol and ISA template use consistent section numbering to allow for easy cross-referencing across the two templates. When new intervention cohorts are started in a platform trial, both the master protocol and new ISA need to be submitted to the Clinical Trials Information System (CTIS) since each ISA will have a unique EUDRA-CT number.

Additional elements in the master protocol include the following:

Interventional Medicinal Product (IMP) or Intervention Selection Committee, including independent experts (which may have different types of expertise, such as scientific, ethics, supply chain expertise, depending on specific needs), to advise on the inclusion of new IMPs into the trial. This committee will continue to evaluate potential arms for the trial and prioritize their importance based on newly emerging preclinical and clinical data. The IMP or Intervention Selection Committee Charter will provide details on the decision rules and what decision criteria should be considered.

Two-step informed consent: The informed consent process may vary across different types of platform studies. The informed consent must be signed before the first study-related activity, which would typically be for the master protocol (e.g., master protocol informed consent form [ICF]). After consent is signed for the master protocol, the informed consent process for the intervention cohort(s) may depend on the number of intervention cohort(s) in a platform study. If only a single intervention cohort is open in a platform study, the master protocol and ISA ICFs may be signed at the same time. If multiple intervention cohorts are open in a platform study and participants are to be allocated or randomized among intervention cohorts after screening for the master protocol, the ICFs may be signed sequentially, e.g., the master protocol ICF would be signed to permit screening procedures for allocation/randomization to an intervention cohort, followed by the applicable intervention-specific ICF. If there are specific screening or eligibility criteria that determine the intervention cohort that participants will be allocated or randomized to, these screening/eligibility criteria should be in the master protocol and the master ICF. Intervention-specific screening/eligibility criteria should only be in the ISA protocol and the ISA ICF.

Participant input into design: overall scientific integrity and regulatory compliance of the study. This section should describe the methodology used to collect patient inputs. If applicable, include a justification of why there is no engagement of patients required. For additional guidance and definition refer to https://eupati.eu/resources/patient-engagement-roadmap or https://patientfocusedmedicine.org/pem-suite.

Compliance with EU CTR in accordance with Clinical Trials Regulation (EU No. 536/2014), procedures for reporting SUSARs, urgent safety measures, serious breaches, and change risk/benefit due to unexpected events were added.

The guidance and considerations in the cover letter are intended to help the reviewers and readers navigate and understand the master protocol across the entire platform trial and across all ISAs. The cover letter also contains ideas and suggestions for different tables and charts. For example, it contains a platform trial tracker, which is a table that provides an overview to keep track of the different versions of the key documents, the amendments, and the current status (e.g., approved or filed), so that they can be easily understood and navigated by its users. Using a graphical visualization in the cover letter depicting all closed, current, and planned sub-protocols/arms (e.g., status overview) as proposed in the EU-PEARL guidance for the cover letter is also encouraged in the Q&A on Complex Clinical Trials by ACT EU.

More details regarding the different templates, as well as their creation and their internal and external review process, are covered in the publicly available report on “Deliverable D2.6—Final Generic Master Protocol Template and Appendix for IRPs” on the EU-PEARL website.

The Platform Trials Best Practices tool spreadsheet is divided into several tabs, each tab applicable to a particular clinical operations sub-team involved in the planning of a platform trial. The tabs are as follows: index, instructions, definitions are covered in the first three tabs, clinical operations, electronic health records (eHR), data management, medical writing, clinical supplies, governance, safety, statistics, regulatory topics to be considered for preparing the submission dossiers, Data Monitoring Committee (DMC) and Data and Safety Monitoring Board (DSMB), patient engagement, data protection, data sharing, and communications. Each tab is organized as a table. There is a row for each task that has been identified. The column headings are as follows: Task, which is a general description of the activity; Platform considerations, a summary of the considerations which the function will consider particularly for the planning of a master protocol; and Name of responsible person that the task is assigned to, which is an empty column to remind the sponsor team to complete while planning for the roles and responsibilities in a collaborative platform trial/integrated research platform and facilitate team dynamics.

More details regarding the creation and the internal and external review process for the tool are covered in the publicly available report on “Deliverable D2.10 Final Report on Clinical Operations Best Practices” on the EU-PEARL website.

Statistical considerations

The use of Complex Clinical Trials, especially platform trials results not only in operational but also in statistical challenges. Statistical challenges specific to platform trials include but are not limited to multiplicity issues due to multiple treatment arms and a common control, the use of concurrent and non-concurrent controls, the use of simulations for trial planning and patient allocation approaches [13,14,15,16,17,18,19,20,21].

To allow aid in the interpretation of trial results originating from a (potentially perpetual) integrated platform trial, the master protocol should describe which the type of error control(s) to be implemented on the platform and sub-study level. If some hypotheses are considered inferentially independent, a framework should be given to (i) decide based on which criteria hypotheses are defined as related and unrelated, (ii) how to define the families within the platform for which error rates such as family-wise error rate (FWER) should be controlled, and (iii) whether changes of the testing strategy are needed when adding new arms in an ongoing trial.

The large flexibility in platform designs with respect to the addition of new study arms, allocation ratio, and concurrent vs. non-concurrent control data usage, may not allow for a conventional sample size calculation to determine the total platform trial size. The master protocol may only provide an approximation based on a set of assumptions defined in the planning stage, and it should describe the guiding principles in sample size calculation for individual interventions instead.

Similarly, the implementation of interim analyses in platform trials typically differs from conventional clinical trials. To minimize interim analyses being conducted with limited data to inform decisions on whether to stop or not to stop and advance an investigational treatment, the interim analyses in platform trials may need to be triggered by the master protocol, instead of intervention-specific appendices. This will require statistical procedures on the sub-study level, which may handle flexibility in the timing of interim analyses. How to address this is explained within the SAP template as there is not a separate SAP template to be used for the ISAs.

The use of non-concurrent controls

Platform trials offer the opportunity to add and drop treatment arms during an ongoing trial. When using a shared control, this will lead to non-concurrent and concurrent control patients. Non-concurrent controls refer to trial participants allocated to the control group, who were recruited in periods of time where the “concurrent” experimental treatment was not yet part of the available treatment options. The statistical power can be substantially increased if non-concurrent controls are used in the comparisons of treatment arms with the control comparisons. The later an arm enters the trial, the larger the potential gain in power by including non-concurrent control data. However, a major concern is a bias introduced by time trends that can lead to a change in the response. Examples are temporal changes in the patient population, the disease, the standard of care, or endpoint assessment, etc. [22]. In a publication on the use of external controls [23], of EU-PEARL members together with external authors, the different sources of bias potentially resulting from external controls are elaborated and the relevance of these issues for non-concurrent controls in platform trials is discussed.

Regulatory feedback

Two interactions with EMA were sought through discussions with the Innovation Task Force (ITF). These discussion meetings provide opportunities for early and product-agnostic engagement on general trial design and methodology topics with regulators (see https://www.ema.europa.eu/en/human-regulatory/research-development/innovation-medicines). Similarly to the FDA, the Critical Path Innovation Meeting (CPIM) (ref added) is also available.

A consultation with the EMA ITF was held on 31 January 2022 with EU-PEARL representatives from the WP4 (MDD). The EMA did not have any issues with the templates. The EMA were supportive of many of the proposed statistical approaches in the study design, including the following:

Two-step randomization process where participants are first randomized to one of the routes of administration (domain) and then randomly assigned to one of the experimental arms within that domain or its control arm with a participant opt-out feature for domain

Intra-domain blinding

The use of a range of placebo allocation ratios and concurrent controls (limited to 35 to 50% because of the risk of inflating the placebo response in MDD if the chance of being allocated to placebo is low)

On whether to permit re-entry and re-randomization of participants into a platform trial, EMA highlighted that further consideration needs to be given to the potential for changes in the patient population over time as this may lead to an increasingly higher rate of resistant participants. The option for a participant re-entering within the same domain or arm should be avoided.

A further consultation with the EMA ITF was held on 9 November 2022 with EU-PEARL representatives from the WP6 (NASH). The EMA was supportive of many of the proposed clinical and statistical features of the study design:

A randomization process that accounts for patient choice with respect to which cohorts they would be willing to participate in if they meet the eligibility criteria for the platform trial

Three-tiered level of evidence linked to clinically meaningful effect size as part of the Bayesian decision rules for stopping early for futility or overwhelming efficacy

The use of concurrent controls across cohorts if the accrual rate allows such data sharing to be performed

The leveraging of an independent data monitoring committee for decision-making.

There were concerns raised with respect to the controlling of the type I error even in a phase 2 setting if dependence exists between treatment arms (multiple doses of the same investigational treatment or investigational treatments with similar mechanisms of action) where controlling type I error in phase 2b would be justified especially if only a single confirmatory phase 3 study is planned. In addition, the EMA experts raised the point that there is some risk of multiple false positives in case a shared control arm is used. Concerns were also raised on the use of non-concurrent controls and not being able to fully characterize time trends. However, it was noted that, if necessary, the range of potential time trends could be simulated to understand how such trends would impact decision-making.

FDA interactions

A consultation with the FDA during a Critical Path Innovation Meeting was held on 28 January 2022 with EU-PEARL representatives from the WP6 (NASH). The FDA shared its view that multiplicity control is not required for a phase 2 design across the entire platform trial or within intervention cohorts. In the situation where the sharing of control data across cohorts within a platform trial is being proposed, the FDA recommended attention to the following topics that are relevant for consideration in the use of the suite of templates:

The expected effect on the main outcome of interest (efficacy or safety) and other/secondary outcomes of interest should be considered. For example, it would not be reasonable to look at safety analyses for injection site reactions for treatments that differ in route of administration (oral vs. injectable).

The comparison between an investigational drug and the control arm should include the inclusion of only the control participants in a comparison that could have been randomized to that drug (i.e., comparable baseline characteristics and would have been eligible to enter the intervention cohort where the treatment is being evaluated).

The potential bias created by participant selection to participate in a specific intervention cohort should be considered.

Any concurrent control should be justified even if the participants would be eligible for multiple cohorts as it is conceivable that the standard of care could change even during the time period of overlap where a concurrent control would be applicable.

During 2022, feedback was obtained from CTCG as part of a formal review of the Master Protocol Template, ISA Template, and guidance for supplementary information to the CTR cover letter.

During the 2nd stakeholder session in 2022, CTCG members added the importance of a consolidated opinion in terms of templates and other aspects. Multinational trials are necessary, but the way how clinical trials are assessed is changing with the new CTR, leading to a multinational assessment. So, the harmonization among regulators, between the different member states, is very important. To get complete high-quality applications for assessment by regulators, it was recommended to have upfront advice, as envisioned by ACT-EU.

The following were the key highlights from their feedback:

1.

Providing separate appendices for new interventions is only one option for maintaining the master protocol of the platform study and alternatively, this could be done as one protocol document.

2.

Updates needed and were made to fully align with the final EU CTR.

(a)

Reference to Clinical Trials Regulation (EU No 536/2014).

(b)

Introduction modified to include guidance for the scientific and social relevance of the trial.

(c)

New section/text added 4.2.1. Participant input into design. This sub-section elaborates further on participant Input for example design, choice of endpoints, communication during the conduct of the trial, and study results (including informing patients on (interim) study results). This section also includes a justification if there is no engagement of patients.

(d)

Sect. 8.3.4. Regulatory Reporting Requirements for serious adverse events (SAEs). Provided guidance on the need for clear agreement between sponsors, co-sponsors, involved pharmaceutical companies, and investigators about roles and responsibilities.

(e)

New section/text added for overdose, medication errors, and misuses or abuses of the medicinal product: Sect. 8.3.9 Overdose, medication errors, and misuses or abuses of the medicinal product.

(f)

Clarification of data protection and publication policy.

(g)

Guidance on storage of biological samples.

Changes will need to be made once ICH M11 is finalized as part of a sustainability plan.

Patient and community engagement

The EU-PEARL patient and community engagement group (PAG) has provided insights into the work of the EU-PEARL suite of templates. PAG was involved in some activities such as defining trial terminology: person vs. patient reviewing and commenting on the Master Protocol Template, and review of the EU-PEARL dictionary in lay terms. Lastly, the benefits of participation of PAG were the inclusion in the planning phase of a project, suiting resources; monitoring and evaluation of activities; and mutual learning process which requires time and confidence. An additional section on participant input was added to the Master Protocol Template.

The relevance of patient engagement in NF is based on a long-term condition with variable disease burden and a rare condition. The variability in disease manifestations requires to first prioritize manifestations. The results of including input from patient representatives in the final selection of manifestations were shown by WP7. WP7 gained patient input in a very early stage, which substantially influenced the NF platform trial design. Some improvements for a future study would be defining the target population and considering trade-offs for scoring.

It is important to get patients and community voices involved in an early research phase. Sometimes, it does not make sense to involve patients at a very early stage, but it is important to get their opinion in what stage they would want to give input. It would be interesting for future projects to have these insights right in the beginning. If patients’ community members are approached very early on, they feel that they are being taken more seriously in their input.

Sustainability

A sustainability plan for the generic templates was developed. The plan includes the review of the suite of Master Protocol Templates on a regular basis and communication to the user community at least on a yearly basis and when the ICH M11 Protocol Template guidance is finalized at a future date. TransCelerate will incorporate learnings from the EU-PEARL templates into the future versions of the CPT.