Language Planning Guidance for Multi-Regional Clinical Trials and ICH E17

It’s been over five years since the ICH published its E17 guideline on multi-regional clinical trials (MRCTs) in 2017. The guideline’s mission was to establish general principles for planning and designing clinical trials conducted in multiple geographic or regulatory regions under a single protocol. Clinical trials conducted in more regions or countries add complexities; not only in clinical operations, but also in the scientific review across regulatory authorities. It’s critical to manage these complexities to ensure that trial results are reliable and applicable across all regions and patient populations. Ultimately, multi-regional clinical trials should benefit all patients by providing relevant, positive health outcomes and rapid, simultaneous access to new and life-saving treatment options.

These overall benefits seem to be well-understood by the industry. However, a survey conducted in 2020 by the European Federation of Pharmaceutical Industry Association (EFPIA) revealed some barriers to the acceptance of the E17 guideline among some National Competent Authorities. These authorities include Japan, China, South Korea, and Brazil. Even though these authorities are ICH members, survey respondents reported that Japan’s PMDA and China’s NMPA always require local clinical trials (with some emerging flexibility when treating unmet medical needs and rare diseases). Other barriers reported were insufficient training in the E17 guideline and operational/logistical considerations. Although limited in scope, the outcomes of this survey indicate MRCTs still aren’t fully adopted and successfully implemented across regions.

Guideline Focused on Technical and Protocol-Specific Issues

The E17 guideline addresses challenges at strategic and protocol levels of multi-regional clinical trials. It also outlines how sponsors and regulators can handle sources of regional diversity. The E17 covers so-called intrinsic and extrinsic ethnic factors in the planning and trial design phase, in addition to their potential impact on applicability of the treatment across diverse patient populations. These factors are also addressed in more detail in the ICH E5 Guidance on ethnic aspects of foreign clinical data. Intrinsic ethnic factors are defined here as genetically or physiologically determined. Extrinsic ethnic factors are culturally and environmentally determined.

At the protocol level, the E17 guideline provides recommendations for managing and planning for regional differences in medical practices, disease definitions, and environment. It specifies identifying protocol eligibility criteria, offering training for site personnel, and establishing mitigating actions to account for diverse patient preferences on drug administration. Endpoint selection and sample sizing are other critical elements to ensure trial results are relevant and applicable across the regions in scope of the protocol.

As these examples suggest, the ICH E17 guidance focuses on technical and protocol-specific aspects, which may impact treatment effects and trial data conclusions. It’s less concerned with intangible or non-technical factors inherent in cross-cultural and local communication for MRCTs, which may also impact trial outcomes.

The Language Gaps of E17 for Multi-Regional Clinical Trials

Language is only briefly addressed in the ICH guideline as a recommendation to implement translation consistency checks of trial documents. However, there are more challenges with language and cultural diversity than language quality checks and reverse translations. Since language is a necessary and critical part of MRCTs, this topic could have been paid more attention in a cross-regional guideline.

Translations can be costly, time-consuming, and barriers to operational excellence and clear trial communications. The challenge with language is not only the great diversity across natural languages in different regions. It’s also how language is prone to individual preferences, which can easily become sources of misunderstanding, misinterpretation, and worst-case misconduct or patient incompliance. In addition, sponsors or investigators may have language conventions or preferences patients don’t understand. Patients may have preferences, disease terminology, and cultural assumptions or values that sponsors or investigators don’t consider.

Moreover, much of the content translated in a clinical study is still prepared in a professional vacuum as one-way communication without patient or user involvement. Exceptions to this are Patient Reported Outcome Assessments (PROs), which are subject to linguistic validation and cultural adaptation that account for local interpretation or cultural sensitivities/ambiguity. Translated content also has many touchpoints across stakeholders in an MRCT. Stakeholders include sponsors, investigators, regulators, and, most importantly, patients or end users. The literacy level across these groups may vary significantly.

Despite the apparent risks of poor language, translations are often not explicitly addressed in regulatory or industry guidelines. The exceptions are if they’re an integrated part of a regulatory approval pathway, such as for labeling, Clinical Outcome Assessments, or patient-facing content subject to ethical review. The E17 guideline is no different. It suggests using reverse translations to ensure consistency across translated documents, with the example of the Case Report Form. However, the E17 doesn’t advise how to tackle language diversity for MRCTs or how it may impact trial outcomes.

Five Tips for Planning and Managing Language in Multi-Regional Clinical Trials

Medicines are developed for patients who take medications in their everyday environments, and MRCTs are executed locally by site staff. Thus, local language should be elevated to a core activity in any MRCT. These are five key recommendations of language aspects for trial management planning.

#1 Implement a Language Strategy: Setting up a language strategy saves time and money because it reduces repetitive, burdensome, or last-minute workarounds. When trial managers establish their trial schedule during the preparation phase, they should include a language strategy and country-specific language activities. Strategy, which can be trial-specific, should describe:

• Language scope
• Translation approach
• Resources
• Any other particular language requirements or precautions

Language strategy can also be created for a full drug development plan, because much of the content may be repeated within the same drug program and disease indication. Successfully implemented strategies drive consistency and efficiency, which benefits all MRCTs stakeholders. Most importantly, this includes trial participants and patients, the end users and beneficiaries of new drug treatments.

#2 Map and Pool Content Types: Most trial documentation is standard for GCP clinical trials. However, trials differ in complexity, length, and the procedures trial participants and site staff must complete. This is especially true in MRCTs, where training needs and language skills vary across regions and users. Listing all document types by purpose, audience, and timing will help plan and streamline language activities. It may also help identify dependencies and common language issues across different content types.

#3 Establish Translation Workflows: A common translation misconception is that it’s a simple rendition from one language to another. Translation is a controlled technical process requiring a step-wise workflow. Ideally, this workflow involves review and input from intended users, such as site staff executing the study and the trial participants. MRCTs may require more than one workflow depending on the content type, intended audience, regulatory controls, and purpose of the trial documents.

#4 Leverage Language Assets: Language assets optimize translation workflows and help drive consistency and accuracy in local language content. They may include glossaries, style guides, and language technologies. Based on strategy and content type listings, trial managers can decide how to leverage assets for a single MRCT, a full development program, or even across a therapeutic area. A language services provider with expertise in clinical trial translations can help establish and build assets for all multi-regional activities and all patient-facing content.

#5 Do Not Underestimate the Importance of Language for Patient Outcomes: Due to an increasing push for transparent communication and patient centricity within global clinical research, the medical writing community and industry at large are becoming more focused on language challenges and skills. Plain language communication is emerging as a professional discipline in its own right. A strong factor in the rise of this discipline is the establishment of clinical trial disclosure specialists, who develop and manage layperson summaries for trial results communication. In a multi-regional context, plain language is frequently in local language. It’s pervasive in content intended for patients. This phenomenon profoundly benefits patients. More focus and resources invested in language skills and content quality is vital for patients who:

• Depend on properly conducted research
• Need clear information on how they contribute to clinical research
• Require clear instructions on taking medication and obtaining intended health benefits

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Need assistance in language planning for multi-regional clinical trials? Looking for support for your multilingual and multi-regional clinical trials? We have the deep experience, knowledge, and technology to provide the clinical trial translation services you need. Contact us today to find out more about Lionbridge’s Life Sciences translation services.