06 Feb PROs and patient questionnaires in global studies: how to avoid putting your endpoint at risk because of language

More and more clinical trials depend on what patients report: symptoms, quality of life, and the impact of treatment on their daily lives. These are PROs in clinical trials, and in 2026 they sit at the centre of the regulatory conversation.

The problem is that a poorly translated PRO can put your endpoint at risk: if a patient in Spain understands one thing, a patient in another country something different, and a patient in Latin America something else entirely, your data ceases to be comparable.

The new regulatory context of PROs

Health authorities have been publishing guidelines on how PROs should be developed and used in medicines development for years. In some therapeutic areas, such as oncology, specific recommendations already exist on how to define and use these instruments.

In Europe, agencies are promoting the systematic use of patient experience data, including PROs and other quality of life instruments, as part of the evidence supporting benefit-risk decisions.

The implication for CROs is clear: it is no longer enough to simply “have a questionnaire”. They must demonstrate that these PROs in clinical trials work equally well in all languages used in the study.

What does a “PRO linguistic strategy” really mean?

A solid strategy goes beyond simply translating the instrument. It includes:

• Selecting instruments that are validated for the target language and population.
• Adapting the items culturally when necessary, without changing the concept they measure.
• Maintaining strict version traceability, especially when ePRO is involved.
• Planning from the outset how PROs in clinical trials will be integrated into the operational flow of the study.
• Regulatory guidelines emphasise that patient questionnaires must measure the same thing in all cultural contexts where they are applied. Otherwise, cross-country comparisons become fragile.

Typical risks when the linguistic aspect is not properly managed

Some common problems a CRO sees:

“Ad hoc” translations carried out by internal staff without a formal validation process.

Improvised changes to items to “adjust” them to the country, without reviewing the psychometric impact.

Misaligned versions between paper and ePRO, with text in the app that differs from the approved PDF.

Confusing instructions that cause erratic response patterns or high levels of missing data.

Any of these situations may cause a reviewer to question the validity of your PROs in clinical trials as endpoints or key secondary endpoints.

Recommended process of linguistic and cultural adaptation

International best practice for PROs and other patient questionnaires includes several phases:

Direct translation in duplicate

Two native translators of the target language, experts in health, work independently.

Reconciliation

A senior linguist combines both versions and agrees on the best formulation for each item.

Back-translation

A different translator, unfamiliar with the original, translates the text back into the source language to check for deviations in meaning.

Clinical expert review

Specialists review the items to ensure they maintain the clinical intent of the instrument.

Cognitive interviews with patients

Patients from the target population complete the questionnaire and explain what they understand by each item; the text is adjusted based on their comments.

Version closure and documentation

The entire process is documented: who has participated, what decisions have been made, and what the final approved version is.

This approach not only protects your data; it also gives you very strong arguments to defend PROs in clinical trials before a regulator.

PROs in ePRO: the additional challenge

When the questionnaire is converted to electronic format (ePRO), additional challenges arise:

• Ensuring that sentences fit on small screens without being cut off in a confusing way.
• Validating that format changes do not alter comprehension or response patterns.
• Keeping all versions of the application synchronised with the approved language version.
• Poor interface design can be just as problematic as a bad translation, especially in patients with low health literacy or little familiarity with digital devices.

Benefits for the CRO of professionalising the linguistic aspect

When a CRO invests in a solid PROs strategy in multilingual clinical trials, it:

• Reduces regulatory queries relating to the validity of patient endpoints.
• Minimises rework on questionnaires, applications, and training materials.
• Improves data quality, with fewer inconsistent responses and less missing data.
• Strengthens its value proposition to sponsors who want a well-integrated and defensible “patient voice”.

Quick checklist for PROs in international trials

Before closing your PROs plan, verify that:

– The instrument is validated or there is a validation plan in each key language.

– Translation and cultural adaptation documentation exists, not just a “translated version”.

– Paper and ePRO use exactly the same wording in each language.

– Monitors and coordinators are well aware of the purpose of each questionnaire and how to explain it to the patient.

-You have a centralised repository with all controlled versions of the questionnaire.

-You can clearly describe the process followed for your PROs in clinical trials.