Table 1 Challenges and potential solutions for PRO/ObsRO development and implementation in paediatrics and orphan indications

Literature Review/Desk Research

• Literature often limited

• Broad age ranges covered

• Consider grey literature (blogs, dissertations)

• Conduct interviews with expert clinicians, nurses and patient advocacy groups

Concept Elicitation

• Limitations in memory, cognitive ability, language by age/condition

• Children can be shy

• Rarity of condition makes recruitment/saturation hard to achieve

• Parents unable to report some symptoms/domains not known to them

• Carefully guided interview guides and well trained interviewers

• Creative interview techniques, toys and drawings

• Collapse age groups where appropriate

• Must achieve saturation within each narrow age range – can this be relaxed for orphan indications? Get FDA feedback early

• Consider other respondents (teachers, nanny etc)

Selection/ development of a measure

• Few disease specific measures exist in paediatrics and orphan diseases

• Existing instruments don’t meet FDA/EMA guidance

• Who is the best respondent?

• How should you administer the questionnaire?

• How should the questionnaire be worded?

• Child can’t remember without a concrete event to recall to

• Parent items must be observable….but they may not be with the child all day

• Think about PRO selection early

• Talk to patient advocacy groups

• Engage FDA early

• Consider EPRO vs pen/paper vs IVRS in context of condition and age of child

• Questions/responses should be clear and simply worded

• Short recall period required

• Consider all types of respondents (parent, teacher, nurse, child, dr)

• Consider ‘child told me’ questions

Cognitive debriefing/ content validity testing

• Hypothetical situations don’t work with children

• Children give you answers they think you want to hear

• Small sample sizes in rare conditions

• Allow child to complete diaries at home for a few days prior

• Use carefully worded interview guides and well trained interviewers

• Questioning should not be too repetitive nor lengthy

• When analysing, check for consistency between behaviour and responses

• Collapse age groups as appropriate

Psychometric validation

• Sample should be stratified by age group, but small samples in orphan indications

• Consider validating as part of trial and/or include data from cognitive debriefing (move forward at risk)

• Consider collapsing across age groups

• Consult regulatory early

• Utilize psychometrics done in other diseases if adapting a measure