SPIRIT-10-PRO Extension

Specify any PRO-specific eligibility criteria (eg, language/reading requirements or prerandomisation completion of PRO).30 If PROs will not be collected from the entire study sample, provide a rationale and describe the method for obtaining the PRO subsample.

Example

Trial group name: South West Oncology Group (SWOG)

Trial name: health status and quality of life in patients with early stage Hodgkin’s disease: a companion study to SWOG-9133 (SWOG S9208)

PRO endpoints: 1°, 2°

‘Eligibility criteria

Ages eligible for study: 18 years and older (adult, older adult)

Sexes eligible for study: All

Accepts healthy volunteers: No

Sampling method: Non-probability sample

Study population: community sample.

Criteria: disease characteristics: patients must be eligible for and registered to SWOG-9133.

Patient characteristics: patients must be able to complete the questionnaires in English. If they are not able to complete questionnaires in English, patients may be registered to SWOG-9133 without participating in SWOG-9208.’

The Symptom and Personal Information Questionnaire #1, the Cancer Rehabilitation Evaluation System Short Form and Cover Sheet must be completed prior to registration and randomisation on SWOG-9133.39

Explanation

Any eligibility criteria relevant to PRO assessment should be considered during the trial design and clearly specified in the protocol for consistent use by research personnel. In some trials, the baseline PRO assessment is required before randomisation as an eligibility criterion.30 This helps to ensure there will be a valid baseline questionnaire from all patients, which is essential for calculation of change scores, or inclusion as a covariate in modelling longitudinal PRO data. For unblinded trials, this also ensures PRO data are collected before participants are aware of the randomisation which may affect some aspects of the participant’s response, for example, anxiety/emotional well-being.40 In the absence of such an eligibility criterion, there is a risk that the baseline assessment may be conducted after randomisation but before the intervention is administered, resulting in detection bias. The maximum time between this assessment and randomisation should be defined and should not be too long.

It may not always be possible to collect PROs from all study participants, for example, due to non-availability of questionnaires in appropriate languages (see SPIRIT-18a(iii)-PRO Extension),9 literacy requirements or due to cognitive function (see SPIRIT-18a(iv)-PRO Extension). These PRO-relevant exclusions typically should not preclude the affected participants from enrolling in the trial, unless the PRO is the primary outcome. Evidence suggests eligibility criteria as stated in trial protocols often differ from what is finally reported in the trial publication,41 and data on use of other language or culturally appropriate PRO instruments is often missing from the protocol.13 42

Where the needs of specific groups have been identified (eg, not fluent in English) but not accommodated in the study protocol (eg, non-English language versions not available, assistance with reading and writing English version not permitted), this should be stated, and the rationale for the sampling method described and justified. Trialists should aim to be as inclusive as possible. Given the significance of PROs, the research community has a moral obligation to, where possible, to address gaps in availability of culturally validated PRO instruments. In the meantime, the implications for generalisability of findings should be discussed in subsequent publications.19

SPIRIT-12-PRO Extension

Specify the PRO concepts/domains used to evaluate the intervention (eg, overall HRQL, specific domain, specific symptom) and, for each one, the analysis metric (eg, change from baseline, final value, time to event) and the principal timepoint or period of interest.

Examples

Trial name: evaluating different rate control therapies in permanent atrial fibrillation: a prospective, randomised, open-label, blinded endpoint trial comparing digoxin and beta-blockers as (RATE-AF)

PRO endpoints: 1°, 2°, exploratory

PRO endpoints: 2°

‘Change in HRQL domain and symptom scores based on the Functional Assessment of Cancer Therapy: Leukaemia (FACT-Leu)—defined as the change from baseline and the time to definitive increments or decrements of 10%, 20% and 40% from baseline; time to definitive increment (better than baseline by the specified amount) is the interval from randomisation to the first timepoint when the HRQL measure is consistently better than at baseline (including that timepoint as well as all the subsequent timepoints) in a subject whose last HRQL score is better than at baseline; and time to definitive HRQL decrement (worse than baseline by the specified amount) is the interval from randomisation to the earliest of death or the first timepoint when the HRQL measure is consistently worse than at baseline (including that timepoint as well as all the subsequent timepoints) in a subject whose last performance status score is worse than at baseline.’29

Explanation

For each outcome, including PROs, the trial protocol should define four components: the specific measurement variable, which corresponds to the data collected directly from trial participants (eg, Beck Depression Inventory score, all-cause mortality); the participant-level analysis metric, which corresponds to the format of the outcome data that will be used from each trial participant for analysis (eg, change from baseline, final value, time to event); the method of aggregation, which refers to the summary measure format for each study group (eg, mean, proportion with score >2) and the specific measurement timepoint of interest for analysis.1 Many PRO questionnaires are multidimensional, assessing multiple facets of the impact of a disease and its treatment and usually include multiple assessments over the course of the trial. The multidimensional nature of PROs is most apparent in HRQL questionnaires, which often include various aspects of functioning and symptoms, which are often scored as distinct ‘domains’. These domains may not be affected equally by the trial interventions. The SPIRIT-7-PRO Extension encourages protocol writers to identify the domains that are most likely to be affected in the trial objectives and hypotheses, drawing on previous evidence (SPIRIT-6a-PRO Extension). The SPIRIT-12-PRO Extension item reinforces the statement of these key domains, and also the most important timepoints (ie, where greatest impact of interventions are expected), and develops that concept further by encouraging protocol contributors to think about how these PRO domains and timepoints will be analysed, that is, the analysis metric.34 To ensure transparency and credibility of the analysis, it is recommended that there is prespecification of the PRO concepts/domains, analysis metric(s) and timepoint(s) of interest, whether the PRO is a primary, secondary or exploratory outcome. These should closely align with the study hypotheses/objectives and the nature and trajectory of the disease or condition under investigation.34 43 The selected key domains, timepoints and analysis metric should be used to specify the PRO endpoints, integrated in the full endpoint model of the trial.

A clearly defined endpoint model, organising all trial outcomes (PRO and non-PRO), typically in primary, secondary and exploratory endpoints, allows rigorous control of the evidence demonstration, especially the control of the statistical testing. Each PRO endpoint in the model should explicitly specify a single domain and a single time horizon. The endpoint model enables procedures for type I error control (risk of false positive finding) (see SPIRIT-20a-PRO Elaboration). Broadly, the concepts and domains (sub concepts) measured by a PRO may be ‘proximal’ in nature, that is, direct impact of the disease and treatment (eg, symptoms such as pain, fatigue, nausea, rash and anxiety) or more distal, ‘knock-on’ effects, (eg, functional status and global quality of life), as illustrated for ovarian cancer in (figure 1, inspired by the Wilson and Cleary model44). Of note, the Food and Drug Administration (FDA) are increasingly focused on the individual measurement of well-defined concepts that impact on HRQL but are more proximal to a therapy’s effect on the patient and the patient’s disease: symptomatic adverse events, physical function and, where appropriate, a measure of the key symptoms of the disease.45

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Figure 1

Proximal and distal effects of therapy on patient symptoms and quality of life. Adapted from Wilson and Cleary.44

Common analysis metrics may include magnitude of event at time t, proportion of responders at time t, overall PRO score over time or response patterns/profiles. These should be prespecified alongside the levels of statistical and clinical significance for the study and any responder definition in use.16 Timepoints for analysis should be chosen to best address the research question, while taking into account aspects such as the natural history of the disease/condition and its treatment, the PRO measurement properties and recall period and participant completion burden.16 46

The example, idelalisib and rituximab improve PFS over rituximab alone in unfit patients with relapsed CLL: a phase III study, illustrates a ‘time to event’ PRO endpoint or analysis metric, where the event is definitive improvement or definitive deterioration in a PRO. This approach allows repeated PRO measurements to be converted to a single measure: time to definitive increment or decrement. This requires quite complex and specific criteria for degree and duration of change. Also, this particular example does not specify any key domains of the FACT-Leu, but rather applies this analysis metric to all HRQL domain and symptom scores. In contrast, the RATE-AF example identifies a single score (the SF-36 physical component score), and a specific timepoint (6 months) as the primary outcome, with other SF-36 domains, questionnaires and timepoints specified as secondary outcomes.

SPIRIT-13-PRO Extension

Includes a schedule of PRO assessments, providing a rationale for the timepoints and justifying if the initial assessment is not prerandomisation. Specify time-windows, whether PRO collection is prior to clinical assessments, and, if using multiple questionnaires, whether order of administration will be standardised.

Examples

Trial group: TROG

Trial name: a randomised phase III trial of HDPRT versus concurrent C-HDPRT in patients with good performance status, locally advanced or metastatic NSCLC with symptoms predominantly due to intrathoracic disease who are not suitable for radical chemo-radiotherapy (TROG 11.03 P-LUNG GP) (figure 2).31

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Figure 2

Example schedule of patient-reported outcome (PRO) assessments in the Trans Tasman Radiation Oncology Group 11.03 P-Lung GP Trial. QoL, quality of life.

Trial group: UK Medical Research Council Scottish Cancer Trials Breast Group in association with: Breast International Group

Trial name: MRC phase III randomised trial to assess the role of adjuvant chest wall irradiation in ‘intermediate risk’ operable breast cancer following mastectomy (MRC SUPREMO TRIAL (BIG 2–04) (figures 3 and 4))

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Figure 3

Example schedule of patient-reported outcome assessments in the MRC SUPREMO TRIAL (BIG 2–04).140 BNP, B-type natriuretic peptide; QoL, quality of life.

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Figure 4

Flow diagram schedule of patient-reported outcome assessments in the MRC SUPREMO TRIAL (BIG 2–04).140 BNP, B-type natriuretic peptide; QoL, quality of life.

Explanation

A clear and concise schedule of PRO assessments (figures 2–4) can: assist trial staff to be organised and prepared for participant visits, inform study participants about the methods and expectations of trial participation and facilitate review of participant burden by research ethics committees/IRBs.30 The scheduled PRO assessments should provide the data required to address the study’s PRO objectives. When selecting appropriate timepoints for assessment, it is important to consider the natural history of disease/progression, the hypothesised impact of therapy over time and practical considerations such as alignment of assessments with clinic visits and recall period of PRO measures. PRO assessments should be described in the protocol text and in the schedule of assessment table along with the other clinical data collection activities, for ease of reference. This is recommended whether the PRO is completed by the participant during study visits or outside of the study visits (eg, at home).

The timing of the baseline PRO assessment relative to other study-related events is important and therefore should be specified in the schedule of assessments. Collecting PRO data prior to randomisation helps ensure an unbiased baseline assessment, and if specified as an eligibility criterion, can promote data completeness (SPIRIT-10-PRO Extension). Baseline PRO data are often used as a covariate in analyses and are essential to calculating change from baseline, however, collecting data from enrolled patients prior to randomisation can be logistically challenging. One approach is to have participants complete the baseline PRO assessment immediately after providing consent, while the site staff obtain the randomisation assignment from the study system. However, there may be scenarios in which prerandomisation PRO assessment is unnecessary or not possible, for example, emergency surgery trials.

Stating the time-windows for each PRO assessment clearly in the protocol text and schedule of assessments table or footnote will help staff adhere to them. Examples of time-windows for PRO assessment are similar to time-windows for other types of assessments, such as a study visit that may occur on day 10–14 postbaseline, or on day 30±3 days postsurgery. Time-windows for each scheduled PRO assessment require an unambiguous reference point, to ensure that PRO data collection captures clinically relevant timepoints of interest. In deciding the size of the time-window for a PRO assessment, consider the trade-off between a smaller, more precise, time-window and a larger more feasible window. One approach is to specify a time-window that is a little larger than the ideal and not allow exceptions; this approach is more consistent than setting a smaller time-window and allowing exceptions. Often PRO assessments that occur during active treatment, for example, chemotherapy, have a smaller time-window to capture acute toxicity that arise and resolve relatively quickly, while those occurring many months or years after treatment completion can have a larger window if the participant’s outcomes are expected to stabilise over time.

When the PRO assessment occurs during a research or clinic visit, it is recommended that PRO assessment is standardised to be completed prior to clinical consultation, assessments or procedures. For example, if a PRO instrument assesses participants’ experiences of pain in the past 7 days, and the study visit includes a bone marrow biopsy, the schedule of assessments should indicate that the PRO assessment be completed prior to the biopsy. This will prevent the pain assessment from capturing pain associated with the biopsy, reduce risk of missing data as participants may not feel well enough to complete PROs following their procedure and offer a ‘routine’ for study staff responsible for data collection.

When more than one PRO questionnaire is scheduled, it is recommended that the order of questionnaires is standardised, with those higher in the endpoint hierarchy being collected first.

These two forms of standardisation of PRO administration are examples of the more general principle in research methodology that standardisation of methods reduces unwanted sources of variation, whether random (ie, no net effect on estimates of interest, such as the impact of interventions on PROs) or systematic (ie, causing bias).

SPIRIT-14-PRO Elaboration

When a PRO is the primary endpoint, state the required sample size (and how it was determined) and recruitment target (accounting for expected loss to follow-up). If sample size is not established based on the PRO endpoint, then discuss the power of the principal PRO analyses.

Examples

Trial name: the chronic autoimmune thyroiditis quality of life selenium trial (CATALYST)

PRO endpoints: 1°

‘The primary outcome is thyroid-related quality of life during 12 months’ intervention, as measured by a composite score from the ThyPRO questionnaire. Sample size estimation is based on this outcome.

The trial should be sufficiently powered to identify a difference between the intervention and the control group of 4 points on the 0–100 ThyPRO composite scale, corresponding to a small to moderate effect. In previously obtained data, the SD of ThyPRO-scores (sigma level) was 20 points. With a correlation between observations on the same participant of 0.50, and a power of 80% and a type I error probability (two-sided α level) of 0.05, a sample size of 236 experimental participants and 236 control participants is required. The sample size estimate is based on a design with five repeated measurements having a compound symmetry covariance structure’.47

Trial name: cosmesis and body image after single-port laparoscopic or conventional laparoscopic cholecystectomy: a multicentre double-blinded randomised controlled trial (SPOCC-trial)

PRO endpoints: 1°, 2°

‘The primary endpoint of the study concerns patient’s satisfaction with cosmesis and body image 12 weeks after surgery. This endpoint is assessed using a validated cosmesis and body image score (CBIS) that was previously used in surgery for Crohn’s disease and in donor nephrectomy. This score is calculated on an 8-item multiple choice type questionnaire ranging between 8 and 48 points.

A clinically relevant improvement of the CBIS is defined as an improvement of 20% of the cosmesis score (8 points). Given the reported SD of the CBIS between 4 and 6 and using (alpha=0.05 and beta=0.90), two groups of 49 patients are needed. This is based on a two-sided significance level (alpha) of 0.05 and a power of 0.90. Estimating a 10% dropout rate, which is common in randomised controlled trials, 55 patients will be randomised per arm.’48

Trial group: TROG

Trial name: a randomised phase III study of radiation doses and fractionation schedules for ductal carcinoma in situ of the breast (BIG 3-07/TROG 07.01)

PRO endpoints: 2°

The sample size for this trial, based on the primary endpoint (time to local recurrence of invasive or intraductal breast cancer in the ipsilateral breast), was 1600 patients. The sample size for the PRO substudy was determined a priori, and was less than that required for the primary endpoint, as explained in the protocol excerpt below. Therefore, patients recruited after the PRO-specific target sample size was achieved did not complete PRO questionnaires, saving trial resources in data collection and management.

‘Sample size determination: for the quality of life study aiming to detect a difference between the tumour bed boost and no boost groups of 0.2 SD of a continuous scale such as fatigue or physical symptoms, with 80% power at a two-sided alpha level of 5%, the required sample size is 790 patients. To allow for attrition at a rate of 5% per year, 1020 patients are required to participate in the quality of life study.’49

Explanation

As with any primary endpoint, including those that focus on PRO, the criteria and methods for estimating the necessary sample size should be specified, with adjustments for expected discontinuation from the clinical study.46 Ideally, the criteria for clinical significance (eg, minimal important difference, clinically meaningful within-patient change threshold, responder definition) should be specified when known.50 51 It is important to note that the FDA is more interested in what constitutes a meaningful within-patient change in score from the patient perspective.16

In cases where the PRO is specified as a key secondary endpoint, the statistical power based on the estimated sample size for the primary endpoint, should be determined. If overpowered, specifying a smaller PRO-specific sample size will save trial resources, as illustrated in the BIG 3–07/TROG 07.01 example. When sufficient power may be achieved by collecting PROs from a representative subset of participants, the sampling strategy should be clearly described.

Only 50.7% of NIHR Health Technology Assessment clinical trial protocols address sample size and statistical power for PRO specified as secondary endpoints.3 If the clinical trial is international in scope, the sampling across countries may be influenced by availability of language translations.52 In addition, the variability of measurement between countries may inflate type 2 error (reduces power).

SPIRIT-18a(i)-PRO Extension

Justify the PRO instrument to be used and describe domains, number of items, recall period, instrument scaling and scoring (eg, range and direction of scores indicating a good or poor outcome). Evidence of PRO instrument measurement properties, interpretation guidelines and patient acceptability and burden should be provided or cited if available, ideally in the population of interest. State whether the measure will be used in accordance with any user manual and specify and justify deviations if planned.

Examples

Trial name: impact of a multimodal support intervention after a ‘mild’ stroke (YOU CALL-WE CALL)

PRO endpoints: 1°, 2°

‘A number of quality of life tools were reviewed (eg, SF-36, Stroke Impact Scale, Quality of Life Index (QLI)) and the tool chosen was a compromise between psychometric properties and adequacy of content for mild stroke. The 32-item questionnaire QLI (Reference) which was developed from Ferran’s conceptual model of quality of life and which has been used with a stroke clientele (Reference) was chosen as the primary outcome. Each item of the QLI as relating to four life domains (health and functioning, socioeconomic, psychological/spiritual and family), is evaluated in terms of satisfaction and importance on a 6-point scale. Scores for each domain and a global score are expressed from 0 to 30, with a higher score indicating a better quality of life. These four life domains relate well with the main issues covered through the WE CALL intervention. It has shown to have adequate psychometric properties (concurrent validity, test–retest reliability and high internal consistency: a=0.90) (Reference) and thus should be responsive to therapy-induced change (Reference). A 1-point difference was observed in the first 6 months poststroke descriptive follow-up (n=63) for an effect size of 0.33 (Reference). A 2-point difference is considered a clinically meaningful change leading to a moderate effect size of 0.66.’53

Trial name: a randomised phase II/III multicentre clinical trial of definitive chemoradiation, with or without cetuximab, in carcinoma of the oesophagus (SCOPE 1: Study of Chemoradiotherapy in Oesophageal Cancer Plus or Minus Erbitux)

PRO endpoints: 2°

Explanation

The justification for the selection of PRO instrument(s) is required in the trial protocol. This will help trial personnel and participants understand why specific measures are being used and how they directly address the trial objectives and stakeholder needs.11 For example, regulatory agencies often focus on physical symptoms and functioning to inform licensing and labelling claims, whereas patients and health-policy makers may be more interested in broader aspects of HRQL, such as engaging in social activities and emotional well-being.55 56 For regulatory trials, it is prudent to seek regulatory advice at an early stage of trial development regarding the acceptability of the instrument and the approach to PRO assessment. Stakeholder-relevant PROs can be identified through patient involvement, qualitative research or core outcome sets,56 57 which alongside clinical outcomes, often include outcomes such as symptom burden, functioning, and disease control, which can be measured using PRO instruments.

Appropriately developed and evaluated PRO instruments can provide more sensitive and specific measurements of the effects of medical intervention, thereby increasing the efficiency of clinical trials that attempt to measure the meaningful treatment benefits of those therapies.58–60 Irrespective of whether the trial is conducted for regulatory purposes, FDA guidance and ISOQOL guidance provide a useful conceptual framework to assist in the selection of measures.16 61 Identifying and selecting valid, reliable tools that are acceptable to patients from the target population may prove challenging. The Consensus Based Standards for the Selection of Health Measurement Instruments (COMET) initiative and the Evaluating the Measurement of Patient Reported Outcomes programme provide useful guidance to support the review of measurement properties.56 62 63

Ideally, the PRO instrument(s) will have been validated in the target population and this evidence cited. This will help reviewers understand if claims being supported by the PRO instrument can be substantiated by the evidence for using that instrument in that, or a related, population. Further details on the domains, number of items, recall period, instrument scaling and scoring (eg, range and direction of scores indicating a good or poor outcome) should be provided. This will assist trial personnel in the collection and analysis of the PRO data. Questionnaires should be used in accordance with user manuals to promote good data quality and ensure standardised scoring. Deviations from user manuals or different ways of capturing PRO data may invalidate the measure; therefore, any deviations should be declared and transparently reported.19

If in the trial there are plans to use a questionnaire which has not been validated in the trial’s target population, or if a new instrument is being developed alongside the trial, it is important to explain this in the protocol. Including an outline of any plans for the evaluation of its measurement properties using the trial data, if this will be undertaken, and if not why. This should be in accordance with established current guidelines for PRO validation.64

Although all the reviewed NIHR Health Technology Assessment clinical trial protocols identified the PRO instrument to be used in the trial, few justified their use in relation to the study hypotheses, PRO instrument measurement properties or expected participant burden (41.3%, 37.3% and 14.7%, respectively).3

Patient partners involved in the design of the study can assist with the selection of PRO instruments and provide feedback on the likely acceptability of the questions, and participant burden (eg, time taken for completion, cognitive burden, emotional burden, repetition across questionnaires).65 The number of PRO instruments/questions to be assessed in a trial requires careful justification. Minimising participant burden has been identified as a strategy to reduce risk of missing PRO data, improve recruitment and retention.30

SPIRIT-18a(ii)-PRO Extension

Includes a data collection plan outlining the permitted mode(s) of administration (eg, paper, telephone, electronic, other) and setting (eg, clinic, home, other).

Examples

Trial name: early surgery versus optimal current step-up practice for chronic pancreatitis: a multicentre randomised controlled trial

PRO endpoints: 1°, 2°

‘The Izbicki pain score will be assessed every 2 weeks during a follow-up period of 18 months. For this end, the Izbicki pain score will be assessed via a web questionnaire. Patients who do not have an email will be given a folder with Izbiki pain score forms and return envelops. Patients will be contacted by telephone every 2 weeks and reminded to fill in the questionnaire and send it to the trial coordinators. The Izbicki pain score is a one page questionnaire, easily completed in <3 min. The folder with the Izbicki score forms will be re-filled at every outpatient clinic visit (scheduled every 6 months).’66

Trial name: a randomised multistage phase II/III study of sunitinib comparing temporary cessation with allowing continuation, at the time of maximal radiological response, in the first-line treatment of locally advanced/metastatic renal cancer (STAR)

PRO endpoints: 1°, 2°

Quality of life questionnaires during the first 6 months will be administered in clinic in order to support participant use before postal questionnaires are instituted after 6 months for the EQ-5DTM/EQ-VAS (Functional Assessment of Cancer Therapy - General (FACT-G) and Functional Assessment of Cancer Therapy-Kidney Symptom Index (FSKI) will continued to be collected at clinic visits). Clinic staff should remind participants of the importance of the quality of life assessments at each clinic visit.

Due to the importance of HRQL data in this trial, measures will be taken to ensure maximum compliance of questionnaire completion. For the 2 weekly questionnaires which participants complete at home from the 24-week timepoint, where the participant consents to this, reminders for completion are sent by email or text message to the participant by the research team at the Clinical Trials Research Unit (CTRU): this is an optional part of the STAR Informed Consent Form. Where a HRQL questionnaire would be completed at a hospital clinic visit, but the local research team forget to give this to the participant, of the participant no longer attends clinic visits at hospital during their follow-up period, a questionnaire for the local research team will send this out by post to the participant’s home after checking the participant’s status and establishing it is appropriate to do so.67 68

Explanation

Standardisation of all aspects of PRO administration is vital to PRO data quality. It is therefore critical that research personnel and trial participants understand how, when and where PRO data will be collected in the study.10 The study protocol should specify the permitted mode(s), method(s) and setting(s) of PRO data collection, including the permitted ‘back-up’ options and preplanned reminders. For example, when PRO assessment is conducted in clinic via a tablet computer, paper forms could be permitted (and available) as a back-up option for instances when the tablet is not available or functioning properly. Offering alternative modes of completion may help improve response rates.30 Of note, the FDA has previously recommended that there is a back-up plan for electronic PRO data collection (eg, web-based, phone-based or paper-based) implemented in case of malfunctions with electronic devices.69

Electronic PRO assessment is increasingly available in trials, but traditional paper-based methods may still be useful or required in some situations. It is therefore important to know whether there are systematic differences induced by mode of administration. A recent meta-analysis that included 31 studies that randomised participants to different data collection modes found no evidence of bias associated with paper versus electronic administration.70 These results support the use of multiple modes of administration within a research study, which may be a useful strategy for reducing missing PRO data. If evidence of equivalence between different modes of administration is available for the specific PRO questionnaires in a trial, it should be considered in determining the PRO administration plan. If electronic administration has not been attempted before for the trial PRO questionnaires, and only minor modifications to layout/presentation are needed with respect to the paper-based versions, it is advisable to pilot-test usability and conduct cognitive debriefing to assess equivalence.70 71 The International Society for Pharmacoeconomics and Outcomes Research provide useful guidance on key considerations for PRO data collection including multiple modes.71 72

The setting for PRO data collection, for example, in clinic or at home (or clinic at baseline, with follow-up at home), should be described and standardised across trial intervention groups and sites. Differential use of settings and modes of administration by treatment arm should be avoided as these may lead to different response rates and potentially biased results.11

The protocol should also specify the types of assistance trial staff can provide patients for completing the PRO assessment. Respondents should be encouraged to self-complete as far as possible. Some respondents may require some assistance, however, the greater the degree of assistance, the greater the potential to influence a respondent’s responses. Assistance should therefore be limited, provided only by a trained member of the research team, or a trained third party, the permissible types of assistance should be clearly specified in the protocol and reviewed in staff training. Allowable assistance might include instructions on how patients can input their answer on the tablet, clarifying the response options, reading questions to the participant or recording the participants’ answer on the form/tablet. This level of assistance facilitates self-administration of the PRO instrument. Completion of a PRO instrument with an interpreter, caregiver or family member should be avoided as these individuals have not been trained, and may influence the individual’s responses, either directly by expressing opinions that influence the participant to alter their answers, or indirectly, for example, if the respondent seeks to avoid embarrassment or to provide a more acceptable answer (social desirability bias).

Furthermore, use of a human language interpreter should be avoided. When planning a study, common languages spoken by patients attending the recruiting centres should be considered so that validated language translations of chosen PRO instruments can be obtained (see SPIRIT-18a(iii)-PRO Extension).

Interviewer administration of PRO instruments should be avoided, but where necessary, should be clearly justified in the protocol. Interviewers should read questions verbatim, ideally using a PRO instrument that has been validated in that mode. Similarly, proxy or observer completion requires a proxy-validated/observer-reported version of the PRO instrument (see SPIRIT-18a(iv)-PRO Extension).

SPIRIT-18a(iii)-PRO Extension

Specify whether more than one language version will be used and state whether translated versions have been developed using currently recommended methods.

Example

Trial name: A Phase III, randomised, open label trial of lenalidomide/dexamethasone with or without elotuzumab in relapsed or refractory multiple myeloma (ELOQUENT – 2)

PRO endpoints: 2°, exploratory

Explanation

Trials involving participants with different language requirements require measures that have been translated and culturally adapted using appropriate methodology.10 12 74 75 Providing culture-appropriate and language-appropriate PRO instruments for use in the trial can lead to a reduction in missing data, ability to recruit people from ethnic minority groups, lower attrition rates and improved generalisability of trial results.76 If the countries/languages are not known at the time of protocol writing then more general protocol content may be appropriate:

multiple language validated versions are available [provide references where these can be found] and the correct language for this patient should be used.

At present, the extent to which this is happening is not clear. A review of protocols and/or subsequent publications from cancer clinical trials with a PRO endpoint, registered on the NIHR portfolio examined reporting of ethnically diverse recruitment and the use of culturally and linguistically validated PRO instruments. The review found a lack of transparency around the use of culturally and linguistically appropriate PRO instruments. Of the 88 studies reviewed, only 14 (17%) reported any type of data on ethnic diversity. Although eight studies were multicentre, multinational cancer clinical trials, none identified if translated versions of PRO instruments were being used.77

There are clear guidelines for translating PRO instruments,74 78 and plans to use translated versions, should be specified in the protocol, citing references when available.10 Specification of use of translated versions in the protocol will help reporting in accordance with CONSORT-PRO.19 74 75 It must not be assumed that linguistic translation equates to cross-cultural adaptation (preparing the instrument for use in another setting). A number of studies79 80 have recommended that cross-cultural equivalence is also an important consideration.74 75 81

Using different language versions of PRO instruments to collect data in a trial ideally requires evidence to support the psychometric equivalence of data being reported, especially if data are going to be pooled for clinical trial evaluation.52 82 83 Where such evidence is unavailable, prespecification in the statistical analysis plan (SAP) of exploratory analyses to assess whether there are differences between PROs by language group may be appropriate. The language in which each patient complete the questionnaire should be recorded in the database to inform such analyses.52

SPIRIT-18a(iv)-PRO Extension

When the trial context requires someone other than a trial participant to answer on his or her behalf (a proxy-reported outcome), state and justify the use of a proxy respondent. Provide or cite evidence of the validity of proxy assessment if available.

Examples

Trial name: cognitive rehabilitation in paediatric acquired brain injury—a randomised controlled trial (CORE-pABI)

PRO endpoints: 1°, 2°

‘[Paediatric Acquired Brain Injury] constitutes a major disruption to child development and may affect cognitive, behavioural, emotional, social as well as academic function.

The primary outcome measure is the BRIEF, parent report (Reference). BRIEF is an 86-item standardised questionnaire that captures parents perceptions of a child’s executive function in his or her everyday environment. Each item’s frequency of occurrence is rated on a 3-point Likert scale from 1 (never) to 3 (often). It has demonstrated good reliability, with high test–retest reliability (r=0.88 for teachers,82 for parents), internal consistency (Cronbach’s α=0.80–0.98) and moderate correlations have been detected between teacher and parent ratings (r=0.32–0.34). The questionnaire has been applied to several clinical groups in Norway.’84

Trial name: evaluating the effectiveness and cost effectiveness of dementia care mapping (DCM) to enable person-centred care for people with dementia and their carers: a cluster randomised controlled trial in care homes (DCM EPIC study 1.0)

PRO endpoints: 2°

‘Relative/friend criteria

To be eligible to provide proxy data about a resident, relatives/friends must: have visited the resident on a regular basis over the past month (ie, at least once per week). Be willing to provide data at a time convenient to them. Have sufficient proficiency in English to contribute to the data collection required for the research.’85

Explanation

In some contexts, such as trials involving young children or cognitively impaired participants or participants who are unable to reliably self-report for other reasons, it may be necessary for a proxy—someone other than a trial participant, to report the participant’s outcomes on their behalf as though they are the patient.10 86

Proxy reports should be used only when necessary. The European Medicines Agency states that ‘in general proxy reporting should be avoided, unless the use of such “proxy raters” may be the only effective means of obtaining information that might otherwise be lost.’16 43 The US FDA also discourages the use of proxy-reported outcomes to inform labelling claims, recommending observer reports for observable phenomenon only (eg, vomiting, but not nausea) instead.

In contexts such as cancer, dementia or palliative care, it is reasonable to anticipate the need for proxy response throughout all or some of the trial. Previous studies have shown varying levels of agreement between participant and proxy ratings, dependent on the variable being measured, the quality, duration and stability of the relationship between proxy and participant.87 88

A trial protocol should indicate clearly who is eligible to provide the proxy report, with explicit administration guidelines for completion of proxy measures including how the report is to be captured, whether that same individual must be the ‘consistent rater’ across all timepoints of assessment (this is preferable, for consistency), or whether varying proxy reports will be permissible. This information should also be provided for observer-reported outcomes.

Just as the measurement properties of the PRO instrument should be specified, so should the properties of measures to be used by proxy reporters.

Given known issues with patient and proxy reporter discordance,88–91 while patient-participants are still able to self-complete, collecting both participant and proxy-reported data enables quantification of the size and direction of any bias, that may later be adjusted for, if needed. Further data may be gathered about the proxy (eg, age, relationship to the patient, gender, proxy literacy, relationship and exposure to the patient92) as these variables may guide interpretation of results and any subgroup/sensitivity analyses. Whether proxy-reported data will be analysed separately or pooled with participant-reported data should also be detailed. Any such plans should be specified in the protocol and SAP. This information should also be provided for observer-reported outcomes.

SPIRIT-18b(i)-PRO Extension

Specify PRO data collection and management strategies for minimising avoidable missing data.

Examples

Trial group: National Cancer Institute, Naples

Trial name: phase III randomised multicentre trial of carboplatin+liposomal doxorubicin versus carboplatin+paclitaxel in patients with ovarian cancer (Multicentre Italian Trials in Ovarian Cancer-2 (MITO-2))

PRO endpoints: 2°

‘Operating procedure:

• It is fundamental that the researchers take great care when collecting the questionnaires, in order to allow good compliance by the patients participating in the protocol.

• The quality of life form must be filled in by the patient herself.

• The quality of life form must be filled in before the clinical examination, and thus before the discussion with the examining doctor which may provide favourable or unfavourable information about the disease’s status.

• When supplying the form to the patient, it is important to explain how to fill it in without going into details about the contents of the questions.

• After the form has been returned, check that the patient has answered all the questions and ask her to reply to any questions she has skipped.

• The quality of life questionnaires must be filled in using a black or blue pen.’93

Trial group: National Cancer Institute of Canada Clinical Trials Group (NCIC CTG)

Trial name: a double-blind randomisation to letrozole or placebo for women previously diagnosed with primary breast cancer completing 5 years of adjuvant aromatase inhibitor either as initial therapy or after tamoxifen (including those in the MA.17 Study) (NCIC CTG: MA.17R)

PRO endpoints: 2°

Explanation

Missing PRO data are a particular problem because data cannot be obtained retrospectively or from medical records. Missing PRO data may arise from different sources95 and, broadly speaking, missing data can be attributed to causes that are unavoidable or avoidable. Unavoidable reasons may include if a participant has died or become too unwell to self-complete PRO instruments. Avoidable reasons may include some type of human error that could have been prevented. Examples of avoidable missing data include: staff failing to hand out a scheduled questionnaire; a participant not realising the questionnaire is double-sided so missing half of the questions; an electronic PRO device not being charged; the internet or server being down; when the PRO assessment is overly burdensome on the patient (eg, due to the burden of multiple questionnaires at one time or repetitive scales) so the patient decides not to complete it.

Although ‘unavoidable’ types of missing data are more challenging for interpretation because the missing data may be related to the measured outcome and it is impossible to accurately calculate the extent of any associated bias,96 97 avoidable types of missing data are also problematic.30 Avoidable missing PRO data compromise the interpretability, accuracy and value of PRO findings because study power is reduced, which increases the risk of type 2 errors,96 and because any assumptions made during the analysis about missing PRO values are not verifiable.98

There are a range of design, implementation and reporting strategies to help minimise and address missing PRO data,30 most of which can be addressed in the trial protocol. Specific recommendations related to data collection and management include: refraining from administering an excessive number of questionnaires to participants (researchers should refrain from collecting more data than they really need), using standardised and documented PRO administration procedures, engaging and educating participants in the trial by providing updates or incentives, maintaining participant records, employing active quality assurance measures (such as real-time compliance/completion monitoring, sending reminders for upcoming or missed assessments, checking completed questionnaires for missing items while the participant is still present at clinic), appointing a dedicated staff member responsible for PRO assessment at each centre, training staff about the importance of PROs as well as procedures for assessment, offering an alternative mode of administration if the participant is not able to complete the questionnaire via the primary mode (eg, completing the questionnaire over the phone if the hardcopy cannot be completed at the clinic within the acceptable time-window) and recording reasons for missed assessments using standardised forms.30 From a regulatory perspective, the FDA encourages maintaining consistency in assessment methods, however, this should be balanced with reduction of missing data. If different modes are used, they should be justified and presented in the study documentation.99 If different modes are used, ‘FDA will review the comparability of data obtained when using multiple data collection methods or administration modes within a single clinical trial to determine whether the treatment effect varies by method or mode.’69 Additional strategies are described in the full review.30

The MITO-2 and MA.17R examples above illustrate some of these strategies. MA.17R comes from the Canadian Cancer Trials Group (CCTG), a multicentre cooperative oncology group that conducts clinical trials in cancer therapy, supportive care and prevention. The CCTG requires completion of the PRO questionnaire(s) as a prerandomisation eligibility requirement (as per SPIRIT-10-PRO Extension). This flags the importance of PRO data to investigators and clinical research associates, indicating PROs are as important as other inclusion clinical criteria. It also helps to maximise compliance.

Our prior work suggests that few trials actively specify such procedures in their protocols; 46.7% HTA protocols3 and 38.5% of international ovarian cancer trials4 included strategies to minimise avoidable missing data.

SPIRIT-18b(ii)-PRO Elaboration

Describe the process of PRO assessment for participants who discontinue or deviate from the assigned intervention protocol.

Examples

Trial name: a multicentre, open-label, randomised, two-arm phase III trial on the effect on PFS of bevacizumab plus chemotherapy versus chemotherapy alone in patients with platinum-resistant, epithelial ovarian, fallopian tube or primary peritoneal cancer (AURELIA)

PRO endpoints: 2°

AURELIA was a multicentre, open-label, randomised, two-arm phase III trial of bevacizumab plus chemotherapy versus chemotherapy alone in patients with platinum-resistant, epithelial ovarian, fallopian tube or primary peritoneal cancer (Reference). The primary endpoint was PFS; quality of life was a secondary endpoint. The protocol stated that:

‘On clear evidence of disease progression (PD) or toxicity, study therapy should be discontinued permanently.’

The protocol also specified postprogression treatment options: women who had been on the chemotherapy alone arm would have the option of bevacizumab alone or standard of care, while those who had been on the chemotherapy plus bevacizumab arm would receive standard of care treatment. The protocol stated that:

‘In case the patient decides to prematurely discontinue study treatment (“refuses treatment”), she should be asked if she can still be contacted for further information’ and that ‘after PD, patients will be followed for survival only.’

However, it lacked an explicit statement about PRO assessment postprogression, which may explain some inconsistency among sites, with some sites collecting PRO data postprogression, and other not.

As stated in the AURELIA PRO paper (reference, p1310), ‘only questionnaires completed until PD were included in the main analyses. Questionnaires completed after PD were excluded based on the medical assumption that these patients were unlikely to be benefiting from their study treatment, may have been receiving another treatment and were therefore not relevant to the intended comparison of chemotherapy alone versus bevacizumab plus chemotherapy. However, post hoc sensitivity analyses were performed to determine the impact of questionnaires completed after PD.’ The latter analyses were consistent with the main analyses, but could perhaps have been avoided, and patients saved unnecessary HRQL assessment burden, if the protocol has contained a clear statement that HRQL assessments should cease at disease progression.100

Trial group: Australasian Leukaemia & Lymphoma Group (ALLG)

Trial name: BLAM-A phase IIb study of blinatumomab+cytarabine (AraC) and methotrexate in adult B-precursor acute lymphoblastic leukaemia (ALLG ALL8)

PRO endpoints: 2°

ALLG ALL8 is a BLAM-A phase IIb study of blinatumomab+cytarabine (AraC) and methotrexate in adult B-precursor acute lymphoblastic leukaemia (B-ALL). It is a single-arm study which aims to demonstrate preliminary evidence of the benefit of frontline blinatumomab in combination with cytarabine and methotrexate in adult B-ALL, and to demonstrate the ability of this combination to attain deep (MRDnegative) remissions and hence to reduce the need for allogeneic stem cell transplantation. The ALLG ALL8 protocol specifies that the decision for allogeneic stem cell transplantation is left up to the investigator, and that patients who proceed to allogeneic stem cell transplant discontinue the assigned intervention protocol. Being recommended for allogeneic stem cell transplant is therefore a withdrawal criteria. However, patients do not have to withdraw—it is optional, the patient’s choice. The trial team is in fact interested in the experience of patients who proceed to allogeneic stem cell transplant. So the protocol states:

Subjects who proceed to allogeneic stem cell transplant who have not withdrawn consent to the study should have FACT-Leu (HRQL questionnaire) assessments performed 6-monthly.

This provides the trial team with the opportunity to document the experience of patients who proceed to allogeneic stem cell transplant in terms of the range of common symptoms and aspects of well-being assessed by FACT-Leu.101

Explanation

A clear plan for collection of PROs for trial participants who withdraw early from a study or who discontinue the intervention helps minimise bias,102 ensures that staff collect all required PRO data in a standardised and timely way, and may assist ethical appraisal of the study.10 102

Often, participants can provide valuable PRO data even after stopping the assigned intervention protocol, whether due to personal choice and/or clinical recommendation, as illustrated in the one-arm phase II trial ALLG ALL8 trial. However, this does not hold in all contexts (as illustrated in the AURELIA trial), a randomised phase III trial, in which participants whose cancer had progressed on their assigned treatments, were then often switched to alternative treatment.

Providing a clear description of the process of PRO assessment for participants who discontinue or deviate from the assigned intervention protocol and how the data will be used, enables all staff to follow a standardised procedure to collect the required PRO data in timely way and to avoid collecting data that will not contribute to analysis.

Correspondingly, the SAP should be clear on how such data will be handled. In the case where postdiscontinuation/deviation PRO data are useful, the SAP should state the study objective that these data will address and how they will be analysed.

Participants should also be aware of this process, so a simple and clear description of whether or not they will be asked to continue to complete PRO questionnaires after stopping or changing the treatment they were initially allocated to should be included in the participant information sheet (PIS).

SPIRIT-20a-PRO Elaboration

State PRO analysis methods, including any plans for addressing multiplicity/type I (α) error.

Example

Trial name: a phase III, randomised double-blind, placebo-controlled study of the efficacy and safety of two doses of tofacitinib (Cp-690,550) in subjects with active psoriatic arthritis and an inadequate response to at least one tumour necrosis factor inhibitor (OPAL BEYOND)

PRO endpoints: 1°, 2°, exploratory

Explanation

Statistical analysis of multiple domains10 104 and timepoints implies multiple hypothesis testing, which inflates the probability of false-positive results (type I error).46 This can be contained by prespecifying the key PRO domain(s) or overall score of interest and the principal timepoint(s) which cross-reference to SPIRIT-7-PRO Extension and SPIRIT-12-PRO Extension.

Any plans to address multiplicity, such as stepwise or sequential analyses, whereby multiple endpoints are tested in a defined sequence that contains the overall type I error to the desired level, or conventional non-hierarchical methods (eg, Bonferroni correction), should be specified a priori.16 There are many strategies and/or choices of methods that may be appropriate.105 Family-wise type I error should be considered for all of the applicable endpoints of the trials together and not for the PRO endpoints separately. Some clinical trials include PROs as exploratory endpoints and no adjustment is made for multiplicity in subscale scores administered at multiple study visits. These analyses may only provide limited information on the tolerability of the intervention.

Protocols should make some reference to key considerations for the analysis of the trial PROs (including any plans for addressing multiple testing), but the detail is often more appropriately included in the SAP, usually developed after the protocol. If no adjustments for type I error are to be made, then this should be clearly stated. However, clinical trial protocols in which PROs are secondary outcomes rarely include any information about PRO statistical analyses, beyond any that are prespecified as primary or key secondary endpoints or when the sponsor is interested in achieving a product label claim. Our review of trial protocols found that fewer than 2% provided information on the statistical analysis plans to address multiplicity for the PRO endpoints.3

SPIRIT-20c-PRO Elaboration

State how missing data will be described and outline the methods for handling missing items or entire assessments (eg, approach to imputation and sensitivity analyses).

Example

Trial group: European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group, and Gynecologic Cancer Intergroup (EORTC-GCG and GCIG)

Trial name: a randomised, multicentre, phase III study of erlotinib versus observation in patients with no evidence of disease progression after first line, platinum-based chemotherapy for high-risk ovarian epithelial, primary peritoneal, or fallopian tube cancer (EORTC 55041)

PRO endpoints: 2°

Explanation

Most clinical trials with PROs will have some missing PRO data,98 yet a review of protocols found that less than half outlined statistical methods to deal with missing PRO data.3

There are two types of missing PRO data: (1) missing items, when the participant completes some but not all of the questions within a PRO instrument and (2) missing assessments, when the participant does not complete a scheduled assessment at all (ie, there are no PRO data available for analysis from the participant at that assessment timepoint). The latter type is more serious, as it potentially affects the choice of analysis method and the interpretation and generalisability of the results. The trial protocol should explain how both types of missing data will be handled in the analysis.

1. Handling missing items: many PRO scoring manuals provide guidance for handling missing items. A common approach is to impute the mean score of the completed items, if less than one-half of items comprising the scale are missing.107 108 This approach is possible for multi-item scales but it is not possible to impute scores for single item scales. Always consult the scoring manual to determine how to handle missing items, and cite the manual in the protocol. Missing items of PRO instruments that are underpinned by modern psychometrics techniques (Item Response Theory or Rasch Measurement Theory) are naturally handled without requiring imputation.34 109

2. Handling missed assessments: missing assessments present a major problem for PRO analyses; lead to a loss of power and wider CIs from a lack of precision,110 111 and potentially to biased results. The risk of bias depends on the underlying cause of why data are missing (called the ‘missing data mechanism’), and this in turn should influence the choice of statistical analysis methods.

In order to gain insights into the mechanism of missing PRO data, it is helpful to ascertain and record reasons for missed PRO assessments during trial conduct. The protocol needs to describe how these reasons will be collected in a standardised manner. Typically, a standard form is used (which can be included in the online supplemental appendix along with the PRO questionnaires). Also, the form can be used to collect additional data (referred to as ‘auxiliary data’) related to ‘missingness’ or the PRO,30 which should be specified in the protocol.

The trial protocol should also provide a summary of how missing data will be described and handled in the analysis,10 and state that comprehensive details about the planned analysis will be provided in a subsequent SAP.112 The SISAQOL Consortium have developed a taxonomy of research objectives that can be matched with appropriate statistical methods for PRO analysis, standardised statistical terminology relating to missing data and are determining appropriate ways to manage missing data, currently focused in an oncology setting. A simulation study was done to assess whether it was possible to have a threshold to define substantial missing data.113 Although no agreement was reached for a threshold, the simulation study showed that the effect of missing data rates on PRO findings depends on the type of missing data (ie, informative or non-informative missing data). It was recommended that collecting reasons for missing data is key in assessing the effect of missing data for PRO findings.34 Additionally, SISAQOL is developing a set of macros to describe patterns of missing data, and to evaluate imputation methods for use in sensitivity analysis.34 36 38

SPIRIT-22-PRO Extension

State whether or not PRO data will be monitored during the study to inform the clinical care of individual trial participants and, if so, how this will be managed in a standardised way. Describe how this process will be explained to participants, for example, in the PIS and consent form.

Example

Trial name: the use of an electronic patient-reported outcome measure in the management of patients with advanced chronic kidney disease (RePROM)

PRO endpoints: 2°

Explanation

To protect participant safety, PRO data may be monitored during a study for signs of psychological distress or physical symptoms that may require an immediate response: so-called ‘PRO Alerts’.115 Examples of PRO data that may raise concern include signs of psychological distress, poor physical well-being or high symptom burden presenting as extreme scores on questionnaires. Concerns can also arise when additional information is provided by the participant (eg, through free text report), or in discussions between the participant and research staff.115 The nature of some studies may mean that participants are more at risk than in others. In studies where prior risk assessment deems the probability of PRO alerts being generated by participants to be minimal, PRO data may not be reviewed until the end of the trial for pragmatic reasons, however, concerning PRO data, may still arise during the course of the study.11 116 If monitoring is not planned this should be stated. If monitoring is planned, steps for how PRO alerts will be dealt with should be included in the trial protocol, to provide immediate reassurance to concerned trial staff about how to proceed and promote appropriate clinical management and transparency considering professional obligations to patient care. Any arising interventions should be recorded. Evidence suggests the absence of such information leads to inconsistent handling of concerning data including administration of non-prespecified interventions to aid the trial participant which risks co-intervention bias that is, bias caused by ‘any intervention other than the experimental manoeuver that alters the frequency of a trial’s outcome of interest’.12 116 117 Identifying participants at risk and in need of urgent attention through PRO monitoring is an ethical issue as is acknowledging that information identified in the completion of a PRO too may be shared with the clinical team when the need arises. Information about how the trial staff will respond to concerns, or alternative support mechanisms where monitoring is not taking place, should be provided to participants (in participant information and consent documentation). This information provided in the patient information sheet (PIS) will manage participant expectations and ensure transparent and explicit communication about the intended use of PRO study data in fulfilment of contemporary data protection laws, for example, the European Union General Data Protection Regulation.118

There is no regulatory requirement from the US FDA that PRO data measuring symptomatic side effects be monitored and alerts for these items created. However, it is good practice to remind participants at each PRO assessment whether their data are or is not being monitored in real time. In the case PRO data are not being monitored, participants should be reminded to speak to clinical staff if they are experiencing a specific problem, symptom or side effect.

Protocol template

The PRO protocol template (online supplemental file 2) aims to support protocol writing for pharmaceutical companies, funders, clinicians and international trials groups by providing PRO content that can be incorporated directly into the relevant sections of existing clinical trial protocols or retained as a dedicated PRO section within the protocol.

Supplementary trial documents

Online supplemental 2 outlines additional items recommended for inclusion in other trial documentation, such as the SAP, PIS and training and guidance documents for staff.10 119 This is not an exhaustive list and further PRO content may be warranted in training materials and patient facing documents dependant on the trial. We recommend input from PRO experts working in conjunction with the clinical team, trials unit or Contract Research Organisation and patient partners involved in the co-design of research with regulatory input as required to optimise the protocol and supplementary resources.