Feasibility Study Protocol: Investigating Family Reported Outcome Measures (FROMs) in the Estimation of Societal Value of Advanced Therapy Medicinal Products (ATMPs)

doi:10.21203/rs.3.rs-2474459/v1

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Study Protocol

Feasibility Study Protocol: Investigating Family Reported Outcome Measures (FROMs) in the Estimation of Societal Value of Advanced Therapy Medicinal Products (ATMPs)

https://doi.org/10.21203/rs.3.rs-2474459/v1

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Background

Advance Therapy Medicinal Products (ATMPs) are a novel class of therapeutics that target chronic and severe conditions, which can have an impact beyond the patient themselves; impacting the lives of partners and other family members. This impact is a major secondary burden of disease that in the past has often been ignored. The Family-Reported Outcome Measure (FROM-16) is the first generic questionnaire designed to measure the impact of any disease on the quality of life of family members of patients with any health condition.

We seek to validate the FROM-16 as an instrument for assessing family impact of patients receiving ATMPs and demonstrate a potential mechanism for measuring this impact.

Methods

Up to 30 patients of any age who are preparing for ATMP treatment, or who have received an ATMP treatment, and their family members aged 18 years or older, attending ATMP provider sites within the Midland-Wales Advanced Therapy Treatment Centre will be recruited into this study.

Family members will be asked to complete the FROM-16 and Global Health Score questionnaires, provide basic demographic information and complete a short semi-structured interview conducted by a member of the study team. The interview will provide data to contextualise the FROM-16 responses and allow construct and content validity to be assessed. Themes of experience will be identified from interview transcripts.

The FROM-16 responses will be evaluated with respect to total score, domain score, and individual item score. Reliability of responses between and within domains will be assessed by intraclass correlation.

Discussion

Collecting FROM data from families can be important for demonstrating the wider impact of disease. This study, if successful, will demonstrate that collecting family-reported outcomes using the FROM-16 is a valid mechanism for demonstrating this impact within the population of ATMP patients and their families, and will provide evidence of the overall quality of life impact experienced by partners and family members of such patients, and the specific impacts as identified from the two domains and 16 questions within FROM-16.

Trial Registration

This trial has been adopted onto the NIHR portfolio (I.D. 51376) and registered with https://clinicaltrials.gov/ct2/show/NCT05141318 (#NCT05141318) in December 2021.

Family-Reported Outcome Measures

FROMs

FROM-16

ATMPs

Advanced Therapy Medicinal Products

Value-based Healthcare

Value

Societal Value

Advanced Therapy Medicinal Products

Advanced therapy medicinal products (ATMPs) comprise a heterogenous class of therapeutics, including gene therapy, somatic cellular therapy, tissue engineered therapies and combined advanced therapies, using material derived from human biological sources [1–3]. Intended as a one-time, potentially curative treatment, ATMPs offer ground-breaking new opportunities for treatment of rare conditions, have been applied successfully in a wide range of medical disciplines, and can have a significant impact on a patient’s quality of life [4, 5]. As industry-funded trials for non-rare conditions increase in number, ATMP treatments are expected to be offered to a wider patient base [6].

The price of ATMPs is a critical consideration: per patient annual treatment costs can exceed £300,000 [7]. This may be unaffordable for healthcare providers, especially given the expected increase of ATMP approvals in the following years, which will place further financial burden on healthcare payers [8]. There are also further considerations around potential complications arising from ATMP treatment, success rates, durability of response, salvage/palliative care requirements and treatment centre capacity that can impact the feasibility of providing an ATMP treatment [7].

Value-Based Healthcare

Family members of patients with severe conditions do experience significant impacts upon their lives, but the extent of this impact is not widely known or measured, nor are these data collected routinely [9]. They may experience feelings of anxiety, depression, stress, anger, fear and/or helplessness, as well as worsening of their own disease symptoms if present [10–18]. By collecting family outcomes and measures of impact, it may be possible to refer the family member towards appropriate support services which may reduce this impact

Addressing these impacts can be valuable not only to family members, but also to healthcare providers and society. Value, defined as the outcomes that matter to the patient, divided by the cost of creating that outcome [19, 20], represents a relationship between resource, outcomes and context, where all components must be considered, if value is to be increased [21]. A person’s productivity, taxable earnings, benefit receipts and community contribution, for example, may all be adversely affected by poor health and there may be impact on family members and informal carers that could be profound [17]. This impact may be improved by effective treatment of the index person and the reduction of the impacts are considered components of societal value [22].

Considering the health, social and economic “value created” by an ATMP may justify the associated costs, and doing so can inform decision-making at a policy level [23]. The recent approval of Zolgensma™ demonstrates how an extremely high price of treatment is acceptable to healthcare payers when the potential value of the treatment is also high, whilst coupled with improved Societal Value [24].

Although jurisdictions assess similar metrics when evaluating the value of ATMPs, such as disease burden, therapeutic impact, safety, socioeconomic impact and efficiency, value is considered differently across jurisdictions, due to differing national priorities, and methodological frameworks for health technology assessment (HTA) [25, 26]. HTA methodologies differ within the UK, with Scotland placing more emphasis on social aspects of an ATMP and less emphasis on cost effectiveness and QALYs, compared to England [27]. Additionally, current HTA principles and practices may impede the demonstration of the value of ATMPs [28]. Currently in the UK, the “value” of a treatment is characterised by the cost per quality adjusted life year (QALY), with gene therapies subject to a variable threshold of £300k per QALY [29]; however QALYs do not account for all outcomes that are valued by, or important to, the patient nor their families. Therefore, in the context of ATMPs broadening the definition of “value”, to capture elements not considered by the QALY, such as societal outcomes, may be necessary [26]. Doing so could support outcome-based pricing models, where consideration of the value requires demonstration of positive or desired outcomes beyond cost-effectiveness, are expected to become more prevalent [30].

Outcome-based pricing models requires reliable tools for collecting outcomes, such as patient-reported outcome measures (PROMs) and family-reported outcome measures (FROMs). Whilst the collection of PROs in research and clinical practice is still limited, it is becoming more widespread, with the NHS expanding its requirement to collect PROs. Guidance has been published to conduct pilot and feasibility PRO studies for new PRO instruments [31]. Generally, PROMs can be divided into generic, or disease-specific. Collection of PROs in the context of rare diseases, such as those targeted by ATMP therapies, can be problematic due to small patient populations and disease heterogeneity. A complementary approach, using both generic and disease-specific measures may be beneficial in the context of rare diseases [32]. Family reported outcomes (FROs) are not yet collected routinely, nor currently is there a requirement to do so.

Family-Reported Outcome Measure-16

The Family-Reported Outcome Measure-16 (FROM-16) is the only generic and user-friendly quality of life questionnaire designed to measure the impact of any disease on family members of patients across all medical specialities [18]. Originally developed following interviews of family members of adult and paediatric patients, covering 144 different diagnoses across 26 medical specialities [9], it has since been used to evalute family impact in the fields of urology [33], oncology [34], COVID-19 [35], acquired brain injury [36], and myalgic encephalitis [37, 38]. The 16-item questionnaire has a mean completion time of < 2 minutes and examines two domains of impact (Emotional, and Personal & Social Life), in which the family member is asked to rate the impact they feel as a result of their relative’s disease, with three possible responses (0 = Not at all, 1 = A little, and 2 = A lot). These response options were selected during the development of the FROM-16: Rasch modelling was employed to ensure maximal discrimination between the fewest number of response options [39]. The scores can be examined as a total for all items, within a domain or as individual items, with a higher score indicating greater impact on the family member’s life. It is also applicable cross-culturally and has been translated into multiple languages [34, 36, 39–41].

The reliability and validity of the FROM-16 has been widely demonstrated: it has shown high internal consistency (Cronbach’s α = 0.80–0.92), high reproducibility (intraclass correlation = 0.85–0.92) and strong construct validity [34, 36, 39–41]. There is excellent correlation both between the FROM-16 and Abbreviated World Health Organisation Quality of Life questionnaire (WHOQOL-BREF) total scores (p < 0.001), which is a longer, more in-depth quality of life questionnaire and the patient's overall health score (p < 0.001) [39].

The FROM-16 has not yet been applied to ATMP patients and their families. As ATMPs are a heterogenous class of therapeutics, developed for a very broad range of conditions, with variable impacts upon the patient, and their family, a generic tool is required to measure family quality of life impact successfully in an ATMP patient population. We hypothesise that the FROM-16 could be suitable for evaluating wider impact of disease in ATMP patients and their families, which may provide a framework for demonstrating part of the societal Value created by the use of ATMPs.

Research Aim(s)

This study will validate the use of the FROM-16 as a tool to measure Family-Reported Outcomes for patients in ATMP pathways, by recruiting family members of patients attending ATMP-providing clinics, and asking them to complete the FROM-16, a Global Health Score questionnaire and to undergo a two-stage semi-structured interview.

If validity of the FROM-16 for this use is confirmed, the results from this study would be used to inform the development of a subsequent prospective study on a larger cohort of family members of ATMP patients, examining the change in quality of life impact as measured by FROM-16 scores taken before and after ATMP treatment. Such a study could demonstrate an important and overlooked component of societal value of these very high cost and resource intensive treatments.

Study Population and Sample Size

Family members of patients, of any age, with diagnosed long-term diseases who are being prepared for ATMP therapy, or have completed an ATMP therapy, in ATMP provider centres primarily within the extended Midlands-Wales Advanced Therapy Treatment Centre (ATTC) network in the UK and with capacity to access patients from the pan-UK ATTC network if required.

The expected range of participant numbers recruited for this study will be between 25–40, based on current enrolment numbers of patients within the Midlands-Wales ATTC network treatment programmes. We anticipate a minimum of 12 patients and their family members will be required to demonstrate the utility of the FROM-16 instrument in this population. If we recruit at least 30 patients and their family members, we will be able to examine the dataset for any subgroups that may appear, for example CAR-T therapy vs non-CAR-T therapy, to investigate any differences in FROM-16 scores between these groups.

Recruitment

Patients and their family members will be recruited from ATMP treatment centres in the extended Midlands-Wales ATTC network (Cardiff, Bristol, Birmingham, Leicester). Research nurses and/or pharmacists within the ATTC Network will identify potential participants through routine medical note review. The recruitment process will depend on the treatment status of the patient, within the ATMP treatment pathway. We are seeking to recruit family members of patients who are being prepared for ATMP treatment, or have finished the ATMP treatment process (regardless of outcome).

Patients being prepared for ATMP treatment and/or their families will be contacted by their clinical team by phone to make the patient and family aware that the study is being performed. If the participant requests further information, an introductory letter will be sent out prior to their appointment. The informed consent procedure will take place during the routine appointments at the ATTC clinic, although participants will be given the opportunity to take study materials away for consideration. If this the case, participants will be able to complete the consent form at home, and return it with the questionnaires in a pre-paid envelope.

Family members of patients who have already undergone ATMP treatment will also be asked to participate. We consider it unreasonable to request these potential participants to return to the clinic to provide consent. Therefore, potential participants will initially be approached by the clinical team by telephone call, who will introduce the study. If the patient and family member agree, the Participant Pack containing the study summary, participant information sheets, consent forms, questionnaires and pre-paid return envelope, will be sent to them.

Recruiting sites will record the number of potential participants approached. Reasons for non-participation and non-completion of the FROM-16 will be recorded by the recruiting site. This will be used to estimate the acceptability of the FROM-16.

Paediatric Patients

Some ATMPs are targeted towards patients that are children; therefore, it is necessary to capture the views and experiences of family members of paediatric patients receiving ATMPs.

The process of seeking consent/assent from paediatric patients will be as follows:

Young people aged 16 years and 17 years are assumed to be able to consent and we will seek consent from them in the first instance, but we will also seek consent from the responsible parent/guardian/carer.
Assent will be sought from young people aged between 12 and 15 years and consent from the responsible parent/guardian/carer. Capacity to give consent will be assessed using the principle of “Gillick Competency”. We will maximise a young person’s chances of understanding what is involved by ensuring the information is presented in terms suitable for young people.
For children younger than 12 years of age, consent will be sought primarily from the responsible parent/guardian/carer, however the child must also give assent. Information will be provided in an age-appropriate manner and the researcher/clinician taking consent/assent will be aware of signs that the child does not want to participate.
We anticipate that it will be inappropriate to seek consent/assent from very young children (less than 5 years) and in these cases, the child’s parent/guardian/carer will be approached in the first instance.

All paediatric participants will have the opportunity to ask questions and take study information materials home for consideration with their parent/guardian/carer. Children and their parent/guardian/carer will be reminded that they do not have to participate and may withdraw at any time.

If consent/assent is given from the child, their parent/guardian/carer will be approached to consent to participate in the study as the affected family member.

Inclusion and Exclusion Criteria

Inclusion Criteria

Patients:

Patients of any age
Ability to read English or Welsh (where age-appropriate).
Capacity to give written informed consent, or assent for their family member to participate
Attending ATMP treatment centre with a family member/carer.
Being considered for, or have recently received, ATMP therapy for any diagnosed condition.

Family Members:

Considered by the patient to be the person most affected by the patient’s condition
Adult family members aged 18 years or older.
A family member or partner, living with or caring for, a patient who is being prepared to receive ATMP treatment or has recently received ATMP therapy for any diagnosed condition.
Have capacity to give written informed consent and complete the interview and questionnaires.

Exclusion Criteria

Patients:

Adult patients: Lacking capacity, or unwilling to give written informed consent for their family member to participate.
Gillick competent paediatric patients: unwilling to give written informed assent and/or consent for their family member to participate.
Non-Gillick competent paediatric patients: patient’s parent/guardian refuses to give consent or is unable to give consent on their behalf.
Not being prepared for ATMP therapy, or is currently receiving ATMPs.

Family Members:

Family members under 18 years of age.
Not considered by the patient to be a family member or carer.
Lacking capacity or willingness to give informed written consent to participate
Having a severe handicap or disability that prevents the completion of interview and/or questionnaires.

Interventions

Patients

The intervention that patient participants will undergo in this study is limited to the recruitment and consent process. Adult patients and paediatric patients who are Gillick competent will be asked to name the family member who they consider to be most impacted by their condition.

Family Members

The family member will be asked to complete the FROM-16 and Global Health Score (GHS) questionnaires, provide basic demographic information, and a recorded, two-stage semi-structured interview. The questionnaires will be provided in paper format with a pre-paid return envelope for posting to the study team. The interview will be arranged for a time convenient for the participant and will involve:

The researcher reminding the participant about the FROM-16 questionnaire, and the areas of their life which it covered,
A cognitive debriefing interview of 5 questions assessing the relevance and acceptability of the FROM-16 to the participant,
A ranking process where the participant will be encouraged to select up to 5 items from the FROM-16 that they perceive to be the most important to them and then to rank these items in order of importance,
Following this ranking process, the participant will be asked a short set of open questions to allow them to describe why these items are the most important to them.

In light of the on-going COVID-19 epidemic, and to lessen participant burden, interviews will be performed remotely using tele-communication methods. The participant will have the opportunity to select their preferred method (telephone/Zoom®/Skype®/Teams®).

Data Collection

The data that are expected to be generated by this study will include written and interview generated information from adult family members/partners of patients being treated with ATMPs. We will recruit patients with any condition and record data on what the condition is, as well as demographic information of the patients and their family members.

FROM-16 and GHS Questionnaires

The completed FROM-16 and GHS questionnaires will provide score-based data. Missing FROM-16 data will be treated using the following procedure:

If only one item has not been answered, item is scored as zero and participant is included.
If more than one item has not been answered, the participant is withdrawn from the study.

We will record the proportion of participants who return incomplete FROM-16 questionnaires, and which FROM-16 items are not answered. This will be used to assess the acceptability of the FROM-16 items.

The GHS question posed will be: "Thinking of your affected family member, on scale of 0–10 (worst to best) how severe do you consider that their disease is now?”

Two-Stage Semi-Structured Interview

Interview of all family member participants will be carried out in a two-stage, semi-structured manner; 1) Cognitive debriefing, and 2) Discussion of impact/change

Establish the content validity and acceptability of the FROM-16 to the family members of patients receiving ATMPs by cognitive debriefing. Establishing content validity is considered to be one of the most important properties of an outcome measuring tool [42]. Cognitive debriefing will use the same validated question-set as was previously used to assess the content validity of the FROM-16 in other disease populations [39], with one additional question: Is the questionnaire easy to complete?; Are the response options straightforward?; Are the instructions and statements clear?; Do the questions cover all areas of your life which have been affected?; and Did you feel that any of the questions in the FROM-16 were not applicable to your situation? [39].
Provide additional context to the FROM-16 responses by allowing the family member to give detailed answers regarding their lived experiences and the impact of the patient’s condition on their quality of life by using the Most Significant Change Technique. This technique is suitable for collecting stories of change/impact from persons who are most directly involved without the use of pre-defined indicators, allowing the participant to describe the outcomes most important to them using detailed stories, whilst allowing the investigator to narrow down components of change [43,44]. The participant will select up to 5 items of the FROM-16 that he/she deems represent the largest impact on their quality of life, and then ranking these items in order of impact. The interviewer will guide the participant through a short series of open questions which will encourage the participant to describe why they consider these items to represent the most impactful changes to their quality of life.

The interview process will provide additional context to the FROM-16 responses in the specific population of patients receiving ATMPs, which may differ from responses given in previous studies of the FROM-16 in other patient populations, as it is likely that family carers of patients with severe disease in receipt of ATMP treatment may have different perceptions of disease and its subsequent impact on their lives.

The interviews will be recorded and transcribed verbatim. A random number of the transcripts will be validated by a member of the study team who was not involved in the interview process. Interview transcripts and participant generated free text will be analysed using a qualitative data analysis software such as NVivo to identify key themes.

Analysis Plan

The score-based results from the completion of FROM-16 questionnaires will be analysed with respect to total score, domain scores and individual item scores. These data will be compared to data from previously published studies to give comparative meaning to the scores, such as the recent study applying the FROM-16 to myalgic encephalomyelitis [37]. The strength of any relationship found between GHS and FROM-16 scores will be compared to previously published data [39,40], to assess if the perceived severity of disease impacts on the family member’s reported outcomes.

Face validity of the FROM-16 for this population will be confirmed by a study team member who was not involved in the data collection examining the responses and the interview themes to determine if the FROM-16 appears to measure family- reported outcomes in this population. Content validity will be investigated by examining the transcripts and responses from the cognitive-debriefing interview (stage 1) process through measuring the intraclass correlation of themes. The construct validity will be quantified by measuring the convergent and discriminant validity using confirmatory factor analysis, with the expectation that two factors corresponding with the two FROM-16 domains: 1) Emotional, and 2) Personal & Social Life.

Individual item, domain and total FROM-16 scores, GHS scores, and FROM-16 item rankings will be initially explored via descriptive statistics and normality testing to examine the data distribution and identify trends and outliers. We anticipate that due to the small sample size and ordinal nature of the data, that the data will follow a non-normal distribution, although this will be confirmed by normality testing. Therefore, hypothesis tests for significance of difference between any participant groupings that may become apparent (for example, CAR-T vs non-CAR-T) will be performed by non-parametric Mann-Whitney U Test with an alpha-level of 0.05.

Thematic analysis of the interview transcripts will be carried out using a qualitative data analysis software, which will identify the key themes of experience, and allow them to be coded into categories, which will be reviewed and revised by all study team members.

Whilst the cohort size in this study is small, ordinal regression and Pearson’s/Spearman’s rank correlation (depending on the distribution of data) will be used to investigate associations between all FROM-16 scores (total score, domain scores & individual item scores) against GHS, FROM-16 item ranks, coded themes of experience, family relation to the patient, demographic details, and disease details.

If we achieve sufficient participant recruitment numbers (greater than 30 participants) it may be possible to perform sub-group analysis, for example assessing the impact of patient’s disease on male vs female family members, and/or assessing the impact of type of condition (inherited/familial, acquired) on FROM-16, GHS and interview responses.

Ethical Considerations

The study was approved by the Yorkshire & The Humber – Sheffield Research Ethics Committee (08/11/21, REC reference 21/YH/0228, protocol no.: RIO 034-21, IRAS project ID 299383). This study is not considered to raise any ethical issues as it is deemed to present a low-risk of harm to the participants. All patients and participants invited to take part have the right not to participate in this study, and to withdraw their consent at any point during the study. All participants shall receive a verbal and written explanation of the study to review. It will be explained to the patients, and family members that their participation is optional and declining to participate will have no impact on the patient's usual care. The participants will be informed at recruitment and reminded before the interview that they may withdraw from the study at any time for any reason.

Safety Reporting

This project is deemed very low-risk. The participants are only required to complete a questionnaire and interview, with no medical testing or medical products being taken. However, as with all projects of this nature where personal data are collected and stored, there is a risk of these personal data accidently being disclosed.

To mitigate the risk of an accidental disclosure all data will be link-anonymised. Participants will be assigned a participant ID number, and the research team will not have access to the participants identifiable personal information. Consent forms will be stored securely by the recruiting site. The questionnaires will not contain identifiable personal information and will be stored in paper form in a locked office in Swansea University. Data management shall comply with the General Data Protection Regulation.

The study shall be conducted in accordance with the ethical principles of the Declaration of Helsinki and the International Conference on Harmonisation: Good Clinical Practice guidelines. If an accidental disclosure occurs, this will be immediately reported to the study principal investigator and the study sponsor (Swansea University) using the standard reporting pathway as per the institution’s guidelines. The Research Ethics Committee will be notified using the non-CTIMP safety report form, as per HRA guidelines. If it meets the relevant threshold, the Information Commissioner’s office will also be notified of the breach.

Public and Patient Involvement

Members of the public were engaged during the study design phase, organised by the MW-ATTC as part of their regular programme of clinician, patient and carer engagement. Two patient and carer representatives were present at the meeting, during which they had the opportunity to provide their input into the study design, such as the study objective, choice of FROs-collecting tool, and the approach towards participant recruitment. We will engage with patient and family representative groups to appropriately disseminate study findings in an accessible manner.

Potential Impact

Collecting family-reported outcomes (FROs) from patients’ families is an important step for demonstrating the wider value of healthcare interventions. This is especially important in the context of very high-cost and resource intensive treatments, such as ATMPs. This study, if successful, will demonstrate that the FROM-16 is a valid instrument for collecting these FROs, and therefore could identify a reliable mechanism for demonstrating an important component of societal value of ATMPs. In addition, this study will provide the framework for a larger, wider-reaching prospective study of FROMs in ATMP patients’ families before and after ATMP treatment, by examining associations between FROM-16 and GHS questionnaire scores, FROM-16 item ranks, coded themes of experience, family relation to the patient, demographic details, and disease details. This in turn could influence approval of more ATMP therapies in the future.

Whilst several studies have shown the FROM-16 is suitable for collecting FROs data reliably, it can be argued that it does not capture the full caring experience. For example, the FROM-16 does not measure any potential positive outcomes that a family member may experience from caring for their relative. In the original 2013 study, the study team reported that some family members identified some positive effects relating to “emotional impact” and “family relationships”, for example improvements in family relationships were reported due to family members “pulling together” [9]. However, these points were not addressed in the design of the FROM-16, and it does not provide an opportunity for the family member to explain in depth how their life may have been affected by their relative’s condition. It is, therefore, likely that it was considered that only negative impacts may require improvement by appropriate intervention. To address this, we will use semi-structured interviews to allow the family members to discuss the impacts they describe in greater depth, which may encourage the participants to describe the importance they ascribe to the impacts, as well as describing any positive impacts they may experience.

It is possible that this study may show that the FROM-16 is not, or specific components of the FROM-16 are not, applicable to this patient cohort and their families. If that is found to be the case, the findings from this study will inform the development of a novel family outcome measuring tool, specific to this population.

Progression Criteria

This study is using a traffic light progression criteria system (Table 1).

Table 1: Progression Criteria

Colour	Criteria	Outcome
Red	Fail to show reliability or validity of the FROM-16 in the ATMP patient population Cronbach’s Alpha < 0.3 Intraclass correlation < 0.3	Study results published. New pilot study of different tool for assessing family quality of life in ATMP patient population to be designed
Amber	If study shows some aspects of validity or reliability but not all.	Publish study results. Assess reasons for mixed results, and design follow-on pilot study with additional parameters (i.e. increased sample size, if required).
Green	Successfully demonstrate face, content and construct validity of FROM-16 Cronbach’s Alpha > 0.8 Intraclass correlation > 0.8	Publish study results. Design follow-on study examining the potential impact of ATMP treatment by comparing perception of family quality of life impact before and after ATMP treatment.

Defining Success

This study aims to validate the FROM-16 by assessing its utility and relevance as an instrument to measure family-reported outcomes in the setting of very-high cost and potentially curative ATMPs. Therefore, a successful outcome will be to demonstrate that the FROM-16 is a suitable tool for gathering FROs in this population, by providing a validated mechanism for collecting FROs in the future before and after ATMP treatment. To demonstrate this suitability, this study must show the reliability, and face, content and construct validity of the FROM-16 within the context of ATMP patients and their families.

Reliability, assessed by Cronbach’s Alpha, should have scores in excess of 0.8, indicating high internal consistency.

Face validity is demonstrated by the FROM-16 collecting information on family impact of disease in our target population. An experimenter independent of the data collection and analysis process will assess the FROM-16 and responses for face validity.

The content validity of the FROM-16 will be confirmed by the cognitive debriefing interview process, where participants will be asked to comment on the relevance of the FROM-16 items to their experience. Thematic analysis of interview responses should show that all FROM-16 items are relevant and that there are no missing items. Intraclass correlation of themes should be in excess of 0.8.

The FROM-16 will be demonstrated to have construct validity if after measuring the convergent and discriminatory validity by confirmatory factor analysis, two factors emerge corresponding to the two parts of the questionnaire.

ATMPs: Advanced therapeutic medicinal products

COAT: Carer Outcome Assessment Tool

EQ-5D: EuroQol- 5 Dimensions

FROMs: Family-Reported Outcome Measures

FROs: Family-Reported Outcomes

FROM-16: Family Reported Outcome Measure-16

PROMs: Patient-Reported Outcome Measures

QALY – Quality-Adjusted Life Year

QOLLTI-F: Quality of Life in Life Threatening Illness – Family Carer Version

WHOQOL-BREF: Abbreviated World Health Organisation Quality of Life questionnaire

Ethics Approval and Consent to Participate

The study was granted ethical approval by the Sheffield Research Ethics Committee (REC 21/YH/0228). All participant gave written informed consent prior to participating.

Consent for Publication

Participants will provide written informed consent for their anonymised data and interview quotes where relevant to be used in any future publications.

Availability of Data and Materials

All data collection instruments are available following an appropriate request for use license. The FROM-16 is licenced by Cardiff University. The structured interview format is available as an additional document. Anonymised versions of the dataset used will be available from the corresponding author upon reasonable request.

Competing Interests

AYF and SS are amongst joint copyright owners of FROM-16. In future Cardiff University may receive royalties, of which AYF and SS would receive a share.

Funding

Funding from Midlands-Wales Advanced Therapy Treatment Centre (MW-ATTC) which is hosted by Welsh Blood Service. The MW-ATTC is Innovate UK funded.

Author’s Contributions

All authors contributed towards the development of the study protocol, read and approved this manuscript.

Acknowledgments

The authors thank Professor Hayley Hutchings for reviewing the study protocol, Dr. Gary Burkhardt for reviewing the statistical analysis plan, and Shannon Carter for project managing the study and administrative assistance.

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Feasibility Study Protocol: Investigating Family Reported Outcome Measures (FROMs) in the Estimation of Societal Value of Advanced Therapy Medicinal Products (ATMPs)

Status:

Version 1

Abstract

Background

Methods

Discussion

Trial Registration

Background

Advanced Therapy Medicinal Products

Value-Based Healthcare

Family-Reported Outcome Measure-16

Research Aim(s)

Methods

Study Population and Sample Size

Recruitment

Paediatric Patients

Inclusion and Exclusion Criteria

Inclusion Criteria

Patients:

Family Members:

Exclusion Criteria

Patients:

Family Members:

Interventions

Patients

Family Members

Data Collection

FROM-16 and GHS Questionnaires

Two-Stage Semi-Structured Interview

Analysis Plan

Ethical Considerations

Safety Reporting

Public and Patient Involvement

Discussion

Potential Impact

Progression Criteria

Defining Success

Abbreviations

Declarations

Ethics Approval and Consent to Participate

Consent for Publication

Availability of Data and Materials

Competing Interests

Funding

Author’s Contributions

Acknowledgments

References

Supplementary Files

Status:

Version 1