Designing a Patient Preference Study on Subcutaneous Medical Devices: Incorporating Health Authority Scientific Advice and Patient Perspectives

doi:10.21203/rs.3.rs-4532442/v1

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Research Article

Designing a Patient Preference Study on Subcutaneous Medical Devices: Incorporating Health Authority Scientific Advice and Patient Perspectives

https://doi.org/10.21203/rs.3.rs-4532442/v1

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This paper describes the planning of a patient preference study for evaluating device features and administrative solutions for the subcutaneous (SC) delivery of high doses / large volumes (e.g., >2mL) of drugs.

A mixed-methods approach was used including qualitative research studies, the involvement of patient partners, and solicitation of advice from the FDA. This resulted in the development of a preference study protocol to investigate what Multiple Sclerosis patients consider important regarding medical device features for high dose SC administration, including refinement of the attributes and levels which will be central to the planned quantitative online patient preference study.

Patient Preferences

Patient Experience Data

Scientific Advice

Subcutaneous Delivery

Device Features

Many patients prefer to take drugs that need to be injected at home and to avoid frequent visits to a heath care center. Many new drugs have larger volumes of liquid that need to be injected, which means a patient can currently only get these drugs at a health care center. To make home injection of these larger volumes of liquid possible, new devices are needed.

Novartis is working on the development of a device that will make it possible to inject larger volumes of drug at home and it is important that this new device is acceptable to patients. What is important to patients are the features of such a device and the different ways the drug can be given.

Patient partners were involved in the planning of a study and the development of a questionnaire to find out what patients would prefer regarding the device features, and how to use the device. The patient partners were also involved in developing the material to be used by the study participants.

The design of the study was also discussed with the USA Food and Drug Administration (FDA) as part of their scientific advice process. The advice from both the FDA and the patient partners led to a simplification of the study design: instead of a study with patients from many countries and with many different diseases, the study was to be run only in the USA and only with patients with Multiple Sclerosis (MS). MS patients were asked which features they would prefer in this type of device, and these preferences were put into the study's questionnaire. The planned study will find an answer regarding which of the different features MS patients would prefer. This information will become the basis of the device's design.

The article describes the steps taken to ensure that the right information will come out of the study being planned, and that the device developed will agree with the preferences obtained from the MS patients.

Patient experience data (PED) increasingly plays a central role in regulatory and health technology assessment (HTA) decision-making¹, although both industry and health authorities are still learning how best to integrate robust patient input into medical product development. A report contracted by the U.S.A. Food and Drug Administration (FDA)² identified good practices and opportunities for improvement in the use of PED in FDA decision-making. Good practices include early and frequent consultation between applicants and the FDA during development programs to discuss the potential value of PED, the types of data to develop, fit-for-purpose tools to use, approaches to collecting data, and the creation of a solid data analysis plan². This report also identified that logistical challenges may limit the opportunity for such consultation with the FDA to receive timely input on using PED in development programs and supporting product registrations. A recent industry survey concluded that expanded guidance and alignment on meeting opportunities are needed to advance PED in FDA decision-making ³.

Patient preferences are one type of PED⁴, increasingly used to inform medical product decision-making. Large, multi-stakeholder initiatives such as the Medical Devices Innovation Consortium (MDIC)⁵ and the Innovative Medicines Initiative (IMI) PREFER project⁶ have developed guidance on when and how to elicit patient preferences to inform medical product decision-making. PREFER recommendations⁶ and endorsement through the European Medicines Agency (EMA) qualification opinion ⁷, advocate early and iterative consultation meetings with regulators and HTA bodies in the form of scientific advice, at the time when the study concept is being finalized for the patient preference study (PPS)⁶. The PREFER Recommendations also advocate working with patients as research partners in PPS to increase the relevance, appropriateness, feasibility, and acceptability of the preference study design, as well as its conduct and the interpretation of study results. Such multi-stakeholder alignment on the purpose and objectives of a PPS and on the design, conduct, and analysis is expected to lead to robust study results accepted by the different stakeholders to inform decision-making.

Currently, there are limited published examples of advice consultations with regulatory or HTA bodies for preference study design^8–12. More examples are necessary to enhance learning, improve the process, and encourage others to seek advice and alignment during preference study design. Patient involvement in preference study design is also underexplored.

This paper describes the process for the preparation of a PPS involving the evaluation of device features and administrative solutions for the subcutaneous (SC) delivery of high doses / large volumes (e.g., >2mL) of drugs. A mixed-methods approach was used including qualitative research studies, the involvement of patients as research partners, and solicitation of advice from the FDA.

The SC injection of high dose/large volume in home environment is an alternative solution to intravenous (IV) administration in the hospital setting with new emerging formulation and device delivery technologies (e.g., co-formulation with hyaluronidase or large volume patch injector)^13–14. Such devices may represent an attractive option for patients across a range of indications.

Previous preference studies, as well as practical experience with different devices, have revealed that most patients and health care providers (HCPs) prefer SC over IV drug administration for several reasons including convenience, time saved, cost, and reduced injection pain^15–18. In situations where different therapies are expected to have generally similar efficacy and safety, patients’ and HCPs’ individual preferences can become an important factor in deciding which treatment to use^19–21. Preference studies have demonstrated the importance of SC device attributes as a factor in patient treatment choice^22,23. Matching device and treatment attributes to patients’ individual preferences has also been associated with increased treatment satisfaction, adherence, and improved health-related quality of life²⁴. The present project seeks to inform the design of a PPS, and specifically the attributes and levels (A&L) grid for use in a discrete choice experiment (DCE), through engagement with different stakeholders and utilization of different qualitative research approaches. A PPS will increase the understanding of the acceptability, preferences and trade-offs made by patients, concerning device features and administration solutions for high volume/dose SC delivery of drugs.

Overview of the project objectives and research

The overall primary objective of this project is to quantify patient preferences and relative importance of attributes for different device and administration features to deliver high-dose/high-volume SC formulations of treatment, regarding different disease areas and across different countries. The initial project consists of qualitative research and of meetings with the FDA to seek scientific advice and to inform the design of a quantitative PPS.

The future stage of the project comprises the execution and reporting of the quantitative DCE; the results will be published in a separate article when available. The initial qualitative research conducted to develop the A&L grid, subsequent meetings with FDA, additional qualitative research in response to FDA recommendations, and the collaboration with patient partners are the focus of this article.

The original planned quantitative PPS involved conducting a DCE with patients from several countries and across a variety of diseases areas. The initial design of the study was based on a targeted literature review and patient and HCP input from a preliminary qualitative study. This study design was presented to the FDA to receive their scientific advice. Based on agency feedback, the sampling design was simplified considerably to involve only one disease (MS) and one country (USA). The three stages of the prior research (a. Qualitative research pre-FDA meetings, b. FDA meetings and c. Qualitative research post-FDA meetings) are summarized in the flow chart given in Fig. 1 and further explained below.

A. Qualitative research pre-FDA Meetings

Initial qualitative research across different diseases and countries

Qualitative research was conducted in the USA and UK with 48 patients and 20 HCPs to select and assess the importance of attributes related to SC injections. The questionnaire design for the qualitative research was informed through a prior targeted literature review based on patient experiences and needs regarding SC and IV administration and devices. This involved conducting telephone interviews with oncology, dermatology, respiratory and neurology patients and/or caregivers and with HCPs. The goal was to understand attributes of importance regarding the SC injection delivery, to gain insights into administration experiences, and elicit perspectives to hypothetical SC device concepts. The telephone interviews were moderator-assisted. Recruited patients had to be currently receiving at least one IV or SC treatment, and recruited HCPs had to have seen at least 10 patients per month receiving IV or SC treatment and been involved in assisting patients with their choice of treatments and administering infusions. The research sample recruitment by disease and specialty area is shown in Supplementary Material S1, together with the discussion topics covered in the qualitative research. The respondents were asked to rank attributes related to SC injection by importance and give their rationale.

The above findings were used to develop the DCE study design presented to the FDA. The study design originally included patients with different diseases (Oncology, Asthma) and different countries (USA, France, Germany, China, Japan).

B. FDA Meetings

Novartis sought scientific advice from the FDA-CDRH PPI group (through the Q-Submission Program) on the quantitative preference study, with the overall process from first contact and briefing book preparation to receipt of the final advice taking approximately six months. Two, one-hour informal meetings were held prior to the formal request for a pre-submission meeting. These informal meetings were key to understanding general requirements on the submission route and introduce the overarching concept of the sponsor’s PPS to the FDA, noteworthy because of the very early stage in the device development when this interaction was taking place (in advance of any drug-device combinations or considerations of benefit/risk trade-offs). The first informal meeting's objective was to obtain guidance on the most expeditious submission pathway and appropriate FDA division from whom to request guidance on the PPS. The potential unmet medical need and rationale for the PPS in the complex context of a device development for potentially different diseases, key aspects of study design, details of the PPS objectives and planned application of the results were presented. A second (follow-up) informal meeting with the FDA PPI team was set up to continue the first meeting's discussions. Those informal meetings helped Novartis to better understand the FDA’s thinking and the FDA’s responses were a key driver for the team to refine the design quite significantly.

The timing of milestones during the advice procedure with the FDA are shown in Table 1. The briefing book content was informed by PREFER and FDA pre-submission guidance^6,25. The document included an introduction, a list of seven questions, covering three substantial topics in line with the recommendations of the FDA Q-Sub Guidance on the number of topics and lastly, background information on the project (see Supplementary Material S3). The topics of discussion at the meeting and the subsequent FDA advice were in-line with the aspects of the PPS framework identified as particularly relevant for discussion during the scientific advice process, as described in the PREFER recommendations⁶. The key questions which were addressed with the FDA covered the following three substantial topics of (1) appropriateness of study purpose and intended use of the study results, (2) appropriateness of study design (study objectives, attributes and levels, patient centric study materials, statistical methods, sample size) and (3) transferability of the results to additional disease areas.

Table 1

Duration and milestones for FDA consultation on a Patient Preference Study for a device (CDRH Q-submission route)
	Project Milestone	Timing
1	Initial FDA contact, informal meetings, and briefing book preparation	3–4 months
2	FDA’s briefing book review and written feedback	70 days from submission
3	Scientific advice meeting	75 days from submission
4	Meeting minutes received	15 days from meeting

C. Qualitative research post-FDA Meetings

Based on the discussions with FDA and their scientific advice, the design of the planned quantitative PPS was simplified to include a single disease (MS) and country (USA). This required additional qualitative research to confirm the choice of attributes and levels in the PPS.

Additional in-depth qualitative research

A second round of qualitative research was conducted to address FDA’s feedback. This round involved conducting in-depth interviews with twenty-four MS patients based in the USA via telephone or screen-sharing software (Microsoft Teams). These interviews adopted a combined concept elicitation (CE) and cognitive debriefing (CD) approach (Fig. 2). The additional interviews aimed to generate evidence to support the A&L development, specifically to ensure the design of the upcoming preference survey was patient-centric and considered fit-for-purpose in the target population of interest (i.e., MS patients). The interviews evaluated comprehensiveness of A&L framing (wording, images) among MS patients and confirmed level differentiation; ultimately to support content validity. Fixed-profile choice tasks (resembling DCE tasks) were also administered and completed by patients with an interviewer to assess usability of the choice task format and determine feasibility of completion. Findings from the in-depth qualitative interviews will inform the upcoming DCE study design by ensuring choice tasks contain meaningful information relevant to the MS patient decision context when evaluating device treatments and confirm suitability of the survey instrument.

Concepts spontaneously discussed by MS patients in the CE section of the interview (e.g., open-ended questioning) were later subject to concept saturation by the research team. Concept saturation is defined as ‘the point at which no new concept-relevant information emerges’²⁶. Concept saturation strengthens the study design by supporting justification of adequate sample size selection tailored to the specific population of interest and supports the notion that interviews were able to sufficiently capture all key treatment drivers of interest to patients. The FDA Patient-Focused Drug Development Series (specifically, FDA PFDD Guidance 2)²⁷ outlines guidance and agency expectations regarding using concept saturation for the purposes of qualitative sample size justification.

The study included participants across MS subtypes: Relapsing Remitting MS (RRMS), Secondary Progressive MS (SPMS), and Primary Progressive MS (PPMS).

The sample size for each MS subtype was in accordance with concept saturation principles ²⁸.

Each interview lasted approximately 60 minutes and was conducted by trained and experienced moderators who were briefed on relevant population-specific considerations. All interviews were transcribed verbatim and subject to framework and thematic analysis methods^29–31. An induction–abduction approach was taken to identify themes emerging directly from the data (inductive inference), and by applying prior knowledge (abductive inference).

The first section of the interview (CE questioning) utilized broad, open-ended questioning to encourage MS patients to discuss their treatment experiences and discuss the features and decision drivers that are relevant and important when evaluating MS injection treatments. The second section of the interview (CD questioning) involved a ‘think-aloud’ approach^27,32,33 to assess content validity and relevance of the content of the draft A&L grid, assess consistency of patient understanding and interpretation of the A&L grid, and confirm that appropriate/understandable language was used. Finally, MS patients ranked the attributes in relative order of importance, providing explanations and thoughts behind their rankings. Responses from the CE questioning was used to enable examination into how newly elicited concepts would be ranked in comparison to the pre-defined attributes in the A&L grid, specifically to explore if new concepts were more important to MS patients than the existing attributes.

MS patients were asked to read aloud each attribute and level while responding to questions from the interviewer regarding their understanding of wording and images, alongside the relevance, importance and impact of each attribute on their decision to take an injection treatment for MS. Additionally, attribute independence was explored, and differences between the levels within each attribute were explored with the MS patients to examine if levels were salient, adequately differentiating and mutually-exclusive.

Study exemptions for the qualitative studies pre and post FDA meetings were granted by a centralized Institutional Review Board in the USA.

A to C Involvement of Patient Partners

The research team worked in collaboration with patient partners on the research work pre- and post- FDA meetings as well as to prepare the Scientific Advice meeting with FDA.

Patient partners helped to develop and review study material from its conception. The patient partners reviewed and provided comments on the concept sheet, giving an overview of the study design and device features, treatment process, attributes, and levels to be tested. The patient partners were later asked to review and comment on the study protocol and the quantitative survey text, including the Informed Consent Form. The patient partners reviewed the educational materials to be provided to study participants (videos and infographics, as built into the study survey; see Supplementary Material S2) and were involved in reviewing and refining a test version of the online quantitative survey. The study team did not provide any guidance or specific direction as to which sections of the documents should be reviewed. Patient partners were also involved in reviewing the outputs of the qualitative research and FDA scientific advice feedback and providing context for the interpretation of the study results.

The feedback and comments from the above were used to develop the first Novartis DCE study design that was presented to the FDA as well as the DCE study design refined after the Scientific Advice with FDA. The design included patients with different diseases (Oncology, Asthma) and different countries (USA, France, Germany, China, Japan).

The patient partners were selected and were adapted as the project progressed to represent the target population in the different study designs and matching the different disease areas and geographies in addition to their confirmed experience with devices (Table 2). Each patient partner was contracted individually and compensated for the time spent on the study, using the Novartis version of the Fair Market Value calculator developed by the National Health Council³⁴. Individual on-boarding sessions with the patient partners were performed by the Patient Engagement representative and Project Lead to ensure sound understanding of the objectives of the PPS as well as their role as patient partners. Interactions with the patient partners were conducted individually and virtually (email, MS Teams), at each key milestone of the study to collect their feedback, discuss and clarify any questions. Based on their feedback, the draft PPS documents were revised as required.

Table 2

Panel of patient partners prior to and following the FDA scientific advice consultation
	Patient Partner	Country	Disease area of expertise	Rationale for involvement	Review
Panel prior to the FDA Consultation	1	Netherlands	Asthma	Research experience - input to the qualitative study phase	Concept sheet, study protocol and quantitative survey; educational material & test version of the online survey.
	2	Japan	Pancreatic cancer	Administration device expertise	Concept sheet, study protocol and quantitative survey; educational material & test version of the online survey.
	3	Germany	Breast cancer	Cancer support community including device experience	Study protocol; educational material & test version of the online survey.
	4	Germany	Lung cancer	Experience with SC injection Involved in previous Human Factor device study	Study protocol; educational material & test version of the online survey.
	5	USA	Leukemia, Lymphoma	Cancer support community including device experience	Study protocol; educational material & test version of the online survey.
	6	USA	Breast cancer	Input to the qualitative research study phase	Study protocol; educational material & test version of the online survey.
Panel Post-FDA Consultation	7	UK	RRMS	Expertise in clinical trials, device experience	Quantitative survey and educational material.
	8	Germany	RRMS	Expertise in clinical trials, device experience	Quantitative survey and educational material.
	9	UK	RRMS	Expertise in clinical trials, device experience	Quantitative survey and educational material.
	10	UK	RRMS	Expertise in clinical trials, device experience	Quantitative survey and educational material.
Additional patient partners with MS and from USA	11	USA	RRMS	Patient Advocate for MS	Study protocol and quantitative survey; educational material video, educational material for qualitative study.
	12	USA	RRMS	Patient Advocate for MS	Study protocol, and quantitative survey ; educational material educational material for qualitative study.
	13	USA	RRMS	Expertise in device, health literacy	Study protocol and quantitative survey ; educational material educational material for qualitative study.
	14	USA	PPMS	Expertise in clinical trials and device experience	Study protocol and quantitative survey ; educational material educational material for qualitative study.
	15	USA	SPMS	Patient Advocate for MS	Study protocol and quantitative survey; educational material educational material for qualitative study.
Abbreviations: MS, Multiple Sclerosis. RRMS, Relapsing Remitting Multiple Sclerosis. PPMS, Primary Progressive Multiple Sclerosis, SPMS, Secondary Progressive Multiple Sclerosis,
USA, United States of America. UK, United Kingdom.

A. Qualitative research pre-FDA meetings and input from patient partners for the quantitative study

The mixed methodology research approach blended qualitative in-depth telephone interviews with quantitative ratings, to gain a holistic view of the current perceptions of SC administration. Fieldwork was conducted between December 2021 and February 2022 in the USA and UK with 14 patients (a mix of oncology, dermatology, respiratory and neurology patients (see Supplementary Material S1), each in the USA and UK, and with 10 HCPs each in the USA and UK.

The results are summarized in Fig. 3. For patients, the three most important device characteristics were ease of injection, simple instructions, and having a device that enables home use. Patients from the UK and USA generally ranked the importance of attributes consistently, while UK patients gave a higher rating to home use (9.7/10) than the USA patients (8.2/10). The USA patients gave a higher importance than this to drug and total care out-of-pocket costs and that their HCP can easily access data from the device. Considering the aggregated results from UK and USA in Fig. 4, for HCPs, the first two highest ranked attributes were the same as for the patients, with ease of training patients to use [the device] ranked third. There was no strong evidence of a difference in the rankings across diseases (see Fig. 5).

In summary, both patients and HCPs welcome the idea of devices that allow SC delivery of a high dose of drug and consider it a currently unmet need over hospital administration and injection timings for IV administration. The insights generated from this qualitative research were used to further develop the design considerations for a new high dose SC device and inform the attributes and levels of greatest importance to be explored further in the design of the quantitative PPS.

Feedback from patients as research partners

The feedback from the patient partners on the qualitative study and to prepare for the quantitative study is summarized in Table 3. It was highly insightful and led to revisions both to the study design and study materials. Key inputs of the patient partners that have led to improvements in the PPS design include: (1) conceptual remarks on the study design related to the inclusion/exclusion criteria and a proposal to revise certain sub-group analyses originally planned, (2) giving consideration to specific societal aspects in the study design (e.g., the potential impact of the recent COVID pandemic on the preference for home treatment) as well as potential sub-groups of interest (e.g., patient willingness to adopt a new technology, and potential differences in preferences between community areas [suburban/rural]). Suggestions were also made to simplify the language, add clarity to definitions and terms used, and improve the layout and educational material to facilitate clearer understanding by the study participants. Some of the feedback from the patient partners (Table 3) aligned with the comments the Sponsor later received from the FDA (Table 4).

Table 3

Feedback from patient partners pre- and post- FDA input
Feedback prior to FDA input:
Subgroups	The patient partners who reviewed the Concept sheet questioned the study team about the proposed subgroup analysis, particularly the geographic subgroups (USA, Europe (France and Germany), and Asia (China and Japan)). They felt that the planned geographic subgroups lacked homogeneity because there are significant differences among them. For instance, the healthcare systems vary across different European countries, and China and Japan have distinct cultural perspectives on medicine. Including China and Japan in a single “Asian” subgroup, for example, would not enable a meaningful analysis. Consequently, China was removed from the study.
Inclusion criteria and disease characteristics	The patient partners raised concerns with the Sponsor’s proposals regarding the criteria for the self-injection experience. As a result, the Sponsor updated the inclusion criteria to include more specific details about the experience. Additionally, the Patient Preference Study initially focused on examining the influence of disease severity on device selection. However, the patient partners emphasized that factors unrelated to disease severity, such as dexterity or living area, may also affect the choice of treatment device. Therefore, additional characteristics were included for analysis.
Feedback post-FDA input
Diversity inclusion	The patient partners provided feedback that the educational material and illustrations may not be representative of the targeted population for the Patient Preference study, as there was a lack of diversity in the representations. Consequently, the Sponsor adapted the educational material to be more inclusive.
Colors and layout	Patient partners living with MS highlighted that the use of colors and color scale could be an issue for the Study participants living with MS, as they may have visual impairments. As a result, the Sponsor removed the colors and color scale from the answer scale.
Definition of terms/specific vocabulary	Several terms used in the questionnaire were still open to interpretation or too complex. The questionnaire has been revised to simplify the vocabulary used, especially the technical aspects of the devices, and new definitions have been added to ensure a good understanding by the Patient Preference Study participants.
Feedback post additional qualitative study
Layout	The layout of the educational material for qualitative study was confusing and the amount of text was increasing the complexity of reading and understanding. The same issue was present on the updated A&L grid, and text was reduced.

Table 4

**Summary of the key FDA advice provided for the PPS design through informal and formal consultation meetings**
FDA advice	Actions taken and modifications to the study
Diversity in the patient population is to be expected: More focus on diversity by monitoring cultural diversity, including health literacy assessment, and measuring dexterity, physical limitation, health status and disease severity.	Study design updates: - Option included to conduct study in Spanish as the second most common language in the US - Screening data to include demographic and cultural profiling metrics, including race, ethnicity, gender, age, income as socio-economic level, educational level, employment status, and insurance status - Inclusion of questions on prior treatment history, patient characteristics, disease severity, current control of disease, physical limitation, dexterity, and comorbidities - Inclusion of health literacy assessment questionnaire - Screening data will be monitored to ensure good diversity of study population, with ongoing recruitment adjusted based on these data
Patients who do not have access to a mobile device, tablet, or laptop should not be excluded	Excluding participants who do not have access to a device, tablet, or laptop is a known limitation of online DCE studies. As we assume patients of lower socio-economic level do not have access to a laptop, efforts will be made to ensure participants of lower socio-economic levels are proportionately represented in the study, with the additional collected data (above) helping to complete the cultural profile of the study participants with recruitment adjusted on an ongoing basis based on these data.
Subgroup analysis by world region: Subgroup results per region (grouping countries) may be too heterogenous to draw a meaningful conclusion on preferences.	The study team acknowledged this issue of known/potential cultural differences within a region drawing preferences. It was agreed to limit the country scope of the PPS to the US only.
Disease areas and data transferability: MS are a different age-group than patients living with different types of cancer, with potentially different disease prognosis and timelines. Consider narrowing the disease scope.	The study team acknowledged this feedback and decided to reduce the disease scope to only multiple sclerosis, but covering the three MS subtypes (RRMS, PPMS, SPMS). Since transferability of the PPS results to other indications such as non-small cell lung cancer, HER2 + breast cancer, chronic lymphocytic leukemia, or follicular lymphoma will no longer be explored within the revised PPS design, the study team acknowledged that additional research will be needed in the future to explore device preferences in these other patient groups.
Differences in preferences between subgroups should be tested first, before determining if aggregating data over the subgroups is possible.	Reducing the scope to only MS patients in the US excludes issues regarding subgroups and analysis. The study objective was modified to determine the patient preference and the relative importance of attributes for different device solutions, delivering high-dose/high-volume SC formulations of treatment (> 2mL − 10mL) to MS patients (RRMS, PPMS, SPMS) in the US. The study will test for differences in preferences between subtypes of MS (RRMS vs combined SPMS + PPMS), prior to aggregation and further analysis of the full data set.
Sample size per subgroup should be sufficient to allow for analysis within a subgroup	Revised focus on MS only and US only, allows for a more robust sample to be recruited in this study population (current target estimate of n = 280–360 MS patients: RRMS, n = 140; PPMS, n = 70–110; SPMS, n = 70–110).
Patient diagnosis / self-reported diagnosis: Patient self-reported diagnosis is not acceptable for FDA.	The study team confirmed that confirmation of diagnosis via reliable sources will be conducted: recruitment through HCPs (estimated as 60% of the target) will include diagnosis verified by the HCP. For the remaining patients, recruited via patient advocacy groups and active patient panels, nurses, fellow patients and/or community leaders ensure members have a confirmed diagnosis. For both recruitment channels, the screening questions will be designed to further verify the MS diagnosis.
Need to obtain preliminary feedback from those populations with various disease severity to better assess the appropriateness of the attributes and levels.	The qualitative research with MS patients (post-FDA meetings) was subsequently conducted to fully ensure study design and attributes and levels were optimized and appropriate for the MS population, including representation of RRMS, SPMS and PPMS patients.
Alignment of the patient partner characteristics (disease area, disease severity) with the target quantitative study population.	Four MS patients were added to the research team (Table 2) and involved in review of materials generated.

Table 5. Current Final Attributes and Levels (A&L) grid

Survey participants will be asked to assume the same drug efficacy and safety profile in all choice scenarios shown for different device options.

Attribute wording*	L1	L2	L3
Handling steps What are the device handling steps?	Three parts to assemble. A vial containing the drug, a connecting part, and an injection device. All parts disposed after single use.	Two parts to assemble. A disposable drug cartridge and an injection device. Device can be re-used for five injections before being disposed. Drug cartridge is disposed after single use.	No parts to assemble. The injection device already contains the drug. Device is disposed after single use.
Device type and injection duration Which device is used & how long does the injection last?	One wearable patch injector It takes 15 minutes to fully inject the treatment.	One handheld autoinjector It takes 30 seconds to fully inject the treatment.	Two handheld autoinjectors (one used immediately after the other). It takes 10 seconds for each autoinjector to fully inject the treatment (20 seconds in total)
Site of care and injection administrator Where and by whom is the injection given?	Injection in a hospital / clinic by a doctor or nurse	Injection in your home by a doctor or nurse	Injection at your convenience (home, place of work, hotel, etc.) by you or a caregiver (family, partner, or friend)
Injection frequency How often is the injection given?	Every two weeks	Every month	Every three months

B. FDA scientific advice and considerations for the PPS study design

The medical device PPS FDA CDRH pre-submission meeting and the two informal preliminary meetings with the FDA resulted in significant refinement of the study design, as summarized in Table 4. Most significantly, the study's scope was restricted to focusing only on MS patients and not to include patients from different disease areas in the target population (as originally intended). It was felt the different patient demographics and disease course could result in significantly different preferences across these indications, such that the planned sample size might not have allowed full examination of the differences. In addition, it was highlighted that differences between countries regarding culture, medical practice, and treatment standard of care, might also lead to preference heterogeneity (and require a much larger sample size to address this appropriately), leading to the decision to focus only on the USA for the PPS, with an increased MS patient target population size.

Other key learnings from the FDA advice included: ensuring sufficient diversity within the target patients recruited in the study and being representative of the overall USA population; ensuring sub-groups were of a sufficient size to allow meaningful analysis at the individual sub-group level, prior to aggregation of the overall study population for further analysis; inclusion of steps to ensure reliable diagnosis of the study respondents; and the need for additional qualitative research with the intended (MS) patient population to ensure appropriateness of the attributes and levels, prior to initiation of the DCE. All these FDA recommendations were addressed (Table 4) in the refinement of the DCE design and subsequent research as described in C, below.

Feedback from MS patients

Following the FDA scientific advice meeting, the updated A&L grid, study materials and PPS questionnaire were reviewed by MS patients. The feedback led to final small refinements of the study materials for the future full quantitative study in MS patients.

C. Qualitative research with MS patients: refinement of the A&L grid for the DCE

An additional round of in-depth qualitative research was conducted following the FDA feedback to focus on MS patients, allowing the opportunity to both characterize this population ahead of the DCE, supporting content validity in an MS population, and allowing for any reframing of certain data collection questions in line with FDA draft guidance regarding diversity of recruited participants³⁵.

The CE section of the interview (Fig. 6) confirmed that the existing attributes and levels selected for the DCE were relevant concepts to MS patients in the context of medical device decision-making; the findings providing supportive evidence of conceptual coverage. Concepts spontaneously elicited in the CE section that were not deemed appropriate for inclusion as an attribute in the DCE were instead accounted for as part of the broader online survey. Concepts were either not varied in the information provided to patients before the DCE survey, assessed outside of the DCE, or were included within the educational materials accompanying the DCE survey.

The results of concept saturation analyses confirmed that the total interview sample size (N = 24) was adequate to incorporate perspectives from a general, heterogeneous MS population into the design of the DCE

How well the MS patients understood the attributes and levels is displayed in Figs. 7 and 8. Looking at Fig. 7, all attributes were well understood (87.5% or 100%), as were their levels, with perhaps the exception of device type and duration (level 1, 79.17%). Figure 8 shows the attribute importance and impact on decision making: all attributes were important (75% or greater) except injection site (58.33%). Figure 8 also shows that all attributes except injection site (50.00%) and device type and duration (66.67% and 62.50%, respectively) were reported as being impactful or influential in injection device choice by most patients (70.8% or more).

Based on these results the current contents of the A&L grid are displayed in Table 5. The injection site attribute has been removed. Also, as injection pain and skin reaction were considered to be similar to other injection devices, and so not a useful differentiator, this attribute was removed.

Feedback from patient partners

During the additional qualitative research, the patient partners were involved in reviewing the educational material used during the qualitative research as well as the updated A&L grid. The educational material was updated to ease the reading and understanding by layout refinement. The feedback on the A&L grid led to final minor refinements.

This research project embraces several recently described best practices for designing a quantitative PPS, in particular the importance of high-quality qualitative research, involvement of patients as partners, conducting scientific advice with a health authority, and initiation of the research very early in the product lifecycle^{2,3,6,36,37,25,35,38–43}. Our manuscript is one of the first examples to describe FDA scientific advice, how the process was conducted and how the input informed and improved the design of the PPS, building on the work of others^37,11,12 to illustrate the value created through this activity.

Early consultation supports the FDA’s recommendation of “early and often” dialogue between the Agency and study sponsors. Scientific advice ensures the design and methodology are fit for purpose and that studies meet Health Authority (HA) expectations, so that results can appropriately inform decision-making. To date, however, there are very few examples in the literature of the scientific advice / HA feedback process as it pertains to the design of a PPS: Tervonen and colleagues¹¹ have described a successful FDA Type C meeting process to inform the design of a DCE with alopecia areata patients, with changes made to the design based on the FDA feedback. Additionally, a recent conference panel discussion on maximizing the impact of patient experience data in regulatory decision-making, presented a case study where a patient preference study was designed to support benefit-risk trade-off discussions with the FDA on new product submissions, with a Type C and subsequent follow-up meetings held to inform the final preference study protocol and study design¹². While the Type C meeting was considered successful, the process took 31 months, leading to recommendations for how the process could be improved in future. Two further examples of scientific advice regarding patient preference studies have been conducted with health technology assessment (HTA) bodies in Chronic Obstructive Pulmonary Disease (COPD) and multiple sclerosis^8,9,10.

Our scientific advice discussions with the FDA CDRH allowed for the PPS design to evolve as an industry/patient/HA interaction. Such collaborative effort in this novel area of preference research is of utmost importance, where all stakeholders are learning and gaining knowledge about acceptable approaches to PPS design that ensure studies and their results will meet the needs of decision-makers. In our experience, working with CDRH at FDA was smooth and was completed within six months. The initial informal discussions helped establish the information needed and format of the formal advice meeting, culminating in an efficient process and advice that was considered appropriate, timely, fit-for-purpose, and not prohibitive. This led to improved focus of the preference study design, which should enhance the richness of the study results. Whilst scientific advice on preference study design, especially advice sought very early in the product or device lifecycle, is still in its infancy and evolving as a concept, our experience was positive and will hopefully serve as a model that others can follow. More such examples are needed from other medicine and/or device developers working with decision-makers on PPS design, so that the advice process can be further optimized.

There is a recent evolution of the interaction between industry and the patient community^6,42, going beyond the more traditional involvement of patients at specific touchpoints of the research, to engage patients as study members across the entirety of a project, as true research partners in all aspects of the research design, conduct and interpretation of results^1,43. Building on other recent best practice examples in this area⁴⁴ the observation that several of the recommendations made by patient partners in our study concerning design aspects and focus, were in alignment with advice obtained from the FDA through scientific advice, is a testament to the value created through their involvement. As discussed during the FDA advice meeting, the preferences of MS patients cannot automatically be assumed to represent the preferences of patients with other diseases (particularly those where characteristics of the disease and its course may differ greatly from MS) and thus, the additional engagement with people living with MS post-FDA meetings helped refine the A&L grid of the future quantitative PPS.

Consistent with previous research^{15–18,23,45,46} the insights generated through the qualitative research with patients, caregivers, and HCPs, suggest an attraction toward easy-to-use devices for self-administration in the home setting. Ross et al.²² have shown in a multi-country study, that independent, easy to perform self-injection were the most important device attributes for autoinjectors ranked by both MS patients and nurses. Our quantitative DCE will further evaluate the relative importance of different SC device features (see Table 5) to MS patients, a population known to place high importance on the mode of treatment administration but also exhibit heterogeneity in their individual preferences¹⁰.

Strengths of our study are based upon the comprehensive qualitative research using mixed methods, with a diverse representation of MS patients, to build a PPS design that is relevant and meaningful to the patient target group and should avoid uncertainties and misunderstandings when patients participate in the survey. The qualitative research addressed improvements to the survey design (target groups, geography, statistical analyses) and to the DCE attributes and levels. Comprehension of the DCE survey by participants will be ensured through the educational materials designed with the input of patient partners and MS patients during these qualitative research phases.

As regards study limitations, the study is designed based on hypothetical devices and features in a virtual research environment, the patients having no physical contact with the devices in consideration.

The research we have conducted was limited to experienced patients in research panels and patient support groups and with internet/computer access, with the risk that this may exclude some segments of the patient population. Nonetheless, the target quotas set, as well as non-screening variables (e.g., income, region, health literacy) aimed to adequately frame outputs with respect to the general USA MS population.

This research has resulted in the development of a study protocol for the investigation of importance to MS patients of medical device features for high dose SC administration, including the attributes and levels which will be central to the DCE in the quantitative online PPS. The research used a patient-centric co-creation approach, involving patients throughout as partners, in addition to the qualitative research conducted with patients, such that attributes and levels were developed that are relevant and comprehensible to patients. Input from a health authority through scientific advice, conducted very early in the development lifecycle, further ensures an optimal design for the PPS which is expected to lead to robust study results that will address stakeholder expectations and needs to inform decision-making. This supports the overall primary objective of the broader project, to determine with MS patients, the preferences and relative importance of attributes for different device and administration features, delivering high dose/high-volume SC formulations of treatment.

Funding Statement

The costs of all the research described in this manuscript and the consultancy fees of the patient partners were borne by Novartis Pharma AG.

Acknowledgements

We would like to express our sincere gratitude to the patient experts – Anita A. William, Birgit Bauer, Claire Saxton (Cancer Support Community ), Damian Washington (Multiple Sclerosis Patient Leader), Dimika V. Cavalier , Ellen Tutton, Ginny Mason (Inflammation Breast Cancer Research Foundation, Broadway VA), Jacqui Martin, Julie A. Stamm, Luis Guerra Phoebe Day, Renate Haidinger (German Breast Cancer Association) – who participated as patient partners and generously contributed their time and expertise to this study. Their invaluable input in reviewing documents and improving the study design has significantly enhanced the quality and relevance of our research.

We also wish to acknowledge the support of Olivia Hughes, Alice Carden (Adelphi Research) regarding the initial qualitative research, Adam Gater, Jessica Middlehurst (Adelphi Values Patient-Centered Outcomes) regarding input to the FDA briefing book, and Sophi Tatlock, Frances White, Eleanor Scouler (Adelphi Values Patient Centered Outcomes) regarding the post-FDA meeting stage of interviews and qualitative research.

Conflict of Interest Statement

Marie Picci, Nigel Cook, Byron Jones, Mo Zhou, Conny Berlin, Christine Sturchler, Clemence Martinez, Irene Garcia Baena and Lauren Ziegler are employed by Novartis and hold Novartis shares.

Conny Berlin, Nigel Cook and Byron Jones were also members of the IMI PREFER project.

Harriet Gaunt is a full-time employee of Adelphi Research, who received funding from Novartis to draft the FDA briefing document and conduct the post-FDA qualitative interview stage of the study.

Brad Mason is a full-time employee of Adelphi Values Patient-Centered Outcomes, who received funding from Novartis to draft the FDA briefing document and conduct the post-FDA qualitative interview stage of the study.

Dominique Hamerlijnck is an independent patient expert consultant for Novartis, Chiesi, Pfizer and Roche, mainly on improving patient engagement. None of her family members are employed by Novartis.

Yoshiyama Majima is an independent patient expert consultant for Novartis, representing PanCAN Japan. None of his family members are employed by Novartis.

Author Contributions

Marie Picci was the study lead for the patient preference study and along with Nigel Cook, Byron Jones, Conny Berlin, Mo Zhou, Christine Sturchler and Clemence Martinez was involved in all stages of the research design, results analysis, and interpretation, as well as in drafting and finalizing the manuscript.

Irene Garcia Baena and Lauren Ziegler drafted the Scientific Advice documents and were involved in all stages of the research design, results analysis, and interpretation, and reviewed the manuscript.

Harriet Gaunt and Brad Mason were involved in drafting the FDA briefing document, study design for the post-FDA additional interviews and associated qualitative analysis, interpretation, and subsequent refinements to the A&L grid, as well as reviewing the manuscript.

Dominique Hamerlijnck and Yoshiyama Majima were patient partners and reviewed the manuscript.

Dominique Hamerlijnck provided an initial draft of the plain language summary.

Yoshiyama Majima contributed to the plain language summary.

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No competing interests reported.

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Designing a Patient Preference Study on Subcutaneous Medical Devices: Incorporating Health Authority Scientific Advice and Patient Perspectives

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Abstract

Figures

Plain language summary

Introduction

Materials and Methods

Overview of the project objectives and research

A. Qualitative research pre-FDA Meetings

Initial qualitative research across different diseases and countries

B. FDA Meetings

C. Qualitative research post-FDA Meetings

Additional in-depth qualitative research

A to C Involvement of Patient Partners

Results

A. Qualitative research pre-FDA meetings and input from patient partners for the quantitative study

Feedback from patients as research partners

Table 5. Current Final Attributes and Levels (A&L) grid

B. FDA scientific advice and considerations for the PPS study design

Feedback from MS patients

C. Qualitative research with MS patients: refinement of the A&L grid for the DCE

Feedback from patient partners

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

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