Global consensus building and prioritisation of fundamental lupus challenges: the ALPHA project

Prior barriers initiatives

The Addressing Lupus Pillars for Health Advancement (ALPHA) project builds on the work of other important initiatives that have been more singular in focus, some of which have been international in scope or are still ongoing. In 2009, the Lewin Group conducted a series of lupus expert interviews and a panel discussion of industry, federal government and academic representatives focused on characterising barriers to drug development, which included use of confounding background medications in clinical trials, severe side effects of current treatment options, and lack of reliable and specific biomarkers for lupus.9 A 2019 landscape analysis outlines numerous insights learnt from clinical trials to date, yet many of the same barriers still exist a decade later.13 14 In the area of clinical care, an international task force involving various specialists and patient representatives began to address the concept of treat-to-target in lupus, developing an extensive research agenda.15 This initiative is ongoing, and has led to the creation of a framework for defining remission in lupus.16 Additionally, research on achieving low disease activity as a clinically meaningful treatment target also shows promising progress.17 These efforts have produced important results that underscore the success of coordinated efforts that engage multistakeholder audiences. To hasten progress and ensure the most urgent needs in lupus are being met, we undertook an initiative to tie together disparate projects and identify priorities common to global lupus research, care and access.

The ALPHA project

The ALPHA project was founded as the first step in an ongoing commitment to identify, prioritise and implement strategies to address the most pressing challenges that limit progress in lupus across the continuum. The ALPHA project was established as a comprehensive effort to engage a global audience of lupus experts to identify barriers impacting drug development, clinical care and access to care across the globe. ALPHA also began to explore how lupus is defined and how that influences major challenges in the field. The ultimate goal is to develop and implement strategies to address the key barriers to improving outcomes in lupus.

The Global Advisory Committee

The Lupus Foundation of America (LFA) and the Tufts Centre for the Study of Drug Development (Tufts CSDD) collaboratively identified the criteria for establishing a geographically and professionally diverse Global Advisory Committee (GAC) of lupus thought leaders to guide and oversee the study. Primary selection criteria included thought leadership in the field; extensive knowledge of the disease; global positioning; and ability to be a team player. The GAC identified a preliminary list of fundamental barriers, shaped the content for subsequent research instrument development, and provided overall direction throughout the study.

The GAC included 13 lupus experts across five countries (USA, Australia, UK, Germany and South Korea) representing clinician, scientist, academic researcher, biopharmaceutical industry, patient advocacy organisation and patient perspectives. GAC areas of expertise included rheumatology, dermatology, immunology, nephrology and paediatrics.

In-depth expert interviews

In-depth expert interviews were conducted to elicit further opinions and detailed rationale for most urgent barriers (including those identified by the GAC), assess the level of agreement across the lupus expert community, and inform content and design of the final survey instrument. LFA, Tufts CSDD and the GAC collaboratively identified interview candidates who were well respected by the lupus scientific and care communities; represented all stakeholders in the scientific community and industry; published relevant lupus articles within the past 2–5 years (for researchers only); were currently providing direct treatment to people with lupus and/or were currently conducting lupus-related clinical research (for clinicians and principal investigators only); or had direct experience managing/helping others manage the disease, and were well-versed in current issues/knowledge of the lupus landscape (for patients/caregivers only).

Seventeen experts were interviewed. Interviewees resided in three different countries (USA, Japan and Netherlands) and represented academia, industry, regulatory agencies, clinicians, researchers, patient advocacy organisations and patients. Disease specialties included rheumatology, paediatrics, immunology, dermatology and musculoskeletal disease. Interviews were conducted by telephone and lasted approximately 1 hour. Interviewees provided their consent to participate and be audio-recorded using WebEx. Recordings were subsequently transcribed for analysis, summarised in Microsoft Excel and analysed using the qualitative analysis software, Nvivo, in which a codebook was created containing a list of thematic ‘nodes’, or topics, and their descriptions. Tufts CSDD conducted inter-rater assessments to ensure coding reliability. Nodes categorised related comments under subheadings to reveal emerging patterns and ideas. Nodes were also organised by the number of agreements and disagreements for each barrier. Barriers were then prioritised based on the highest frequency of mentions and agreements.

Survey assessment

Tufts CSDD, LFA and GAC collaborated to develop and refine the survey instrument. The final survey consisted of 23 questions focused on attitudes and perceptions about lupus and prioritisation of the most pressing challenges to improving diagnosis, care, treatment and research. Participants were asked to rank primary obstacles according to their relative impact on delayed lupus drug development, inaccurate or delayed diagnoses, suboptimal clinical care and delayed access to care, as well as identify lupus-related disorders. Survey respondents were solicited from prior expert lists developed while identifying GAC and interview candidates, and expanded based on the same criteria for in-depth interviews. The online survey was programmed through Qualtrics survey software and distributed over a 6-week period beginning November 2018.

Survey responses were cleaned in Microsoft Excel and imported into the Statistical Analysis Software program V 9.4. Descriptive statistics, frequency comparisons, subgroup stratification and weighted scoring were performed. Subgroup analyses used χ² tests to look for significant differences by geography (US vs non-US), years of experience in the field and time spent in direct care for individuals with lupus. Significance was defined at the p<0.05 level.

A weighting system was applied to prioritise barriers ranked by survey respondents depending on the frequency of being placed first, second or third in the high, medium and low priority categories. Higher ratings represented challenges of highest impact, while lower ratings represented those of lower impact. The highest possible rating was 9 and the lowest was 1. For categories with less than nine barriers able to be ranked, a rating of 1–9 was still applicable given the limitations of forced-response programming on Qualtrics ranking questions. The weighted prioritisation score followed the algorithm:

Each phase of the research study was reviewed and deemed exempt by the Tufts Health Sciences Institutional Review Board.

Foundational barriers

Clear findings emerged as pressing needs that are fundamental and necessary to address, before addressing other barriers. The known heterogeneity of lupus affects many other issues such as drug development, clinical care and access, and fully addressing this will take some time. For instance, the diversity of lupus manifestations means that two individuals with active disease may have non-overlapping manifestations. Addressing this using a single outcome measure therefore presents significant challenges. From a therapeutic perspective, identifying consistent subsets of patients at the molecular level will be needed to match the right targeted therapy to the correct patient group(s).

The high ranking of the development of biomarkers, whether prognostic, diagnostic or predictive, as an important challenge in lupus is not surprising as advances in this area will help accelerate drug development and movement towards precision medicine as well as more practical aspects of clinical care. Biomarkers can also provide value for clinical trials through disease stratification.18 While biomarker research has been prolific in the last decade and of top priority for clinical care and drug development,19 20 it has not yet resulted in major breakthroughs.21 Researchers have suggested more concerted, longitudinal efforts across multiple study sites to identify and validate biomarker candidates,22 and the ALPHA project findings highlight that this has yet to be fully implemented.

The heterogeneity of lupus has also meant that many clinical trial designs may be fundamentally flawed. In addition, the lack of validated biomarkers to stratify and predict response limits progress and means many outcome measures remain suboptimal. Under-represented study populations, including paediatric populations, as well as common comorbidities, and a lack of adjustment in studies for non-adherence, all create limitations and challenges in current studies and trials. Any, or all, of these factors relate to patient and disease heterogeneity, which contribute to apparently ‘unsuccessful’ trials and, in particular, may lead to a drug which has efficacy not being taken forward in the drug development cycle.23 Recently in 2018, a panel of lupus experts, clinical trial investigators, biopharmaceutical developers and government stakeholders initiated an ongoing dialogue with the US Food and Drug Administration on optimising trials in part to accommodate for heterogeneity,24 and ALPHA results support addressing clinical trial design through synchronous efforts to bring more effective treatments to people with lupus.

Lupus umbrella

The ALPHA project also began to investigate how the lupus community views and categorises lupus as a spectrum, or umbrella, of related disorders. Lupus may coexist with and often presents with clinical features similar to other autoimmune diseases.25–28 Varying case definitions of lupus have been applied in epidemiological studies,29 30 which hinders the field’s ability to produce consistent and comparable epidemiological data to further our understanding of the impact of lupus across populations.2 31 To address the spectrum concept, survey respondents were asked to select diseases from a list that they considered to be a part of the ‘lupus’ umbrella. Almost all respondents indicated lupus nephritis and cutaneous lupus, with a majority also selecting APS, mixed connective tissue disease and undifferentiated connective tissue disease. There were mixed opinions on numerous other diseases, supporting the need for further clarification of the ‘lupus spectrum’ and the disease definitions which may fall under this term to obtain and validate consensus.

Feasibility

The goal of the first phase of ALPHA was to identify and develop concrete and feasible strategies to address the fundamental challenges in lupus across drug development, clinical care and access. All of the mentioned challenges require large, concerted efforts among stakeholders who can lead the field and influence key decision makers with an agreed-on direction. Undoubtedly, substantial funds are needed to address top priorities and some issues may be more easily addressed than others. In the past decade, the overall funding landscape for lupus has been on a decline,32 particularly through the National Institutes of Health— the largest public funder of lupus research in the world— during a time in which arguably, lupus research has been prolific. Ongoing engagement of all lupus stakeholders is essential for addressing these barriers, and every stakeholder has a role, whether researcher, clinician, biopharmaceutical representative, regulatory official, insurer or patient.

Limitations and strengths

Limitations include potential bias among the respondent groups as the expert interview panel and survey used convenience samples. However, criteria were thoughtfully specified to identify a diverse group of lupus experts. There was also limited patient involvement in this first phase, as extensive understanding of the global lupus field was necessary to elicit and characterise fundamental challenges. However, both patient and patient advocacy representatives served on the GAC and were included in the interview stage. There may also be limitations in the survey instrument due to wording and question structure. For instance, under clinical care, ‘lack of diagnostic, predictive and prognostic biomarkers for lupus’ encompasses several different uses for biomarkers, so it was not possible to distinguish which specific use, if any, stakeholders considered most important. Additionally, the survey required forced-ranking among barriers in order to clearly identify challenges seen as top priorities to the field. All listed barriers were included in the survey based on concept elicitation from the expert interviews and thus all have unmet need. Therefore, low-ranking barriers are not synonymous with low importance. The overall response rate of 35% was not considered low, as it is consistent with typical responses rates among physician groups for web surveys.33

Particular strengths of this study include the global nature of this project and the engagement of a diverse set of lupus experts. There is international representation throughout all stages of this mixed-methods project, and the global survey received responses from individuals across 20 countries. Categories of stakeholders were also consistent for each stage of the project, and included lupus experts representing research, clinical practice, industry, government and patient advocacy in a variety of specialties.

Future directions

Phase II of this effort will include organising an international stakeholder meeting to develop a global road map of specific recommendations to address identified barriers, which may include multipronged strategies using regulatory and advocacy approaches, scientific consensus building, communication efforts, among other possible tactics. Special approaches may be needed to address issues specific to childhood lupus, as long-term outcomes and psychosocial impact of disease in children are likely different than in adults. Next steps include continued stakeholder engagement and further research efforts to characterise top barriers and lupus as a spectrum.