Patient-focused Drug Development Research Articles

Patient reported perspectives of disease burden in acromegaly: data from the acromegaly community patient-focused drug development meeting

Patient reported perspectives of disease burden in acromegaly: data from the acromegaly community patient-focused drug development meeting

What facets of physical function are most important to adults diagnosed with cancer?

Successful patient-focused drug development involves selecting and measuring outcomes in clinical trials that are important to patients. The U.S. Food & Drug Administration's definition of clinical benefit includes how patients feel, function, or survive. Patients are considered the experts in describing how they feel and function. In cancer trials, patient-reported measures of physical function provide insight into how patients function at baseline, benefit from the interventions being studied, and the impact of treatment side effects. We conducted a qualitative study with adults diagnosed with cancer to describe facets of physical function from their perspective and to identify which facets are most important to this patient population. Using concept elicitation and cognitive interviewing techniques, we conducted semi-structured interviews with 72 adults ≥ 22years of age with cancer who received treatment with an anticancer drug or biologic within six months of the interview. We selected participants using purposive sampling with the aim to elicit diverse experiences regarding how they may interpret and respond to questions related to physical function. Participants were presented with patient-reported outcome (PRO) items representative of PRO measures used in cancer and general populations. Five facets of how physical function relates to activities were defined from the patient perspective: ability, difficulty, limitation, satisfaction, and completion. More than half of the participants indicated that ability was the most important facet of physical function. The next most important were satisfaction (18.3%), limitation (14.1%), difficulty (5.6%), and completion (2.8%). This study demonstrates that we must be more specific about the facets of physical function that we set out to assess when we use PRO measures to describe the patient experience. These results have implications for the specificity of physical function facets when measured in cancer clinical trials.

Pathway for Development and Validation of Multi-domain Endpoints for Amyloid Light Chain (AL) Amyloidosis.

Immunoglobin light chain (AL) amyloidosis is a rare disease in which a plasma cell dyscrasia leads to deposition of insoluble amyloid fibrils in multiple organs. To facilitate development of new therapies for this heterogenous disease, a public-private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify clinical trial endpoints and analytic strategies across affected organ systems and life impacts via specialized working groups. This review summarizes the proceedings of the Statistical Group and proposes a pathway for development and validation of multi-domain endpoints (MDEs) for potential use in AL amyloidosis clinical trials. Specifically, drawing on candidate domain-specific endpoints recommended by each organ-specific working group, different approaches to constructing MDEs were considered. Future studies were identified to assess the validity, meaningfulness and performance of MDEs through use of natural history and clinical trial data. Ultimately, for drug development, the context of use in a regulatory evaluation, the specific patient population, and the investigational therapeutic mechanism should drive selection of appropriate endpoints. MDEs for AL amyloidosis, once developed and validated, will provide important options for advancing patient-focused drug development in this multi-system disease.

Caregiver perspectives on patient-focused drug development for Phelan-McDermid syndrome

BackgroundPhelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by SHANK3 haploinsufficiency with clinical manifestations that can be devastating and profoundly affect quality of life.ResultsThe Externally Led Patient-Focused Drug Development (EL-PFDD) meeting was an opportunity for families affected by PMS to share with the Food and Drug Administration (FDA) how symptoms impact their lives and how treatments could be most meaningful. The Voice of the Patient report serves as a summary of this meeting to influence upcoming drug development and clinical trials. The purpose of this report is to provide a clinical perspective on the results of the EL-PFDD meeting to amplify the voice of these caregivers to the scientific community.ConclusionsCaregivers prioritize an improved quality of life for their loved ones characterized by improved cognitive function, improved communication, increased independence, and reduced risk of regression. With these caregiver priorities in mind, this report provides the FDA and the scientific community with a clear understanding of which aspects of PMS should influence the development of future therapeutics.

Caregiver experiences and observations of intrathecal idursulfase-IT treatment in a phase 2/3 trial in pediatric patients with neuronopathic mucopolysaccharidosis II

BackgroundApproximately two-thirds of patients with mucopolysaccharidosis II (MPS II) have a severe, neuronopathic phenotype, characterized by somatic, cognitive, and behavioral issues. Current standard of care for the treatment of MPS II is enzyme replacement therapy with intravenous recombinant human iduronate-2-sulfatase (idursulfase). To target cognitive manifestations of MPS II, idursulfase has been formulated for intrathecal administration into the cerebrospinal fluid (idursulfase-IT). In accordance with recommendations for patient-focused drug development, semi-structured interviews were conducted to assess caregiver experiences and observations in a 52-week phase 2/3 trial of idursulfase-IT, in addition to intravenous idursulfase in pediatric patients with neuronopathic MPS II, or a substudy which enrolled patients younger than 3 years old, all of whom received idursulfase-IT.ResultsOverall, 46 caregivers providing care for 50 children (mean [range] age 7.9 [3–17] years at interview) took part in a single 60-min exit interview; six of these children had participated in the substudy. Qualitative and quantitative data were obtained demonstrating the burden of MPS II experienced by caregivers and their families. Following participation in the trials, 39 (78%) of the children were reported by their caregivers to have experienced improvements in the symptoms and impact of disease. Of those with improvements, 37 (95%) experienced cognitive improvements and 26 (67%) experienced emotional/behavioral improvements. Overall, 43 children (86%) were rated by caregivers as having moderate or severe symptoms before the trials; after the trials, 28 children (56%) were considered to have mild or no symptoms. For the six children who participated in the substudy, these proportions were 83% and 100%, respectively. Caregivers’ qualitative descriptions of trial experiences suggested improvements in children’s verbal and non-verbal functioning and spatial and motor skills, as well as a positive impact on family life.ConclusionsThis study revealed caregiver-reported improvements in children’s MPS II symptoms and the impact of the disease on patients and their families. There was a trend for cognitive improvement and a reduction in severity of MPS II symptoms. After many years of extensive review and regulatory discussions of idursulfase-IT, the clinical trial data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Patient listening on social media for patient-focused drug development: a synthesis of considerations from patients, industry and regulators.

Patients, life science industry and regulatory authorities are united in their goal to reduce the disease burden of patients by closing remaining unmet needs. Patients have, however, not always been systematically and consistently involved in the drug development process. Recognizing this gap, regulatory bodies worldwide have initiated patient-focused drug development (PFDD) initiatives to foster a more systematic involvement of patients in the drug development process and to ensure that outcomes measured in clinical trials are truly relevant to patients and represent significant improvements to their quality of life. As a source of real-world evidence (RWE), social media has been consistently shown to capture the first-hand, spontaneous and unfiltered disease and treatment experience of patients and is acknowledged as a valid method for generating patient experience data by the Food and Drug Administration (FDA). While social media listening (SML) methods are increasingly applied to many diseases and use cases, a significant piece of uncertainty remains on how evidence derived from social media can be used in the drug development process and how it can impact regulatory decision making, including legal and ethical aspects. In this policy paper, we review the perspectives of three key stakeholder groups on the role of SML in drug development, namely patients, life science companies and regulators. We also carry out a systematic review of current practices and use cases for SML and, in particular, highlight benefits and drawbacks for the use of SML as a way to identify unmet needs of patients. While we find that the stakeholders are strongly aligned regarding the potential of social media for PFDD, we identify key areas in which regulatory guidance is needed to reduce uncertainty regarding the impact of SML as a source of patient experience data that has impact on regulatory decision making.

Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.

Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs. The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy's prominence in DMD and the burgeoning field of gene therapy. The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

Patient Preference Studies in Hematologic Malignancies: A Systematic Review

Background: New therapies have brought about an unprecedented expansion of treatment options for patients with hematologic malignancies that require a greater understanding patient preferences, both to inform treatment decisions and direct further patient-focused drug development. We sought to synthesize existing literature evaluating the preferences of patients with hematologic malignancies to consolidate relevant knowledge and identify future directions for research. Methods: We conducted a systematic review in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (PROSPERO 2022 CRD42022364647). We searched for articles published in English from PubMed and Embase. Included articles reported primary data on the preferences of patients with hematologic malignancies or patient proxies. Review articles, articles utilizing only secondary data, and abstracts without full text were excluded. Two authors independently reviewed all abstracts and assessed studies for full-text eligibility. Conflicts were resolved by group discussion. Risk of bias (quality) and conflict of interest were assessed. Data extraction included population, method of preference elicitation, attributes included, and relative strength of preferences. Results: A total of 3,520 studies were identified, 2,960 abstracts were screened following removal of duplicates, 239 underwent full-text review, and 74 were included in data extraction. Among the 74 studies, 59 (80%) were published in the last 10 years. In total, 16,986 patients or patient proxies were represented across selected studies. Studies included patients with lymphoma (n=33, 45%), myeloma (n=25, 34%), acute myeloid (n=15, 20%) and lymphoid (n=12, 16%) leukemia, and chronic lymphoid (n=11, 15%) and myeloid leukemia (n=10, 14%). Most studies included patients from Europe (n=30), the United States (n=26), or Canada (n=10). Nearly all (n=70, 95%) included only adults. Most studies were cross-sectional (n=60, 81%), qualitative (n=13, 18%), or mixed-methods (n=13, 18%). Only 1 study was a prospective randomized trial. Preference elicitation methods included study-specific surveys (n=31, 42%), discrete choice experiments (n=28, 38%), and qualitative interviews (n=19, 26%). Most studies elicited patient preferences for treatment outcomes (n=50, 68%) followed by communication (n=14, 19%), and route of administration of therapies (n=7, 9%). Attributes included in treatment outcome studies varied but many included overall/progression free survival (n=30, 60%), side effects (n=28, 56%), route of administration (n=16, 32%), or cost (n=11, 22%). Strength of preference for outcomes was heterogeneous across studies though overall survival was frequently most important to patients. Most studies sought to inform clinical decisions (n=49, 66%), followed by policy (n=13, 18%) and regulatory decision-makers (n=6, 8%). Most studies were of high (n=44, 59%) or moderate (n=26, 35%) quality. Funding for the studies came from pharmaceutical companies (n=25, 34%), government grants (n=20, 27%), and foundations (n=18, 24%). Some studies had apparent (n=16, 22%) or likely (n=9, 12%) conflicts of interest. Only 4 studies (5%) reported implementation outcomes such as acceptability or feasibility. Conclusions: Numerous well-designed studies have been published describing the preferences of patients with hematologic malignancies. Most of these studies were cross-sectional and relied on direct elicitation or discrete choice experiments to elicit preferences. Treatment outcome preferences varied widely across studies and patient populations. This heterogeneity supports the essential role for shared decision-making and individualization of treatment recommendations for each patient. Although many studies sought to generate data to inform clinical decisions, studies evaluating how patient preference data inform individual treatment decisions are largely absent. Future work is needed to support the clinical implementation of preference measures and to standardize relevant attributes for individual diseases and populations.

Artificial intelligence-driven approach for patient-focused drug development.

Patients' increasing digital participation provides an opportunity to pursue patient-centric research and drug development by understanding their needs. Social media has proven to be one of the most useful data sources when it comes to understanding a company's potential audience to drive more targeted impact. Navigating through an ocean of information is a tedious task where techniques such as artificial intelligence and text analytics have proven effective in identifying relevant posts for healthcare business questions. Here, we present an enterprise-ready, scalable solution demonstrating the feasibility and utility of social media-based patient experience data for use in research and development through capturing and assessing patient experiences and expectations on disease, treatment options, and unmet needs while creating a playbook for roll-out to other indications and therapeutic areas.

Eyes on the Prize: Decoding the Ophthalmic Product Regulations and Intricacies of the U.S. Food and Drug Administration Approval.

The dynamic and continuously evolving field of ophthalmology necessitates rigorous regulatory oversight in the United States. This review outlines the multifaceted Food and Drug Administration's (FDA) approval process for ophthalmic products, detailing the classifications, pathways, and regulatory compliance for devices, drugs, biologics, and combination products. Particular emphasis is placed on distinct frameworks for Class I, II, and III devices, as well as regulations for drugs, biologics, and combination products. The organizational structure of the FDA is detailed, with highlights on specific Ophthalmology oversight divisions, historical regulatory evolution, and initiatives such as Patient-Focused Drug Development. An in-depth examination of the regulatory journey, ranging from initial research to post-marketing surveillance, includes practical guidance through stages such as Pre-Investigational New Drug/Pre-Submission consultations, clinical trials, new drug application/biologics license application/premarket approval submissions, and FDA advisory committee interactions. The article underscores the importance of early interactions with the health authorities, interdisciplinary team collaboration, adherence to current standards, and the anticipation of policy changes to ensure patient safety. It concludes with an analysis of 4 key FDA-approved ophthalmic products, including Eylea®, Luxturna®, Alphagan P®, and the Raindrop® Near Vision Inlay, detailing their contributions to ophthalmic care and offering valuable insights into their respective clinical trials, regulatory pathways, and potential implications. These case studies are included to illustrate both successful and failed ophthalmic product launches, thereby highlighting the importance of alignment with regulatory compliance.

An Updated Review of Food and Drug Administration Warning and Untitled Letters for Clinical Outcome Assessment Claims Between 2013 and 2021

ObjectivesWe aimed to ascertain the frequency and types of Food and Drug Administration (FDA)-identified clinical outcome assessment (COA) violations in US pharmaceutical promotional materials from 2013 to 2021 by updating the review by Symonds et al (covering the period 2006-2012 for patient-reported outcomes [PRO] measures), expanding to infringements across all types of COAs, and grouping by efficacy or overall patient experience. MethodsWarning letters (WLs) and untitled letters (ULs) issued by the FDA’s Office of Prescription Drug Promotion were reviewed for COA violations and classified by their type: (1) COA measure not fit for purpose, (2) issue with study design or interpretation of results, and (3) inadequate statistical analysis. ResultsFrom 2013 to 2021, the FDA issued 22 WLs and 65 ULs. Year 2013 showed the highest number of letters issued (n = 24). Of the total 87 letters reviewed, 22 (25%) contained a COA violation, consisting of 6 WLs (27%) and 16 ULs (25%), including 20 (23%) with a PRO-related violation. The most common violations cited “study design or interpretation of results” (21 of 22 [95%]). ConclusionsOverall, the absolute number of WLs and ULs issued declined when comparing 2006 to 2012 with 2013 to 2021. Despite the overall reduction, this review still identified 25% of letters citing COA infringements (23% with PRO issues), which was similar to the prior review (19% PRO infringements). This may be due to increased FDA attention to patient-focused drug development.

Aiding the Adoption of Master Protocols by Optimizing Patient Engagement.

Master protocols (MPs) are an important addition to the clinical trial repertoire. As defined by the U.S. Food and Drug Administration (FDA), this term means "a protocol designed with multiple sub-studies, which may have different objectives (goals) and involve coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure." This means we now have a unique, scientifically based MP that describes how a clinical trial will be conducted using one or more potential candidate therapies to treat patients in one or more diseases. Patient engagement (PE) is also a critical factor that has been recognized by FDA through its Patient-Focused Drug Development (PFDD) initiative, and by the European Medicines Agency (EMA), which states on its website that it has been actively interacting with patients since the creation of the Agency in 1995. We propose that utilizing these PE principles in MPs can make them more successful for sponsors, providers, and patients. Potential benefits of MPs for patients awaiting treatment can include treatments that better fit a patient's needs; availability of more treatments; and faster access to treatments. These make it possible to develop innovative therapies (especially for rare diseases and/or unique subpopulations, e.g., pediatrics), to minimize untoward side effects through careful dose escalation practices and, by sharing a control arm, to lower the probability of being assigned to a placebo arm for clinical trial participants. This paper is authored by select members of the American Statistical Association (ASA)/DahShu Master Protocol Working Group (MPWG) People and Patient Engagement (PE) Subteam. DahShu is a 501(c)(3) non-profit organization, founded to promote research and education in data science. This manuscript does not include direct feedback from US or non-US regulators, though multiple regulatory-related references are cited to confirm our observation that improving patient engagement is supported by regulators. This manuscript represents the authors' independent perspective on the Master Protocol; it does not represent the official policy or viewpoint of FDA or any other regulatory organization or the views of the authors' employers. The objective of this manuscript is to provide drug developers, contract research organizations (CROs), third party capital investors, patient advocacy groups (PAGs), and biopharmaceutical executives with a better understanding of how including the patient voice throughout MP development and conduct creates more efficient clinical trials. The PE Subteam also plans to publish a Plain Language Summary (PLS) of this publication for clinical trial participants, patients, caregivers, and the public as they seek to understand the risks and benefits of MP clinical trial participation.

Recommendations on the Selection, Development, and Modification of Performance Outcome Assessments: A Good Practices Report of an ISPOR Task Force

In evaluating the clinical benefit of new therapeutic interventions, it is critical that the treatment outcomes assessed reflect aspects of health that are clinically important and meaningful to patients. Performance outcome (PerfO) assessments are measurements based on standardized tasks actively undertaken by a patient that reflect physical, cognitive, sensory, and other functional skills that bring meaning to people’s lives. PerfO assessments can have substantial value as drug development tools when the concepts of interest being measured best suit task performance and in cases where patients may be limited in their capacity for self-report. In their development, selection, and modification, including the evaluation and documentation of validity, reliability, usability, and interpretability, the good practice recommendations established for other clinical outcome assessment types should continue to be followed, with concept elicitation as a critical foundation. In addition, the importance of standardization, and the need to ensure feasibility and safety, as well as their utility in patient groups, such as pediatric populations, or those with cognitive and psychiatric challenges, may enhance the need for structured pilot evaluations, additional cognitive interviewing, and evaluation of quantitative data, such as that which would support concept confirmation or provide ecological evidence and other forms of construct evidence within a unitary approach to validity. The opportunity for PerfO assessments to inform key areas of clinical benefit is substantial and establishing good practices in their selection or development, validation, and implementation, as well as how they reflect meaningful aspects of health is critical to ensuring high standards and in furthering patient-focused drug development.

Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: Report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference.

Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) in June 2022 with the primary goal of achieving consensus on chronic HBV and HDV treatment endpoints to guide clinical trials aiming to "cure" HBV and HDV. Conference participants reached an agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is a "functional" cure, defined as sustained HBsAg loss and HBV DNA less than the lower limit of quantitation (LLOQ) 24 weeks off-treatment. An alternate endpoint would be "partial cure" defined as sustained HBsAg level < 100IU/mL and HBV DNA < LLOQ 24 weeks off-treatment. Clinical trials should initially focus on patients with HBeAg positive or negative CHB, who are treatment-naive or virally suppressed on nucleos(t)ide analogs. Hepatitis flares may occur during curative therapy and should be promptly investigated and outcomes reported. HBsAg loss would be the preferred endpoint for chronic hepatitis D, but HDV RNA < LLOQ 24 weeks off-treatment is a suitable alternate primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA < LLOQ assessed at on-treatment week 48. An alternate endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase level. Suitable candidates for phase II/III trials would be treatment-naiive or experienced patients with quantifiable HDV RNA. Novel biomarkers (hepatitis B core-related antigen [HBcrAg] and HBV RNA) remain exploratory, while nucleos(t)ide analogs and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs.

PCR249 Advancing Equity, Diversity, Inclusion, and Belonging in Patient Centered Drug Development with Patient Preference Research

Regulators and pharmaceutical and medical device manufacturers acknowledge the role patient-preference research can play in patient-focused drug development (PFDD). The growing recognition of the value of equity, diversity, inclusion, and belonging (EDIB) initiatives has challenged stakeholders to identify opportunities to promote diverse healthcare perspectives from underserved populations. Applying EDIB principles to the collection, interpretation, and use of patient preference information (PPI) in PFDD can support more inclusive and equitable health outcomes. We present specific examples of how PPI can advance EDIB in PFDD, as well as challenges.

PCR104 How Do Chinese Draft Guidelines (2021) on Patient Focused Drug Development Compare with Those of EMA and FDA?

PCR104 How Do Chinese Draft Guidelines (2021) on Patient Focused Drug Development Compare with Those of EMA and FDA?

SA41 Evolving Payer Perception on Patient Centricity and Real-World Evidence: Insights from a Quantitative Survey

Regulatory bodies, including the FDA and EMA, endorse real-world evidence (RWE) as a part of patient-focused drug development, encouraging manufacturers to conduct RWE research. Despite the potential for RWE to strengthen randomized clinical trial (RCT) data, there is notable divergence in how HTA and payer organizations incorporate RWE into their decision-making. This research aimed to understand payer perception and evolution of patient-centric approaches in clinical trials and RWE in health technology assessment (HTA) submissions and payer decision-making.

PCR51 Qualitative Synthesis of Cognitive Debriefing and Usability Testing Studies to Inform Good Electronic Clinical Outcome Assessment Design

Regulatory agencies are placing increasing importance on the patient voice in clinical drug development. The FDA’s Patient-Focused Drug Development guidances emphasize the importance of high-quality measures and recommend developers follow best practices when designing clinical outcome assessments (COA) to avoid common issues that could interfere with respondent understanding as intended. The gold standard for measuring respondent understanding is the cognitive interview or cognitive debriefing (CD). However, access to the findings of CDs across a diversity of therapeutic areas is limited. Therefore, the objective of this research was to perform a qualitative synthesis of cognitive debriefing and usability testing (CD/UT) studies of electronic COA (eCOA) across several therapeutic areas to ascertain common issues identified by patients/caregivers to help inform good eCOA design.

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

Clinical Implications•Pemphigus and pemphigoid can be severe life-threatening diseases that cause significant burden on the day-to-day lives of patients.•Access to therapy can remain an issue for patients because rituximab is only clinically approved for pemphigus vulgaris, so most therapies are prescribed off label.•Patients must weigh the burden of disease versus burden of therapy. The goal of therapy is to control disease without serious side effects.•Given the side effects of steroids, minimal therapy is the primary goal of therapy, and complete remission of disease is secondary. New therapies do not have to be perfect, as long as they provide meaningful benefits to patients.•Validated tools for measuring disease activity in pemphigus and pemphigoid have been published. The five-point Investigator’s Global Assessment scales in pemphigus and pemphigoid are not validated.•The definition of clear or almost clear disease is overly stringent and not fair compared with the endpoints used for clinical trials in other autoimmune diseases with pathophysiology similar to that of pemphigus. Clinical trial data indicate that patients’ QOL can be restored despite not achieving clear or almost clear disease activity. Clinical trials should use endpoints that reflect meaningful benefits to patients and consider the physical and psychological impact of treatments.•There has been a steady increase in clinical trials in pemphigus and pemphigoid over the last several years. The International Pemphigus and Pemphigoid Foundation seeks to continue its collaboration with the patient community, industry, and the United States Food and Drug Administration to improve access to treatment and QOL for all people affected with pemphigus and pemphigoid.Developing new treatments for intractable diseases is essential to improve patients’ health and QOL. The United States Food and Drug Administration (FDA) evaluates the safety and efficacy of treatments to ensure that the benefits of a new product outweigh its risks. Understanding what patients look for in new drugs and how patients and caregivers view the risks of therapy can help to identify areas of unmet need and guide the drug development process. Over the last decade, the FDA has incorporated patients’ perspectives and experiences into drug development process through Patient Listening Sessions and Patient-Focused Drug Development (PFDD) meetings. In contrast to Patient Listening Sessions, which are not open to the public, PFDD meetings aim to ensure that patients’ experiences, needs, and priorities are captured and meaningfully incorporated into drug development and evaluation. From the patient's perspective, PFDD meetings raise awareness and engagement in the patient community by discussing patient perspectives on the burden of disease, clinical trial participation, and risk−benefit tradeoffs of drugs used to treat their condition. From the drug development perspective, PFDD meetings can help the FDA to conduct risk−benefit assessments, advise drug sponsors on their development programs, and identify areas of unmet need or potential trial endpoints. Patients are the experts in these meetings, sharing their lived experiences so that clinicians and researchers can better understand the unmet needs of the patient community and develop tools that better assess the benefits of patient therapies. A summary of PFDD meetings relevant to dermatology is listed in Table 1.Table 1FDA and EL-PFDD Meetings Relevant to DermatologyDisease or ConditionType of MeetingMeeting DateAmyloidosisEL-PFDD Meeting16 November 2015PsoriasisFDA-led PFDD Meeting17 March 2016Alopecia areataFDA-led PFDD Meeting11 September 2017LupusEL-PFDD Meeting25 September 2017Hereditary angioedemaFDA-led PFDD Meeting25 September 2017HyperhidrosisEL-PFDD Meeting13 November 2017Hypereosinophilic syndromesEL-PFDD Meeting23 March 2018Pachyonychia congenitaEL-PFDD Meeting6 April 2018Dermatitis (eczema)EL-PFDD Meeting23 September 2019Systemic sclerosisFDA-led PFDD Meeting13 October 2020VitiligoFDA-led PFDD Meeting8 March 2021Gorlin syndromeEL-PFDD Meeting8 October 2021Pemphigus and pemphigoidEL-PFDD Meeting25 January 2023Abbreviations: EL, externally led; FDA, United States Food and Drug Administration; PFDD, Patient-Focused Drug Development.Data were obtained from https://www.fda.gov/industry/prescription-drug-user-fee-amendments/condition-specific-meeting-reports-and-other-information-related-patients-experience. Open table in a new tab •Pemphigus and pemphigoid can be severe life-threatening diseases that cause significant burden on the day-to-day lives of patients.•Access to therapy can remain an issue for patients because rituximab is only clinically approved for pemphigus vulgaris, so most therapies are prescribed off label.•Patients must weigh the burden of disease versus burden of therapy. The goal of therapy is to control disease without serious side effects.•Given the side effects of steroids, minimal therapy is the primary goal of therapy, and complete remission of disease is secondary. New therapies do not have to be perfect, as long as they provide meaningful benefits to patients.•Validated tools for measuring disease activity in pemphigus and pemphigoid have been published. The five-point Investigator’s Global Assessment scales in pemphigus and pemphigoid are not validated.•The definition of clear or almost clear disease is overly stringent and not fair compared with the endpoints used for clinical trials in other autoimmune diseases with pathophysiology similar to that of pemphigus. Clinical trial data indicate that patients’ QOL can be restored despite not achieving clear or almost clear disease activity. Clinical trials should use endpoints that reflect meaningful benefits to patients and consider the physical and psychological impact of treatments.•There has been a steady increase in clinical trials in pemphigus and pemphigoid over the last several years. The International Pemphigus and Pemphigoid Foundation seeks to continue its collaboration with the patient community, industry, and the United States Food and Drug Administration to improve access to treatment and QOL for all people affected with pemphigus and pemphigoid. Abbreviations: EL, externally led; FDA, United States Food and Drug Administration; PFDD, Patient-Focused Drug Development. Data were obtained from https://www.fda.gov/industry/prescription-drug-user-fee-amendments/condition-specific-meeting-reports-and-other-information-related-patients-experience. On January 25, 2023, the International Pemphigus and Pemphigoid Foundation hosted an externally led PFDD meeting with the FDA in collaboration with international patient advocacy organizations PEM Friends (United Kingdom), Association Pemphigus Pemphigoïde France, and Pemphigus/Pemphigoid Friends Association (Japan). This commentary discusses patient and physician perspectives relevant to PFDD in pemphigus and pemphigoid. Pemphigus vulgaris and pemphigus foliaceus are autoimmune blistering diseases caused by autoantibodies directed against desmosomal adhesion proteins (Schmidt et al., 2019Schmidt E. Kasperkiewicz M. Joly P. Pemphigus.Lancet. 2019; 394: 882-894Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). Pemphigoid encompasses a group of autoimmune blistering diseases caused by autoantibodies directed against various adhesion proteins of the dermal−epidermal junction (Egami et al., 2020Egami S. Yamagami J. Amagai M. Autoimmune bullous skin diseases, pemphigus and pemphigoid.J Allergy Clin Immunol. 2020; 145: 1031-1047Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Pemphigus and pemphigoid are orphan diseases. The rarity of the disease as well as limited access to specialty centers with experts in autoimmune blistering diseases often results in delays in diagnosis. The main complaints of patients are pruritus (particularly for bullous pemphigoid), pain from oral and genital erosions, dysphagia and weight loss, insomnia, fatigue, corticosteroid side effects, stigmatization from visible blisters and scarring, anxiety over the danger of treatment, and fear of relapse and having to take corticosteroids again. Pemphigoid can lead to erosions and scarring of the skin in addition to the eyes, larynx, esophagus, and genitourinary mucosa, in some cases resulting in blindness or death. Patients have elevated mortality relative to age-matched controls (Langan et al., 2008Langan S.M. Smeeth L. Hubbard R. Fleming K.M. Smith C.J. West J. Bullous pemphigoid and pemphigus vulgaris--incidence and mortality in the UK: population based cohort study.BMJ. 2008; 337: a180Crossref PubMed Scopus (472) Google Scholar). In addition, difficulties due to disease or complications of treatment can lead patients to lose work, income, and QOL (Sebaratnam et al., 2012Sebaratnam D.F. McMillan J.R. Werth V.P. Murrell D.F. Quality of life in patients with bullous dermatoses.Clin Dermatol. 2012; 30: 103-107Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Treatments for pemphigus and pemphigoid aim to stop the production of autoantibodies and inflammation. Corticosteroids are clinically approved for the treatment of pemphigus. Rituximab is clinically approved only for the pemphigus vulgaris subtype. Other therapies are prescribed off label for pemphigus, such as oral immunosuppressives and intravenous Ig. All therapies for pemphigoid (including immunosuppressives, anti-inflammatory agents, intravenous Ig, and mAbs such as omalizumab or dupilumab) are prescribed off label. The ideal goals of treatment are to have complete healing of blisters and resolution of the functional impairment associated with the disease, improve QOL, prevent disease recurrence, and limit treatment side effects related to corticosteroids and immunosuppressants. The efficacy of rituximab and corticosteroids for pemphigus is supported by two pivotal randomized controlled trials, indicating 40−90% rates of complete remission off corticosteroids with the use of maintenance rituximab infusions every 6 months (Chen et al., 2020Chen D.M. Odueyungbo A. Csinady E. Gearhart L. Lehane P. Cheu M. et al.Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect.Br J Dermatol. 2020; 182: 1111-1119Crossref PubMed Scopus (40) Google Scholar; Joly et al., 2017Joly P. Maho-Vaillant M. Prost-Squarcioni C. Hebert V. Houivet E. Calbo S. et al.First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.Lancet. 2017; 389: 2031-2040Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar; Werth et al., 2021Werth V.P. Joly P. Mimouni D. Maverakis E. Caux F. Lehane P. et al.Rituximab versus mycophenolate mofetil in Patients with pemphigus vulgaris.N Engl J Med. 2021; 384: 2295-2305Crossref PubMed Scopus (35) Google Scholar). Real-world data have described temporal outcomes of rituximab therapy for pemphigus vulgaris when used as part of standard clinical care, indicating that 43% of patients who receive repeated cycles of rituximab for relapsed or refractory disease achieve complete remission off corticosteroids (Tovanabutra et al., 2022Tovanabutra N. Bax C.E. Feng R. Kushner C.J. Payne A.S. Temporal outcomes after rituximab therapy for pemphigus vulgaris.J Invest Dermatol. 2022; 142: 1058-1064.e7Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Limitations of rituximab and corticosteroids include their transient therapeutic effect, which necessitates repeated infusions for disease control. Chronic immune suppression can lead to serious infections and impaired response to vaccines. Studies have shown increased mortality from COVID-19 in patients with autoimmune blistering disease treated with immunosuppressive therapies (French study Group on auto immune bullous skin diseases, and the French network of rare diseases in Dermatology, 2022Joly P. French study Group on auto immune bullous skin diseases, and the French network of rare diseases in Dermatology (FIMARAD)Incidence and severity of COVID-19 in patients with autoimmune blistering skin diseases: A nationwide study.J Am Acad Dermatol. 2022; 86: 494-497Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). As a result, many patients feel that they can no longer safely do the things they used to do, such as gatherings with family and friends, vacation or work travel, dining out, and working in indoor office spaces. This has led to substantial social and professional isolation, in some cases forcing patients to seek other lines of work. In addition, chronic corticosteroid use can lead to numerous side effects, including weight gain, mood swings, insomnia, bruising, and stretch marks, in addition to serious medical complications such as hypertension, diabetes, glaucoma, cataracts, and bone fractures. These limitations highlight several unmet needs in pemphigus and pemphigoid therapy. The main problems in pemphigus management are relapsing and refractory disease, which require higher cumulative steroid doses and result in more side effects from therapy. Physicians and patients must remain vigilant for rare and potentially life-threatening infections due to immunosuppressive treatments. Patients are in need of drugs that are safe and well-tolerated, which avoid chronic immune suppression and the need for regular blood work. Oral, topical, or subcutaneous routes of administration would be beneficial to patients who may have difficulty arranging travel or logistics for intravenous infusions. Drugs that work fast to control disease would be important because most drugs for pemphigus and pemphigoid take several months to have therapeutic effects. For QOL, patients want to avoid the use of corticosteroids. Validated disease activity scales for pemphigus and pemphigoid have been developed over the last 15 years by an international panel of medical experts, who have performed studies to compare the reliability with the validity of different disease activity instruments (Hébert et al., 2019Hébert V. Boulard C. Houivet E. Duvert Lehembre S. Borradori L. Della Torre R. et al.Large international validation of ABSIS and PDAI pemphigus severity scores.J Invest Dermatol. 2019; 139: 31-37Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar; Masmoudi et al., 2021Masmoudi W. Vaillant M. Vassileva S. Patsatsi A. Quereux G. Moltrasio C. et al.International validation of the Bullous pemphigoid Disease Area Index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid.Br J Dermatol. 2021; 184: 1106-1112Crossref PubMed Scopus (26) Google Scholar; Murrell et al., 2012Murrell D.F. Daniel B.S. Joly P. Borradori L. Amagai M. Hashimoto T. et al.Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.J Am Acad Dermatol. 2012; 66: 479-485Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar; Rosenbach et al., 2009Rosenbach M. Murrell D.F. Bystryn J.C. Dulay S. Dick S. Fakharzadeh S. et al.Reliability and convergent validity of two outcome instruments for pemphigus.J Invest Dermatol. 2009; 129: 2404-2410Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). These studies have identified indices with high inter-rater and intrarater reliability, such as the Pemphigus Disease Area Index (PDAI) and the Bullous Pemphigoid Disease Area Index (BPDAI). Using the consensus-based standards for the selection of health measurement instruments, the PDAI and BPDAI perform better than the PASI or eczema activity and severity index (EASI), which have been used by the FDA for drug approvals in their respective diseases. Patients would value 50% or 75% improvement in pemphigus or pemphigoid disease activity, similar to endpoints that have previously led to drug approvals for atopic dermatitis (EASI-50) and psoriasis (PASI-75). A major challenge for pemphigus and pemphigoid drug development is that recent clinical trials in pemphigus and pemphigoid are being required by FDA to use an endpoint of clear or almost clear disease using a five-point Investigator’s Global Assessment (IGA) scale. However, IGAs have not been validated for pemphigus and pemphigoid. Validated instruments that separate disease activity from damage and are sensitive to changes in disease activity are better to show a response to therapy than IGA five-point scales. Past experience with a similar scale known as the Physician Global Assessment (PGA) shows that the PGA is far less reliable than autoimmune bullous disease−specific instruments (Rosenbach et al., 2009Rosenbach M. Murrell D.F. Bystryn J.C. Dulay S. Dick S. Fakharzadeh S. et al.Reliability and convergent validity of two outcome instruments for pemphigus.J Invest Dermatol. 2009; 129: 2404-2410Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). In addition, in current IGA scales for pemphigus and pemphigoid, a single blister would be classified as mild disease and would prevent a patient from achieving the endpoint of clear or almost clear disease. For example, a patient with near total oral mucosal blistering (PDAI score = 42) could experience complete disease clearance with therapy but could develop one transient small blister (PDAI score = 1) on the day of the clinical trial assessment, which can easily occur given the skin and mucosal fragility in patients with pemphigus and pemphigoid. Despite a nearly 98% improvement in PDAI score, the single blister would result in an IGA score of 2 and would be counted as a treatment failure. Hence, the IGA definition of clear or almost clear disease is overly strict given the burden of disease and the risks and limitations of current therapies. Endpoints for pemphigus and pemphigoid clinical trials should be comparable with those used for other similar autoimmune diseases such as myasthenia gravis, which have received drug approvals on the basis of a two-point reduction in disease activity scales, without the requirement for complete or near complete disease clearance (Howard et al., 2021Howard Jr., J.F. Bril V. Vu T. Karam C. Peric S. Margania T. et al.Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial.Lancet Neurol. 2021; 20 ([published correction appears in Lancet Neurol 2021;20:e5]): 526-536Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Less stringent criteria for almost clear including up to three small blisters or a PDAI/BPDAI activity score of up to 5 should be considered, or endpoints could be based on a minimal clinically important difference or percentage reduction in disease-specific activity scores. Consensus outcome definitions and endpoints for pemphigus and pemphigoid have been published (Murrell et al., 2012Murrell D.F. Daniel B.S. Joly P. Borradori L. Amagai M. Hashimoto T. et al.Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.J Am Acad Dermatol. 2012; 66: 479-485Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, Murrell et al., 2008Murrell D.F. Dick S. Ahmed A.R. Amagai M. Barnadas M.A. Borradori L. et al.Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus.J Amer Acad Dermatol. 2008; 58: 1043-1046Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar), which included definitions of complete or partial remission of systemic therapy or minimal doses of systemic therapy. These consensus definitions were intended to assess standard-of-care therapies (mainly oral immunosuppressives) because they were published before clinical trials for pemphigus and pemphigoid were in development in the United States. Endpoints for clinical trials may include complete or partial remission on minimal steroid doses or off steroids while remaining on the investigational therapy being evaluated. In pivotal clinical trials of rituximab for pemphigus, the last rituximab infusion was performed 6 months before assessment of the primary endpoint, a logical timepoint because the effect of rituximab on total B-cell counts lasts longer than 6 months. In the context of rituximab and corticosteroids, off therapy means off steroids for 8 weeks—this definition was not intended to indicate that clinical trials of other therapies with different mechanisms of action must achieve disease remission off the investigational therapy being tested. For example, medications with a shorter pharmacodynamic effect than rituximab (such as efgartigimod, whose effects on IgG begin to reverse within a week of stopping the drug) need to be continued to the endpoint to see the steroid-sparing effect. Minimal steroid doses for endpoints should also be considered carefully because prednisone doses of 10 mg or greater can have a substantial therapeutic effect. The oral Bruton’s tyrosine kinase inhibitor rilzabrutinib failed to show a significant difference compared with placebo in a phase 3 trial for pemphigus when a minimal steroid dose of 10 mg daily was evaluated in the comparator arm. A minimal steroid dose of 5 mg daily or a weight-based dose such as 0.1 mg/kg/day may be more appropriate to show a difference compared with steroids alone. Defining meaningful improvement is critical. In the PEMPHIX phase 3 randomized controlled trial of rituximab and corticosteroids, 40% of patients achieved the primary endpoint of complete remission off steroids. However, 87.2% of clinicians and 80.9% of patients rated the disease as very much improved at week 52, despite not having sustained a complete response to therapy. In the nomacopan clinical trial in bullous pemphigoid, a 75% reduction in BPDAI score was associated with a 100% improvement in QOL in some patients. These data indicate that patients’ QOL can be restored despite not achieving complete remission of disease activity. Hence, requiring complete disease clearance or an IGA endpoint of clear or almost clear for clinical trials in pemphigus and pemphigoid is not tied to meaningful response for patients. The use of nonvalidated and insensitive IGA scales will ultimately impede drug development for pemphigus and pemphigoid and prevent effective therapies from getting to patients. Dozens of patients with pemphigus and pemphigoid shared their experiences living with the disease. Current therapies present barriers to care that add to the already overwhelming burden patients face from the symptoms of the disease. Patients often have to try multiple therapies to find one that achieves disease remission. Many drugs used to treat pemphigus and pemphigoid have to be prescribed off label, which can create financial difficulty and delays in treatment. Additional and better treatment options are needed. Other challenges included delay in diagnosis, the physical and mental toll of the disease on themselves and their family, debilitating pain and itch from widespread lesions, limited access to blistering disease specialists or therapy, and the need to seek other lines of work owing to constraints imposed by disease or its therapy. The impact of disease on their QOL, patient perspectives on the limitations of current therapies, what characteristics they would look for in a new drug, and what outcomes of therapy are desirable were discussed. The PFDD meeting aims to highlight the physical, psychological, and emotional impact of disease on patients to identify what is most important to those living with these diseases. After the PFDD meeting, a Voice of the Patient Meeting Report will be published, summarizing input shared by patients and their caregivers, along with results of the patient polls and survey (https://www.fda.gov/industry/prescription-drug-user-fee-amendments/condition-specific-meeting-reports-and-other-information-related-patients-experience). Rebecca Strong: http://orcid.org/0009-0007-8957-3655 Dedee F. Murrell: http://orcid.org/0000-0003-2971-0199 PD is an employee with the International Pemphigus & Pemphigoid Foundation. PJ is a consultant for Roche, Amgen, Principia Biopharma, Argenx, AstraZeneca, Thermo Fisher, Sanofi Regeneron, Janssen, and Akari. DFM is a consultant/investigator for Roche, GlaxoSmithKline, Novartis, Principia Bio, Immune Pharmaceuticals, Eli Lilly, Sanofi, argenx, Astra Zeneca, Bristol Myers Squibb, Genentech, Janssen, Pfizer, and Regeneron. VPW is a consultant for AbbVie/Abbott, AnaptysBio, Argenx, Astra Zeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galderma, Genentech, Gilead, GlaxoSmithKline, Horizon Therapeutics, Janssen, Kirin, Merck/Merck Sharp & Dohme, Nektar, Novartis, Octapharma, Pfizer, Principia, Regeneron, Rome Pharmaceuticals, and Sanofi and received grant/research support from Amgen, argenx, Biogen, Corbus, CSL Behring, Genentech, Horizon Therapeutics, Pfizer, Regeneron, and Syntimmune. ASP holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen. We would like to thank Amethyst Yale, Anna Lane, and the patients with pemphigus and pemphigoid who graciously gave their time and shared their experiences.

Health-Related Quality of Life Instruments for Clinical Trials in AL Amyloidosis: Report from the Amyloidosis Forum HRQOL Working Group.

Systemic AL (light chain) amyloidosis is a rare protein misfolding disorder associated with plasma cell dyscrasia affecting various organs leading to organ dysfunction and failure. The Amyloidosis Forum is a public-private partnership between the Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research with the goal of accelerating the development of effective treatments for AL amyloidosis. In recognition of this goal, 6 individual working groups were formed to identify and/or provide recommendations related to various aspects of patient-relevant clinical trial endpoints. This review summarizes the methods, findings, and recommendations of the Health-Related Quality of Life (HRQOL) Working Group. The HRQOL Working Group sought to identify existing patient-reported outcome (PRO) assessments of HRQOL for use in clinical trials and practice deemed relevant across a broad spectrum of patients with AL amyloidosis. A systematic review of the AL amyloidosis literature identified 1) additional signs/symptoms not currently part of an existing conceptual model, and 2) relevant PRO instruments used to measure HRQOL. The Working Group mapped content from each identified instrument to areas of impact in the conceptual model to determine which instrument(s) provide coverage of relevant concepts. The SF-36v2® Health Survey (SF-36v2; QualityMetric Incorporated, LLC) and Patient-Reported Outcomes Measurement Information System-29 Profile (PROMIS-29; HealthMeasures) were identified as instruments relevant to patients with AL amyloidosis. Existing evidence of reliability and validity was evaluated with a recommendation for future work focused on estimating clinically meaningful within-patient change thresholds for these instruments. For sponsors, the context of use-including specific research objectives, trial population, and investigational product under study-should inherently drive selection of the appropriate PRO instrument and endpoint definitions to detect meaningful change and enable patient-focused drug development.