Highlights
- •Evaluating the clinical benefit of interventions aimed at treating conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present quite differently across individuals and change within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) Food and Drug Administration-approved labeling claims that used these approaches.
- •A total of 6 approaches to assessing clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom, goal attainment scaling, sliding dichotomy, and adequate relief. Based on Food and Drug Administration-approved labeling claims, multicomponent endpoints have been the most successful approach in common and rare diseases. The most bothersome symptom, goal attainment scaling, multidomain responder index, and adequate relief approaches may also have potential applications in rare disease trials.
Abstract
Objectives
Evaluating the clinical benefit of interventions for conditions with heterogeneous
symptom and impact presentations is challenging. The same condition can present differently
across and within individuals over time. This occurs frequently in rare diseases.
The purpose of this review was to identify (1) assessment approaches used in clinical
trials to address heterogeneous manifestations that could be relevant in rare disease
research and (2) US Food and Drug Administration (FDA)–approved labeling claims that
used these approaches.
Methods
A targeted literature review was conducted examining peer-reviewed publications and
FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating
clinical outcome assessments. Approaches were then assessed for their potential application
in rare diseases.
Results
A total of 6 assessment approaches were identified: composite or other multicomponent
endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment
scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling
claims associated with these approaches were identified: composite or other multicomponent
endpoints (n = 49), MBS (n = 9), and adequate relief (n = 1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints,
were identified for rare diseases.
Conclusions
Multicomponent, MBS, and adequate relief have been included in FDA-approved labeling
claims. Multicomponent endpoints, including composite endpoints, were the most frequent
way to address heterogeneous manifestations of both common and rare diseases. MBS
may be acceptable to regulators, whereas multidomain responder index is unlikely to
be. The goal attainment scaling and adequate relief approaches may have potential
utility in rare disease trials, assuming the theoretical and statistical challenges
inherent in each approach are managed.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Value in HealthAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Patient-reported outcome and observer-reported outcome assessment in rare disease clinical trials - an ISPOR COA Emerging Good Practices Task Force Report.Value Health. 2017; 20: 838-855
Congress. Gov. H.R. 5238-Orphan Drug & the Orphan Drug Act, 97th Congress (1981-1982). Food and Drug Administration. https://www.congress.gov/bill/97th-congress/house-bill/5238https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/e-cfr-21-part-316-orphan-drug-orphan-drug-act-1983. Accessed March 30, 2021.
- The European Union policy in the field of rare diseases.Adv Exp Med Biol. 2017; 1031: 561-587
- Estimating cumulative point prevalence of rare disease: analysis of the Orphanet database.Eur J Hum Genet. 2020; 28: 165-173
- Rare disease terminology and definitions—a systematic global review: report of the ISPOR Rare Disease Special Interest Group.Value Health. 2015; 18: 906-914
- Measuring what matters to rare disease patients – reflections on the work by the IRDiRC taskforce on patient-centered outcome measures.Orphanet J Rare Dis. 2017; 12: 171
- BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Food and Drug Administration.(Accessed March 15, 2022.)
- Challenges in research and health technology assessment of rare disease technologies: report of the ISPOR Rare Diseases Special Interest Group.Value Health. 2018; 21: 493-500
- The patients’ voice in the evaluation of orphan drugs.Value Outcomes Spotlight. 2018; (May/June): 28-30
- Innovative research methods for studying treatment for rare diseases: methodological review.BMJ. 2014; 349 (g6802)
- Clinical outcomes assessments: use of normative data in a pediatric rare disease study.Value Health. 2018; 21: 508-514
- Patient reported outcome measures in rare diseases: a narrative review.Orphanet J Rare Dis. 2018; 13: 61
- An overview of the impact of rare disease characteristics on research methodology.Orphanet J Rare Dis. 2018; 13: 14
- Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA).(Accessed March 12, 2021)
- NCTR Bioinformatics Support. Food and Drug Administration (FDA).(Accessed September 20, 2020.)
- PROLABELS™.(Accessed December 10, 2020.)
- A new method of applying randomised control study data to the individual patient: a novel quantitative patient-centred approach to interpreting composite end points.Int J Cardiol. 2015; 195: 216-224
- Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA).(Accessed March 12, 2021)
- Some issues with composite endpoints in clinical trials.Fundam Clin Pharmacol. 2005; 19: 609-619
- Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA).(Accessed March 12, 2021.)
- Guidance for industry irritable bowel syndrome—clinical evaluation of drugs for treatment. Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA).(Accessed March 12, 2021)
- Assessing COVID-19-Related Symptoms in Outpatient Adult and Adolescent Subjects in Clinical Trials of Drugs and Biological Products for COVID-19 Prevention or Treatment. Guidance for Industry. Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA).(Accessed September 9, 2020)
- Summary of product characteristics: nusinersen. European Medicines Agency (EMA).(Accessed March 12, 2021)
- Patient-focused drug development guidance workshop: incorporating clinical outcome assessments into endpoints for regulatory decision-making. Food and Drug Administration (FDA).(Accessed March 2, 2020)
- A novel Blind Start study design to investigate vestronidase alfa for mucopolysaccharidosis VII, an ultra-rare genetic disease.Mol Genet Metab. 2018; 123: 488-494
- Highlights of prescribing information of MEPSEVIITM. Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA).(Accessed March 15, 2021.)
- Application of Bother in patient reported outcomes instruments across cultures.Health Qual Life Outcomes. 2014; 12: 18
- Goal attainment scaling as a measure of clinically important change in nursing-home patients.Age Ageing. 1999; 28: 275-281
- Statistical analysis of Goal Attainment Scaling endpoints in randomised trials.Stat Methods Med Res. 2019; 28: 1893-1910
- A systematic review to investigate the measurement properties of goal attainment scaling, towards use in drug trials.BMC Med Res Methodol. 2016; 16: 99
- Center for Health Policy, Duke.https://healthpolicy.duke.edu/sites/default/files/2020-03/meeting_summary_4_5_17.pdfDate accessed: January 11, 2021
- Identifying important outcome domains for chronic pain clinical trials: an IMMPACT survey of people with pain.Pain. 2008; 137: 276-285
- Pain outcomes in patients with advanced breast cancer and bone metastases: results from a randomized, double-blind study of denosumab and zoledronic acid.Cancer. 2013; 119: 832-838
Article info
Publication history
Published online: November 28, 2022
Accepted:
November 20,
2022
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2023 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc.
