NIHR | Manchester Biomedical Research Centre

PhDs in Focus: Developing a Core Outcome Set for a rare condition

Zelpha D’Souza

Author: Zelpha D’Souza View Profile

PhD student

Welcome to our PhDs in Focus blog series, where our PhD students are showcasing their pioneering research projects at the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (BRC).

In this blog, Manchester BRC PhD student Zelpha D’Souza outlines how their PhD project is investigating how to improve clinical trials in rare conditions, as part of the Rare Conditions theme.

Can we improve clinical trials in rare conditions from data collected from those who are affected, those who treat and those who research these conditions? Core outcome sets may be an answer…

Why are rare conditions special?

Rare conditions are challenging in different ways – for affected individuals, their families, clinicians, and researchers. The challenges can be physical, psychosocial, emotional and financial, for patients with a rare condition and their families.1

A rare condition is defined in Europe as affecting fewer than 1 in 2000 people and though individually rare, are numerous overall, affecting 3.5 to 5.9% of the worldwide population.

Zelpha D'Souza

In the UK, rare conditions affect about 1 in 17 people (about 3.5 million individuals). 70% of rare conditions have a childhood onset, and unsurprisingly, paediatric healthcare is an important area of medicine and research as these conditions can be severely progressive, life-limiting and can have a huge negative impact on patients, and their families2, leading to healthcare systems not being able to effectively serve them.3

What treatment can an individual with a rare condition receive?

Globally, there is significant research into the genetic causes of rare conditions 1, and whilst the causes for many have been identified, there are many with an unknown cause. Many rare conditions cannot be cured; symptoms associated with a rare condition that patients experience are managed by clinical assessments, specialist treatment and clinical trials. 4 Treatments are currently only available for very few rare conditions, with the eligibility criteria being rigorous and largely dependent on the clinical presentation of the condition at that point in time.

Challenges for clinical trials in rare conditions

Choosing the appropriate outcome (for example, improvement in pain, reduction in rash, increasing mobility) in evidence-based healthcare is essential in evaluating clinical care and understanding the benefits or harms of the chosen intervention – critical for clinical trials. How the outcome is measured to reflect a change that is relevant and significant to patients, clinicians and researchers is important.5

Outcome selection and measurement in rare conditions is not straightforward, as these conditions can affect people differently, even within the same family, so can be challenging to have validated measures that can identify very subtle differences in how an individual is affected, or the disease progresses.6 Furthermore, the number of efficient clinical trials for rare paediatric conditions need to be improved. The use of core outcome sets can be of significant benefit in this improvement.

What are core outcome sets?

Core outcome sets (COS) are an agreed upon standardised collection of outcomes that should be measured and reported as a minimum, in all clinical trials in that area of health or healthcare, with other outcomes continuing to be explored. 7 COS aim to improve how the data from similar trials can be compared and pooled in meta-analysis that increases our understanding whether treatments work and/or harm.

The Core Outcome Measures in Effectiveness Trials (COMET) Initiative is an online searchable database where COS studies are registered, and promotes the development, identification and use of COS. More information about COS can be found on the COMET initiative website.

COS and rare conditions

The most recent COMET Initiative database update reports a very limited number of COS studies registered for rare genetic conditions (12 COS in 2023)8, and fewer still for rare paediatric conditions. Key published guidelines for COS development7,9-11 have been effectively used for numerous conditions8, however recent evidence shows that an improvement is needed in this methodology for rare conditions, as the current guidelines are not optimum to achieve a COS for a rare paediatric condition.

My PhD and clinical interests

My PhD with the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre Rare Conditions theme aims to improve the methodology for COS development for rare conditions.

A systematic review I am currently working on to understand children’s involvement and participation in COS development will help identify methods that have been used to engage with children, their families, and other key stakeholders, generating outcomes that are important in a clinical trial. This will provide a foundation for effective engagement with children and their families to identify the ‘most bothersome symptom’ to gather clinically meaningful outcomes, thereby incorporating the variable nature of a rare condition for COS development.

My background as a Genetic Counsellor at Saint Mary’s Hospital, part of Manchester University NHS Foundation Trust (MFT), allows me to use my skills working with families affected by a rare genetic condition. Within the combination of my clinical role and my PhD topic, the patient has, and continues to be the central focus.

My primary PhD supervisor is Professor Jamie Kirkham, Professor of Biostatistics and Head of Division of Population Health, Health Services Research & Primary Care at The University of Manchester. My co-supervisors are Dr Ramona Moldovan, Senior Lecturer at The University of Manchester, Principal Clinical Psychologist and Principal Genetic Counsellor at Saint Mary’s Hospital, and Dr Jack Wilkinson, Senior Lecturer in Clinical Trial Statistics at The University of Manchester.

I aim for my PhD to help amend and improve the current methodology for COS development that will be effective for rare conditions.

Read more blogs in the PhDs in Focus series to find out how we’re developing a research talent pipeline.

Follow Manchester BRC on X/Twitter and LinkedIn to keep updated with the series.

References

  1. National Institute for Health and Care Research & Medical Research Council. NIHR & MRC – Rare Diseases Research Landscape Project Report 2023.
  2. Baumbusch J, Mayer S, Sloan-Yip I. Alone in a Crowd? Parents of Children with Rare Diseases’ Experiences of Navigating the Healthcare System. J Genet Couns 2018.
  3. Haendel M, Vasilevsky N, Unni D, et al. How many rare diseases are there? Nat Rev Drug Discov 2020; 19(2): 77-8.
  4. Orphanet. 2023. https://www.orpha.net/consor/cgi-bin/index.php (accessed 30 November 2023.
  5. Tambuyzer E, Vandendriessche B, Austin CP, et al. Therapies for rare diseases: therapeutic modalities, progress and challenges ahead. Nat Rev Drug Discov 2020; 19(2): 93-111.
  6. Augustine EF, Adams HR, Mink JW. Clinical trials in rare disease: challenges and opportunities. J Child Neurol 2013; 28(9): 1142-50.
  7. Williamson PR, Altman DG, Bagley H, et al. The COMET Handbook: version 1.0. Trials 2017; 18(Suppl 3): 280.
  8. Dodd S, Gorst SL, Young A, Lucas SW, Williamson PR. Patient participation impacts outcome domain selection in core outcome sets for research: an updated systematic review. J Clin Epidemiol 2023; 158: 127-33.
  9. Kirkham JJ, Davis K, Altman DG, et al. Core Outcome Set-STAndards for Development: The COS-STAD recommendations. PLoS Med 2017; 14(11): e1002447.
  10. Kirkham JJ, Gorst S, Altman DG, et al. Core Outcome Set-STAndards for Reporting: The COS-STAR Statement. PLoS Med 2016; 13(10): e1002148.
  11. Kirkham JJ, Gorst S, Altman DG, et al. Core Outcome Set-STAndardised Protocol Items: the COS-STAP Statement. Trials 2019; 20(1): 116.