Objective 1: Rigorous and efficient trial designs to evaluate interventions for rare diseases

• New therapies with potential to change natural history and improve outcomes for patients with rare diseases are appearing at an accelerating pace, and knowledge users (patients, care providers, payers) need timely and rigorous evidence regarding their efficacy, effectiveness, safety, and costs.

• Despite this need for evidence, the small and geographically dispersed patient populations, clinical heterogeneity, and limited resources that characterize rare diseases have resulted in a comparative paucity of randomized trials to evaluate treatments. Addressing this gap requires robust and efficient trial designs that focus on knowledge user-prioritized questions.

• Registry-based randomized trials are at the centre of our research as a strategy to efficiently generate evidence about interventions for rare diseases. To inform their design, conduct, and reporting, within INFORM RARE and generally, we recently reviewed existing registry-based trials. We focused on how trial data are collected and handled from registries and outside sources, including changes in timing of registry data collection specific to trials, and on the selection and reporting of trial outcomes [1]. We have also identified key recommendations for registries to optimize their “trial-readiness” [2].

• We are building capacity in other design and analytic strategies for rare disease trials through collaborations with other research groups and networks. This includes stepped wedge trial, n-of-1 trials, and the use of various adaptive designs.

Objective 2: Developing core outcome sets

• Core outcome sets are important to support the efficient use of limited rare disease research resources by promoting harmonized outcome selection and measurement across all trials in a disease area. Core outcome set development methods that are inclusive of the perspectives of patients and caregivers, healthcare providers, methodologists, and policymakers also help to ensure that the outcomes included in trials are meaningful and prioritized by knowledge users.

• Our team has expertise in core outcome set development, within and beyond rare diseases. We have developed core outcome sets for rare diseases that have been the focus of INFORM RARE [3,4] (see INFORM MPS and INFORM PKU). These outcome sets are being used to guide the collection of data in INFORM RARE’s Canadian Metabolic Registry project, and in our registry-based trials.

• Dr. Martin Offringa (methods lead) has also led international initiatives in the selection, measurement, evaluation and reporting of outcomes and outcome measurement instruments in health research [5-14].

Objective 3: Co-developing patient-centred clinical trial knowledge translation tools

• INFORM RARE, including members of our Patient Engagement and Methods research themes, recently collaborated on a knowledge mobilization study led by Dr. Nancy Butcher (INFORM RARE methods co-lead). Funded by CHILD-BRIGHT, this team worked with youth and parents to co-develop a freely accessible results template that researchers can use to communicate the results of pediatric clinical trials to child participants and their families, “CommuniKIDS”.

• Our ongoing work, also among members of our Methods and Patient Engagement research themes, will include co-developing informational materials with youth (e.g., animations, videos) designed to inform children and youth about participating in pediatric rare disease clinical trials.

• Research reporting guidelines for child health clinical trials, SPIRIT-Children and CONSORT-Children, are being developed to support transparent reporting in all child health clinical trial protocols and final reports, in partnership with young people, family caregivers, and various pediatric clinical trial stakeholders.

• These projects will be used by INFORM RARE-supported trials to support patient-centred enrollment and communication with trial participants and their families.

1. Baba A, Tay J, Sammy A, Douglas WA, Goren K, Krause KR, Howie AH, Little J, Oskoui M, Taljaard M, Thombs BD, Potter BK, Butcher NJ, Offringa M. Heterogeneous use of registry data for participant identification and primary outcome ascertainment is found in registry-based randomized controlled trials: a scoping review. J Clin Epidemiol. 2023 May 3:S0895-4356(23)00104-X. doi: 10.1016/j.jclinepi.2023.04.016.

2. Krause KR, Tay J, Douglas WA, Sammy A, Baba A, Goren K, Thombs BD, Howie AH, Oskoui M, Frøbert O, Trakadis Y, Little J, Potter BK, Butcher NJ, Offringa M. Paper II: thematic framework analysis of registry-based randomized controlled trials provided insights for designing trial ready registries. J Clin Epidemiol. 2023 May 4:S0895-4356(23)00103-8. doi: 10.1016/j.jclinepi.2023.04.015.

3. Howie AH, Tingley K, Inbar-Feigenberg M, Mitchell JJ, Butcher NJ, Offringa M, Smith M, Angel K, Gentle J, Wyatt A, Campeau PM, Chan A, Chakraborty P, El Turk F, Mamak M, Mhanni A, Skidmore S, Sparkes R, Stockler S, Potter BK and in collaboration with the INFORM RARE Network. Establishing a core outcome set for mucopolysaccharidoses (MPS) in children: study protocol for a rapid literature review, candidate outcomes survey, and Delphi surveys. Trials 2021; 22:816, doi: https://doi.org/10.1186/s13063-021-05791-8.

4. Pugliese M, Tingley K, Chow A, Pallone N, Smith M, Chakraborty P, Geraghty MT, Irwin JK, Mitchell JJ, Stockler S, Nicholls SG, Offringa M, Rahman A, Tessier LA, Butcher NJ, Iverson R, Lamoureux M, Clifford TJ, Hutton B, Paik K, Tao J, Skidmore B, Coyle D, Duddy K, Dyack S, Greenberg CR, Jain S, Karp N, Korngut L, Kronik J, MacKenzie A, MacKenzie J, Maranda B, Potter M, Prasad C, Schulze A, Sparkes R, Taljaard M, Trakadis Y, Walia J, Potter BK in collaboration with the Canadian Inherited Metabolic Diseases Research Network. Core Outcome Sets for Medium-Chain Acyl-CoA Dehydrogenase Deficiency and Phenylketonuria. Pediatrics 2021; 148(2):e2020037747, doi: https://doi.org/10.1542/peds.2020-037747.

5. Goren K, Monsour A, Stallwood E, Offringa M, Butcher NJ. Pediatric core outcome sets had deficiencies and lacked child and family input: A methodological review. J Clin Epidemiol. 2023 Mar;155:13-21. doi: 10.1016/j.jclinepi.2022.12.009. Epub 2022 Dec 15. PMID: 36528231.

6. Stallwood E, Monsour A, Rodrigues C, Monga S, Terwee C, Offringa M, Butcher NJ. Systematic Review: The Measurement Properties of the Children's Depression Rating Scale-Revised in Adolescents With Major Depressive Disorder. J Am Acad Child Adolesc Psychiatry. 2020 Oct 29:S0890-8567(20)32050-5. doi: 10.1016/j.jaac.2020.10.009. Online ahead of print.PMID: 33130251.

7. Stallwood E, Elsman EBM, Monsour A, Baba A, Butcher NJ, Offringa M. Measurement Properties of Patient Reported Outcome Scales: A Systematic Review. Pediatrics. 2023 Aug 1;152(2):e2023061489. doi: 10.1542/peds.2023-061489.PMID: 37439131.

8. Manyara AM, Davies P, Stewart D, Weir CJ, Young AE, Wells V, Blazeby J, Butcher NJ, Bujkiewicz S, Chan AW, Collins GS, Dawoud D, Offringa M, Ouwens M, Ross JS, Taylor RS, Ciani O. Definitions, acceptability, limitations, and guidance in the use and reporting of surrogate endpoints in trials: A scoping review. J Clin Epidemiol. 2023 Jun 26:S0895-4356(23)00160-9. doi: 10.1016/j.jclinepi.2023.06.013. Online ahead of print.PMID: 37380118.

9. Baba A, Webbe J, Butcher NJ, Rodrigues C, Stallwood E, Goren K, Monsour A, Chang ASM, Trivedi A, Manley BJ, McCall E, Bogossian F, Namba F, Schmolzer GM, Harding J, Nguyen KA, Doyle LW, Jardine L, Rysavy MA, Konstantinidis M, Meyer M, Helmi MAM, Lai NM, Hay S, Onland W, Choo YM, Gale C, Soll RF, Offringa M; Core Outcome Reporting in Neonatal Trials Study Group. Heterogeneity and Gaps in Reporting Primary Outcomes From Neonatal Trials. Pediatrics. 2023 Aug 29:e2022060751. doi: 10.1542/peds.2022-060751. Epub ahead of print. PMID:37641881.

10. Webbe J, Baba A, Butcher NJ, Rodrigues C, Stallwood E, Goren K, Monsour A, Chang ASM, Trivedi A, Manley BJ, McCall E, Bogossian F, Namba F, Schmolzer GM, Popat H, Nguyen KA, Doyle LW, Jardine L, Rysavy MA, Konstantinidis M, Muhd Helmi MA, Lai NM, Hay S, Onland W, Choo YM, Gale C, Soll RF, Offringa M; CORE OUTCOME REPORTING IN NEONATAL TRIALS (CORINT) STUDY GROUP. Strengthening Reporting of Neonatal Trials. Pediatrics. 2023 Aug 29:e2022060765. doi: 10.1542/peds.2022-060765. Epub ahead of print. PMID: 37641894.

11. Krause KR, Hetrick SE, Courtney DB, Cost KT, Butcher NJ, Offringa M, Monga S, Henderson J, Szatmari P How much is enough? Considering minimally important change in youth mental health outcomes. Lancet Psychiatry. 2022 Dec;9(12):992-998. doi: 10.1016/S2215-0366(22)00338-8.PMID: 36403601.

12. Butcher NJ, Monsour A, Mew EJ, Chan AW, Moher D, Mayo-Wilson E, Terwee CB, Chee-A-Tow A, Baba A, Gavin F, Grimshaw JM, Kelly LE, Saeed L, Thabane L, Askie L, Smith M, Farid-Kapadia M, Williamson PR, Szatmari P, Tugwell P, Golub RM, Monga S, Vohra S, Marlin S, Ungar WJ, Offringa M. Guidelines for Reporting Outcomes in Trial Protocols: The SPIRIT-Outcomes 2022 Extension. JAMA. 2022 Dec 20;328(23):2345-2356. doi: 10.1001/jama.2022.21243.PMID: 36512367.

13. Butcher NJ, Monsour A, Mew EJ, Chan AW, Moher D, Mayo-Wilson E, Terwee CB, Chee-A-Tow A, Baba A, Gavin F, Grimshaw JM, Kelly LE, Saeed L, Thabane L, Askie L, Smith M, Farid-Kapadia M, Williamson PR, Szatmari P, Tugwell P, Golub RM, Monga S, Vohra S, Marlin S, Ungar WJ, Offringa M. Guidelines for Reporting Outcomes in Trial Reports: The CONSORT-Outcomes 2022 Extension. JAMA. 2022 Dec 13;328(22):2252-2264. doi: 10.1001/jama.2022.21022.PMID: 36511921.

14. Elsman EBM, Butcher NJ, Mokkink LB, Terwee CB, Tricco A, Gagnier JJ, Aiyegbusi OL, Barnett C, Smith M, Moher D, Offringa M. Study protocol for developing, piloting and disseminating the PRISMA-COSMIN guideline: a new reporting guideline for systematic reviews of outcome measurement instruments. Syst Rev. 2022 Jun 13;11(1):121. doi: 10.1186/s13643-022-01994-5. PMID: 35698213; PMCID: PMC9195229.