Core Outcome Measures in Effectiveness Trials

Catalyzing registry-based randomized comparative effectiveness trials for inherited metabolic diseases in children: establishing a core outcome set and data collection tools

General Information

Summary:
Potential impact

Inherited metabolic diseases (IMD) are a large group of single gene disorders that are individually rare but collectively affect ~3,000 Canadian children. There are important questions about the comparative effectiveness of both new and long-standing therapies for IMD that have either not been addressed in clinical trials or have not been addressed in trials that consider meaningful outcomes across a broad range of patients, with suitable comparators.

These evidence gaps are in part due to challenges in conducting randomized trials for rare diseases.

The registry-based randomized trial design presents a unique opportunity to address comparative effectiveness questions for IMD. It involves the rigorous collection of meaningful and standardized outcomes on an on-going basis across a population-representative registry of patients, to allow rapid development of randomized trials in order to compare interventions that are an important source of uncertainty for patients, providers, and policy makers. Registry-based randomized trials thus provide a cost-efficient method for generating evidence for rare pediatric disease such as IMD, making trials possible in areas where robust evaluations are not otherwise feasible.

Scientific merit

The purpose of the proposed catalyst research is to further develop a pan-Canadian resource, the Canadian Inherited Metabolic Diseases Research Network (CIMDRN) cohort and network, to support registry-based randomized comparative effectiveness trials. Our specific objectives are to:
1. Establish standardized sets of core patient-oriented outcomes to be used in future registry-based comparative effectiveness trials for children with IMD, beginning with two example IMD, phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase deficiency (MCADD);
2. Define, develop, and incorporate measures of these outcomes into the CIMDRN platform; and
3. Conduct pilot feasibility studies with these outcomes and measures in preparation for future multi-year innovative clinical trial (iCT) applications to the SPOR iCT initiative.

To address the first objective, we will use established methods for developing core outcome sets for clinical trials, including a review to identify potential clinical and patient or family-reported outcomes, and a Delphi consensus approach to arrive at an agreed core outcome set for each disease. To pursue the second objective, we will identify candidate measures and data collection tools reflecting the outcomes and evaluate their face validity, measurement properties, relevance, and feasibility. Finally, we will integrate the outcome measures into the CIMDRN platform and database and conduct a pilot evaluation of their feasibility in five Canadian centres. Deliverables from this catalyst research will include: (i) core outcome sets and measures for PKU and MCADD, suitable for dissemination to stakeholders; (ii) at least two study protocols for registry-based randomized trials, with
primary and secondary outcomes specified from the core sets, for submission to future funding opportunities including the SPOR iCT initiative; (iii) a methodological tool kit that can be used to extend our methods to both other IMD and other rare pediatric diseases; and (iv) sustainable partnerships among stakeholders to support future trials and methods development.

Research team and engagement with knowledge users

Our team has expertise in registry science, clinical trial design and analysis, clinical paediatrics, metabolic care, epidemiology, and health services and policy research and includes knowledge users reflecting patient, provider, and policy perspectives. By mobilizing these diverse communities through a strong engagement plan, we will advance the science of innovative clinical trials through the collaborative development of new tools to study the comparative effectiveness of interventions for rare pediatric diseases.

Contributors:
-Beth K Potter (principal investigator), University of Ottawa, Ottawa
-Tammy Clifford (co-principal investigator and knowledge user), Canadian Agency for Drugs and Technologies in Health (CADTH), Ottawa
-Nicole Pallone N (co-principal investigator and knowledge user), CanPKU, Vancouver
-Sylvia Stockler (co-principal investigator), BC Children's Hospital, Vancouver
-Maureen Smith (co-investigator and knowledge user), Canadian Organization for Rare Disorders (CORD), Ottawa
-Pranesh Chakraborty (co-investigator), Children's Hospital of Eastern Ontario, Ottawa
-Douglas Coyle (co-investigator), University of Ottawa, Ottawa
-Cheryl Rockman-Greenberg (co-investigator), Winnipeg Regional Health Authority, Winnipeg
-Lawrence Korngut (co-investigator), University of Calgary, Calgary
-Alex MacKenzie (co-investigator), Children's Hospital of Eastern Ontario Research Institute, Ottawa
-John J Mitchell (co-investigator), McGill University Health Centre, Montreal
-Stuart Nicholls (co-investigator), Children's Hospital of Eastern Ontario, Toronto
-Martin Offringa (co-investigator), Hospital for Sick Children, Toronto
-Andreas Schulze (co-investigator), Hospital for Sick Children, Toronto
-Monica Taljaard (co-investigator), Ottawa Hospital Research Institute, Ottawa

Further Study Information

Current Stage:
Ongoing
Date:
April 2017 - August 2018
Funding source(s):
CIHR Catalyst Grant: SPOR Innovative Clinical Trials

Health Area

Disease Category
Metabolic

Disease Name
Inherited metabolic diseases
phenylketonuria (PKU)
medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency)

Target Population

Age Range
0 - 18

Sex
Either


Nature / type of Intervention
Any

Method(s)

Delphi process
Literature review

The purpose of the proposed catalyst research is to further develop a pan-Canadian resource, the Canadian Inherited Metabolic Diseases Research Network (CIMDRN) cohort and network, to support registry-based randomized comparative effectiveness trials. Our specific objectives are to:
1. Establish standardized sets of core patient-oriented outcomes to be used in future registry-based comparative effectiveness trials for children with IMD, beginning with two example IMD, phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase deficiency (MCADD);
2. Define, develop, and incorporate measures of these outcomes into the CIMDRN platform; and
3. Conduct pilot feasibility studies with these outcomes and measures in preparation for future multi-year innovative clinical trial (iCT) applications to the SPOR iCT initiative.

To address the first objective, we will use established methods for developing core outcome sets for clinical trials, including a review to identify potential clinical and patient or family-reported outcomes, and a Delphi consensus approach to arrive at an agreed core outcome set for each disease. To pursue the second objective, we will identify candidate measures and data collection tools reflecting the outcomes and evaluate their face validity, measurement properties, relevance, and feasibility. Finally, we will integrate the outcome measures into the CIMDRN platform and database and conduct a pilot evaluation of their feasibility in five Canadian centres. Deliverables from this catalyst research will include: (i) core outcome sets and measures for PKU and MCADD, suitable for dissemination to stakeholders; (ii) at least two study protocols for registry-based randomized trials, with
primary and secondary outcomes specified from the core sets, for submission to future funding opportunities including the SPOR iCT initiative; (iii) a methodological tool kit that can be used to extend our methods to both other IMD and other rare pediatric diseases; and (iv) sustainable partnerships among stakeholders to support future trials and methods development.


Stakeholders Involved

Clinical experts
Consumers (caregivers)
Consumers (patients)
Economists
Epidemiologists
Families
Methodologists
Patient/ support group representatives
Policy makers
Researchers
Service providers
Service users
Statisticians

Study Type

COS for clinical trials or clinical research
COS for practice

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