Cure Sickle Cell Initiative recommendations on common data elements for sickle cell disease gene therapy trials

Key Points

• •CureSCi CDE recommendations build upon current consensus and allow for outcome comparison across SCD gene therapy studies.
• •A library of hierarchical CDE recommendations is available on the CureSCi website.

Visual Abstract

Abstract

The Cure Sickle Cell Initiative (CureSCi), created by the National Heart, Lung, and Blood Institute, has developed data standards to increase interoperability and meta-analysis of studies specifically investigating gene therapy for sickle cell disease (SCD). The aims of the CureSCi Common Data Elements (CDE) initiative are to facilitate the development of safe, effective, and accessible gene therapies. Five working groups (WGs) comprising people living with SCD, stakeholders, clinicians, and researchers reviewed current definitions used for SCD clinical studies, including those from the American Society of Hematology, US Food and Drug Administration, PhenX catalog of consensus measures for phenotypes and exposures, and others. The WGs met over 1.5 years to develop a comprehensive list of defined data points and variables recommended for any gene therapy clinical trial that incorporated feedback from a 60-day public review period. The SCD CDEs are publicly available on the CureSCi (curesickle.org/datatools-overview) and the National Institutes of Health (NIH) Repository (cde.nlm.nih.gov/home) websites. In addition to data elements, there are 42 instrument recommendations, including those from the Patient-Reported Outcomes Measurement Information System and NIH Toolbox, and 49 template case report forms for various stages of a study (eg, demographic, disease history, treatment, and outcome). CureSCi data element recommendations build upon current consensus data elements and facilitate the start-up of multicenter clinical research efforts. This standardized set of clinical research recommendations will increase the ability to compare outcomes across studies, increase data quality, and help educate new clinical investigators in the field of SCD gene therapy research.

Introduction

The Cure Sickle Cell Initiative (CureSCi) has actively engaged the community of people living with SCD, family members, caregivers, and stakeholders to work together on a path to cures. CureSCi is a collaboration among researchers, industry, nonprofit organizations, and policymaking agencies that was publicly launched in 2018. The initiative is funded by the National Heart, Lung, and Blood Institute, which is part of the National Institutes of Health (NIH). Common data elements (CDEs) have been developed for other diseases,¹ and the CureSCi CDE initiative used a similar methodology to establish a set of consensus data elements for SCD clinical investigations.

In alignment with the CureSCi goal of building a community among people living with SCD, industry, academic researchers, health care providers, and government, representatives from each of these groups were an integral part of the CDE working groups (WGs). In particular, individuals living with SCD were vital to bringing a needed perspective to the review of recommendations within each group. WG members with various backgrounds used their own experiences with the SCD community in developing these recommendations in hopes that they would provide the best outcomes for individuals and families affected by SCD. A listing of all WG members and contributors are included in supplementary Materials.

Methods

The CureSCi CDEs were developed using a modified Delphi method for achieving consensus. The process was similar to prior CDE development conducted for neurologic disorders.^1,2 The following 5 WGs were tasked with drafting CDE recommendations: Genetics and Assays (14 members); Physical Examination and Medical History (16 members); Cardiopulmonary, Renal, and Cerebrovascular (19 members); Outcomes (16 members); and Monitoring Side Effects (15 members). Each WG included a person living with SCD or an advocate. This inclusion allowed for invaluable insight and consideration toward ensuring that the case report forms and instruments are patient friendly and that the content is acceptable for people living with SCD and the SCD community. The WGs aimed to capture the diversity and complexity of the clinical presentation of SCD.

Monthly 1-hour WG meetings were convened over a 6- to 12-month period and facilitated by 2 cochairs. During these sessions, WG members identified and used existing forms from various sources (Figure 1) and then systematically reviewed and discussed the CDEs, examining each data element individually to achieve consensus and consulting with other WGs as needed throughout this iterative process.

Figure 1.

Iterative development process. ASH-FDA, American Society of Hematology/FDA; BMT CTN, Blood and Marrow Transplant Clinical Trials Network; caDSR, Cancer Data Standards Registry; CMPT, Center for Medical Technology Policy; CRFs, case report forms; Med., medical; PhenX for SCD, consensus measures for phenotypes and exposures for SCD.

Once deliberations ended with the WGs, the recommendations were combined into a library of recommendations in a hierarchical presentation of data elements:

• •Core: question/instrument/data element that collects essential/required information applicable to any SCD gene therapy study. It is anticipated that investigators will need to collect the disease Core CDEs.
• •Supplemental, highly recommended: this classification includes those that are considered important elements that are not required in all SCD gene therapy studies.
• •Supplemental: a data element, which is commonly collected in clinical research studies, whose use depends upon the study design, protocol, or type of research.

Classifications were determined through group deliberation, with particular attention to identifying elements that should be designated as Core. Data elements considered essential for collection were classified as Core based on consensus among WG members.

Initial drafts of CDEs were harmonized across WGs to reduce overlap and redundancy. The finalized set of CDEs was then uploaded for public review via the CureSCi website (curesickle.org). The public review allowed for the SCD community, stakeholders, and clinicians to review the product over a period of 60 days and provide feedback. Upon the conclusion of the 60-day public comment period, stakeholder feedback was compiled and shared with the WGs for review. Proposed revisions were considered and adjudicated by the WG members, with modifications incorporated based on group consensus. After the public review, a subset of CDEs underwent Clinical Data Interchange Standards Consortium (CDISC) Clinical Data Acquisition Standards Harmonization (CDASH) compliance. The use of CDISC standards Study Data Tabulation Model (http://www.cdisc.org/sdtm) and the CDASH standard (https://www.cdisc.org/standards/foundational/cdash) allowed the CDEs to be more reusable and findable. CDISC’s Study Data Tabulation Model standard, which is used in CDASH, is one of the required standards for data submission to the US Food and Drug Administration (FDA).

Version 1.0 of the standardized data forms was released on the CureSCi website in 2021 and subsequently underwent a rigorous governance process to be entered into the NIH CDE repository (https://cde.nlm.nih.gov/). Future updates should be undertaken as needed to ensure continued refinement of the CDEs and alignment with evolving scientific standards and advances in the field.

This study was reviewed and determined to be exempt by the institutional review board of the Emmes Company, LLC.

Results

The WGs worked both separately and collaboratively on the data element recommendations. For example, the Genetics and Assays WG focused on genetic diagnostic testing for SCD³ and measures of red blood cell (RBC) quality, quantity and function, hemolysis, and erythropoiesis.^4,5 The WGs collaborated on specified gene therapy–specific assays with a primary focus on tracking modified cell production, location, and function in vivo, as well as biomarkers of interest, including inflammation-ischemia reperfusion assays, vasculopathy/endothelial activation assays, and molecular assays (proteomics/genomics and epigenetics/metabolomics).

The Genetics and Assays WG explored how to assess the long-term durability of genetic manipulation as well as the quantification of gene therapy–derived hemoglobin. Many of the core assay recommendations are consistent with standard clinical assays (eg, complete blood count and iron measurements).³ The WG acknowledged the wide array of RBC characterization assays available or in development^6,7,8 that are critical for the understanding of SCD and the impact of investigational drugs on RBC health. The WG categorized these RBC-specific assays by considering whether they were clinically validated, in development, and accessible (ie, requiring expensive and specialized equipment), and whether they were similar to other assays to limit the number of required/core recommendations. The recommendations also included some of the more advanced RBC assays (adhesion assessments), even if they are still exploratory.

Drug product release assays were discussed and summarized with the intent of providing an overview of the required release tests and links to the available FDA guidance documents.^9,10 The WG did not provide recommendations for specific methods or instruments in drug product assays, given the lack of standardization of assays in the cell and gene therapy field, as well as the growing number of gene editing technologies and methods in development.^11,12,13

The focus of the Physical Examination and Medical History WG was to define the basic framework of data to be collected for clinical studies in SCD. The group reviewed data collection forms from prior clinical trials in SCD and developed case report forms for laboratory tests, hospitalization history, prior or concomitant medication, reproductive history, and other medical history, including acute and chronic conditions.

Similarly, the Cardiopulmonary, Renal, and Cerebrovascular WG focused on these specific organ functions and used previous research derived from the 2020 American Society of Hematology central nervous system guidelines,¹⁴ the American Heart Association/American Stroke Association, the World Health Organization, and a 2019 Blood Advances publication on end points for SCD trials¹⁵ in addition to other current research to develop data element recommendations.

The Outcomes WG focus was on patient-reported outcomes (PROs), and they considered several measures, including those addressing pain, physical function, executive function, PROs, quality of life, sleep, and fatigue. They noted that for several outcome domains, different measures with varying levels of validation were available. Some were measures applicable to a broad range of conditions that might be applied to SCD but with varying levels of validation in the SCD population, and others were specifically developed for SCD. In addition, many measures were validated for pediatric or adult populations but not both. For PROs, Patient-Reported Outcomes Measurement Information System (PROMIS), the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me), and the Pediatric Quality of Life Inventory (PedsQL) SCD modules were available. In general, PROMIS measures were broader, applicable across multiple age groups, and could facilitate comparisons in outcomes with non-SCD conditions. ASCQ-Me^16,17 and PedsQL’s SCD module^18,19 were developed and validated specifically for SCD, and there is some evidence that ASCQ-Me may at least capture more disease-relevant information than similar measures included in PROMIS.²⁰ In addition, ASCQ-Me and PedsQL SCD module measures differ and are validated in different age groups (adult and pediatric, respectively).

People living with SCD, caregivers, and stakeholders on the panel were strongly of the opinion that a measure of overall health and quality of life should be included as a core measure. All measures in the global health domain included items redundant with other measures, some of which are core and highly recommended, such as mood, pain, and function. Factors weighed included accessibility, participant burden, suitability to extract preference-based utilities for cost-utility estimations, and applicability to SCD. At the end of this process, PROMIS Global Health measures were selected as core measures of global health. The strengths of PROMIS included accessibility, ability to be administered by multiple methods, modest participant burden, availability of child and parent-proxy measures, and item-level validation.

There are some domains of symptoms and impairments that are common and clinically significant but for which agreement on optimal measures was lacking. For example, cognitive function and more specifically processing speed and executive function were cited as important domains. However, studies have used different measures^21,22 and how these compare with each other, the natural history of cognitive dysfunction, and how they predict patient-relevant life problems are still unsettled. Therefore, recommendations in this area were driven largely by pragmatic considerations, such as the cost of measures and the necessity for highly specialized staff for their administration.

Monitoring side effects after experimental therapy with gene and genomic modifications for curative effect in SCD was addressed by the Monitoring Side Effects WG. The Monitoring Side Effects WG approached the topic by organizing the timing of the side effects as early, through the initial 100 days after the infusion of modified autologous cells (acute), through the first 2 years (mid), and in the long-term follow-up phase extending from 2 to 15 years (late). Ideally, the optimal gene therapy would have modest, limited side effects in the short- and long-term while extending a durable curative effect. In practice, the WG determined that an ideal therapy is not highly likely to emerge in every iteration. Therefore, having a uniform methodology to track the timing and severity of side effects would help establish standards in acceptable toxicity, compare different therapies more accurately, and compare established supportive care to conventional allogeneic hematopoietic cell transplantation. The WG also attempted to minimize overlap with other WGs, although this was not possible to achieve in every side effect nor was it possible to attribute a cause to every side effect without ambiguity. However, the scope of defining key data elements for determining outcomes was comprehensive because these relate to genomic modifications and preparative regimens. Resolution, as opposed to the persistence of disease-related signs and symptoms, was to a lesser extent a focus because both these topics were assigned to other WGs.

The collection of treatment-related side effects and serious adverse events after curative therapies, applying a uniform set of core elements supplemented as feasible, will assist in the comparison of curative therapies as these emerge. This tool also has the potential to assist in the discovery of novel, unexpected adverse events, particularly those that only become apparent in the long term.

The 5 WGs analyzed the scope, findings, and implications relevant to their subject areas. The CureSCi CDEs are publicly available under “Data Standards” on curesickle.org and organized by domain and subdomain. Table 1 lists the Core data element topic areas or instrument recommendations by WG.

Table 1.

Core data element topic areas or instrument recommendations by WG

WG	Core data collection topic areas or instruments
Genetics and Assays	Gene product Immune reconstitutio Drug product Genetic diagnostic testing
Physical Examination and Medical History	SCD-related acute painful episodes Laboratory tests Baseline abnormal hematopoiesis Medical history Transfusion history Endocrine, infertility, and bone Priapism Acute anemia Chronic anemia Acute spleen Behavioral history Physical examination Vital signs and blood gases
Cardiopulmonary, Renal, and Cerebrovascular	Acute chest syndrome Echocardiogram Cardiac MRI CNS assessments 6-minute walk test Pulmonary function test Renal function assessment
Outcomes	Numeric Pain Rating Scale ASCQ-Me pain impact ASCQ-Me pain episodes NIH toolbox global cognition PedsQL multidimensional fatigue scale PedsQL pain impact SCD module (children) PedsQL pain and hurt, SCD modules PROMIS fatigue/pediatric fatigue PROMIS 10 global health PROMIS 7+2 global health PROMIS Item Bank version 1.0–fatigue-calibrated items PROMIS pain interference; adult and pediatric modules
Monitoring Side Effects	Iron overload Endocrine, fertility, and bone Serious adverse events Mortality and survival

CNS, central nervous system; MRI, magnetic resonance imaging.

Discussion

The purpose of the CureSCi CDE initiative was to establish a set of consensus data elements for SCD gene therapy clinical investigations. The focus of this work was to develop forms for collecting data for genetic research studies in SCD based on recommendations from all sources, including experts in adult SCD, pediatric SCD, people living with SCD, stakeholders, industry, and data managers.

Two gene therapy products for people with SCD have now been FDA approved, and additional trials are ongoing. The studies that have led to approval have been single-arm studies using a predesign/postdesign assessment to demonstrate effectiveness. Given the number of participants in these trials and their design, it is essential that all studies use clearly defined data elements across enrollment criteria and data collection before, during, and after the intervention. The use of the CDEs will allow comparison across studies and enable useful meta-analysis using data from these studies. The purpose of the CureSCi CDE WGs was to define these essential data elements.

The WGs defined CDEs for evaluating the drug product in vivo and collecting data, allowing for a well-phenotyped population undergoing gene therapy, including assessments of end-organ disease. In addition, the WGs assessed and recommended PROs and monitoring for side effects. It is expected that all future studies will use the core data elements developed by the WGs, and investigators will be mandated to use the core elements if funded by the federal government. The CureSCi website portal will be used to disseminate these tools and provide free template forms with instructions for investigators.

Several unmet needs were identified by the WGs, including defining the natural history of symptoms and impairments. Many validation studies for SCD-related measures were shown to differentiate disease exacerbations (periods of hospitalization or crisis) from baseline and/or people with more severe disease from those with less severe disease.^23,24 However, their sensitivity to more moderate or slow changes in illness, such as partial improvement from treatment and long-term changes in chronic symptoms, is largely unproven. The most significant unmet need is the definition of cure, which will require genetic, functional, and organ-based assessments that will need many years of study.

Future review for updating these CDEs should consider areas such as how pain is measured and tools to allow the robust collection of data on mental health and fertility outcomes such as preservation, and the intersection between these 2 common problems. A more nuanced ability to capture pain phenotypes as well as the identification of PRO tools that can be used across the age range of transition from pediatric to adult care may be needed. People living with SCD have different tolerances to painful stimuli, and given its subjective character, it is often a challenge to find tools to capture the full pain phenotype for each individual. In addition, there should be greater focus on the mental health needs of people living with SCD and their family members. Other areas that require new or vetted tools for assessment are related to medical trauma and how it intersects with decisions about care and treatment, tools for the assessment of stress associated with having a chronic illness characterized by intermittent, unexpected episodes of pain, and tools to better measure the impact of acute pain on an individual basis. Although participant burden was considered during discussions, the time to complete the CDEs will depend on each individual study, and future studies should assess the burden on participants. In addition, the financial burden of participating in a clinical gene therapy trial or receiving an approved gene therapy treatment was not within the scope of this project but should be a future topic of emphasis. Ultimately, establishing a composite curative end point that brings together the WG’s genetic, clinical, organ function, and PRO measures would offer a transformative tool to guide clinicians and empower people living with SCD because they consider how these therapies may shape their lives.

Conclusions

The goal of these recommendations is to include data elements that can be followed across the growing number of gene therapy approaches and to be captured using the same standard to compare outcomes across the different approaches. It is important that we continue to robustly account for differences in gene therapies, including the type and function of hemoglobin induced as well as long-term durability, which may differ between therapies. In addition, it is important that all therapies are vigilant in monitoring the ongoing durability of therapy with transparency for people living with SCD and the clinicians who care for them. Currently, there are no tests (genetic assays or otherwise) that can be used to assess for “cure”’ in these outcomes. Defining cure is an essential step in better analysis and decision-making for people living with SCD who are seeking gene therapies.

The SCD data elements version 1.0 recommendations are on the CureSCi website (https://curesickle.org/system/files/Sickle_Cell_Disease_CDE_Highlight_Summary.pdf). These recommendations should be viewed as a living document, and the assessment of their usability and implementation in research projects will contribute to creating a better future for people with SCD. Feedback is welcome and encouraged to enable CDEs to be further refined and become a useful resource for SCD researchers. Although not explicitly stated, the appropriate use of CDEs in applications seeking NIH funding should be viewed as essential, and their incorporation should move the science forward in a more harmonized and comprehensive manner.

A summary of the recommendations can be found in tabular format at Sickle Cell Disease CDE Highlight Summary, and the Core instruments and data elements are available at CDE Start Up Resource.

Conflict-of-interest disclosure: S.L. served on an adjudication committee for bluebird bio, Novo Nordisk, and Beam Therapeutics; received consulting fees from Agios, Fulcrum, and Pfizer; and received research support from Cellarity, Agios, PCORI, HRSA, and National Institutes of Health. The remaining authors declare no competing financial interests.