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DATACC BY DIME PROJECT

Defining core digital measures for
Pediatric rare disease research & care

Timeline & checklist for digitally-enabled pediatric rare disease trials

This timeline and checklist will aid you in mapping digital measures integration from planning through regulatory submission with stage-specific guidance for clinical development and operations teams.

This resource provides goals and objectives for each trial stage, detailed checklists to plan activities and guide execution towards study milestones, and practical tips for working with pediatric rare disease populations.

STAGE 1

Program alignment & study planning

When the disease course is poorly defined, meaningful-change thresholds are unknown, heterogeneity is high (genotype/phenotype, age of onset), or external controls are needed. FDA offers guidance on running natural history studies in this specific guidance.

Use stratified or model-based approaches to retain power with sparse strata. Plan to use repeated-measure or Bayesian methods to still detect real change. For example, FDA outlines where FDA expects Bayesian/adaptive designs.

Add reference growth charts or age-adjusted scoring (examples: WHO or CDC growth references). For example, NIH offers age-normed digital cognitive/motor/social-emotional measures useful for DHT-based endpoints defined in NIH Toolbox or NIH Baby Toolbox. Record which aids the child uses and adjust data interpretation (wheelchairs, speech assisted devices, etc).

Visit this project’s resources on navigating FDA & EMA pathways to decide on a specific avenue of regulatory engagement.

Note the higher up-front investment with longer-term payoff in decentralized clinical trials. Budget for replacements, accessories (chargers/straps), and helpdesk coverage.

Children may require chewable, liquid, or flavor-adjusted versions of drugs, which may affect trial costs and timelines. Some children cannot tolerate wearables or flashing screens – evaluate comfort and usability for each type of device. Check EMA’s paediatric formulation guidance for more information.

In rare diseases, data and research sharing has high engagement and relevance.

Goals

Establish your cross-study strategy, define the role of digital measures, and align with regulators.

Objectives

✔ Define program strategy

✔ Establish endpoint hierarchy

✔ Review the technology landscape

✔ Develop comprehensive budget

✔ Seek early regulatory alignment

✔ Scope Stage 2

Gate 1GATE: Early regulatory alignment

Before moving on to Stage 2, perform this readiness check:

Have you secured agreement (or clear feedback) on the disease concept model (a structured description of how the disease affects patients, including key symptoms, functional impacts, and meaningful aspects of health), the endpoint hierarchy (which specifies how primary, secondary, and exploratory endpoints (including digital measures) map to those disease impacts), and the preliminary plan for analytical and clinical validation (if required for digital measures)?

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STAGE 2

Protocol design & vendor selection

Schedule interim analyses around realistic enrollment milestones; add simulations to confirm trial feasibility (error control, power) with small sample sizes. Useful sources of design options can be found in publication: A New Toolkit for Conducting Clinical Trials in Rare Disorders.

Specify where patients serve as their own control where feasible (e.g., intra-patient change designs). Specify when and how you’ll use real-world evidence (RWE) or external control groups, and confirm data matches your trial’s eligibility criteria and endpoint definitions. For additional control-arm strategies, see the FDA/Duke-Margolis workshop “On the RISE: Controls in Rare Disease Clinical Trials for Small and Diminishing Populations.”

Pediatric rare disease studies often require broader criteria due to limited patients. Develop a strategy to manage the resulting variability in analysis.

Use flexible visit windows and DCT elements to reduce burden on patients and families. You can use Decentralized Clinical Trials (DCTs) FAQs for finding more options and details.

Pediatric trials usually require parental consent + child assent; plan workflows to avoid delays. Use available consent/assent templates. If applicable, include a re-consent plan and explain who owns the data after age 18.

If DHTs are used, reference relevant terms of service and data policies in the informed consent form.

Digital tools generate more raw data, so choose platforms to ingest, aggregate, transform, and analyze at scale. Include these data maps in consent and training materials.

Use consistent data models to align trial, natural history, and RWE sources. Define what data refresh cadence (e.g., weekly DSMB feeds) is feasible without unblinding risk.

Goals

Finalize the “how” of the trial – locking the protocol, data plans, and vendor stack.

Objectives

✔ Engage patients/advocates

✔ Draft core documents

✔ Develop consent & language

✔ Select vendor stack

✔ Evaluate DHT validation

✔ Specify data infrastructure

Gate 1GATE: Protocol & operations lock

Before moving on to Stage 3, perform this readiness check:

Are all core documents and plans finalized? This includes the protocol, SAP (statistical analysis plan; with defined estimands and hierarchies), DMP (data management plan; with data flows and privacy docs), eConsent/assent, and the full vendor stack selection.

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STAGE 3

Study start-up & enrollment

Study start-up & enrollment

Define de-identification policies, access governance, and retention timelines. Ensure adherence to regional requirements (e.g. HIPAA, GDPR).

Enable remote consent/visits and home health for assessments to reduce burden. Build multi-country/site feasibility and travel support; partner with patient advocacy groups. For example, CTTI offers pediatric trials & recruitment recommendations.

Include training, reminders, gamification, caregiver support, and backup paper/phone workflows, target the patient as well as parents/families/caregivers.

Pediatric rare disease populations are small and geographically scattered, so informal/community channels are vital for recruitment and enrollment. You can use examples from Charter for Clinical Trials in Rare Diseases or Guidance for patient involvement in industry-led medicines R&D.

Offer to share select study data back to families to motivate participation. Good resources to guide you are Good Lay Summary Practice (GLSP) or Plain English summaries guidance.

Develop strategies for long-term monitoring post-therapy administration that leverages DHTs and digital clinical measures.

Consider centers of excellence as potential sites.

Include explaining studies to children; managing dual consent/assent; cultural/literacy barriers; who to contact in what situation; include visual/video options; anticipate repeated support for digital tools.

Provide caregiver action guidance and enable 24/7 escalation. Define what happens when alerts trigger and who responds. Review concomitant/rescue meds interactions and create prohibited/conditional lists. Consider increased tolerance for minor deviations in monitoring and tracking logs.

Goals

Initiate sites and enroll the study, managing operations and monitoring data.

Objectives

✔ Obtain ethical approvals

✔ Activate sites

✔ Launch operations

Key milestones

◆ Ethical approvals received

◆ Site(s) initiated

◆ First Patient Enrolled (FPE) / First Patient Dosed (FPD)

Gate 3GATE: Interim analysis & expansion

Decision point: At the pre-specified interim analysis (N=X), assess futility/success boundaries:

GO Decision: If criteria are met, proceed with expansion to the full registrational cohort.

Check: If using Real-World Evidence (RWE) or external controls, confirm that eligibility and endpoint definitions remain aligned. Confirm the sDHT version control plan for the remainder of the trial.

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STAGE 4

Analysis, close-out & submission

Include plan for re-consent/assent logistics (e.g. if the child ages into a new category). Consider post-trial access/continuation of treatment when no alternatives exist. For gene therapies, FDA offers Long Term Follow-Up After Administration of Human Gene Therapy Products and EMA offers Guideline on follow-up of patients administered with gene therapy medicinal products.

For provisioned DHTs, consider options for participants to keep them. Provide participant/caregiver data access and enable ongoing consent control for access rights and use of their data.

Plain language summaries bridge the gap between complex scientific findings and a broader audience, making it easier for non-experts to understand, trust, and use the information.

Goals

Lock the database, analyze the data, and prepare the regulatory submission.

Objectives

✔ Engage patients/advocates

✔ Generate core reports

✔ Prepare submission

✔ Pre-submission meeting (Optional)

Key milestones

◆ Last Patient Enrolled (LPE)

◆ Final follow-up complete; Last Patient Visit (LPV)

◆ Database Lock (DBL)

Gate 3GATE: Submission readiness

Readiness check:

Is the complete data package ready? This includes the final Clinical Study Report (CSR), an integrated data package (across all sources, including RWE if used), and a clear plan for publications and plain-language summaries (PLS).

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Want a physical copy of this checklist as you run through this exercise?

Next steps

The regulatory bodies FDA and EMA offer numerous programs to support and expedite the development of medicines for rare diseases.

Learn more about rare disease acceleration pathways