Table 2 Requirements and safety/efficacy profile recommendations for phase I, II and III trials

Product-regulatory requirements

Kinetics, biodistribution of the cells. Purity, potency and karyotype stability of particular cells. Ensure traceability

Short-term side effects and risk associated with particular cell-based biologics

Performed after preliminary evidence suggesting effectiveness of particular cells

Objective

Safety

Safety/surrogate endpoints

Safety/therapeutic benefit/improved survival

Patient restriction/criteria

Identify target group (safety analysis)

Identify potential responders and non-responders

Include only responders

Sample size

Usually 20 per cohort

From a few dozen to a few hundred

Several hundred or more

Design

Randomized, open label or placebo

Randomized, placebo-controlled

Randomized, double-blinded, placebo-controlled

End-points (feasibility - product and procedure related)

Procedure safety, biological activity of the cells

Safety/feasibility of the procedure, adequate number of cells/dose response

Long-term, substantial evidence of previously observed feasibility/safety

Safety endpoints

Patient tolerance, abnormal cell growth, mutagenesis, tumorigenicity

Patient tolerance, tissue injury, possibility of arrhythmias

Clinically relevant objective: death, clinical events

Efficacy endpoints

Detect surrogate endpoints sensitive to track the therapeutic benefit

1) Further analysis of previously detected surrogate endpoints 2) Exploratory analysis of clinically relevant endpoints

1) Clinically relevant endpoints. Objective (single or composite): improved survival, reduced clinical events/number of hospitalizations. Subjective: symptom score, health-related quality of life 2) Surrogate efficacy endpoints that meaningfully correlate with clinical endpoints