A Potential Paradigm for the Robust and Systematic Prioritisation of Assets in Academic-Led, Multi-Industry Collaborative Trials in Rare Populations (Glo-BNHL)

Overview

Given the rarity of children and adolescents with relapsed and refractory (r/r) B-cell Non-Hodgkin Lymphoma (B-NHL) and the large number of potential agents in development for adult mature B-cell malignancies, there is urgent need for prioritisation of agents as proposed by the ACCELERATE Paediatric Strategy Forum for medicinal development in paediatric B-NHL (Pearson 2019). The process developed for the global platform study Glo-BNHL (published separately) is described here.

Prioritisation process

Assets submitted for review by industry collaborators are prioritised under Confidentiality Disclosure Agreements by the Glo-BNHL Trial Steering Committee (TSC) comprising expert clinicians, statisticians and patient representatives. The assessment includes a quantitative element addressing each of the following areas, with greater weighting given to more relevant criteria such as paediatric-specific and clinical data.

• Target and scientific rationale

• Asset position within current prioritisation strategy*

• Pre-clinical data evaluating in vitro sensitivity, including the number, heterogeneity and relevance of cell lines tested and quality of the submitted elements of evidence

• Pre-clinical data evaluating in vivo activity of the asset including the number, type and relevance of models and quality of the elements of evidence submitted

• Clinical data regarding monotherapy efficacy in single arm and randomised trials, including the disease-type and therapeutic regimen studied

• Clinical data regarding combination efficacy (if studied)

• Clinical data regarding safety of the agent with regard to frequency, severity and modifiability of adverse events, including applicability to the paediatric population

• Feasibility of delivery in paediatrics, including formulation and dose-confirmation processes

*Classes of novel agents prioritised for inclusion at the initiation of the trial were: (1) Bispecific antibodies (2) antibody-drug conjugates (3) chimeric antigen receptor T-cell products. The TSC has committed to updating this list as the field evolves.

The assessment also includes a qualitative element incorporating expert opinion regarding relevance of the target, mechanism of action, and overall impression of the asset. These elements are combined to inform the final discussion before a decision is made.

A formal written response from the Sponsor and TSC Chair outlining the TSC decision on whether the asset has been prioritised for evaluation within Glo-BNHL, and associated rationale, is issued to the relevant industry partner (now also copied to the European Medicines Agency (EMA)) within 28 days of receipt of the asset information pack. A follow-up clarification meeting is offered. For prioritised assets, following agreement from the relevant industry partner, the process of formal inclusion in Glo-BNHL then begins.

Scope of assets reviewed

Between September 2020 and June 2023, information packs for 7 assets were submitted for review from 6 pharmaceutical companies. The assets spanned 5 classes of drugs: 3 bispecific antibodies, 1 antibody-drug conjugate, 1 chimeric antigen receptor T-cell product, 1 small molecule inhibitor and 1 immunomodulator. Formal responses were issued within a median of 20 days (mean 21.3 days) followed by a clarification meeting on 5 occasions.

Prioritised assets

Four of the 7 reviewed assets were prioritised for inclusion within Glo-BNHL. At time of planned opening only 2 of these assets are included. The other 2 assets are being investigated in industry-led competitive trials. A further asset was deemed to be of potential interest but insufficient data were available due to the early stage of development to reach a final conclusion (further review pending).

Non-prioritised assets

The rationale for non-prioritisation of assets included irrelevant target in paediatric B-NHL, insufficiently convincing mechanism of action, and lack of superiority over other agents within a non-prioritised class. The EMA has subsequently waived the obligation to submit the results of paediatric B-NHL studies for both non-prioritised assets reasoning they do not represent potential for significant therapeutic benefit.

Summary

The Glo-BNHL international platform trial prioritisation process represents a model for handling the challenge of development of multiple potential agents in very rare populations in the global arena.