Advancing neurofibromatosis and schwannomatosis clinical trial design: Consensus recommendations from the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration

Neurofibromatosis and schwannomatosis (collectively known as the neurofibromatoses (NF)) are a group of rare, genetic syndromes that predispose individuals to develop multiple benign nerve sheath tumors. Following recently revised nomenclature, this group includes neurofibromatosis type 1 (NF1), NF2-related schwannomatosis (NF2-SWN, formerly known as neurofibromatosis type 2 (NF2)), and multiple other forms of schwannomatosis (SWN).^1,2 Although these conditions are distinct entities causing a wide variety of physical, cognitive, and psychosocial complications, they share common challenges in drug development and clinical trial design due to their rarity, wide spectrum of disease manifestations, and predominantly slowly progressive nature.

Due to the slower growth trajectory of benign tumors compared to their malignant counterparts, assessing traditional oncology clinical trial endpoints such as survival or disease progression in NF is often logistically infeasible and cost-prohibitive. Following the Food and Drug Administration (FDA) guidance that new therapies must demonstrate clinically meaningful improvements in the way patients survive, feel, or function, the identification of outcome measures that can accurately and reliably document improvements in the functional, cognitive, aesthetic, and/or psychological impact of NF-related disease manifestations is needed to support regulatory approvals. ³ Finally, given the small patient populations available for clinical trials in these rare conditions and the desire to maximize the efficiency of the drug development process, there is a need for consensus guidelines on clinical trial design and outcome measures for NF. Without well-defined and widely accepted endpoints, it can be challenging to compare the results of different clinical trials and demonstrate the effectiveness of new therapies for these conditions.

To address these needs, the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration (REiNS) was established in 2011. The organization’s mission is to establish international consensus on NF clinical trial endpoints and response criteria in order to accelerate the development of effective therapies for these rare diseases. It is a collaborative effort that includes experts from academia, industry, and regulatory agencies, as well as patient advocates. The organization consists of a steering committee, eight working groups focused on specific areas of NF research, and a robust patient and family representative program. Working groups meet virtually to conduct research on and develop consensus recommendations for clinical trial design. In addition, two hybrid in-person/virtual meetings are held each year to get input from the wider NF community.

Since its founding, REiNS members have helped promote numerous standardized, feasible, and clinically meaningful outcome measures for NF clinical trials. Three previous supplements published in Neurology^® in 2013, and 2016, and 2021 set forth a variety of recommendations for clinical trial design, gathered stakeholder perspectives on clinical trials, and generated empirical evidence on the reliability of proposed outcomes.^4–6 A summary of all currently recommended measures is available at the REiNS website at https://ccrod.cancer.gov/confluence/display/REINS/Recommendations; these include the use of volumetric magnetic resonance imaging (MRI) analysis to assess response in clinical trials and the use of various functional and patient-reported outcome measures to evaluate clinical benefit. Many of these measures were incorporated into the SPRINT registration trial, which established the efficacy of selumetinib for treatment of inoperable plexiform neurofibromas in pediatric patients with NF1. ⁷ Based on these results, selumetinib was approved for this indication by the FDA, European Medicines Agency, and other regulatory agencies. REiNS-recommended measures have continued to be adopted within multicenter trials in the United States and across the world, further demonstrating the real-world impact of the organization’s work.

The REiNS International Collaboration now extends these efforts with the publication of seven additional manuscripts in this issue of Clinical Trials. Using systematic review and rating methods, REiNS recommends the FACE-Q Craniofacial Module Appearance Distress scale to assess NF1 patients’ appearance concerns related to plexiform and cutaneous neurofibromas ⁸ and the Tinnitus Functional Index to assess the impact of tinnitus on NF2 patients. ⁹ When a single recommendation may be premature, REiNS also reviews state-of-the-art methodologies and their available evidence to provide guidance on options for clinical trial measures, as with this issue’s review on potential endpoints to assess bone health in individuals with NF1. ¹⁰ And as best practices evolve over time, REiNS seeks to update its recommendations as needed. To this end, our biomarker working group has updated and expanded their 2016 recommendations for collecting and annotating biosamples in NF clinical trials. ¹¹

A new key area of focus for REiNS is the development of recommendations for trial designs for gene-directed therapies for NF. Following the March 2022 REiNS Winter Meeting on gene therapy, a new working group dedicated to this topic was established within REiNS. These therapies have the potential to revolutionize the treatment of NF1 and SWN, and REiNS is working to proactively ensure that the clinical trial endpoints for gene-directed therapies are meaningful and relevant to patients. The group also seeks to discuss ethical issues surrounding trials of gene-directed therapy in NF to ensure that issues of safety and ethics are adequately considered prior to initiating human clinical trials. To this end, in this supplement, REiNS shares its’ initial exploration of the path toward clinical trials for gene-directed therapy for all forms of NF. ¹²

Finally, including the perspectives of patients and their family members into clinical trial design is paramount for the REiNS organization. ¹³ As of June 2023, REiNS includes 55 patient representatives from 9 countries, with 66% representing NF1, 25% representing NF2-SWN, and 9% representing other forms of SWN. In addition to serving with clinicians and researchers on REiNS working groups, patient representatives also meet monthly to give feedback on grant applications and study protocols; 20 unique research projects have been presented for community input to date. In addition to directly engaging patients representatives, REiNS also solicits broader input on clinical trials from the NF community using recruitment tools such as the NF Registry. ¹⁴ In this issue, we share surveys assessing the perspectives of adolescents with NF1 on clinical trials for cutaneous neurofibromas ¹⁵ and the preferences of adults with all forms of NF for psychosocial clinical trials. ¹⁶

In conclusion, cross-sector collaboration between academics, regulatory officials, the pharmaceutical industry, and patient organizations is crucial for the development of effective therapies for rare diseases. REiNS is a prime example of how such collaborations can advance the science and practice of clinical trials, and the organization welcomes all new members interested in this mission. We look forward to continuing to work with all stakeholders to better meet the needs of patients with NF and SWN. This includes continued engagement with representatives from the FDA and European Medicines Agency, who have most recently presented at REiNS meetings on the utility of natural history studies and other real-world evidence within drug development for rare diseases. ¹⁷

Supplemental Material

sj-docx-1-ctj-10.1177_17407745231201345 – Supplemental material for Advancing neurofibromatosis and schwannomatosis clinical trial design: Consensus recommendations from the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration

Supplemental material, sj-docx-1-ctj-10.1177_17407745231201345 for Advancing neurofibromatosis and schwannomatosis clinical trial design: Consensus recommendations from the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration by Vanessa L Merker, Andrea M Gross, Brigitte C Widemann and Scott R Plotkin in Clinical Trials