Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID

Abstract

BackgroundStrimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies. Furthermore, for extended monitoring of Strimvelis, the young age of children treated, small patient numbers, and broad geographic distribution of patients all increase the risk of loss to follow-up before sufficient data have been collected. Establishing individual investigator sites would be impractical and uneconomical owing to the small number of patients from each location receiving Strimvelis.ResultsAn observational registry has been established to monitor the safety and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years. To address the potential challenges highlighted above, data will be collected by a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and entered into the registry via a central electronic platform. Patients/families and the patient’s local physician will also be able to submit healthcare information directly to the registry using a uniquely designed electronic platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded by GlaxoSmithKline) who will ensure that necessary information is collected and flows between OSR, the patient/family and the patient’s local healthcare provider.ConclusionThe Strimvelis registry sets a precedent for the safety monitoring of future gene therapies. A unique, patient-focused design has been implemented to address the challenges of long-term follow-up of patients treated with gene therapy for a rare disease. Strategies to ensure data completeness and patient retention in the registry will help fulfil pharmacovigilance requirements. Collaboration with partners is being sought to expand from a treatment registry into a disease registry. Using practical and cost-efficient approaches, the Strimvelis registry is hoped to encourage further innovation in registry design within orphan drug development.

Barriers and Opportunities for Implementation of Outcome-Based Spread Payments for High-Cost, One-Shot Curative Therapies

“…Organising and performing data collection are two of the most frequently discussed barriers for implementation of OBAs for payers, developers and healthcare providers ( Sudlow and Counsell, 2003 ; de Pouvourville, 2006 ; Carlson et al, 2010 ; McCabe et al, 2010 ; Raftery, 2010 ; Stafinski et al, 2010 ; Williamson, 2010 ; Jaroslawski and Toumi, 2011b ; Klemp et al, 2011 ; Neumann et al, 2011 ; Cascade et al, 2012 ; Goldenberg and Bachman, 2012 ; Xoxi et al, 2012 ; Bibeau et al, 2014 ; Gibson and Lemmens, 2014 ; Li et al, 2014 ; Garattini et al, 2015 ; Lu et al, 2015 ; Lucas and Wong, 2015 ; Mohseninejad et al, 2015 ; Barlas, 2016b ; Carr and Bradshaw, 2016 ; Malik, 2016 ; Pouwels et al, 2016 ; van de Wetering et al, 2017 ; Duhig et al, 2018 ; Ernst and Young, 2018a ; Ernst and Young, 2018b ; EXPH, 2018 ; Goldenberg et al, 2018 ; Jorgensen et al, 2018 ; Stirnadel-Farrant et al, 2018 ; Urbinati et al, 2018 ; Federici et al, 2019 ; Macaulay and Turkstra, 2019 ; Mundy et al, 2019 ; Pace et al, 2019 ; Kannarkat et al, 2020 ). First, experiences with OBAs in the Netherlands and the United Kingdom highlight that payers should perform a value of information analysis to guide the decision to engage in an OBA to confirm that the benefits from additional evidence collection are higher than the cost of collecting the data ( Ferrario and Kanavos, 2013 ; Pauwels et al, 2017 ; Makady et al, 2019 ; Towse and Fenwick, 2019 ).…”

“…Therefore, stakeholders are encouraged to act in a trustworthy manner by being transparent about their goals and respect the terms dictated in the agreement ( Thompson et al, 2016 ; Mahendraratnam et al, 2019 ). To enhance trust, several authors propose working with an independent third party such as academic institutions or non-profit, publicly funded organisations to perform all stages of the data collection process ( Adamski et al, 2010 ; McCabe et al, 2010 ; Stafinski et al, 2010 ; Menon et al, 2011 ; Goldenberg and Bachman, 2012 ; Ferrario and Kanavos, 2013 ; Drummond, 2015 ; Thompson et al, 2016 ; Kanavos et al, 2017 ; Bouvy et al, 2018 ; EXPH, 2018 ; Mahendraratnam et al, 2019 ; Wenzl and Chapman, 2019 ). The importance of such independence was shown by the decision made by the scientific advisory group, consisting of representatives with high interest in continued access to the medicines, of the United Kingdom multiple sclerosis (MS) agreement to maintain reimbursement even though many patients experienced worse outcomes ( Raftery, 2010 ; Towse et al, 2012 ; Gibson and Lemmens, 2014 ).…”

Immobilization of Growth Factors for Cell Therapy Manufacturing

“…The first ex vivo stem cell-based therapy to receive regulatory approval, Strimvelis, treats the rare congenital disease adenosine deaminase severe combined immunodeficiency (ADA-SCID) (Stirnadel-Farrant et al, 2018). Strimvelis is based on the modification of autologous CD34 + cells through ex vivo retroviral transduction, to express functional adenosine deaminase.…”

“…This therapy has demonstrated a 100% survival rate up to 7 years post-injection (EMA-European Medicines Agency 2016). In 2018, Strimvelis treatment cost was e594,000 (Stirnadel-Farrant et al, 2018).…”

Tailoring cells for clinical needs: Meeting report from the Advanced Therapy in Healthcare symposium (October 28–29 2017, Doha, Qatar)

“…The first gene therapy drug to hit the market was Strimvelis, a gamma-retroviral based hematopoietic stem cell gene therapy process for ADA-SCID patients [ 3 , 4 ].…”