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

Clinicians treating patients with ADA-SCID can currently submit data to disease registries encompassing broader disease classes, such as primary immunodeficiency or SCID, but there are as yet no registries dedicated to ADA-SCID [43, 44]. Indeed, to create a specific registry for ADA-SCID would be an unusual undertaking because of the rarity of the disease and the fact that most patients receive treatment in transplant centres which already participate in large multi-disorder registries. For example, long-term follow-up data from patients with ADA-SCID are included in the transplant procedure registries from EBMT (ProMISe) and ESID (SCETIDE); however, these registries are tailored towards outcomes of HSCT and only collect limited information pertinent to the long-term monitoring of gene therapy. Thus, for Strimvelis, it was necessary to establish a new, observational, patient registry to record long-term longitudinal health data.

A novel approach to the design of the registry was required to address the following barriers to adopting a traditional registry design. The rarity of ADA-SCID and the low number of patients treated with Strimvelis emphasises the need for high patient retention rates in the registry in order to obtain safety and effectiveness data over an extended time frame. The risk of patients being lost to follow-up is exacerbated in a rare disease population formed predominantly of paediatric patients, particularly when monitoring is to be conducted over a minimum 15-year period starting from early infancy. Patients may be lost to follow-up due to movement within/outside their original country arising from progression through schools and on to college in adolescence, or from a family move or changes in the family unit. Children tend to progress through multiple healthcare practitioners (HCPs) as their care is passed between paediatric immunologists, general paediatricians, other specialists and family physicians. Compliance with registry participation may diminish over time if long-term efficacy is achieved and patients start to identify less with their disease. Therefore, long-term follow-up necessitates a commitment on the part of the patient and treating physician to maintain communication links with the registry and to continue to provide ongoing medical information.

Patients from several continents have already been treated with Strimvelis so the follow up system needs to have international coverage. As ADA-SCID is ultra-rare, in many countries there may only be a single child who has received or will receive Strimvelis and who would need to be followed in the registry. Establishing a traditional clinical investigational site with its requisite contracting process, set-up, training and oversight costs would be neither practical nor affordable for such limited numbers of patients per site. For patients who move within/outside their original country, it would not be feasible to establish several investigational sites, potentially contributing to follow-up attrition and missing information. These aspects are both practical and economical, not only affecting the Strimvelis registry, but also gene therapy registries to follow, and any cost efficiency that can be gained from an astute registry design would be expected to encourage further innovation in data collection in the orphan drug space. The objective of developing gene therapy treatments is to create ‘one-off’ interventions. The single treatment model has associated commercial challenges, i.e. recouping research and development costs for commercial sponsors. While it is appropriate that long-term registries are developed to monitor safety and effectiveness of gene therapies, the cost of managing them needs to be controlled such that they do not inhibit innovation.

The aim of this article is to explore the benefits, challenges and overall journey taken to establish a patient-centric registry for this rare disease gene therapy. This registry-based post-authorisation safety study (PASS; EU PAS Registration Number: EUPAS15795) fulfils the EMA guideline for the follow-up of patients administered gene therapy medicinal products.

This registry will enrol a total of 50 patients who received Strimvelis during clinical development, compassionate use and early access programmes, and after marketing authorisation. Patients treated with Strimvelis are eligible to participate in the registry if they (adult patients) or their parents/legal guardians provide informed consent for participation. Each patient will be followed for a minimum of 15 years after treatment with Strimvelis as part of a post-authorisation safety study that will be sponsored by the marketing authorisation holder (MAH) for its duration. Given the extended time frame of the registry, patients will be reconsented as appropriate. Registry closure will occur when the 50th patient has been followed for 15 years. Safety information on any events relating to fertility and pregnancy outcomes, oncogenesis and survival will continue to be solicited every 2 years past a subject’s 15-year post-gene therapy anniversary until the registry is completed. It is anticipated that the majority of subjects enrolled into the registry will be followed-up for longer than 15 years.

Safety concerns evaluated will include, but are not limited to: i) autoimmunity, ii) oncogenesis; presence of replication competent retrovirus (RCR) and retroviral insertion site (RIS) analysis, where these tests have been performed, and iii) medical and surgical procedures associated with Strimvelis administration, including placement and maintenance of central venous catheter and busulfan conditioning (Table 1). Long-term evaluation of safety data from the registry may also provide information relating to immunogenicity, fertility and pregnancy outcomes.

Effectiveness will be evaluated by outcomes including survival, intervention-free survival and growth (Table 1). Where patient-reported outcomes are collected during routine medical practice, the registry will capture quality of life (QoL) data collected using validated instruments (PedsQL™ Pediatric Quality of Life Inventory and the Ages and Stages Questionnaire).

The Strimvelis registry has been designed for streamlined data collection and to optimise patient engagement. In order to address the challenges associated with a 15-year follow-up duration in this patient group, in addition to supporting physician data entry, the registry data collection tools focus on and facilitate patient-mediated data entry.

Data will be collated via an electronic platform and coordinated by a gene therapy registry centre (GTRC), run by a contract research organisation (CRO) with local personnel at each country where the patient resides. The intention is to retain a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, where the treatment was initially developed and is currently administered (Figure 1). Data from OSR will be collected as electronic case report forms (eCRFs), based on information extracted from patient medical records. The patient’s local physician in their country of residence will also be invited to contribute data via an eCRF following permission from patients/families (Figure 2a). In addition, patients and their families will be able to enter data and upload medical records for processing by the GTRC to an electronic registry platform. To enable use by patients, the platform will be prepared in patient-friendly language and will undergo validation and user acceptance testing before release. To encourage patient and family engagement and provide a convenient platform, data input will be facilitated by the use of patients’ own electronic devices. Interactive elements, including a tailored patient app, are included as part of the registry design and will be available for patients to download in multiple languages (Figure 2b).

The GTRC will be operated by trained personnel with the knowledge to ensure data entered by patients/parents/carers is meaningful and accurate. GTRC staff are to maintain regular contact with participating patients/families as part of active follow-up (e.g., quarterly in the first 2 years, annually thereafter until the 11th year and then every 2 years at 13 years, 15 years and beyond), ensuring that patient medical information is collected and flows between the investigator site, the individual patient/parent/carer and the patient’s local HCP (Figure 1). By building relationships with patients and carers, it is anticipated that the inclusion of the GTRC into the registry model will help to mitigate against patients becoming lost to follow-up.

Reporting of an adverse event (AE) to the electronic platform by the local physician (Figure 2a) will trigger a notification to be sent to the GTRC, who will then liaise with the physician as necessary to confirm causality and severity. If an adverse drug reaction (ADR) or serious AE (SAE) is reported, either by the local physician via the GTRC or by the single investigator site (OSR), then the GTRC or OSR will be required to submit the report to the MAH in accordance with protocol-defined time frames, at which point the safety team will follow-up. Other AEs will be added to the database and reviewed periodically. Strimvelis is subject to additional safety monitoring (as indicted by an inverted black triangle symbol), which will encourage patients and HCPs to report AEs. The design of the registry to have a single investigator site (treating centre) will allow for cohesive ongoing monitoring of the safety of Strimvelis as well as detection of disease-related issues (including non-immunologic manifestations) that could arise over time.

The quality of data obtained is of paramount importance to the success of the registry. The design of the registry will need to support patients and their families if they are to provide information with sufficient depth and correct use of medical terms. The GTRC will be integral to this process, maintaining contact with registry participants and performing quality control of inputted data (e.g. manual checks for missing information and inconsistencies and system checks). Query resolution processes, including follow-up with participants where necessary, will help to ensure the integrity of data, and data verification will be sought via HCPs if queries arise. Thoughtful design of user-friendly data entry forms/screens will provide a framework for data input. The GTRC will be available to provide training and guidance to patients and HCPs as required for the duration of the study, in addition to which the platform provider will give technical support. As part of the validation procedure, the MAH or representative will monitor the data provided by OSR to verify, according to the study-specific monitoring plan, that: data are authentic, accurate, and complete; the safety and rights of patients are being protected; and the study is conducted in accordance with the currently approved protocol and any other study agreements, good pharmacovigilance practice, and all applicable regulatory requirements. Representatives of the MAH’s quality assurance unit/monitoring team and regulatory authorities will be permitted to inspect all study-related documents and other materials including but not limited to completed eCRFs and the patients’ original medical records held at OSR. Audits may be conducted at any time during or after the registry at the request of the sponsor or local/international regulators to ensure the validity and integrity of the study data.

Completeness of data is a critical aspect of the registry’s utility, which relies on co-operation of the patient and their HCP. As a divergence from a traditional, investigator-site led PASS, the Strimvelis registry will not establish a formal contract with patients’ HCPs. Instead, HCPs will be asked to acknowledge an agreement via the electronic platform recognising that: the patient/family has provided consent for them to disclose requested information; data they submit should be accurate and complete; they should abide by relevant data privacy provisions, and they agree to ongoing contact with the GTRC. The introduction of GTRC to oversee data collection is expected to aid continued participation from patients and HCPs; however, the nature of data requested from patients and HCPs will have to respect the accepted standard of care and routine clinical practice conducted in each participant’s country of origin to maintain the observational design of the registry. The GTRC will not monitor HCP sites; rather, data quality control will be performed at the level of the single investigator site at OSR.

Data privacy is of paramount importance, and the individual patient profile containing sensitive clinical data must be protected as robustly as possible. In the Strimvelis registry, patients access their individual patient profile in a manner consistent with EU privacy regulations and the platform is built with validated security protections. Platform access is controlled by having predetermined authorised user roles allowing blinded or unblinded access to the data, depending on the user’s specific function. Access to personally identifiable information (PII) will be restricted to OSR and relevant HCPs (e.g. patient’s local physician or specialist), GTRC staff involved in running the registry, and other authorised entities like regulatory agencies, ethics committees or review boards, and persons delegated by the MAH to monitor the registry to make sure it is running properly and that it meets regulatory requirements. All PII will be replaced by code numbers before data are shared with the MAH.

Inevitably, some patients may decide not to participate in the Strimvelis registry or will withdraw or be lost to follow-up. In the case of loss to follow-up or decision to withdraw, all data collected up to that point will be included in the analysis. For patients who complete 15 years of follow-up, the MAH will request permission to continue to collect vital information (e.g. death, oncogenesis, fertility and pregnancy outcomes) every 2 years until registry closure.

The value of a patient-centric model lies in linking the data with the patient, rather than the clinician, avoiding attrition through changes in HCP [45]. Engaging patients as the main contributors of data circumvents the need for multiple investigator sites while also simplifying the administrative burden on local clinicians. The international ‘borderless’ GTRC-based registry is anticipated to reduce geographical and cultural barriers to registry participation.

A patient-centric model provides motivational factors for patients to stay engaged with the Strimvelis registry, helping to ensure the longevity of registry data collection. Using up to date technology, patients feel supported by GTRC staff, and the adherence to follow-up of the patient/ family may be better if contact with the treating centre via the GTRC is maintained. Patients and their families are encouraged to engage more with their health condition and healthcare by accessing their individual patient profile through the patient app. The collection of patient-reported outcomes through the registry platform considers the patient experience, facilitating a holistic evaluation of the impact of treatment. Participating in a registry for a rare disease helps patients, families and clinicians to feel that they are positively contributing to the knowledge base of sometimes poorly understood and undertreated conditions [45].

Transparency and sharing of data analyses and publications with participants can help to reinforce the kind of information required, and may act to reassure patients of the value of their contributions [45]. Furthermore, communication of research findings in peer-reviewed journal articles and at scientific meetings is seen by the European Platform for Rare Disease Registries (EPIRARE) as a marker of quality in rare disease registries [46].

The value of patient-centric registries is increasingly being recognised in rare disease research. In the USA, the National Organization for Rare Disorders recently launched a National Patient Registry initiative, choosing 20 rare disease patient groups to work with on the development of registries for their patient communities [47]. Through these patient groups, patients and parents/legal guardians of patients are invited to participate in the respective disease-specific registry.

As well as providing the foundation to evaluate the long-term safety and effectiveness of Strimvelis, the registry has the potential to contribute to the overall understanding of ADA-SCID, providing a more complete overview of outcomes in patients with the disease. To achieve this, the registry would need to evolve to include outcomes from all available patients with ADA-SCID independent of treatment received, rather than remain a single treatment registry. Collaboration with additional partners is currently being sought, in accordance with EU privacy regulations. This approach requires cooperation from all key stakeholders, including clinicians, academics, industry, patient groups and payers. Compatible data sharing between registries would be facilitated by similarities in registry design and the use of common data elements, health indicator values and comparable procedures and definitions during data collection [48]. The benefits of a broader registry are multiple, including determination and comparison of the long-term safety and benefit of different treatments (especially if more treatment options become available), the natural history of the disease, and greater linkage of treatment outcomes to patient characteristics [45]. Identification of patient factors that influence health outcomes in ADA-SCID could lead to treatment algorithms that can be tailored to the individual patient profile or that allow more choice.