With regulatory approval of the first gene therapy for clinical use outside of clinical trials anticipated in mid-2020, there is an urgent need to collect long-term data on safety, variability and durability of efficacy. Data will be required by regulators for post-marketing surveillance the need for enhanced understanding of gene therapy outcomes and impacts in people with hemophilia. The World Federation of Hemophilia (WFH) and the American Thrombosis and Hemostasis Network (ATHN) have begun working together as part of a global collaboration on long-term harmonized data collection on hemophilia gene therapy. Michael Recht, ATHN Chief Science Officer, spoke on behalf of ATHN on the registry being established (ATHN 14 – Gene Therapy Outcome Study) to collect data from the 140 treatment centres (HTCs) in the United States that receive federal funding as well as other centres affiliated with ATHN. Dr. Barbara Konkle, Associate Chief Scientific Officer at Bloodworks Northwest, described the WFH Gene Therapy Registry (see separate report). Caroline Voltz, Product Lead in the Oncology, Haematology and Diagnostics Office of the European Medicines Agency, and Peter Marks, Director of the Center for Biologics Evaluation and Research (CBER) at the U.S. Food and Drug Administration, discussed regulatory considerations and guidelines for gene therapy, registries and long-term follow-up from the perspectives of their respective organizations.
From the perspective of ATHN, it has been less than 12 years since a patient first received adeno-associated virus (AAV) gene therapy and there are still many unanswered questions surrounding the need for immune modulation as well as safety, effectiveness and patient outcomes. ATHN 14 will be a real-world, longitudinal observational cohort study of hemophilia A and hemophilia B patients who have undergone or will receive gene therapy. Several Canadian recipients of gene therapy were enrolled in clinical studies at hemophilia centres in the U.S. and can expect to be part of ATHN 14 while also being followed by their local HTC. The ATHN 14 database is strictly confidential and no personal identifiers are included. Follow-up will be every three months for a year, then every six months or so for possibly 15 years. Safety parameters of interest include allergic reactions, transfusion-related infections, liver function, thromboembolic and cardiovascular events, malignancies, neurological events, unexpected poor efficacy, excessive efficacy, and death. Data collection will include type of vector, vector dosing and use of immune modulation. Patient-reported outcomes will be captured using EQ-50 and PROMIS quality-of life-scales to assess clinical, social and economic experiences. Regular ad hoc analyses will be performed to detect adverse events requiring intervention. A unique feature will be the inclusion of a biorepository of blood samples for future research. Built into the study design of ATHN 14 will be sub-study modules to allow specific clinical studies. It is important to note that ATHN 14 will be harmonized with the WFH Gene Therapy Registry (GTR). Data will be uploaded annually to avoid duplication and linked to all other ATHN cohorts via ATHN TRANSCENDS.
Dr. Konkle reiterated the benefits of a global registry and emphasized that each centre submitting data will need to obtain informed consent from all patients enrolled as well as ethics approval. Such a global registry will increase the likelihood of identifying events of low incidence and will reflect all patient populations. Using the framework of knowns/unknowns, we know there is a risk of liver function changes and we want to look out for malignancies, unforeseen outcomes, and unanticipated problems. The hope is that collaboration with many other organizations, industry partners and regulatory authorities will bring answers to many questions regarding gene therapy.
Both regulatory authority representatives stressed that their mandate is to look at each individual gene therapy submission independently in terms of safety and efficacy, and not to compare one therapeutic approach to another. Both authorities have guidelines for gene therapy products and long-term requirements for post-marketing surveillance. Peter Marks of CBER drew attention to regulatory considerations, such as the type of vector used for gene therapy delivery and the technology used in its development (e.g., integrating, non-integrating or genome editing technologies). Data requirements in addition to data collected in clinical trials may include risk management plans for hepatoxicity, immunogenicity, binding and neutralizing antibodies (inhibitors), number of bleeds, clinical evaluations such as arthropathy, perioperative management, use of replacement clotting factor, and surgical outcomes and rating. Registries will need to comply with national regulations on informed consent and data privacy. Harmonization of required data, elements and analytics would be helpful and authorities will want to see escalation strategies in case of adverse findings. The EMA Road Map encourages a holistic patient-centric approach. It should also be noted that health technology assessments and payers are increasingly seeking outcomes-based data upon which to base funding and reimbursement decisions.
During the Q&A session, there was discussion on how to assess gene therapy costs and benefits and on value-based pricing agreements as a possible avenue for making these therapies accessible. A question was asked about redosing of gene therapy and whether to use the same or a different product. The answer would depend on the market authorization for each product. It will also be important to know capture rate of patients compared to number of patients who received gene therapy and number of patients who declined to enroll in the registry.