Background
Developing a gene therapy in rare hematology conditions, such as hemophilia, presents a unique combination of hurdles to overcome:
- Limited and geographically dispersed patient populations, requiring broad global site activation and tailored recruitment strategies
- Eligibility challenges, as these patients have significant prior treatment exposure, and complex clinical histories
- Evolving regulatory expectations, particularly for novel treatments and long-term safety follow-up
- Considerable operational complexity, needing precise coordination across different phase studies with differing objectives
- Specialized site requirements, such as handling advanced therapies, and managing long-term patient monitoring
This case study concerns a sponsor’s single-administration gene therapy for hemophilia through a large, multi-year, multi-study clinical program, spanning early development and dose exploration, through pivotal stages and multiple confirmatory studies, leading to regulatory approvals in major regions.
Rare bleeding disorders and gene therapies
Patients with rare bleeding disorders face lifelong management challenges, including the need for frequent intervention (based on severity), and the risk of serious complications and associated comorbidities [1–4]. A one-time, single infusion of a gene therapy viral vector could reduce or remove the need for regular prophylactic treatment, and could potentially allow patients to live relatively normal lives [5].
Patient stories have highlighted the life-changing potential of gene therapy in hemophilia; the considerable positive impact of gene therapy for patients with rare bleeding disorders is evident.
The solutions
From the outset of the program, both the sponsor and PSI anticipated challenges. Together, we employed proactive and reactive problem-solving, and the close collaboration resulted in novel solutions:
- Program-level governance across studies:
A centralized oversight model ensured consistency in execution, data quality, and communication across multiple concurrent and sequential trials, while allowing the flexibility to incorporate protocol amendments and regulatory feedback. - Strategic site selection and activation:
PSI prioritized high-performing sites with access to the relevant patient populations, balancing experience in rare hematology disorders with the readiness to participate in trials with advanced therapies. Activation timelines were further optimized through parallel regulatory and operational workflows. - Developing new regulatory guidance:
The novel approach of gene therapy prompted regulatory authorities to proactively participate in developing new assessments and procedures. In Brazil, the collaborative efforts of the sponsor and PSI’s local teams, the local KOL, and the Brazilian MOH resulted in the creation of assessment templates to facilitate the approval process and move forward with the necessary regulatory steps. - Employing customized enrollment tools:
Screen failure rates across some trials in the program were high, which also meant difficulties in predicting enrolment numbers. Traditional forecasting methods were ineffective due to this program’s indication. To address these issues, PSI developed a custom enrollment prediction tool based on real-time screening rates. The tool’s analytical capabilities helped the team proactively manage screen failure risks, implement targeted strategies, and improve enrollment outcomes. - Specialized training and support:
Study teams and sites received targeted training on gene therapy handling, administration procedures, and long-term follow-up requirements, ensuring adherence to protocol and patient safety throughout the program. - Building and maintaining relationships:
Finding time in KOL and PI busy schedules can be tricky, but in this trial, collaboration between sites and clinical teams was notably efficient. One PI who had switched sites brought his patients along to the new site to participate in the program – the connection between patients with rare bleeding disorders and their doctors is often lifelong. Seamless transition allowed for the continuation of patient involvement in a different study of the program. - Long-term follow-up infrastructure:
Systems and processes were established early to support extended patient monitoring, including data collection (including the development of new systems to aid in data transfer), retention strategies, and compliance with post-treatment follow-up requirements. Sites were open and ready for patients who had the opportunity to roll over to other studies in the program, so there were no delays.
I work at [participating hospital], and our research group has participated in the [gene therapy] studies with you. I just wanted to reach out to thank you for how absolutely outstanding your team has been to work with from Day 1. The PSI monitors are easily two of the best we’ve had the pleasure of working with in the last 5 years. They email back immediately, are always available for help no matter what, and have helped walk us through a lot on these intricate studies. They simply know their studies inside and out. They also are very accommodating when scheduling visits and have just made this process much easier all around. With our site running a lot of studies, with a lot of different CROs and sponsors, we‘ve had a lot of “interesting” and “trying” experiences. Because of this, my team and I just wanted to reach out to thank you and your staff for being a top of the line group to work with. Thank you for your time, we look forward to working with you again in the future.
The outcome
Despite a limited eligible population, hundreds of participants across numerous specialized sites worldwide received the sponsor’s gene therapy. of this large-scale, multi-study, global clinical program meant the delivery of robust late-phase data packages for regulatory submissions worldwide, with its approval ultimately advancing a transformative treatment approach for patients with rare bleeding disorders.
Across this life-changing gene therapy program and others, witnessing patients’ transformations, and being granted “a new lease of life” is just the beginning.
Key takeaways
Running gene therapy programs in rare diseases isn’t simply about the science, it is about orchestrating complexity over years. Small patient pools, evolving regulations, specialized sites, long-term follow-up – what makes the difference is having a partner that stays consistent across the entire journey, keeping studies aligned, adapting with changes in requirements, and solving practical problems without slowing momentum. The value is not scale, it is continuity, adaptability, and understanding how these programs behave in the real world.
We are very grateful for all the time and effort that patients, you & your staff have put into the study. We celebrate this milestone with you.
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Abbreviations
CRO, Contract Research Organization;
KOL, Key Opinion Leader;
MOH, Ministry of Health;
PI, Principal Investigator.
References
1. Mahlangu, J., Diop, S., and Lavin, M., Diagnosis and treatment challenges in lower resource countries: State-of-the-art. Haemophilia, 2024. 30 Suppl 3: p. 78–85.
2. Makris, M., Lassila, R., and Kennedy, M., Challenges in ageing persons with haemophilia. Haemophilia, 2024. 30 Suppl 3: p. 5–11.
3. Presky, K.O. and Kadir, R.A., Women with inherited bleeding disorders – Challenges and strategies for improved care. Thromb Res, 2020. 196: p. 569–578.
4. Dorgalaleh, A., et al., Challenges and concerns of patients with congenital bleeding disorders affected by coronavirus disease 2019. Blood Coagul Fibrinolysis, 2021. 32(3): p. 200–203.
5. Arruda, V.R., Weber, J., and Samelson-Jones, B.J., Gene Therapy for Inherited Bleeding Disorders. Semin Thromb Hemost, 2021. 47(2): p. 161–173.
