By Jessie Hanrahan, Solid Biosciences
Last year I was invited to moderate a panel at the Alliance for Regenerative Medicine’s Cell and Gene Meeting on the Mesa and though much was discussed, one idea seemed to catch fire: applying the FDA Oncology Center of Excellence’s Project Orbis to cell and gene therapies (CGT) regulated within CBER.
During that panel, CBER Director Dr. Peter Marks highlighted that a lack of regulatory convergence between countries is especially difficult for development of treatments for diseases with very limited populations. He explained that CBER has heard of multiple instances in which sponsors have discontinued development of a product entirely due to barriers to getting the product into another market outside the U.S.
I asked Dr. Patrick Celis, the lead scientific officer at the ATMP Office at the European Medicines Agency (EMA) if FDA were to pilot a program similar to Project Orbis for cell and gene therapies, would EMA have interest in participating. “The short answer is yes,” he replied.
Fast forwarding to today, Dr. Marks has recently in his speaking engagements started promoting the development of a Project Orbis-like program for cell and gene therapies, which would coordinate review with other regulators. Now the time has come to see if the embraceable concept can be converted into an impactful, worthwhile program.
The benefit is that if other countries can approve CGT products efficiently, it allows the product access to larger populations, potentially creating markets large enough to support the expense of development, especially in very rare diseases.
OCE’s Project Orbis: What Is It And Why Is It A Good Idea For CGT?
Project Orbis provides a framework for concurrent marketing application submission and review for oncology products among international partner agencies, which can significantly decrease the time to ex-U.S. approvals. While each agency conducts its own independent review and renders independent regulatory decisions, regular interactions on the criteria for approvals in different countries decrease review time and more broadly facilitate future convergence of global standards for the design of oncology trials.1
Since its inception in May 2019, 59 products have been approved in both the U.S. and at least one other participating country through the program.2 The FDA, together with the Australian Therapeutic Goods Administration and Health Canada, took part in the first Project Orbis collaborative review. Since then, other countries have joined and become Project Orbis Partners:
At the FDA’s OCE, there are five designated employees who drive the project. Participating sponsor partners agree to a minimum of five cross-agency meetings for original applications and at least three for supplements. The regulatory review is conducted in a collaborative manner, which allows for sharing of materials such as information requests. Typically, sponsors concurrently submit applications to partnering countries, i.e., within 30 days of FDA submission. After the program started, an option was added to allow staggered submissions to partnering countries after the initial FDA filing if a sponsor chooses, to provide some flexibility in submission timing.
Such a framework has proven useful in oncology, and a similar framework would be beneficial for CGT companies now, especially those working in the rare disease space, as it would allow for expedited contemporaneous approvals in multiple regions, in some cases even simultaneous approvals.1 This approach may save regulatory dollars and time by aligning standards and regulatory expectations, but more importantly, it could help patients outside the U.S. and EU access medications for which companies ordinarily may seek approvals only in those regions.
Relatively small companies like mine — Solid Biosciences, which is focused on DMD, Friedreich’s ataxia, and rare cardiac diseases — will need to use very time- and cost-efficient approaches to bring products to market and meet diverse regulatory requirements in the U.S. and internationally.
How Much Time & Resources Does It Save?
In the first year of the program, a total of 60 oncology marketing applications were received, resulting in 38 approvals internationally. Across the program, the median time to approval was similar between FDA (4.2 months, range 0.9–6.9, N ¼ 18) and the participating partners (4.4 months, range 1.7–6.8, N ¼ 20).3
As a case study, Seagen’s product, TUKYSA (tucatinib), which gained approval in April 2020, was the first new molecular entity to be approved through Project Orbis. Approvals were received in participating partner regions within four months of the U.S. approval, representing a 50.8% reduction in the review timeline across regions. All approvals from participating partners were received in advance of standard timelines.4
Merck used the staggered option, submitting to partnering countries after the initial FDA filing over a five-month period, for its product WELIREG (belzutifan). Information sharing through the program reduced the volume of follow-up questions and eliminated duplicative information requests from participating partners.4
While the program is resource-intensive for regulators due to the need for additional meetings conducted with participating partners, there are significant synergies from the sponsor perspective. Sponsors can leverage the assessments of major regulatory agencies like FDA3 and benefit from collaboration across agencies.
Other Benefits Of A Project Orbis-like Approach For CGT
In the example of TUKYSA, there was increased regulatory alignment across partners. As a specific example, most of the specification limits were aligned across participating agency partners. For Merck’s WELIREG, there was overall alignment in feedback received across participating partners, suggesting positive effects of transparency and information sharing through Orbis. In a report on an American Association of Pharmaceutical Scientists meeting, FDA and industry authors concluded that “Project Orbis has been greatly beneficial for patients by allowing products to reach multiple markets sooner.”4
Where Is CBER On Adopting A Project Orbis-like Program?
Although this program for CBER seems to be in early stages, it would not be surprising to see it gather momentum in 2024.
There are some challenges that will have to be addressed due to the differences in review processes among various countries, especially if the EMA is to be included. For example, the EMA review clock typically stops while an applicant prepares responses to questions from the regulatory authority, but Project Orbis has a continuous review timeline. Another potential reason for nonparticipation of some regulatory health authorities would be the Project Orbis requirement for the marketing application and review documents to be in English.3 I am sure there are others, too; however, these issues seem manageable, as OCE has successfully paved the way for success.
So, I am hoping that the concept is included in CBER’s reorganization. Though Dr. Pazdur and Dr. Marks vie for clever naming rights (Project Optimus, Socrates v. Warp Speed), perhaps we could call it Project Gene-Orbis.
Dr. Marks and others recognize now is the critical time to put in place and staff creative programs like this as CBER undergoes a significant reorganization with the creation of the Office of Therapeutic Products super office. Putting programs in place like this will demonstrate CBER’s commitment to thinking differently and adopting relevant programs to help innovators, as well as address significant unmet needs for patients around the globe. Standing up a Gene-Orbis type program in CBER would be an enormous step forward.
- Guram J, de Claro RA, Pazdur R. (2020). Project Orbis: Strengthening international collaboration for oncology product reviews, faster patient access to innovative therapies. Accessed at https://www.fda.gov/news-events/fda-voices/project-orbis-strengthening-international-collaboration-oncology-product-reviews-faster-patient.
- de Claro RA, Spillman D, Hotaki LT, Shum M, Mouawad LS, Santos GML, Robinson K, Hunt M, Healy C, Chan A, Looi YH, Rodrigues C, Rohr UP, Walther C, Pazdur R. Project Orbis: Global Collaborative Review Program. Clin Cancer Res. 2020 Dec 15;26(24):6412-6416.
- Algorri, M., Acharya, A., Bernstein, J. et al. Meeting report: Advancing accelerated regulatory review with Real-Time Oncology Review (RTOR), Project Orbis, and the Product Quality Assessment Aid. AAPS Open 8, 19 (2022).
About The Author:
Jessie Hanrahan, Ph.D., serves as chief regulatory officer at Solid Biosciences. She is a leader in global regulatory affairs and drug development. Through her career, she has obtained numerous global regulatory designations and approvals, including from the FDA and EMA. Hanrahan holds a Ph.D. in biology, as well as an MS and MPH, from Yale University, and obtained her BA from Mount Holyoke College.