OCE Insights is an occasional department developed for The ASCO Post by members of the Oncology Center of Excellence (OCE) at the U.S. Food and Drug Administration (FDA). In this installment, Preeti Narayan, MD, a medical oncologist and clinical reviewer on the Breast and Gynecologic Disease Team, Division of Oncology; Dianne Spillman, BS, Associate Director for Global Regulatory Outreach; Lauren Hotaki, PharmD, BCPS, BCIDP, Senior Regulatory Health Project Manager; R. Angelo De Claro, MD, Associate Director for Global Clinical Sciences; and Richard Pazdur, MD, Director of the OCE, explore the collaboration between the FDA and international regulatory agencies aimed at enabling communication on various issues related to drug development, approvals, and policy unique to each agency.
Update on Project Orbis
What is Project Orbis?
Project Orbis was initiated in May 2019 by the OCE with a vision to provide a framework for concurrent submission and review of oncology products among international partners. A key goal of this project is to accelerate the availability of novel cancer treatments to patients globally.
Did the FDA have international collaborations before the formation of Project Orbis?
Although the Project Orbis initiative was formed recently, collaboration with international agencies and the FDA has been ongoing for many years. In 2004, the FDA’s Office of Hematology and Oncology Products, now known as the Office of Oncologic Diseases,1 and the European Medicines Agency began holding regular teleconferences under a confidentiality agreement to allow for exchange of information and collaboration on specific topics related to applications under review. This “oncology cluster” was progressively expanded to include Health Canada (HC), Japan’s Pharmaceuticals and Medical Devices Agency, Australia’s Therapeutic Goods Administration (TGA), and Swissmedic (SMC).
Benefits of Project Orbis
What are the benefits of Project Orbis?
Pivotal clinical trials in oncology are commonly conducted internationally, and these global trials are important for investigating the safety and effectiveness of cancer drugs for approval in the United States. Further drug development may benefit by establishing a greater uniformity of new global standards of treatment, leading to the optimal design of these important trials.
Collaboration among international regulatory agencies may allow patients with cancer to receive earlier access to products in other countries, where there may be significant delays in regulatory submissions. Development of anticancer therapies may be slowed due to varying standards of care across the world, and this can impact the design and conduct of trials. With a framework for near-concurrent submission and review of oncology drugs, Project Orbis facilitates a collaborative review to identify any regulatory divergence across review teams at each participating agency.
Applications and Review Process
What are the types of applications considered for Project Orbis and the general review process?
Potential applications appropriate for this pilot are either identified by the FDA or can be suggested by companies and then reviewed by the FDA for appropriateness for inclusion in the project. Once the company has agreed to participate, Project Orbis partners are contacted to see whether they are interested and/or able to participate.
Drug applications can include those that are new molecular entities (ie, no prior approval for any indication) or supplemental applications for a new indication for a drug or treatment that already has a prior approval. For applications already under FDA review, there is also a pathway for a “modified Orbis” or “Type B Orbis,” where any Project Orbis partners who receive the application later but still overlap with the FDA review can communicate with the FDA on major review issues. If an application has already been reviewed by the FDA and approval action has been taken, there is a “Type C” pathway, where a written report alone will be provided to Project Orbis partners.
Once an application is chosen to be part of Project Orbis, regular teleconferences between the participating agencies are conducted to discuss any safety and/or efficacy concerns. For the FDA, the review process remains the same, irrespective of whether it is under Project Orbis, and the FDA conducts its own usual review of the drug application. The FDA also continues to incorporate other pilot projects such as the Assessment Aid and Real-time Oncology Review into Project Orbis reviews, if deemed appropriate and companies agree to participate.2-4
An important aspect of the process is that each regulatory participant involved in a Project Orbis application ultimately determines the decision on whether to approve a treatment in its country, as well as the pathway of the approval. Similarly, labeling of the drug is done independently within each regulatory agency and country. Regulatory decisions may occur as simultaneous actions across all Project Orbis partners, if resources permit, but this is not mandated.
Approvals Under Project Orbis
What are some of the approvals that have occurred under this new initiative?
The first Project Orbis action took place on September 17, 2019, in conjunction with Australia’s TGA and HC. An approval was granted to lenvatinib in combination with pembrolizumab for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability–high or mismatch repair–deficient and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation therapy.5 This was a “Type A” Orbis, with the FDA and TGA granting approval on September 17, 2019, and HC granting approval on September 20, 2019.
“Each regulatory participant involved in a Project Orbis application ultimately determines the decision on whether to approve a treatment in its country, as well as the pathway of the approval.”— Preeti Narayan, MD, and colleagues
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On April 17, 2020, tucatinib in combination with trastuzumab and capecitabine was the first new molecular entity approved under Project Orbis for treatment of adults with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior HER2-based regimens in the metastatic setting.6 Subsequently, tucatinib in combination with capecitabine and trastuzumab was approved by SMC on May 7, Singapore’s Health Sciences Authority (HSA) on May 19, HC on June 5, and TGA on August 10, 2020. This important milestone for Project Orbis marked the first approval for a therapy that was not previously available in any country, facilitating earlier access to this treatment regimen for patients globally.
In the first year of Project Orbis (June 2019 to June 2020), a total of 60 oncology marketing applications were received. They represented 16 unique projects and resulted in 38 approvals.7
More Countries Joining Project Orbis
Which countries are participating in Project Orbis?
Australia’s TGA and the HC were the initial international agencies that participated in Project Orbis applications. More recently, with the tucatinib approval, Project Orbis expanded to include the HSA and Swissmedic, as these four countries already have an existing collaboration with each other under the Australia-Canada-Singapore-Switzerland Consortium. The regulatory health authority
of Brazil, ANVISA (Agência Nacional de Vigilância Sanitária), and the United Kingdom’s Medicines and Healthcare Products Regulatory Agency have also joined Project Orbis.8
Other agencies share their perspectives on participation in Project Orbis.
Comment from Australia’s TGA: “Collaboration with the U.S. FDA in Project Orbis is highly valued by the TGA, a part of the Australian Department of Health, in providing both an additional pathway for earlier access to the Australian public to new medicines for the treatment of oncology conditions and as an opportunity to work with other international regulators to enhance regulatory evaluation and decision-making.”
Comment from Health Canada: “During this first year, Health Canada has collaborated in several reviews under Project Orbis. The experience thus far has resulted in very positive outcomes. The project provides a framework for concurrent submission, review, and information sharing among international partners, which encourages earlier drug submission in Canada. These collaborations also involve beneficial discussions among experts from each regulatory agency, supporting faster review times while maintaining high review standards, sovereign decision-making, and providing earlier access to therapies for a greater number of patients across participating jurisdictions. Health Canada looks forward to ongoing collaborations with international partners through Project Orbis, providing timely access to therapies for patients.”
Comment from Swissmedic: “The Project Orbis Framework fits perfectly to Swissmedic strategic goals: a) to foster international collaborations and b) to accelerate time critical processes. In line with those [goals], the Orbis framework can lead to faster drug submissions or drug approval times in Switzerland while maintaining SMC’s high-quality review standards. Meanwhile, 17 drugs have been reviewed, are in review, or have been accepted for review within the Project Orbis framework, and our Swissmedic pilot experience so far has been excellent. Experts from all agencies independently perform their evaluation but jointly discuss the critical, identified issues. This forms the perfect basis for a well-informed sovereign decision for each jurisdiction.”
Comment from Singapore’s Health Sciences Authority: “The collaborative review through Project Orbis has facilitated expeditious access to innovative medicines to patients in Singapore in the area of critical oncology therapeutics. With the coordinated submission to participating regulatory agencies and the synchronized review, review teams from each regulatory agency had the opportunity for greater scientific exchange as well as furthering regulatory convergence. HSA looks forward to continuing this journey with our Project Orbis partners.”
What are the next steps for Project Orbis?
Since its initiation, Project Orbis has expanded rapidly. There are currently multiple applications under review with various Project Orbis partners under each of the Project Orbis pathways. Multiple meetings to discuss this initiative have already occurred with international regulators not only at the FDA headquarters in Silver Spring, Maryland, but also at the headquarters of other regulatory agencies such as the TGA, HSA, and Swissmedic. The FDA is also in discussions with other international regulatory agencies about joining Project Orbis applications in the future.
We look forward to continuing to work with international agencies and expanding efforts to harmonize policies that can help streamline future clinical trial designs and approval of drugs that may serve to allow faster access to new oncologic products for the global patient population.
DISCLOSURE: All authors reported no conflicts of interest.
1. U.S. Food and Drug Administration: FDA office of hematology oncology products reorganizes, renamed office of oncologic diseases. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-office-hematology-oncology-products-reorganizes-renamed-office-oncologic-diseases. Accessed November 23, 2020.
2. U.S. Food and Drug Administration: Assessment aid. Available at https://www.fda.gov/about-fda/oncology-center-excellence/assessment-aid. Accessed November 23, 2020.
3. U.S. Food and Drug Administration: Real-time oncology review pilot program. Available at https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review-pilot-program. Accessed November 23, 2020.
4. de Claro RA, Gao JJ, Kim T, et al: U.S. Food and Drug Administration: Initial experience with the real-time oncology review. Clin Cancer Res. August 19, 2020 (early release online).
5. U.S. Food and Drug Administration: FDA takes first action under new international collaboration with Australia and Canada designed to provide a framework for concurrent review of cancer therapies, approving treatment for patients with endometrial carcinoma. Available at https://www.fda.gov/news-events/press-announcements/fda-takes-first-action-under-new-international-collaboration-australia-and-canada-designed-provide. Accessed November 23, 2020.
6. U.S. Food and Drug Administration: FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer. Accessed November 23, 2020.
7. de Claro RA, Spillman D, Hotaki LT, et al: Project Orbis: Global collaborative review program. Clin Cancer Res. October 9, 2020 (early release online).
8. GOV.UK: Cutting-edge treatments to be fast-tracked to patients through international collaborations. Available at https://www.gov.uk/government/news/cutting-edge-treatments-to-be-fast-tracked-to-patients-through-international-collaborations. Accessed November 23, 2020.