Authors: Rob Stringer & Luis Jimenez
Project Orbis is an initiative of the US FDA Oncology Centre of Excellence (OCE). The intent of Project Orbis is to provide a framework for concurrent submission and review of oncology products among international regulators. 1
Whilst the US FDA has facilitated the exchange of selected information and collaboration between international regulators for over 15 years, Project Orbis represents the next level of international regulatory co-operation and transparency, with close proximity filings in several different jurisdictions and a concurrent, yet independent evaluation, by participating agencies accelerated through access to inter-agency regulatory evaluation information. Project Orbis has consistently resulted in remarkably quick regulatory evaluation timelines, and for some territories, substantially earlier regulatory approvals of medicines than would otherwise have been possible.
How do I get involved?
US Companies can be invited by the US FDA OCE to participate in Project Orbis and/or propose applications and the OCE acts as the primary coordinator for the process. Acceptance into the initiative is contingent upon meeting key clinical criteria (for example clinically significant and/or compelling data demonstrating improved safety or efficacy) and a commitment by the applicant to be able to facilitate the submission of applications in close proximity in all participating territories. For US-based entities with limited international operations, this may require either establishment of a legal entity in the intended territory and/or engagement of a 3rd party to act as the applicant.
Once a viable applicant/pathway for regulatory filing has been identified for each of the intended jurisdictions, the FDA will liaise directly with the respective regulatory agencies to inform them of the potential for evaluation under the Project Orbis framework. Once participation by the agency has been confirmed, the application can proceed to the next stage.
Which countries have participated?
To-date, applications facilitated by the US FDA under Project Orbis have involved the following regulatory agencies.
| Country | Regulatory Authority |
| Australia | Therapeutic Goods Administration (TGA) |
| Canada | Health Canada |
| Singapore | Health Sciences Authority (HSA) |
| Switzerland | Swissmedic |
Whilst initial Project Orbis evaluations appeared to predominantly involve Health Canada and/or TGA, more recent reviews have also included Swissmedic and Singapore’s HSA.
What products have been approved in Australia under Project Orbis?
The first action under the international collaboration of Project Orbis was the September 2019 accelerated approval of lenvatinib in combination with pembrolizumab for patients with endometrial carcinoma. 2 The US FDA, the Australian TGA and Health Canada collaboratively reviewed line extension applications for the two oncology drugs, allowing for positive decisions in all three countries. Subsequent Project Orbis approvals have occurred for both line extensions and new entities, including: acalabrutinib (November 2019),3 nivolumab + ipilimumab (July 2020),4 5 ripretinib (July 2020),6 ibrutinib (August 2020),7 8 and tucatinib (August 2020). 9
Type of regulatory pathways?
Due to the collaborative nature of the review, the regulatory pathways which may impact timeline and/or the level of evidence required for the review should be aligned, i.e. if an application will be submitted as a Priority Review in the US, equivalent designations/determinations should be sought in Australia.
| USA | Australia |
| Breakthrough Designation | No equivalent |
| Accelerated Approval | Provisional Approval |
| Priority Review | Priority Review |
How does it work?
Regulatory dossiers must be ideally lodged in close proximity in accordance with each participating agency’s respective regulatory requirements. For Australian submissions, an eCTD regulatory dossier will need to be submitted consisting of an Australian specific Module 1 and accompanying Modules 2-5. Any differences between the components of Modules 2 to 5 should be described and contextualised in Module 1.
Thereafter, the application will proceed as per the designated milestone pathway. Throughout the regulatory evaluation process, whilst the participating regulators will collaborate with each other, they each conduct their own review, and engage directly with the local applicant/sponsor. Participating applicants are requested to ensure that all information request responses submitted to the individual participating Orbis agencies are also provided to all participating Orbis agencies, thereby minimising duplication and allowing for the efficient allocation of regulatory evaluation resource. The only exception to this process is labelling/Product Information request responses which are negotiated directly with the respective regulator.
Advantages of participating in Project Orbis?
Whilst in principle a parallel, independent regulatory review by 5 different regulatory agencies sounds very resource intensive, in practice the real-time collaboration between the agencies can actually reduce the regulatory resources required by both the participating agencies and applicants. Utilisation of common dossiers, shared evaluation questions and responses seems to have resulted in some impressively fast regulatory evaluation timelines. The available Australian regulatory review timelines for products evaluated via Project Orbis are summarised in the following table:
| Product | Application type | No. of working days |
| lenvatinib / pembrolizumab | Line Extension Provisional Approval |
54 |
| acalabrutinib* | Line Extension | 35 |
| nivolumab / ipilimumab | Line Extension | 68 |
| ripretinib | New Chemical Entity Priority Review |
123 |
| tucatinib | New Chemical Entity Priority Review |
113 |
*regulatory approval for the new entity occurred via a COR-B pathway utilising the US FDA as the Comparable Overseas Regulator, subsequent concurrent review of a line extension via Project Orbis
Other considerations
- Products participating in US FDA’s OCE Real-Time Oncology Review (RTOR) which permits FDA access to key data prior to the official submission of the NDA, can also participate in Project Orbis, with documents from the RTOR evaluation shared between agencies.
- For oncology applications which may have already been reviewed by the FDA – a modified Orbis process may be possible, whereby access to the FDA evaluation documentation can be facilitated to abbreviate the regulatory review.
- https://www.fda.gov/about-fda/oncology-center-excellence/project-orbis
- https://www.tga.gov.au/media-release/provisional-application-receives-approval-through-first-international-collaborative-review-initiative-between-tga-fda-and-hc
- https://www.tga.gov.au/media-release/acalabrutinib-receives-tga-approval-cll-and-sll-cancers
- https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc
- https://www.tga.gov.au/prescription-medicines-new-or-extended-uses-registered-medicines
- https://www.tga.gov.au/apm-summary/qinlock
- https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ibrutinib-plus-rituximab-chronic-lymphocytic-leukemia
- https://www.tga.gov.au/apm-summary/tukysa
