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Post-Brexit, the UK’s MHRA is looking to join Project Orbis, a global program to speed up patient access to innovative cancer treatments. This article looks at the implications of Project Orbis for commercialization in the UK and the key considerations for industry in considering the project as a pathway.
With the UK leaving the European Medicines Agency (EMA) regulatory process in late 2020 as part of Brexit, the UK Government and the Medicines and Healthcare products Regulatory Agency (MHRA) rolled out new approaches for the commercialization of pharmaceuticals. One central tenet was to establish the UK as an attractive market with the potential for fast marketing authorization pathways, and a keynote program was the UK joining Project Orbis.
Project Orbis is a global, collaborative, program launched by the FDA Oncology Center of Excellence (OCE) in 2019, which aims to speed up patient access to innovative cancer treatments through a framework of concurrent regulatory submission and review. Today, there are six Project Orbis Partners (POPs): Australia (TGA), Canada (Health Canada), Singapore (HSA), Switzerland (Swissmedic), Brazil (ANVISA) and most recently the United Kingdom (MHRA). While FDA serves as the coordinator for application selection and review, each country remains fully independent on their final regulatory decision.
Selection of applications for Project Orbis is coordinated by FDA, although the participating regulatory agencies can also identify candidate products. When selected, the FDA approaches the manufacturer and, once confirmed, a product or indication is shared with all POPs to confirm interest in participation. Notably, manufacturers can be selective in the markets they include in their Project Orbis submissions, even down to engaging only one other POP market in addition to the FDA. This permits manufacturers to assess the accelerated approval opportunity-risk trade-offs per market, and only include markets where there is a positive case for their commercialization strategy.
There are three types or Project Orbis submissions which depend on the timeline of submission to the FDA and the POPs:
Type A – Regular
Applications submitted concurrently or near-concurrently (within 30 days) to FDA and the POPs; Type A submissions allow for maximal collaboration during the review phase and the possibility of concurrent marketing authorization with the FDA
Type B – Modified
Applications submitted with a greater than 30-day delay or a regulatory action greater than 3 months of the FDA action. These allow the possibility of concurrent review with FDA but no concurrent marketing authorization
Type C – Written report only
In cases where FDA has already taken regulatory action, it allows the FDA to share their completed review documents with the POP but there is no concurrent review or marketing authorization with FDA.
In an analysis from de Claro et al.,1 we find that in the first year of Project Orbis, to June 2020, 60 marketing applications were submitted across the 6 participating markets (FDA + 5 POP), across 16 unique products. 21 of these applications were to the FDA with a median of 2 additional POPs involved; the most included POPs were Australia (N=14) and Canada (N=12), notably both cost-effectiveness driven HTA markets like the UK. No application included all markets, and Brazil only received one application under Project Orbis.
From these applications, 38 marketing authorizations were granted; the FDA approved 18 of 21 applications (86%), Australia’s TGA approved 7 of 14 (50%), Health Canada approved 8 of 12 (67%) Swissmedic approved 1 of 7 (14%), Singapore’s HSA approved 4 of 5 (80%) and Brazil’s ANVISA had not approved the single marketing application it received at time of analysis.
Since leaving the EMA Centralized Authorization Procedure, the MHRA,2 has published guidance on eight new routes by which a manufacturer can apply for a license to market a medicine in the UK, including 6 national routes and 2 international routes. Most products are expected to be assessed through the national routes, with a procedure timelines ranging from 67 to 150 days, depending on the type of application, level of innovation and whether the product is already marketed in another country.
Project Orbis is one of the two available international routes, aiming to speed up regulatory approval timelines for innovative oncology products. From a patient access point of view, Project Orbis has received significant positive press however an open question remains on whether access timelines are truly expedited in all markets.
From the analysis of de Claro et al., the median time-to-approval of all products in the first year of Project Orbis was 4.2 months for FDA submissions (range 0.9–6.9, N = 18) and 4.4 months for the POPs (range 1.7–6.8, N = 20). For new active substances, the timeline was slightly longer taking a median of 5.1 months for the FDA (range: 3.9-6.9, N=6) and 5.9 months for the POPs (range 3.9-6.8, N = 7).
These timelines are significantly shorter that the average EMA marketing authorization timelines which last around 1 year, suggesting MHRA marketing authorization under Project Orbis hold potential to deliver faster access than if the UK had remained part of the EMA.3
It is worth noting however, that whilst some national routes are depended on other regulatory body processes (e.g., EC Decision Reliance Procedure) the standalone MHRA process is the National procedure, which is expected to take 150 days for marketing authorization. Comparing this to the Project Orbis timelines of 5 to 6 months, MHRA timelines are projected to lead to faster UK access than engaging in Project Orbis.
Regardless of the type of Project Orbis submission, to be eligible for Project Orbis in the UK, the drug under consideration must also qualify for the national Innovative Licensing and Access Procedure (ILAP). While the manufacturer does not necessarily have to have engaged with the ILAP prior to requesting inclusion in Project Orbis with the UK as a POP, the MHRA will arrange an “Innovation Passport” meeting to confirm eligibility. Reversing this rationale, manufacturers who do not want to engage the UK in Project Orbis are likely to remain eligible for, and gain the advantages of, other innovative access routes into the UK.
While considering the advantages and risks of Project Orbis, the second “Access Consortium” international route must also be considered, defined as work-sharing procedures between national regulators. Notably this consortium includes all Project Orbis markets, excluding the US and Brazil, and not restricted to oncology indications. While there may be synergies through this approach, offering a more attractive commercial opportunity than to the UK market alone outside the EU, the benefits of this route will likely be dictated by manufacturer engagement and submission.
In the UK, NICE acts as primary gatekeeper to the public coverage of the majority of the population, with reimbursement recommendations derived from clinical and cost-effectiveness assessments. Aligning the UK marketing authorization process with the US through Project Orbis potentially expedites marketing authorizations and as a result expedites HTA assessments. With a significant proportion of oncology drugs going through the FDA accelerated approval route in parallel to Project Orbis, and in some cases approval granted in advance of trial data publication4 or before key efficacy endpoints (such as overall survival) reach maturity, it can be inferred that these expedited NICE HTA assessments could be conducted with a limited and early data package. Consequently, this will result in less robust evidence submissions, greater uncertainties surrounding the product’s efficacy and therefore greater difficulty in demonstrating cost-effectiveness.
Oncology therapies launching in the UK with limited evidence packages (e.g., immature outcomes) are able to utilize the UK’s Cancer Drugs Fund for funding through time-limited Managed Access Agreements whilst awaiting future clinical trial read-out. However, there are current uncertainties on the future composition of the CDF, potential changes to the entry requirements and risk of proportional rebates on budget overspend. Furthermore, additional discounts are expected on entering the CDF resulting in lower net prices for the interim funding period and potentially a signal of the net price potential during reappraisals. In the current policy, the net price agreed through the Managed Access Agreement is disconnected from any future achieved price through routine commissioning (although a true separation is unlikely in practice).
One response for manufacturers is to pursue marketing authorization through Project Orbis and then delay HTA evidence submission until further supportive data becomes available, a trend that can be observed in other comparable markets. This enables manufacturers to take advantage of a single Marketing Authorization submission across several markets, and expedited licensing, but pursue reimbursement at a commercially viable subsequent timepoint. For example, the five latest TGA submissions through Australian participation in Project Orbis, indicate a delay between marketing authorization and HTA submission to PBAC. New chemical entity priority review submissions of Qinlock (ripretinib) and Tukysa (tucatinib), which received marketing authorization through Projsct Orbis in July and August 2020 respectively, have yet to go through a PBAC assessment. Both are expected to be evaluated in March 2021, more than 6 months after marketing authorization. Similar delays in submission between marketing authorization and HTA evidence submission can be observed in the other cost-effectiveness-based market, Canada, and across multiple products, including Qinlock (ripretinib), Tukysa (tucatinib) and Calquence (acalabrutinib).
The entry of the UK into Project Orbis presents an opportunity to leverage a coordinated submission approach across multiple markets and to gain patient access earlier with marketing authorization feasible with less mature data. However this must always be considered alongside reimbursement expectations; consequent delays to NICE submissions or data collection agreements through the Cancer Drugs Fund may be required to ensure data is available to support cost-effectiveness.
We outline three considerations for pharmaceutical manufacturers to evaluate whether the UK should be one of the markets engaged through Project Orbis, if invited to make a submission.
1. Consider Project Orbis and ILAP early in clinical development
Alignment across Medical, Regulatory and Market Access functions will be required to evaluate the feasibility of meeting UK ILAP requirements depending on clinical trial data cuts. Early cross-functional understanding of the requirements of the UK ILAP Target Development Profile and Global-to-Local support in its development with the MHRA is essential to reflect expectations for clinical outcomes and increase chance of success.
2. If UK early marketing authorization through Project Orbis is feasible, consider the potential NICE evaluation outcomes
The implication of NICE Single Technology Assessment based on the clinical evidence submitted for Project Orbis must be anticipated. Modelling cost-effectiveness based on the early data cut will be required, and areas of uncertainty identified. The likelihood of a recommendation at an acceptable cost-effective net price must be taken into consideration as part of the decision to pursue Project Orbis regulatory approval for the UK. Therefore close dialog between Global/Regional and UK affiliate Market Access and HEOR teams is required, with consideration for the net price floor and international list price referencing implications.
3. Evaluate alternative funding routes available in the UK
A focus on cancer funding in the UK has delivered earlier access for patients in the UK through mechanisms such as the Cancer Drugs Fund. While this may be undergoing changes, into the £500 million Innovative Medicines Fund, this has been reported to include a ring-fenced budget for oncology. However, uncertainty on the future entry requirements, opening to wider therapeutic areas and net price position signaling may make the CDF a less attractive option for manufacturers in the future, thereby risking the benefits of an earlier marketing authorization.
Marc Matar is a Partner, Graham Tatham is a Partner, Rachel Rowbottom is a Director, Sam Calderwood is a Senior Consultant, and Katerina Stavri is a Consultant in Simon-Kucher & Partners Life Sciences division based in the company’s London office.
 Clin Cancer Res December 15 2020 (26) (24) 6412-6416
 https://www.cancertherapyadvisor.com/home/news/conference-coverage/american-society-of-clinical-oncology-asco/asco-2020/fda-approval-oncology-cancer-drugs-disconnect-between-publication-results-trial/; accessed 01/02/2021