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FDA's Project Orbis Facilitating Earlier Access to Precision Oncology Drugs Outside US


This article has been updated to note that the company previously known as Seattle Genetics is now called Seagen.

NEW YORK – The US Food and Drug Administration's Project Orbis, a pathway through which drugmakers can launch their cancer therapies in different countries in quick succession, is helping other nations gain access to precision oncology treatments months, sometimes years, earlier than they would have otherwise.

The FDA's Oncology Center of Excellence launched Project Orbis in 2019 as a collaboration between regulators in multiple countries who jointly review cancer drugs with the goal of expediting access to innovative therapeutics globally. Currently, regulatory authorities in six countries are participating with the FDA in the project: Australia's Therapeutic Goods Administration, Health Canada, Singapore's Health Sciences Authority, Switzerland's Swissmedic, Brazil's Health Regulatory Agency (or Agencia Nacional de Vigilancia Sanitaria), and the UK's Medicines & Healthcare Products Regulatory Agency.

From June 2019 to June 2020, before the UK's MHRA joined earlier this year, Project Orbis received 60 marketing applications for cancer drugs, and the participating regulatory agencies approved 38 applications. R. Angelo de Claro, associate director for global clinical sciences at the FDA's Oncology Center of Excellence, told Precision Oncology News last week that 35 of those 38 approved drugs were targeted therapies and 10 were drugs indicated for molecularly defined patient populations.

Seagen's tucatinib (Tukysa), which the FDA approved last year in combination with trastuzumab (Genentech's Herceptin) and capecitabine for HER2-positive, metastatic breast cancer, is an example of a precision oncology drug that regulators in the US, Switzerland, Singapore, Australia, and Canada collaboratively reviewed within Project Orbis.

During the second session of the American Association for Cancer Research's annual meeting last month, Richard Pazdur, director of the FDA's Oncology Center of Excellence, moderated a discussion with the regulatory, academic, and industry experts involved with the tucatinib development program and provided an inside look at how the Project Orbis review process works and the impact it is having.

Luke Walker, VP of clinical development at Seagen, noted that the 600-patient, registrational HER2CLIMB trial for tucatinib enrolled patients in the US, Canada, Australia, and 11 European countries, including Switzerland. However, Pazdur revealed that the company hadn't initially set out to submit registrational data on tucatinib nearly simultaneously to multiple regulatory bodies through Project Orbis and had to "scurry" to do so.

The effort ultimately paid off. "[Seagen] is still a growing company and a lot of it just comes down to bandwidth," Walker said during the discussion at the meeting. "The ability to concentrate these efforts in coordination with the agencies really helped substantially because … there would have been months-to-years delays getting [the drug] to some of these jurisdictions outside of the US if we hadn't gone through Orbis."

The FDA approved tucatinib in April 2020. A little over a month later, Swissmedic also approved the tucatinib-trastuzumab-capecitabine regimen for HER2-positive metastatic breast cancer. By August, regulators in Canada, Singapore, and Australia had all made positive regulatory decisions on tucatinib based on their review of the HER2CLIMB data submitted through Project Orbis.

That study, in which randomized patients received either the tucatinib-trastuzumab-capecitabine regimen or trastuzumab-capecitabine, showed a median overall survival of 21.9 months for those who received tucatinib compared to 17.4 months for those who did not. Oncologists like Nancy Lin, a breast cancer specialist who led the registrational tucatinib trial at Dana-Farber Cancer Institute, noted during the AACR discussion that the results were particularly impressive given nearly 50 percent of enrolled patients had brain metastases.

Ulrich Rohr, head of the division of clinical review of hematology and oncology therapies within Swissmedic, said during the AACR session that typically it would take his agency 500 days to review the submitted evidence on a new drug. But by participating in Project Orbis that review timeline was shorted to 123 days. "This is very reassuring … that good drugs are coming earlier to patients, not only in Switzerland but also in other parts of the world," Rohr said.

Working together, retaining autonomy

In an article published in December in Clinical Cancer Research, the FDA's De Claro and other regulatory stakeholders described how Project Orbis operates and discussed its growth since its launch. In 2019, only health regulators from Australia and Canada were part of the effort. Subsequently, oversight bodies from other countries joined, with the UK's MHRA the most recent partner as of January.

Before launching the project, the agency held 90-minute monthly calls with health authorities in the European Union, Japan, and other countries to discuss drug marketing applications. However, through this project the FDA created a more formal process through which industry sponsors submit a core review document with the registrational data that participating regulators discuss.

The FDA or drug sponsors can propose therapies for the regulators to take up once top-line data within registrational studies have reported out, and the participating authorities then decide if they're interested in reviewing an application. The project tends to take up applications for drugs to which the FDA has granted priority review and that have better safety and efficacy data than therapies available in a particular indication.

Although sponsors submit data to the project through a core document, they still have to meet each country's submission requirements. Ultimately, each country's regulatory body retains its independence in deciding whether to approve the drug, and upon approval, the language they want to include in the product labeling describing the drug's intended use.

In Switzerland, where drug labeling is published in Italian, French, and German, regulators ultimately decided on a slightly different wording for tucatinib's indication than the FDA. The FDA-approved indication notes that tucatinib in combination with trastuzumab and capecitabine is for previously treated patients with advanced, unresectable, or metastatic HER2-positive breast cancer, "including brain metastases." The Swissmedic-approved label doesn't mention brain metastases.

Suparna Wedam, a medical officer who reviewed the tucatinib data within the FDA, said during the AACR session that the indication was a major point of discussion among Project Orbis collaborators. "Many would say it seems redundant. Metastatic breast cancer covers [metastases to] all locations," Wedam said. Ultimately, the FDA decided to explicitly mention that the drug can be given to those with brain metastases because Seagen put forth a significant effort to enroll this subset of patients who are often left out of clinical trials.

Dana-Farber's Lin agreed that in the US the specific mention of "brain metastases" in the drug label can help oncologists decide between multiple therapeutic options for advanced, HER2-positive breast cancer patients based on their specific disease characteristics.

These labeling differences will happen within Project Orbis, Pazdur said, because ultimately, regulatory bodies retain their autonomy. "It is not an attempt to have a uniform package insert or uniform decisions amongst the countries," he said, adding that regulators in different countries can participate only in collaboratively reviewing the applications they wish to. "The attempt is to get these drugs out earlier to a more general world audience rather than having significant delays."

Right thing to do

When participating in Project Orbis, sponsors must provide a global submission plan, laying out their timeline for filing data with the FDA and at least one other Project Orbis regulatory body. Within the project there are different kinds of submissions based on how quickly sponsors submit to regulatory authorities after they file with the FDA.

Type A submissions are designed to facilitate simultaneous or near-simultaneous approvals and require sponsors to submit to other countries within 30 days of submitting to US regulators. Type B submissions are when sponsors file more than 30 days after filing with the FDA or when other regulators issue decisions more than three months after US regulators. Type C submissions are when the FDA has already approved the therapies and shares its complete review documents with other Project Orbis collaborators.

For the 38 applications approved through Project Orbis between 2019 and 2020, the median time gap between when sponsors submitted applications to the FDA and other regulators ranged between 0.8 months to 9 months, with a median time gap of 0.6 months. The median time regulators took to approve these applications was similar between the FDA and other oversight bodies: 4.2 months and 4.4 months, respectively.

For type A submissions, which require the most collaboration among Project Orbis review teams, sponsors submitted 90 percent of the applications to other Project Orbis countries within 1.1 months of their FDA submission. Similarly, regulators in other countries approved 90 percent of these type A applications within 2.4 months of the FDA's approval.

The level of collaboration needed to approve a type A submission is not easy to achieve. Given time differences and busy schedules of regulators in different countries, setting up meetings to discuss applications is one of the more challenging aspects of the program, multiple experts said during the AACR discussion. Although Project Orbis has steadily added new countries since its launch, this organizational difficulty only increases with more collaborators.

When asked why Project Orbis currently lacks representation from certain regions of the world, such as Africa, the FDA's De Claro said that adding more collaborators increases the logistical complexity of meetings. More participants "would also require pharmaceutical sponsors to coordinate more application submissions," he said, noting that despite these challenges, efforts are underway to continually grow the project.

In the Clinical Cancer Research paper De Claro and his colleagues recognized that Project Orbis' requirement that all marketing application and review documents be in English may also hinder some regulatory bodies form partaking. Importantly, there must be "reasonable alignment" in review processes between countries, they wrote, adding that the differences between the European Medicines Agency and the FDA have hindered the EMA's participation in the project.

Within multiple countries partaking in Project Orbis, drugs must pass regulatory muster in terms of safety and efficacy but also undergo health technology assessment and demonstrate cost-effectiveness before they are available to patients. This means that even if regulators decide a drug is safe and effective through the project, additional negotiations may be needed to facilitate early access.

For example, the UK's MHRA announced in May that after reviewing data through Project Orbis on osimertinib (AstraZeneca's Tagrisso) as an adjuvant, post-surgical treatment for EGFR-mutated, early-stage non-small cell lung cancer patients, the National Health Service England, the drugmaker, and the National Institute for Health and Care Excellence struck up an agreement to provide early access to the therapy "on a budget-neutral basis." NICE, meanwhile, will still conduct its cost-effectiveness analysis and is expected to publish its recommendation as to whether NHS England should fully fund access to this drug in September 2021.

"The access agreement for England is only in place until NICE has made a decision about whether to recommend the medicine or not," said an AstraZeneca spokesperson, adding that if NICE ends up issuing a negative health technology assessment, then no new patients will be able to access the treatment. "Patients who have already started treatment will be able to continue until their treating physician deems [it] appropriate."

Regulatory differences between countries have also impacted how project collaborators review precision oncology drugs that rely on companion diagnostics to identify patients likely to benefit. Project Orbis facilitated multicountry approvals for around 10 drugs for molecularly defined indications that rely on companion diagnostics between mid-2019 to -2020, but these collaborative reviews didn't discuss the test data. This, De Claro said, is because the participating countries have very different regulatory frameworks for diagnostics, and the US is the only country that requires CDx approval when the safe and effective use of a drug necessitates a test.

The complexity of the evidence underlying precision cancer drugs, particularly for cell and gene therapies, may also be challenging to review within the project given present resources. "The … review of more complex products [such as] CAR T-cell products [and] radiopharmaceuticals, involves addition of more specialized teams, which would increase the resource utilization and logistical complexities of the application review," he said. "These additional teams could include product quality experts, as well as highly specialized experts such as radiologists, dosimetrists, and nuclear physicists for radiopharmaceutical products."

While Project Orbis grapples with these growing pains, the program has already demonstrated its value to oncologists like Lin by broadening access to innovative cancer therapeutics for patients around the world. During the AACR session, she pointed out that by facilitating simultaneous or near-simultaneous access to oncology drugs, Project Orbis is making it easier to promulgate international treatment guidelines, which is often a difficult task due to the disjointed commercialization timelines of therapies from country to country.

"When things can happen in a coordinated fashion, it's really helpful," she said, adding that general oncologists, who are not specialists in a specific tumor type, really turn to these guidelines when treating patients. "The more [treatment guidelines] can be aligned, the better for our patients."

FDA's Pazdur agreed. When the FDA was starting up Project Orbis, he recalled that folks in industry and within other regulatory bodies asked him, "What's in it for the FDA?" He said his response was, "Well, it's the right thing to do."