In the first regulatory action of its kind, FDA and drug approval authorities in Canada and Australia simultaneously approved a new treatment for patients with endometrial carcinoma.
The joint approval was made under FDA’s Project Orbis. FDA, the Australian Therapeutic Goods Administration, and Health Canada each reviewed and approved Lenvima (lenvatinib) in combination with Keytruda (pembrolizumab) for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.
For humanitarian reasons, we want people with cancer anywhere in the world to have access to safe and effective therapies.
Richard Pazdur
“We are pleased to be working alongside our Australian and Canadian colleagues to help make potentially life-changing treatments available to patients as quickly as possible while still ensuring the FDA’s high standards of safety and effectiveness,” Acting FDA Commissioner Ned Sharpless said in a statement. “As Project Orbis expands, we look forward to welcoming additional international partners to collaborate with us in this important initiative as we work to help further serve the global patient community.”
Keytruda is sponsored by Merck Sharp & Dohme Corp., and Lenvima is sponsored by Eisai Inc. In the U.S., the drug combination received an accelerated approval. Canada and Australia also provided approvals contingent on post-marketing commitments.
“In addition to the international collaboration with Australia and Canada, this review used the Real-Time Oncology Review pilot program, which can streamline the submission of data prior to the completion and submission of the entire clinical application,” Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products, said in a statement. “RTOR, and its accompanying Assessment Aid, facilitated discussions among the regulatory agencies, expediting the approval in the three countries. These applications were approved three months prior to the FDA goal date.”
The approval of the Lenvima-Keytruda combination was based on the results of a clinical trial of 94 patients with endometrial carcinoma tumors that were not MSI-H or dMMR. Of the 94 patients, 10 patients (10.6% of responders) had a complete response, or disappearance of all lesions on imaging, and 26 patients (27.7% of responders) had a partial response, or shrinkage of lesions by at least 30%, leading to an objective response rate of 38.3%. Of these, 25 patients (69% of responders) have a duration of response of greater than 6 months.
Pazdur, as well as members of the oncology center and spokespersons for the Canadian and Australian regulatory authorities, spoke with Paul Goldberg, editor and publisher of The Cancer Letter.
Paul Goldberg: Drugs are generally approved faster in the U.S. than in Europe and the rest of the world; correct?
Richard Pazdur: Correct. It’s an urban myth that the FDA is slower than other countries—that myth has been debunked in several studies comparing review times between the U.S. and Europe over the past few years.
Two-thirds to three-quarters of new drugs are approved first in the U.S. For one thing, the pharmaceutical companies submit their applications to the FDA first, because the U.S. market is so large. So, we get a head start.
Then, because of Congressional mandates, such as priority review, breakthrough designation, accelerated approval, the FDA, especially in oncology, uses expedited programs designed to streamline the review process for serious and life-threatening diseases. We also have a larger medical oncology staff than other regulatory agencies.
How did Project Orbis start? Is this the first time the OCE has collaborated with international regulatory agencies?
Pazdur: In the Office of Hematology and Oncology Products, we have held regular teleconferences—under a confidentiality agreement—with other regulatory agencies since 2004.
This allows us to exchange information and collaborate on specific topics related to applications under review. We currently hold a monthly teleconference with Australia’s Therapeutic Goods Administration, Health Canada, the European Medicines Agency, Japan’s Pharmaceuticals and Medical Devices Agency, and Switzerland’s Swissmedic. We also recently began a quarterly teleconference with China’s National Medical Products Administration to discuss non-product specific regulatory issues facing worldwide development.
As we discussed issues with drug applications, we noticed that the other countries often didn’t have applications from companies that we were working on or had already approved. In some countries, pharmaceutical manufacturers do not apply for marketing approval for an oncology product until several years after FDA approves the product.
What about Europe; is Europe a part of Project Orbis?
Pazdur: We have not had discussions with Europe at this time. We would welcome future discussions with the European Medicines Agency and other countries.
Why are you concerned about delays?
Pazdur: Two reasons. First, it’s simply the right thing to do. For humanitarian reasons, we want people with cancer anywhere in the world to have access to safe and effective therapies. Second, these long delays may result in different standards of care in different geographic areas, and this may have implications for the selection of control arms in future clinical trials.
Cancer clinical trials are predominantly conducted internationally. Greater uniformity of new standards of treatment may lead to oncology trials that are more broadly applicable around the world, and thus, more efficient drug development and earlier access to therapies for people with cancer in the U.S. and worldwide.
Orbis, of course, means “globe” in Latin. Could you describe the process for the first Project Orbis review?
Pazdur: Prior to initiation of the review, the review team and I discussed the application with both Australia and Canada to ensure that both agencies were aligned with us on the application’s major issues—i.e., single arm trial of a combination treatment and demonstration of effect of the components from external trials. During this collaborative process, FDA completed our standard approach to the application examining both safety and efficacy.
Also, this application was completed under our Real-Time Oncology Review process and Assessment Aid. During the Real-Time Oncology Review, the sponsor submits data prior to the formal submission of the clinical portion of the application, allowing the staff to jump-start the review, interrogating the efficacy and data sets.
The Assessment Aid is a single document that serves as the FDA review comprised of data sections, sponsor evaluation of the specific sections, and subsequently the FDA evaluation of that section. This single document eliminates substantial duplication of tables and data and focuses the review on areas of disagreement and agreement.
This collaborative review provided the framework for regular dialog among the review teams from the three agencies. My hat’s off to everyone’s flexibility, because we had to deal with the substantial time differences between North America and Australia, necessitating interactions at unusual times—not during normal government business hours. Our staff has enjoyed the collegial interactions, not only benefiting from the perspectives of other regulators concerning this specific application, but also on the regulatory policies and regulations of the other agencies.
Project Orbis, the Real-Time Oncology Review, and the Assessment Aid are pilot programs conceived by the Oncology Center of Excellence and have had enthusiastic acceptance by our review staff—Less documentation, more thoughtful scientific input.
I will turn to our clinical reviewer, Shaily Arora, Gynecologic Malignancy Team Leader Sanjeeve Bala, and their Division Director Julia Beaver to discuss the specific application.
What’s the indication that was granted, and what was the trial design supporting the approval?
Julia Beaver: We granted accelerated approval to the combination of pembrolizumab plus lenvatinib for the treatment of patients with advanced endometrial cancer that is not microsatellite instability high or mismatch repair deficient, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.
This is a population based on absence of a biomarker and one for which there are limited treatment options. This was the first approval for a population that is not MSI-H or dMMR.
Shaily Arora: The pharmaceutical sponsors conducted a multi-cohort, international trial of the combination of pembrolizumab with lenvatinib for a variety of cancer types. This particular application focused on a single-arm cohort of 94 women with endometrial cancer that was biomarker negative for MSI-H and/or dMMR.
Tumor MSI status was determined using a polymerase chain reaction test. Tumor MMR status was determined using an immunohistochemistry test. Patients were treated with lenvatinib 20 mg orally once daily in combination with pembrolizumab 200 mg administered intravenously every three weeks until unacceptable toxicity or disease progression.
What were the efficacy results?
Sanjeeve Bala: The objective response rate in the 94 patients whose tumors were not MSI-H or dMMR was 38.3% (95% CI: 29%, 49%) with 10 complete responses (10.6%) and 26 partial responses (27.7%). Median duration of response was not reached at the time of data cutoff and 25 patients (69% of responders) had response durations of at least 6 months.
What about safety?
Arora: The safety profile of lenvatinib and pembrolizumab were consistent with the known toxicity profile of each individual drug and the toxicity of the combination taken with the efficacy results were deemed acceptable for the intended population. The prescribing information for each drug contains detailed safety data, including dosage adjustments required for patients with renal or hepatic impairment.
So, this a large positive result for a patient population with an unmet medical need—clearly a candidate for accelerated approval, correct?
Beaver: Patients with advanced endometrial cancer with non-MSI-H or proficient MMR represent a population with a clear unmet medical need with no FDA approved therapies, and a life-threatening diagnosis. Accelerated approval was appropriate because of this life-threatening nature of advanced endometrial cancer coupled with a result in objective response rate and duration of response, endpoints considered reasonably likely to predict clinical benefit, that were clearly better than available therapies.
Bala: Additionally, both drugs have other approvals in the U.S. as well as Canada and Australia; this gives us a large safety database with which to understand the safety of the combination, which isn’t possible with drugs that weren’t previously approved. So, the safety findings in the 94 women on this trial were understood in the context of that large base of information.
Did you have to modify the routine U.S. review process?
Bala: We conducted the review of this application in approximately three months, which was three months ahead of our due date as this application was granted Priority Review status. This review was performed by FDA using the same processes we always use, which requires a close examination of the submitted data.
Different from Canada and Australia, we require companies to submit the datasets that contain the clinical results for each patient on the trial, and then we evaluate those data ourselves. This includes, for example, each tumor measurement, each patient demographic and disease characteristic, and every lab value and graded toxicity, among the list of all collected datapoints.
Arora: This evaluation includes an analysis of data supporting efficacy by examining the endpoints in detail. For this application, we also performed a number of sensitivity analyses, such as using propensity scores to help us to better approximate the cross-trial comparisons to the performance of the single agents. This gave us a more robust look at the efficacy of the treatment.
We also performed detailed safety analyses, where we scrutinized all of the toxicity data submitted in the application in order to have a good understanding of the treatment’s adverse reactions, and also to determine whether additional communication to the oncology community might be required for safety purposes. This might include steps such as boxed warnings in the label or a REMS, which we determined would not be required for this application.
Did you have to change approval standards?
Spokesperson for Australian Government Department of Health: No. This approval was made within the Therapeutic Goods Administration’s existing regulatory framework and standards.
As part of the Australian government’s response to the Medicines and Medical Devices Regulation review, the Department of Health, through the TGA, implemented a new pathway for the provisional registration of prescription medicines on the basis of preliminary clinical data where there is a substantial benefit to Australian patients. This occurred in March 2018.
Spokesperson for Health Canada: Project Orbis uses a collaborative review process where each country conducts its own review according to its national standards and makes its own decision with respect to the approval of the drug product.
The simultaneous review of the submission and the simultaneous decisions allow for beneficial discussions among the experts from each country involved and provide access to a new therapy for a greater number of patients across the multiple jurisdictions at the same time. All Health Canada’s stringent standards and requirements were respected during the accelerated review of these products.
Did the company submit the one application to all the countries?
Beaver: We initially discussed this pilot program with both drug companies, Merck and Eisai. They agreed to participate and then submitted three applications, one to each country per each country’s individual requirements. However, each application was very similar.
Describe the process for collaboration. What new processes did you develop?
Bala: We completed our review using our standard review process, using the RTOR and Assessment Aid pilots. What was different about Project Orbis is that during the review, we discussed various aspects of our findings with the review teams from Australia and Canada in a series of teleconferences.
These were interesting discussions that highlighted features of the applications as they pertained to the regulations in the different countries. There were some nuances that we got to discuss, but they did not change our overall evaluation of the benefit vs. the risk of this combination for the indicated population.
Beaver: For this application, all countries agreed on the approval decision and were able to act at similar times. However, for future pilots in Project Orbis it is not required that all countries agree on the decision action, and one or more countries could take separate actions if they view the application differently.
What was the role of the reviewers from the different countries?
Bala: The review team at FDA undertook our standard, detailed review of the submitted clinical data from the entire application. During this process, we discussed our findings with the review staff from Australia and Canada, who had each performed their evaluation of the sponsor’s study reports.
Through this mechanism, we were able to uncover any safety concerns and mutually agree that the safety of this treatment combination did not appear to be markedly different from that of the individual agents. Similarly, we discussed the data supporting the effectiveness of the combination, and a variety of sensitivity analyses, and determined that they were robust and did indeed support the conclusion that the combination is more efficacious than either monotherapy in the indicated population.
Did the three countries issue the same drug labels for the two products involved?
Bala: Labeling is negotiated between the regulatory agency and the pharmaceutical sponsor; in this case, each country negotiated their label separately. The clinical trial submitted as evidence for approval enrolled only women with metastatic endometrial cancer that had progressed following platinum-based chemotherapy.
Our staff has enjoyed the collegial interactions, not only benefiting from the perspectives of other regulators concerning this specific application, but also on the regulatory policies and regulations of the other agencies.
Richard Pazdur
However, FDA determined that there is no scientific rationale that women with incurable, but not metastatic, advanced endometrial cancer wouldn’t also benefit to a similar extent from this combination, and so the indication was extended to this population in the US.
Similarly, patients who progressed following platinum-based systemic therapy and those who progressed following non-platinum regimens should also respond to this therapy similarly, so we did not exclude women who, for example, were intolerant of platinum in the front-line setting.
Australia: FDA, Health Canada, and the Australian Therapeutic Goods Administration collaboratively reviewed this application allowing for separate and simultaneous decisions in all three countries (provisional approval in Australia).
The labels (called Product Information in Australia) differ in layout and detail between countries however the content with respect to the new indication is very similar. Slight differences in the indication wording take into account the local healthcare setting and regulatory framework.
Canada: There will be minor differences in the labels since each country has its own requirements for the format and content of the drug label.
In Canada, the approved indication is slightly different from the approved indication in the United States and Australia in that it is more closely aligned to the patient population in the clinical trials. This reflects Health Canada’s standard approach to wording indications. However, the use of the products will be very similar in all three countries.
Was approval in each of the countries completed on the same day?
Bala: Not exactly. We all made our decisions public on the same day, though Australia, being 14 hours ahead of the Eastern Daylight Time zone, announced their action a few hours later at the start of the next business day.
Australia: Yes, noting the different time zones between jurisdictions.
Canada: Yes. All three countries reached a decision at the same time.
This application received accelerated approval in the U.S. Are there similar approval pathways in Australia and Canada? How many oncology drugs received the equivalent of accelerated approval in Australia and Canada?
Australia: The new provisional approval pathway (similar to the FDA accelerated approval) allows sponsors to apply for time-limited provisional registration on the Australian Register of Therapeutic Goods. It provides access to certain promising new medicines where we consider that the benefit of early availability of the medicine outweighs the risk inherent in the fact that additional data are still required.
This is the second approval through the new provisional pathway. In July 2019, pembrolizumab (Keytruda) as a monotherapy became the first medicine to have additional indications registered via our provisional approval pathway.
Canada: In Canada, there are two expedited approval pathways. For submissions following the Priority Review pathway, the target review time is reduced to 180 calendar days from 300. For submissions following the Advance Consideration Notice of Compliance with Conditions pathway, which is similar to FDA accelerated review, the target review time is reduced to 200 calendar days. Information on these pathways can be found here and here.
In the last 12 months, 21 oncology drug submissions were approved by Health Canada after an expedited review.
What factors promoted the development of this drug combination in this setting?
Bala: Both lenvatinib and pembrolizumab have multiple prior approvals in all three countries, which means that we have good clinical understanding of both drugs, and especially their toxicity profiles based on data from many patients. Based on the data, we didn’t see any preliminary suggestion of a new concerning safety signal.
Arora: And as FDA completed its thorough analyses of the submitted data, we were able to confirm that the data did not indicate any new safety concerns with the combination, despite the fact that adverse reactions were more common than with either drug alone.
Beaver: While pembrolizumab is approved for refractory MSI-H tumors including endometrial cancer, each individual agent had limited single agent activity in the non-MSI-H or proficient MMR endometrial cancer and thus it appeared appropriate to study the combination in this setting.
Comparing the combination results to each drug’s single agent results demonstrated the need for each drug in the combination, a finding that was particularly relevant to ascertain contribution of effect in a single arm study. Multiple other randomized studies of the combination are ongoing in the same line and earlier lines of therapy for patients with endometrial cancer with endpoints of progression free and overall survival.
Since this was an accelerated approval in the U.S., there must be postmarketing commitments. Do Australia and Canada also have similar postmarketing commitments? Are they the same as the U.S.?
Bala: The Accelerated Approval regulations stipulate continued approval for the indication may be contingent upon additional evidence of clinical benefit. In the U.S., this translates into a postmarketing requirement, which may include supporting clinical results using endpoints considered to be direct measures of clinical benefit, such as PFS or OS.
The companies have ongoing randomized studies that could meet this requirement. In addition, we had a number of post-marketing commitments agreed upon with the companies to provide additional clinical or device-related data.
Australia: Sponsors of provisionally approved medicines in Australia are required by the TGA to conduct and submit confirmatory studies for evaluation according to a clinical study plan. The clinical study plan is applied as a condition of registration. Although the legislative framework for post-authorization commitments in Australia and U.S. are different, in this instance the same clinical evidence is required for the confirmatory clinical trials conducted by both sponsors to obtain full registration.
Canada: The post-market commitments in Canada are very similar to those in the U.S. for similar reasons. In particular, we are requesting the same confirmatory clinical trial as in the U.S. As with all new drug approvals, Health Canada will continue to monitor the safety of these drugs for these new indications and will take prompt and appropriate action should any new health concerns arise.
Have Australia and Canada done any other collaborative reviews?
Australia: The Department of Health, through the TGA, is involved in a number of international collaborations and more are planned for the future. Details of another initiative, the Australia-Canada-Singapore-Switzerland (ACSS) Consortium are available on our website.
This was the first evaluation facilitated through the International Collaborative Review Initiative between TGA, United States Food and Drug Administration (FDA) and Health Canada, and heralds an important step forward in strengthening international relationships and harmonizing regulatory outcomes.
Ultimately, these activities enable learning and consistency amongst regulators and potentially, earlier access to important new treatments for the Australian community. The Department of Health, through the TGA, will continue to build these international partnerships recognizing the positive outcomes that they bring.
Canada: Health Canada has conducted several collaborative reviews with members of the Australia-Canada-Singapore-Switzerland consortium. This is the first collaborative review with FDA, but given the very successful outcome, Health Canada anticipates continuing with Project Orbis.
OCE has 100 medical oncologists who are clinical review staff. How many medical oncologists are on the review staff at TGA? At HC?
Australia: The Department currently has 12 staff focused on pre-market clinical review of oncology products (haematology and solid tumours). Additionally, there are a contingent of chemistry, toxicology and post-market review staff, business support and communications staff as well as expert external advisors who are engaged on a case-by-case basis.
The TGA also regularly engages with external independent experts in oncology to assist with our regulatory decision-making.
Canada: Health Canada’s pre-market clinical review teams are a mix of physicians and scientific staff with various backgrounds and training, including medical oncology expertise.
We currently have some 20 staff focused on reviewing new biologic oncology products and another 20 reviewing small molecule oncology products.
What is the future of Project Orbis? Will it be extended from supplemental oncology approvals to New Drug Applications or original Biologics License Applications?
Pazdur: We hope to continue with other pilots under Project Orbis and have the potential to expand to involve additional countries, as well as expand to review new molecular entities or original biologics under this program.
