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Richard Pazdur, M.D., is the director of the FDA’s Oncology Center of Excellence (OCE), established in 2017 to leverage the combined skills of the FDA’s regulatory scientists and reviewers with expertise in drugs, biologics, and devices to expedite the development of novel cancer products. The Office of Global Policy and Strategy recently spoke to Dr. Pazdur about his extensive international efforts to advance oncology product development.
I understand you have worked at the FDA for 26 years. Is it fair to say that over the course of your career here that you have become increasingly interested in international outreach? How has your thinking evolved, and why?
When I began my career in the late 1970s, most oncology trials were performed exclusively in the United States. Over the past 45 years, more trials were done in Europe, and now we're seeing an increasing number of trials conducted partially or solely in Asia. I always had an interest in how drugs are developed outside of the United States. Before I came to the agency, I was a clinical investigator and did a lot of work with international drug companies. Over the years at the FDA, I became aware that oncology trials were increasingly conducted globally. I decided that the FDA needed to assume leadership and encourage a dialogue with global regulatory agencies. We began the concept of “cluster calls” where multiple regulatory agencies could speak freely about ongoing applications. To enable this interaction about specific applications, all agencies had signed confidentiality agreements. The thought was that this dialogue would facilitate an understanding of potential differences in our regulatory decision-making. These cluster calls began with the European Medicines Agency (EMA) and later expanded to Canada, Australia, Switzerland, and Japan. The purpose was not to achieve consensus but to understand our differences and why they exist.
You established Project Orbis six years ago to further expand the scope of the FDA’s international oncology work. It has grown in prominence since then. What is Project Orbis? Why was it needed, and has it been successful?
Well, first of all, the success of Project Orbis is well documented and goes beyond my expectations. The program emanated from our oncology cluster calls with the EMA and other agencies. During these calls, we noticed that the most important drug applications were filed first in the United States.
The smaller regulatory authorities, including Canada and Australia, would experience a lag in the receipt of applications. This filing delay could extend for several months, several years, or sometimes the agencies never received an application. This posed a pragmatic problem. In initiating oncology trials, we want control arms to be the contemporary standard of care in the United States. However, if the standard of care is not uniform across countries, global trials may not be feasible using the most recent treatment that is approved in the United States. We need to have these standards of care established as quickly as possible. As a further challenge for regulators, oncology is a rapidly evolving field, with 10 to 15 new molecular entities approved annually, representing approximately 30 to 40 percent of pharmaceutical companies’ yearly activities.
So, after noticing this delay in international regulatory submission, I asked, what can we do to address this? I realized that if the company files an application to the United States, this application, with minor modifications, could be submitted nearly simultaneously to other countries that may be experiencing this time lag. Project Orbis started out first with Australia and Canada. We targeted significant drugs that had a major impact on patients with cancer – not “me-too” drugs. We asked sponsors to submit applications to other countries as closely as possible to the FDA submission. Of course, the regulators from other countries had to agree to participate prior to contacting the pharmaceutical sponsor. We would then review applications collaboratively with these agencies.
After receiving submissions, we would invite other countries to attend both sponsor meetings and our internal review meetings. Many regulatory agencies do not have the requisite number of staff to keep up with this workload and choose to wait until formal FDA drug approval and use our reviews to assist them in formulating regulatory decisions. The idea is to get these drugs to smaller agencies and achieve a collaborative working environment. I would like to emphasize that the FDA does its entire review as usual, and we do not outsource our work to these other agencies.
Our reviewers really like to interact with these international reviewers. With the exception of advisory committee meetings, our review process is behind closed doors. With Project Orbis meetings, we discuss the independent viewpoints of these other regulators and are not simply listening to our own FDA voices and opinions. These interactions also build camaraderie among international drug regulators. We all attend meetings of the American Society of Clinical Oncology and other professional society yearly meetings where we foster a collaborative, collegial working environment between our review staff and medical officers and the scientific personnel from other Project Orbis member countries.
Project Orbis began with three Partner countries in May 2019: the FDA, Canada, and Australia. Singapore and Switzerland joined in December 2019; Brazil in May 2020; the U.K. in January 2021; and Israel in July 2021.
One of the rate-limiting steps for Project Orbis has been sufficient personnel to manage the program. The FDA has done a lot with a small team. I'd like to publicly acknowledge Dianne Spillman and her staff for their innovation and problem-solving in establishing this program. As I said earlier, we've been very successful, with 633 applications for 79 products, and the companies have told us they really consider this a major advance. When our Project Orbis international partners met in June at the FDA, participants uniformly expressed interest in expanding Orbis to other countries or other therapeutic areas. We will be discussing that further.
So, when you say new therapeutic areas, you mean outside of oncology?
Yes. What we have done in oncology could serve as a framework for other therapeutic areas. Agencies have requested that we consider expanding Orbis to other disease areas. We have an oncology-specific expertise that facilitates the review of complex applications. For example, we have teams that deal exclusively with breast cancer, teams for lung cancer, teams for head and neck cancer, multiple myeloma teams, sarcoma teams and pediatric experts. We are sub-specialized, reflecting the structure of many university and cancer center programs. Oncology changes so rapidly that teams need expertise in the selected oncology diseases. Outside of the United States, smaller agencies do not have this internal expertise. Project Orbis enables these agencies to confer with FDA regulators who have disease-specific knowledge.
 I understand you are also developing Project Nozomi in Japan. What is that?
It's to promote further collaboration specifically with the Japanese regulatory authorities. One potential aspiration is to host Japanese regulators here at the FDA to interact directly with our oncology staff. There may be a significant lag in the submissions in Japan, and at times applications may not be filed. We would like to work with Japan to facilitate submissions and review. They also have an observer status with Project Orbis, as does the EMA. By the way, Nozomi means “hope.” It's named after one of the bullet trains.
You traveled to the EMA in 2023 and to Canada, the U.K., Belgium, and Switzerland in 2024. What did you learn from these travels, and how have you used that information?
Many of these travels focused on Project Orbis and our interactions with the specific country. We meet with the actual review staff involved with Project Orbis, as well as regulatory leadership, clinical investigators, and patient groups. Our aim was process improvement. As with any process-oriented project, there's always room for improvement — the timing, the types of meetings, and so forth — not only for Project Orbis, but also for our monthly cluster calls. As a result of our visit to the EMA, we established monthly meetings to review scientific advice provided to sponsors. This is different from our conversations on our cluster calls where we primarily discuss submitted applications under review.
Much has been written about oncology trials being done exclusively in China. How extensive is that, and does that concern you?
This is one of the reasons that we have emphasized the importance of doing multiregional trials. There is an ever-growing number of trials being conducted exclusively in China or with a significant enrollment from China. We must have confidence in the results of these trials. From an FDA perspective, we have limited experience with some of these sites. Therefore, participation of sites in China in truly multiregional trials will potentially provide this experience and allow us to analyze data from China in comparison to other sites, including the U.S. and other established sites.
You coauthored a January 2 perspective article in the New England Journal of Medicine that discussed your perspective on multiregional clinical trials. Could you expand on why they are especially important to the United States?
Approximately 20% of the participants in these large multiregional oncology trials are enrolled in the United States. The U.S. has a heterogeneous population and a sophisticated medical delivery system, and we need to have confidence that the data are generalizable to our population and medical practice.
Why just 20%? Is it because of costs?
Many reasons. For example, there are structural reasons involving contract negotiations with individual clinical sites that tend to take longer in the United States. If you have multiple institutional review boards [IRBs], multiple IRBs will review the protocol, and that may result in delays. Also, since newer drugs come on the market earlier in the United States, investigators may have less interest in putting patients on a trial if the control arm does not represent the current standard, in the investigator’s opinion.
Do you see some pressure or movement to do more trials in the US?
Well, we're promoting drug development in the United States, that's for sure. The U.S. is the largest market for oncology drugs, and we think there needs to be a push to get more patients into trials in the United States and to explore and address these challenges. We have a project in OCE called Project Site Selector. Drug regulators have traditionally not thoroughly queried companies prior to the trial initiation on methods to select sites and the generalizability of the data collected from these sites to the U.S. population and medical practice. We traditionally spend a lot of time discussing the trial design, but then frequently not enough time is spent on clinical trial site locations. In oncology, we will be spending more time with sponsors discussing this topic.
I’d like to conclude by asking where your international work in oncology is heading in the next five and 10 years?
We'd like to move toward greater collaboration. We'd like to see more countries enter Orbis. We'd like to see other therapeutic areas outside of oncology participate in Orbis. I’ve mentioned before that this has been requested when we met with the other Orbis countries. Consideration of these aspirations depends on FDA resources. Under FDA regulations, a country that will potentially participate in Orbis must be able to enter confidentiality agreements as needed to facilitate information sharing among Orbis partner countries.
Expanding to other therapeutic areas would require having both FDA and international country staff who want to participate in Orbis. Our staff has been very supportive of the program. Expanding Orbis to more countries will take some time as we assess their regulatory processes and orient them to ours. Enacting confidentiality commitments across eight partner agencies may take some time. There may be other avenues like reliance pathways via the other partners that may be more achievable than adding more Orbis partners. As for other therapeutic areas, that’s beyond OCE but we are always willing to share our experiences and processes with FDA colleagues interested in facilitating global collaboration.
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