Good data are essential for staying competitive in the world of cancer drug development.
Pfizer and Merck & Co. know the requirement well, as they operate in the increasingly crowded immuno-oncology field. Just among themselves, the companies face off in three different cancer markets with their respective drugs Bavencio and Keytruda.
The two drug giants are looking to grow their oncology businesses with additional data readouts. Merck has over 8,700 active clinical trial sites supporting its oncology trials, which include more than 1,000 just for Keytruda, while Pfizer has north of 125 ongoing trials across nearly 3,200 sites for solid tumors and blood cancers.
BioPharma Dive spoke separately with Eric Rubin, vice president of global clinical oncology at Merck Research Laboratories, and Chris Boshoff, chief development office at Pfizer Oncology, about how they select sites and communicate with the physicians who run cancer clinical trials.
These interview answers have been condensed and edited for clarity.
BIOPHARMA DIVE: From a high level, walk us through the site selection process.
Rubin: Is it a first-in-human trial at one end of the spectrum, versus a Phase 3 registrational-intent trial? Our view in terms of site selection does differ according to to that.
At a high level, we're looking for sites that are experienced in doing clinical research. They're investigators who are familiar with informed consent and monitoring patients, on experimental treatments, that are familiar with all the regulatory requirements with [testing] investigational agent drugs.
Then one other [thing] that we look at frequently is their ability to both have the study start up quickly — get through all of their governance interactions, IRBs and so forth — and then rapidly enroll patients.
BOSHOFF: For oncology, let's divide this into Phase 1 or early-phase clinical studies versus our large, registrational, usually Phase 3 studies.
The early studies we usually conduct at academic institutions, and the majority of those are in the U.S. We look for sites with deep clinical expertise, a track record of conducting and executing Phase 1 studies, significant infrastructure for Phase 1 studies — and that includes onsite capabilities, research, nursing support, the correct imaging, they can collect [and store] samples.
For our large, randomized studies, these are global studies. We have sites in North America, including Canada, Western Europe, Eastern Europe, Japan, Southeast Asia, sites in China, Australia, the Middle East, Central America and South America. In general, any Phase 3, registration-intent oncology study for Pfizer needs to be a global study with representation from all regions of the globe.
How does tumor type affect site selection?
RUBIN: There are academic groups that have become sort of focus sites for rare diseases. They're just a known referral place. So there might be very few patients who have the disease ... but they'll travel around the world to be seen at that site.
Of course, if you're studying that disease, you want to look at those places because that's going to help with your accrual.
I'll just take the MSI-high situation for Merck. It's pretty rare, like 5-10% of most cancers. It's not easy to find those patients. I don't think there's necessarily a big difference between a big academic center versus a community [site]. You just have to recognize that a lot of patients are going to be screened and most of them are not going to be positive for that test. So it can be a pretty inefficient process.
BOSHOFF: Prevalence of a specific disease could play a role.
We're not currently conducting a study in liver cancer. But if we did, we will be recruiting mainly in Asia. When Pfizer conducted the Phase 3 studies for our EGFR inhibitors, there was again a focus more towards the east because the prevalence of EGFR mutations are higher in certain populations.
[But] in general, when we conduct these studies globally ... there's no preference for site.
Are there particular institutions that you think of first when considering a new clinical trial?
RUBIN: Before coming to Merck, I was a Phase 1 doc and I worked at what's now known as the Rutgers Cancer Institute of New Jersey. So I'm very familiar with both sides of this.
One of the things about Phase 1, particularly if it's a first-in-human study, is there are extra precautions from a risk-benefit perspective, from a regulatory compliance perspective that makes it hard to do those outside of an academic setting.
Most community practices don't really have the infrastructure to do that. There are some exceptions, and there have been places that have been very successful in basically converting what would be a community-type setting into a Phase 1 program.
BOSHOFF: The first criteria always is: can these sites conduct the studies? Do they have the expertise, the infrastructure, the capabilities and the track record, and have they conducted previous studies for Pfizer? What is the efficiency at the site? What is the quality of the data?
For most of our registration-intent, Phase 3 studies, we aim to have a global steering committee that will be the key investigators representing the different regions. Of course, the sites with the main steering committee members we will include. But they're not necessarily the sites where we have most patients recruited, because they often have other competitor studies as well.
Have you run into situations where an institution says it can't do your trial right now because it's working on a competitor study, or even because of more general resource constraints?
BOSHOFF: It's not a significant problem.
Remember, in the early-phase, Phase 1 clinical studies there's only a few patients actually recruited. It's a slow recruitment, so we don't have that issue. For the large, Phase 3 studies, in general we do site feasibility before the site is opened.
Another reason why it's not a major issue is the reality that, globally, less than 5% of patients get into clinical trials for oncology. So there's a lot of space for improvement.
How are you working to make cancer clinical trials more equitable for patients or more efficient for investigators?
RUBIN: We're always on the lookout for new sites that offer promising capabilities. Maybe areas where there's an underserved population or an ethnically diverse population, that might be a new place where there's a new investigator, and so we'll look for those types of folks to incorporate them.
An interest of mine, and generally the industry as well, is to improve the overall efficiency of clinical trials for cancer. One [potential advancement] that comes up a lot is what would be called umbrella trials.
It's more efficient, especially from the patient perspective, when chances of being enrolled in an experimental drug arm are going to be higher than if you're just going into a two-arm study.
BOSHOFF: The first is to make sure we have representation from all different regions. In the future, we are looking to recruit more patients from sites in China, for example.
But again, the criteria for selecting a site will be the infrastructure, the capabilities, clinical expertise and whether they can deliver this study with quality and in a timely fashion.
How do you communicate and keep in touch with clinical trial sites, either during the trial itself or between trials?
RUBIN: We interact with investigators who are well known in their particular disease area on a frequent basis. We're exchanging ideas about unmet need in a particular tumor type, maybe we'll get feedback about the drug we're interested in studying and how interesting they think it is for that particular tumor type.
So even before we get into actually picking the site, we've gotten input from prominent people. Because of that, there are somewhat repetitive elements; we've worked with many sites many times over the years, so it's natural for us to go back to them.
Our operations folks are all Merck employees, so we don't use CROs. That, to me, makes it much simpler.
BOSHOFF: For most of our studies we will have investigator meetings, which are global meetings. These are either conducted in specific regions, for example west coast, east coast, western Europe, South Korea, or sometimes at a big conference like ASCO or ESMO or AACR where everyone will be together.
These investigator meetings are also sometimes just virtual, and then in between it's obviously an opportunity for an investigator to reach out if there's any challenges or any additional questions they have. So there's regular contact.
With some investigators, there will be additional interests. For example, they may have interest in a specific study to conduct translational research -- and that's a different type of relationship.
Dr. Alice Shaw at MassGen Hospital in Boston is a world authority on ALK-positive lung cancer and she's investigated many of the new drugs for ALK-positive lung cancer. She has an interest to understand which patients respond, so she was involved in the initial development of crizotinib, or Xalkori, and more recently lorlatinib, or Lorbrena. When we conducted the Phase 2 registration study, we worked closely with her for the sample collection from all sites and testing both of primary tumors and blood samples.
So we selected her site for recruitment because there's a lot of deep expertise, there's capabilities, there's infrastructure, there's a big referral patient population with ALK-positive lung cancer.