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Clinical Trials The St. Jude Way



Editor's Note 9/6/18: Some of Dr. Santana's quotes have been clarified. 

August 27, 2018 | An average of 7,500 young cancer patients are treated at St. Jude Children’s Research Hospital in Memphis, Tenn. each year. And an astounding 95% of them participate in clinical research. (For adults with cancer, only about 5% are enrolled in cancer clinical trials.) Surely this high percentage has something to do with another eye-opening St. Jude statistic: treatments invented at St. Jude have helped push the overall childhood cancer survival rate from 20% to more than 80% since the hospital opened in 1962.  

Victor Santana, associate director, Clinical Research Cancer Center, is a 34-year veteran of St. Jude and oversees all of this clinical research and the infrastructure that supports it. He works with investigators to develop clinical research protocols, ensuring that each study progresses St. Jude’s scientific goals.  

Patients come to St. Jude from a geographic priority zone, St. Jude affiliate hospitals, or collaborating research institutions. Most patients must qualify for a clinical trial offered at St. Jude or one of its affiliates, and must be referred by a clinician. None pay for treatment. Many participate in both a treatment trial—comparing standard of care to another oncology treatment, for example—and a non-treatment trial—perhaps a study of changes in the brain after chemotherapy.

Clinical Informatics News Editor, Allison Proffitt, sat down with Santana in his Memphis office to learn more about how St. Jude runs its clinical research program. Our conversation has been edited for clarity and length.

Clinical Informatics News: St. Jude is primarily a research hospital, I’ve learned today. How many St. Jude patients are part of a trial?

Victor Santana: For treatment trials, we enroll about 60% of the new patients. When you add on the non-therapeutic trials, then the rate of enrollment is up to 95%, which is very high. For example, you may have a tumor for which we have an active clinical treatment trial and you can still participate in other non-therapeutic trials. Or you may have a very rare tumor for which there is no active clinical trial, and treatment would be considered as standard of care but you could participate in a non-therapeutic trial. It's very impressive, the number of patients that go on trials here.

That is impressive. Do you consent these trials individually or is there some sort of front door consent for St. Jude because it's a research hospital? 

Every trial has to have its own consent approved by the IRB for research.

Did you have an IRB here?

We actually have two IRBs, our own IRBs. They're registered as two separate entities. One IRB deals with the regular protocol submission and approval process and the second IRB deals with emergency requests, expedited requests that can't go on a regular schedule and so we have to deal with them immediately.

We have also established in the last year a central IRB. The NIH is now requiring—for NIH funded multi-site studies—that there be one IRB of record and then all the institutions that are participating enter into reliance agreements with a central IRB. We have established a central IRB for our studies being conducted at our affiliate sites. So, we have eight affiliate sites that are basically partner institutions where patients come from. In order to make the IRB process work better, we established a central IRB that they can use. I think that's working very well.

What are the advantages of the central IRB?

It allows more efficiency in the review process. First of all, because we are a pediatric cancer hospital and these affiliates are all smaller hospitals that are not necessarily just pediatrics, they may not have the level of expertise to do the rigorous review that's required. So that's one advantage.

The second advantage is that it helps get studies open a lot faster. Once the central IRB approves the study, then technically it's just a matter of paperwork to get it open at the other sites, because there's no full additional internal IRB review that is required at those sites. There is some review that's required, but it's most for administrative things.

I think that's been very helpful and it's had a major impact for us in terms of getting the studies open a lot faster, and helping patients moving back and forth between our affiliate sites and St. Jude to be able to participate in clinical research. That's been a major advantage for patients.

StJude-Santana

Which parts of the clinical trial review do affiliates handle themselves?

There is a difference between having a central IRB be responsible for the ethical review and then having an IRB responsible for the human subjects protections. They go hand-in-hand, but they're really two separate activities. Initial review asks questions like: Is this study ethical? Is it scientifically sound? Are you going to watch out for the safety of participants? What does a consent look like? What are the risks? What are the benefits? What are the alternatives? That's what that central review should be doing. At the local level, there has to be protection of the people who are going to sign up. Who's obtaining consent? Are the people obtaining consent qualified? Under what circumstances does consent occur? Are there local or state laws that and regulations that have to be followed? We refer to that as local context, because it's occurring locally. Central review allows St. Jude to do that first part, but the sites still have to do that second part.

Do they need an IRB to do that?

Yes, but it's done in a very rapid way. They usually have already identified the local context issues that they need to address, and their review is focused on assuming that those are reflected in the consent and in how they obtain consent. For example, are the people obtaining consent and conducting the trial at that site qualified and trained? That's an aspect of human subjects protections at the local level. The central IRB doesn't assume those responsibilities. Those are handled at the site level. It's a system that I think is good because it respects the unique environment in which the clinical trial is been done.

How do you monitor studies?

We monitor our own studies through a centralized protocol office, not through the IRB. Within the protocol, there is a segment or a component that's called the monitoring group and so we have our own monitors that go out to all the sites where our studies are being conducted and they monitor the studies for us.

Let's talk about protocol design. How do you design clinical trials for pediatric cancer, each of which is a rare disease?

There's no one answer to that. You have to know the disease, what are the unanswered questions for that disease or condition, what data are available, and how you can use different trial designs to obtain answers to the questions. Now, as you know, from a regulatory perspective, the FDA considers as a gold standard to approve a new drug or treatment use of active control, randomized trials. But this is difficult in certain diseases, particularly rare diseases, like pediatric cancer where that may not be always possible. You may have a non-randomized phase two trial, with well-defined end points, and with good historical data, that provides a mechanism for potential approval of that particular drug without having to do a randomized phase three trial.

At St. Jude, because we tend to be [obsessive] about data collection, whenever we do a trial we have historical data we can always go back to as a comparative because we collect data fairly rigorously, and of good quality. We can do comparator trials that are historically controlled, not randomized with active controls. That's one option that we have because of the richness of the data we have here. In certain diseases, there are enough patients that we can do active control.

Here at St. Jude, we have been moving to a collaborative model. We may not have the 500 patients that we need to randomize, but if we do this trial with Memorial [Sloan Kettering Cancer Center], or with Cook, or with Stanford, or Seattle—between the five of us we can get 500 patients. It's not really design. It's more, how do you assure that that design can be realized? And that's through collaboration.

The third option is this new direction that we're moving. Now that we understand the molecular signatures, should we be doing smaller trials that are more defined to that genetic alteration, where you don't need 100 patients, you don't need 500. But you can prove [a molecular signature] with 50 patients, or 30 patients because it's so specific.

Do you ever have to go find patients that you want? If you're looking at a particular rare cancer, and you've got so few here you go find them?

Yep. A good example is melanoma. Melanoma is very rare in children—exceedingly rare. So we established a melanoma clinic here a couple of years ago. Any child who has melanoma, anywhere in the United States, can come here. It's so rare that that's the only way we could learn more about the disease and potentially develop trials and things like that.

How do you match patients who are already at St. Jude with trials? Who is making sure that the right patients are in the right trials, especially when it comes to non-therapeutic ones?

It's all based on eligibility. If you are eligible for a trial, you are offered that trial by a clinician.

It's so big, though. How do clinicians know who is eligible?

It is big compared to when I came here 34 years ago. But it's happening at the collaborative level. For example, there's the solid tumor program. So all the solid tumor physicians—which includes not only the oncologists but the surgeons, the radiotherapist, the psychologist, a representative from the survivorship clinic—we all get together every two weeks, and we talk about the protocols in development. Basically, the whole team knows what's happening and what's available here. Then, whenever there is a new protocol, the protocol office sends a blast: “We opened this new study.” Everybody gets copied on the notification that there is a new study and what the general criteria are for it. It's very transparent that everybody knows what is available. Similar information is also posted on our St. Jude website for external physicians and others to know what is available.

Can clinicians scan the patient population as they are planning to assess the feasibility of a protocol?

Yes. In that case, they won't have access to specific patient data. They'll have aggregate data. But they can go ahead and say, “How many kids do we have who are four years old, in the last 10 years, who had a neuroblastoma, that was stage three, that was MYNC-amplified?” The database would say, “We have 50 of those.” So they already know, if they're going to design a trial with those type of patients, that potentially they could have 50 patients. That's more research planning.

Speaking of planning, what changes or shifts do you see in the industry that will impact clinical research at St. Jude?

One of the things that I think is going to be a challenge is that the FDA has come up with some new regulations based on the 2002 Best Pharmaceuticals for Children Act (BPCA) and 2003 Pediatric Research Equity Act (PREA). Now industry—pharma—is going to have some additional requirements when they develop drugs to look at those drugs in children. The relationships that pediatric centers have with pharma, I think, are going to have to evolve, because I view that more as a partnership now.

Second, the area of molecular targets and precision therapy, I think is an experiment in progress. I’m a clinician scientist, so I view things as an experiment. You have a hypothesis and you prove it or disprove it. The question is if you identify specific molecular targets, and you’re able to develop drugs for those targets, do they do what they’re supposed to do? Do you cure more people? In addition there maybe limitations and you may not be able to develop a drug for each one of those targets.

It’s not skepticism, it’s more scientific caution. If you apply the scientific methodology to this concept of targeted therapy, it’s an experiment. We’ve proven it in certain diseases, but we haven’t quite proven it in others.

Targeted medicine as a therapy can be interpreted this way: “ I’ve got this tumor that has a specific genetic alteration and a drug is available specific to that alteration. I'm going to be cured.” It’s not as simple as that. We have not yet proven that for the majority of cancers precision medicine has a role. We don’t know. The experiment is ongoing.

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