Ellen Sigal: Pragmatica-Lung may be a model for other trials that are unnecessarily complex

The Pragmatica-Lung trial required many people to start to think differently about conducting phase III clinical trials—and it took a lot of advocacy to make the trial launch quickly, said Ellen Sigal, founder and chair of Friends of Cancer Research.

“Given the amount of existing data, it doesn’t have to be a trial that asks 20 questions,” Sigal said to The Cancer Letter. “Here we have one question and one question only: Will survival hold up?” 

Roughly seven months will have elapsed between June, when the innovative approach at the heart of Pragmatica-Lung started to evolve, and next January, when enrollment is expected to begin.

Pragmatica-Lung is a phase III trial designed to assess overall survival for ramucirumab plus pembrolizumab in patients with non-small cell lung cancer who were previously treated with immune checkpoint inhibitors and chemotherapy and had progressive disease at least 12 weeks after initiation of checkpoint inhibitor therapy.

The phase II results, published in June, showed a 31% reduction in the hazard of death in the treatment arm compared to standard of care.

How does Pragmatica-Lung differ from all other phase III trials?

In Pragmatica-Lung, FDA is primarily interested in overall survival, according to Richard Pazdur, director of the agency’s Oncology Center of Excellence, and Harpreet Singh, director of the Division of Oncology 2 in the Office of Oncology Diseases. 

“Rick was explaining what he wanted to do, alongside NCI leadership, Lung-MAP leaders and the original trial PIs—and it was met with enormous enthusiasm,” Sigal said. “The companies were also enthusiastic to move ahead with this novel approach and help design an optimal way forward.

“Enthusiasm! I had to say, ‘What? I’ve never been on a call where so many people agree and want to do things differently.’”

Without agreement from all stakeholders involved, the trial would likely have taken at least two years to launch. 

Sigal and Friends played an essential role in building support for the pragmatic trial and in accelerating the process, insiders say.

“You cannot do these things without people who genuinely believe and are willing to push the system and change the system, and this started with Rick and Harpreet,” Sigal said. “We don’t need to wait a long time. Patients are waiting for answers.”

Sigal spoke with Matthew Ong, associate editor of The Cancer Letter.

Matthew Ong: First of all, congratulations on bringing everyone back in-person for your annual meeting. You’ve kicked off the conversation on pragmatic trials. The idea isn’t new, but why is this the perfect time to get moving on it?

Ellen Sigal: Thank you. It was a real thrill to be able to have the annual meeting back in person. 

I’m proud that we were able to keep important projects moving ahead throughout the pandemic without missing a beat, but being back in-person with so many friends and colleagues was terrific. You could feel an energy in the room.

With regards to pragmatic trials, I think we’re at a point where creativity and thoughtfulness needs to span the continuum of drug development. Doing things the way we’ve always done them brings familiarity, but it doesn’t mean it’s the best, most appropriate, or most efficient approach.

We have a specific case in the Lung-MAP clinical trial where we already have a lot of information about two drugs being studied, but we need to find out quickly whether the initial overall survival signal from the phase II can be confirmed when used in combination. 

We don’t need to wait a long time. Patients are waiting for answers.

In this case, given the amount of existing data, it doesn’t have to be a trial that asks 20 questions. Here we have one question and one question only: Will survival hold up?

And if it does, it’s going to be incredibly important for patients and importantly, in the future, this may be a model for other trials that are unnecessarily complex.

I know how you’ve been central to this effort, but I would very much like to get your account of the chronology of events here. What did it take for you to make this work?

ES: A lot, because it requires changing culture. It started with Rick [Pazdur] and Harpreet [Singh] calling me about this trial. 

They wanted to do a fast, pragmatic trial, with a randomized design to measure the key outcome of survival yet explore this in a more representative population by broadening eligibility criteria and making it easier for sites to participate. 

Roy Herbst [Ensign Professor of Medicine, professor of pharmacology, and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital] was essential in this.

And I was excited, but it seemed like a challenge, because things can move slowly in the academic world, so it would require a change in the way we do things and a change in culture to do this in an appropriate time.

There were a lot of parties that needed to be okay with it. The National Cancer Institute, the cooperative groups, with SWOG in particular as the lead group, and FDA were on board, but there were a lot of issues, a lot of people that had to believe in it and move quickly and differently. 

So, it wasn’t necessarily a done deal that this was going to happen.

After I heard from Rick and Harpreet, who were essential, I spoke to [NCI Deputy Director] Jim Doroshow and [NCI Principal Deputy Director] Doug Lowy—[NCI Director] Monica [Bertagnolli] was not there at the time—and they were incredibly excited. 

Rick was explaining what he wanted to do, alongside NCI leadership, Lung-MAP leaders and the original trial PIs—and it was met with enormous enthusiasm. 

The companies were also enthusiastic to move ahead with this novel approach and help design an optimal way forward.

Enthusiasm! I had to say, “What? I’ve never been on a call where so many people agree and want to do things differently.” 

It was just kind of, I’m used to: “Well, this doesn’t work;” “I need to do this or that, and we can’t move that quickly.” 

There’s all sorts of excuses or reasons.

This time it was different. And my plea was to get it done quickly, to not look at process, but look at outcome, look at the ability to do things that were going to be important for patients rapidly.

And it is my belief that this may be a model to inform the conduct of some future similar trials. 

We don’t have to make them overly complicated. We have to get them into the community, lower the burden for patients and sites that may not normally participate in trials, and ultimately get the answer quickly.

ES: Well, my answer would be Yes, but it will likely be case-dependent. 

Multiple stakeholders have to be enthusiastic about it. You have to understand the data FDA will require and what they’re going to be looking for. 

This one was greeted with great enthusiasm, and it started with FDA. So, you have to make sure they’re comfortable. You have to make sure the NCI and the groups and the companies agree that this is the best approach for the study question at hand.

So, you have lots of moving parts that have to work together to get these things done. And in this case, we were very fortunate, the study leadership, cooperative groups, NCI, FDA, Merck and Eli Lilly were all enthusiastic.

You really need to have people who care deeply. If you’re going to allow the normal system to operate the way it normally does, it’s very difficult. 

You have to have people who are uniquely behind this and are advocates.

Can we anticipate that FDA would publish a guidance on pragmatic trials anytime soon? Or are we waiting for Pragmatica-Lung to become proof of concept?

ES: Well, I don’t know. 

I know that Rick and Harpreet thought this was ideal. I think they call this Pragmatic-Lung because they want to do it in other cancer types, and each trial is different with its own set of circumstances and behavior and questions. So, I would hope so.

I think all trials can be unnecessarily burdensome and the origins can be a reflex assumption that FDA wants more and more data, so companies want to make sure they answer every question, and clinical researchers want to make sure that they answer questions, and on and on and on.

At some point, we have to think about what’s important for the patient. What questions need to be answered and how can we collectively design and implement trials that are able to get those answers as quickly as possible? 

So, everybody has to understand just in general, Pragmatica is different and it’s unique and I hope we can do more to simplify trials like this. But I just think in general, a re-look at the way we do trials is in order.

I’ve been pushing this for a long time and I know [FDA Principal Deputy Commissioner] Janet Woodcock has always said we have to get into the community, we have to train people, support the sites, and we have to design simpler trials.

So, I do think that our trials are overly burdensome and we have to really think a little bit about how we can do them not necessarily just like Pragmatica, but find creative and efficient designs to answer vital questions in a reasonable timeframe.

Did anyone get nervous initially at the idea of limiting the primary analysis to overall survival and limiting subgroup analyses, etc.? I can imagine why, but could you describe the thought process?

ES: I think it’s natural to want to maximize the data coming out of any clinical trial and ask more questions. 

Should we do PFS? Should we have PROs? 

All those things, but in this case, these weren’t the key metrics needed for the question at hand. We needed one thing in this trial—OS.

Let’s talk about the rollout for the trial and getting everyone—the investigators, FDA, patients—what they need. What’s next, and what do people need to know?

ES: First of all, we really need to make sure that this trial accrues. This is incredibly important. 

Monica, of course, now is at NCI, and she’s solidly behind that. She was aware of this early on, and I think has been a great ally to make sure we can activate trial quickly.

But I think what is really important is to gain broad participation of sites for the trial, to accrue to the trial, and to make sure that this model can work, because we really need to get these simpler trials done.

Did we miss anything?

ES: I think the most important part of it is not only is this a new way of doing things, you need advocates. 

You cannot do these things without people who genuinely believe and are willing to push the system and change the system, and this started with Rick and Harpreet.

But I will say that we did get a lot of enthusiasm from the people at NCI, and then Monica, and the companies. And I think the cooperative groups also. 

It started with Lung-MAP, and is now an extension to be conducted as a SWOG trial. Their group chair, Charles Blanke, has been terrific. He’s enthusiastic, and wants to do this.

I think everybody got it. Everyone understood that this is different, and they want to do this. But I think if it went through the normal system, it might take two years. 

So, this is record time.

Thanks for taking the time to speak with me.

ES: Thank you.