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Nature – Reflections on 10 years of the FDA’s breakthrough therapy designation

Nature – Reflections on 10 years of the FDA’s breakthrough therapy designation

Ellen Sigal, the founder of the patient advocacy group Friends of Cancer Research (FOCR), is a self-described accidental tourist in the world of drug discovery. After completing a PhD in Russian History and launching a career as a real estate developer, the death of her 40-year-old sister from breast cancer forced her to confront medicine’s shortcomings. “It was extraordinarily traumatic,” says Sigal. To spare others from the same grief, she has been amplifying the patient voice ever since.

This work helped to enable the creation of the FDA’s Breakthrough Therapy designation (BTD), a mechanism to provide additional regulatory support to drugs that may provide “substantial improvements” to patients. The need for such a pathway was initially raised by the FDA’s Janet Woodcock and Rick Pazdur, says Sigal, and got a first public airing in 2011 at a joint meeting organized by the FOCR and the Brookings Institution, a think tank. In 2012, BTD was enacted into law.

BTD advocates initially thought 1–2 drugs would qualify per year. A decade on, the FDA has granted BTD to 470 candidates. 240 of these have been approved (Fig. 1). “I’m very, very proud of this,” says Sigal. “It took a village,” she adds.

Others have concerns. Do these drugs deliver the magnitude of clinical benefit the BTD name promises? What is the impact of the regulatory pathway on drug development programmes and clinical evidence collection? Is widespread use of BTD the best use of limited regulatory resources?

The programme is still evolving, concedes Sigal. But by codifying the need for speed, BTD has accelerated a culture change at the FDA that benefits patients, she argues. “I don’t think it’s perfect, but it’s a vast improvement over what we had,” says Sigal.

What were your plans when you founded FOCR in 1996?

When the National Cancer Act turned 25, Rick Klausner, who was then the extraordinary director of the NCI, wanted to do something to mark that anniversary. He’s one of these amazing people who wants to do everything. I asked him where he really wanted to focus, and he said the importance of research. So I formed a non-profit dedicated to highlighting the importance of cancer research.

The formula that I developed was very different to what was around at the time. We did advocacy work, around the country, meeting with members of Congress where patients were being treated to highlight the value of the NCI’s research. We wanted to show Congress that this money does not stay in Washington; it gets distributed to constituents around the country.

I thought we’d do this for 1 year. But I realized that this was my calling. This is what I really need to do.

When did you pivot to regulatory reform?

We did this work for 8 years, and I think we were successful in raising awareness. But I couldn’t really measure exactly the impact we were having. I was about ready to close down FOCR, but Rick Klausner asked me to look into the state of phase I clinical trials in community cancer settings.

At that time, the advocacy community really didn’t know the FDA. It was a black box to us. We knew that we didn’t like it, but we didn’t exactly know why we didn’t like it. So I studied — with colleagues at ASCO and the AACR and elsewhere — the regulatory environment and how approvals were made. And we came to understand that substantial changes were needed. We wrote a letter, along with 20 to 30 other organizations, to the FDA suggesting that there be a dedicated Cancer Center with a more integrated approach. Ultimately, this led to the Office of Oncology Drug Products [later re-organized and renamed the Office of Oncologic Diseases].

The regulatory environment became very interesting to me, to think about enhancing the organizational structure to be fit for the innovation that we knew was coming.

And from there to BTD?

Jeff Allen became Executive Director of FOCR, because I knew that if I really wanted to continue along this path I needed to bring serious science. And we decided to team up with [former FDA commissioner] Mark McClellan, who was then at the Brookings Institution, to convene meetings on regulatory policies, with the purpose of solid outcomes. We worked with various groups, including the FDA, to figure out where to focus our efforts.

The breakthrough designation idea came from Janet Woodcock and Rick Pazdur. We were preparing for our annual 2011 meeting, and we asked Janet and Rick what was on their minds. They said, “well, what do you think we should do with applications that show substantial activity?”

It seemed to me like a pretty easy question, but it turned out to be really complicated. We convened the experts for a panel, and nobody agreed on anything. What is evidence? How do you define substantial? What indication is it in? We published a White Paper on this panel session. It was an okay paper. It wasn’t great. But we realized we could take it to the hill. A lot of crazy proposals were being circulated at that time in the preparation for PDUFA V [the law that enables the FDA to collect user fees from drug manufacturers, as long as the agency meets agreed-on performance benchmarks and regulatory goals]. We thought this was a pretty substantial proposal.

Believe it or not, some of the early opposition was from pharma. They just wanted a clean PDUFA. It wasn’t clear or obvious to them in those days what BTD was. So we had some work to do. But it was enacted in 2012.

10 years on, the FDA has approved BTD drugs for over 240 indications. What do you make of this?

When we proposed this designation, we didn’t really know what to expect. I testified before Congress that we were expecting there would be maybe 2 drugs per year that would be eligible. We assumed they would be for cancer. We didn’t understand what a transformational change it could be for the culture at the FDA. It became statute that they would work together — all hands on deck — to support the development of the most promising drugs.

It’s been an incredible success.

What about concerns that many BTD drugs don’t provide breakthrough efficacy, or that in many cases use of BTD has not impacted a drug’s development path?

It depends in part on how you want to really define magnitude of benefit. Certainly in some cases there are patients that are living longer and have better quality of life. Specifically in lung cancer, data show that drugs with a BTD have greater clinical benefit, offering increased overall survival, than those without. And although not everything is as transformative as the checkpoint inhibitors in melanoma, many BTD drugs are making differences in patient’s lives.

You also have to look at the different indications.

Another thing is that early on everyone submitted whatever drugs they had for breakthrough designation. And in some cases these drugs were ready for approval anyway. Now, I think that people are going earlier with more evidence. And obviously, the earlier the better. I think the design of the trials will change as a result. They still won’t always pan out, but the issue is what is the right way to show that a promising drug has substantial benefit?

Another concern is that overuse of BTD will strain the FDA’s limited budget.

Well, I think that’s legitimate. More resources are needed.

Certainly in the beginning every company thought everything was a breakthrough, just like everyone thinks that they have a brilliant child. There wasn’t any real definition of what really constitutes a breakthrough other than “substantial early activity”. But I think the FDA has become more selective about what they consider to be suitable for BTD.

BTD requests have also slowed since 2019, though this could be due to COVID-19. If you were starting again, would you be more restrictive in your definition of breakthrough?

It is hard to define specifically what a breakthrough is. But it has changed, and I do think that it will continue and should continue to change. And I do think the initial intent — to change FDA culture — was still important.

I think there is now a good cadence, there is a compelling need for the designation, and we have to be realistic about the expectations. Not everything is a breakthrough and not every big breakthrough is going to cure cancer.

How has the broader patient advocacy landscape changed over the past 25 years, since you launched FOCR?

It has completely changed. The patient voice used to be about funding and research. We’ve seen it transform. There are so many groups out there that have changed the course of the treatment for their disease. Patient groups are highly sophisticated, they want a seat at the table, they are educated, and they are science-oriented. They want drug developers to pay attention to the right things.

I could not imagine this current landscape 25 years ago.

COVID-19 has been a strong reminder that we are all potential patients, and that we don’t always want the same things. What does that mean for patient advocacy and for drug developers?

You are right. I mean, look at breast cancer, there are probably 50 to 100 patient advocacy groups for just that disease. Everyone can start their own group. But there has been a lot of research into the patient voice and what patients want. And it’s very clear, they want to know: will this drug help me? What are my choices? What will this mean for me?

I always tell the scientists that if we don’t hear the voice of the patient, our work is not meaningful.