After nearly 5 years as Director of the National Cancer Institute (NCI), interrupted by 7 months as Acting Commissioner for the U.S. Food and Drug Administration (FDA), Norman E. “Ned” Sharpless, MD, left his position on April 29 to concentrate on his family and contemplate his next career choice. Douglas R. Lowy, MD, NCI’s Principal Deputy Director, was named Acting Director of the agency effective April 30, 2022. Sworn in as the 15th Director of the NCI on October 17, 2017, and later serving as Interim Director of the FDA in 2019 before returning to the NCI, Dr. Sharpless leaves behind a formidable legacy with the cancer agency.
Norman E. “Ned” Sharpless, MD
The NCI is the largest of the 27 institutes that make up the National Institutes of Health (NIH). During Dr. Sharpless’ tenure, the NCI budget grew substantially from $5.7 billion to $6.9 billion. He also developed and implemented important programs in data science, including the Childhood Cancer Data Initiative, which aims to increase the understanding of the molecular characteristics of pediatric cancers to advance precision oncology in this patient population and improve outcomes. He was also instrumental in modernizing cancer clinical trials to increase the understanding of tumor biology and the discovery of new types of cancer treatment, led the creation of the NCI’s Equity and Inclusion Program, and was Chair of the NIH Clinical Center Governing Board. But perhaps Dr. Sharpless’ greatest impact on the NCI was his push to increase NCI grant paylines from 8% to 11% over the past 3 years, with the goal of funding the top 15% of grant proposals by fiscal year 2026.
In a wide-ranging interview with The ASCO Post, Dr. Sharpless discussed his future professional goals; his accomplishments at the NCI and the challenges that remain for the next director; and his optimism that President Biden’s goal of reducing cancer deaths by 50% over the next 25 years is attainable and may even be surpassed.
Choosing the Right Time to Move on
You are leaving the NCI just as the Cancer Moonshot is reigniting and a new NIH agency, the Advanced Research Projects Agency for Health (ARPA-H), is being launched to speed biomedical and health research. Why did you choose to step down as Director this spring, and what are your future professional plans?
It felt like the right time. The past 5 years in government have been tumultuous. There was a chaotic transition from the prior administration, I had the stint as Acting Commissioner of the FDA, and we had a global pandemic—all of which have been very grinding. On a personal level, my wife and I have been living in different cities because of our careers, so there were also personal reasons why it felt like the right time to leave the agency.
Lastly, the NCI and the White House are beginning to plan for the massive, supercharged Cancer Moonshot and how the NCI is going to work with ARPA-H. Rather than work on these new initiatives for 6 months and get halfway down the road, now seemed like a good time to bring in a new director. However, please don’t misconstrue this to mean I’m not excited about these new initiatives. I fully support President Biden’s agenda, and his call to end cancer as we know it is galvanizing. I believe his goal of reducing cancer mortality by 50% in 25 years is bold but achievable.
I similarly think the creation of ARPA-H to improve the government’s ability to speed biomedical and health research is also very exciting, although it’s not exactly clear yet how the program will work. The NCI should work with ARPA-H to collaborate on advancing cancer science.
These initiatives are very exciting, and I hope there will be many people who will want to apply for this job. It is great to work for a president who is so committed to cancer research and to have the opportunity to lead these new initiatives. The job is awesome.
What is next for you? Do you have future professional plans in place?
I will take a bit of time off to focus on my family and to recharge. I see myself likely ending up working in academia and probably working with a small biotech company that addresses the unmet needs in the treatment of cancer the way I did before I came to work in the government.
Leaving Behind a Lasting Legacy
You have had many accomplishments during your 5-year tenure at the NCI, including growing the NCI budget from $5.7 million to $6.9 billion; developing important programs in data science to accelerate work across the cancer research enterprise; advancing the goals of the Cancer Moonshot Initiative, including work to modernize cancer clinical trials to improving the understanding of tumor biology and developing new types of cancer treatments; increasing the agency’s payline for RO1 grants from 8% to 11% in the past 3 years, with the goal of achieving the 15th percentile by FY2026; and championing health equity. What do you consider your greatest accomplishment at the NCI? What legacy would you like to leave behind?
The continued commitment to investigative-initiated science, which is the business of the grant paylines, has been in certain ways the most challenging of my time as Director of the NCI and perhaps the most important. There are a lot of people who are excited about cancer research and are passionate about progress, but they are frustrated with the NCI because it doesn’t spend more of its budget in a specific area, such as the launch of more clinical trials or on cross-cutting initiatives such as cancer centers. These areas are wonderful and important to fund and are high priorities at the NCI, but it is the group standing up for basic biologic investigation in science that really drives cancer progress, and it is not nearly as vocal. So, there is tension there, and it requires real effort for the NCI to continue to preserve that support.
“The one problem that keeps me up at night and that could make it difficult to reach the President’s goal is the obesity epidemic.”— Norman E. “Ned” Sharpless, MD
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Starting in 2013, and then picking up during the launch of the Cancer Moonshot in 2016–2017, we had an increase in grant applications on the order of 50%—more than the grant applications to the rest of the NIH combined. Many people were coming to the NCI with new ideas. Some successes, such as increasing the numbers of cancer discoveries and the basic biological understanding of cancer, have led to an impressive period in terms of new scientific ideas and innovations in cancer research, which all led to new grant applications. But even though we have been putting more money into the Research Project Grant (RPG) pool, which supports investigator-initiated grants, our paylines went down. They were as low as 8%, which is way too low, because we weren’t putting in new funds quickly enough to match the rate of increase in new applications.
We consciously decided that for cancer research to be sustainable and to attract young scientists, we had to bring grant paylines and success rates up. This year, we put about $200 million into the RPG pool just to pay the grants we have already awarded.
I hope the next NCI director will continue the goal of raising paylines, because even at the current rate of 11% for established investigators, it is too low for scientists to build a sustainable career. Our goal was to reach funding for the top 15% of proposals by 2025, but we are not going to achieve that goal; even though we had a robust increase in the total funding for the NCI this year, the aggregate costs of paylines are flat, so the new goal is to reach 15% by 2026. This is a good goal, especially with the initiation of the supercharged Cancer Moonshot. One of the first considerations of the Cancer Moonshot should be to prioritize investigator-initiated science, so NCI grant paylines could be more in line with the rest of the NIH.
Setting Priorities for Program Funding
The NCI is at a critical juncture for cancer research. What are the greatest challenges facing the agency and its new director?
The NCI is at a very exciting juncture. There are so many interesting studies going on in cancer research, and so much progress in a variety of areas, it will be a challenge for the new director to look at all the new opportunities and decide, given the NCI’s limited resources, which of them should be addressed first.
I thought it was important to fund investigator-initiated science in areas such as pancreatic cancer and small cell lung cancer. We also found significant new funding for data aggregation and data usage, which was a reaction to the spiraling costs of large, randomized, placebo-controlled clinical trials, which have been successful in advancing cancer medicine but are very expensive to launch.
The goal from this support of real-world data collection is to learn from every patient. One area of focus for these initiatives has been children with cancer, which is why we started the Childhood Cancer Data Initiative (CCDI). Through enhanced data-sharing, we can increase our understanding of cancer biology to improve treatment, quality of life, and survivorship in pediatric cancer. And those goals apply to adult oncology as well.
If we could solve the troublesome issues of data aggregation, data privacy, and data de-identification and combine real-world data to create virtual cohorts and synthetic controls, then we could learn how to treat patients more quickly, learn about the prognoses of subsets of patients, and learn about the epidemiology exposures and risk factors for cancer. However, data aggregation is quite expensive, and the next NCI director will have to decide how much more should be done in this space.
Any new director will be enthusiastic about the work of the CCDI, but what should be done in addition to that program or done differently? We recently announced a concept related to cellular immunotherapy. This is an area of cancer research where there is a lot of industry interest, but it hasn’t coalesced yet, because there are manufacturing and clinical trial issues, so it is still quite a difficult space.
The FDA has approved a few chimeric antigen receptor (CAR) T-cell therapies for hematologic malignancies (eg, directed by CD19 or B-cell maturation antigen). However, these successes have not yet led to the raft of products many of us envisioned, for example, in solid tumors.
“We will come to look at the past decade and the next decade as a Golden Age of cancer research and cancer progress. It is a terrific time to be a cancer scientist.”— Norman E. “Ned” Sharpless, MD
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The NCI would like to incentivize multisite clinical trials in which different institutions can participate in a national network to get past the single-institution experience in clinical trials for cellular immunotherapy. This is something I’ve wanted to do since I arrived at the NCI. We recently announced the first large funding initiative, the CAN-ACT Initiative. This initiative will create this multisite network for solid tumor cellular immunotherapy programs, which will be very helpful in accelerating progress in this important field.
The new NCI director will have a good problem in that the agency has great programs to fund and the support of President Biden, Congress, and the American public, because everyone wants to see progress in cancer. So, he or she will have many exciting funding opportunities to choose from, and setting priorities will be the challenge.
Reducing Cancer-Related Deaths
President Biden’s goal with the reinvigorated Cancer Moonshot is to cut the death rate from cancer by at least 50% over the next 25 years and improve the long-term quality of life for survivors. Despite tremendous improvements in cancer therapies over the past decade, and a continuing drop in the risk of dying of cancer, cancer is still the second most common cause of death in the United States, with nearly 610,000 people dying each year.1 How realistic is the President’s goal, and how will cancer-related deaths be reduced through more effective therapies and prevention strategies?
The President’s goal is very realistic. I strongly supported that goal to cut the age-adjusted death rate by at least 50% over the next 25 years. In fact, I think it could have been a bit more aggressive. If you look at the opportunities in cancer for increased progress, I believe we can do even better than cutting the death rate from cancer by 50% in 25 years. I really applaud the President for picking a hard metric and a measurable one rather than saying we can improve the patient experience or accelerate progress, or something more nebulous. This sort of clear-eyed thinking is incredibly useful.
I’m glad the administration picked a goal that is clear and meaningful. If we achieve that goal, it will result in a massive reduction in cancer suffering every year, and it would change the national experience with cancer. It would be a significant step toward the overarching goal of “ending cancer as we know it.”
What are the research opportunities for the NCI to fund to try to meet that mortality-reduction goal? I’m sure it won’t be achieved from any one area. It won’t be achieved from just a new therapy or prevention or screening strategy. It will require an all-modalities approach. A big part of that approach must include reducing the incidence of lethal cancers. Increased tobacco control measures is an example; they have had significant success over the past few decades, but we still have a long way to go to eliminate the major causes of cancer in the United States.
The one problem that keeps me up at night and that could make it difficult to reach the President’s goal is the obesity epidemic. Obesity-related cancers are increasing in incidence and mortality, especially gastric, pancreas, liver, and breast cancers, and early-onset colorectal cancer.
One product that could improve cancer mortality is the early detection liquid biopsy test. However, we do not know the accuracy of these tests yet, because the technology is so new and complicated, and it’s not clear which of these tests are accurate and for which types of cancer and patients. There is a lot of clinical research that needs to be done; for these tests to be meaningful, they need a mortality endpoint. It’s not enough to find more cancers. We must show they have a benefit to patients. This is a key area for the federal government to research. We can’t just leave this research up to industry, because the trials are too big and too difficult to do. Industry and the federal government, ideally the NCI, should partner on this research. This may also be a good opportunity for a partnership between industry and the new NIH agency, ARPA-H.
There should be a transgovernment approach to develop these technologies; they could be transformative, but they also have some risk. Overdiagnosis and overtreatment are almost built into screening tests, so we must make sure these new technologies can help patients in a way that doesn’t just find indolent cancers but that detects clinically important cancers, so they can be treated in an earlier, more curable stage.
I predict this will be a major focus of early detection clinical trial screening efforts over the next 10 years. The NCI is very excited about playing a role in these trials. However, we must make sure these tests do not displace screening modalities that we know work, including mammography and colonoscopy.
Funding the Science of Cancer Survivorship
It is expected that this year, there will be nearly 18 million cancer survivors in the United States. How focused is the NCI on long-term survivorship, financial toxicity from the high cost of treatments, and access to high-quality cancer care for all patients?
The science of cancer survivorship is still in development, and that is a really important area for the NCI to fund the clinical and basic research that will help us understand survivorship challenges, including the risk of second malignancy, late treatment-related toxicity, as well as the need for aggressive large surgeries and large radiation fields to treat cancer, because we would like to reduce the toxicity of cure.
You also bring up the issue of financial toxicity. This is an area the NCI has had a big interest in from a research point of view, including what causes financial toxicity, who is at risk for experiencing financial toxicity, and what are the outcomes associated with financial toxicity? The data show that a new cancer diagnosis, especially an advanced cancer diagnosis, is highly likely to cause financial toxicity, even for patients with good health insurance. And the effects can be devastating and may lead to suboptimal care of the disease and long-term stress, anxiety, and worsened outcome.
The NCI cannot address these problems on its own, but our mission is to provide the science that will allow other agencies, such as the Centers for Medicare & Medicaid Services, as well as private payers to institute policies and best practices that will be beneficial to patients.
Prioritizing Funding at the NCI
What advice do you have for the next NCI director?
There are a few areas I would advise the next NCI director to continue funding. They include the NCI Equity and Inclusion Program and the support for grant paylines.
The scientific community has heard that the NCI knows its paylines are too low and could do something about it. It would be tempting to give up on reaching the goal of funding the top 15% of proposals by 2026, because they cost so much money, and there are a lot of other programs that need funding. I would strongly recommend the new NCI director not do that, because funding 11% of proposals is just too low, and our field will suffer if we do not sustainably employ great cancer researchers.
I would also encourage the next NCI director to do the hard work to understand the workings of the Frederick National Laboratory for Cancer Research and the NIH’s Clinical Center—the nation’s largest hospital devoted entirely to clinical research.
I want to end on an optimistic note: We will come to look at the past decade and the next decade as a Golden Age of cancer research and cancer progress. We will see this period as one where we made transformative advances that changed the national experience of cancer and helped end cancer as we know it. We will look back on the early part of this century the way we look back on the early part of the past century and the development of antibiotics for infectious diseases. This is a great time in the field of oncology research. It is a terrific time to be a cancer scientist.
We can make a big impact on decreasing the number of deaths each year from cancer. The NCI wants to continue to lead in this transformative moment in our history.
DISCLOSURE: Dr. Sharpless reported no conflicts of interest.
1. American Cancer Society: Cancer Facts & Figures 2022. Available at www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html. Accessed June 16, 2022.