A Virtuous Cycle Is Fueling the Engine of Cancer Research

Norman E. Sharpless

Abstract

Optimism and excitement are invigorating the cancer research field, making it the most exciting area of biomedical research today. Long-term commitment to basic science is paying off with a much-improved understanding of cancer biology and new approaches to treatment. The engine of cancer research is working extremely well and benefiting from a virtuous cycle. This paper considers how this cycle came to be and what can be done to facilitate similar successes in other, non-cancer areas of drug discovery.

Throughout my career as an academic in oncology and an advisor to the biotechnology industry, I was involved in the development of drugs. Subsequently in 2019, as Acting Commissioner of the United States Food and Drug Administration (FDA), I oversaw the regulation of drugs and devices. Currently, I serve as director of the National Cancer Institute (NCI), which annually funds billions of dollars of cancer research, including development of new therapies. As singer-songwriter Joni Mitchell might say, “I’ve looked at drug discovery from both sides now.” From my perspective, cancer is the most exciting area of biomedical research today. The engine of cancer research is working well and benefiting from a “virtuous cycle.” It is worth considering how this cycle came to be and what can be done to facilitate similar successes in other areas of drug discovery.

The National Cancer Act of 1971 Paved the Way

Much of the progress we have made in cancer is a result of programs and infrastructure enabled by the National Cancer Act (NCA) of 1971. The NCA was important because it brought hope to patients at a time when a diagnosis of “cancer” was something patients did not want to discuss. The NCA also provided additional funding to the NCI and created key infrastructure for cancer progress: the NCI-designated Cancer Centers Program; what is now the Frederick National Laboratory for Cancer Research; the nation’s cancer clinical trials networks; and the Surveillance, Epidemiology, and End Results (SEER) Program. The NCA created a national mission to address cancer suffering.

Fast forward to today, and one sees how that mission has led to optimism and excitement invigorating cancer research. Take, for example, the dramatic increase in new investigators entering the field. Since 2013, the NCI has witnessed a nearly 50% increase in the number of grant applications received yearly—an increase that is greater than that seen for the rest of the National Institutes of Health (NIH). Recent progress and a wide array of scientific opportunities have inspired young researchers to believe they can make a difference for patients. This influx of new talent and ideas is unquestionably good for cancer research. The scientific advances produced by this research influx have in turn led to a steadily declining mortality for patients with cancer, and the pace of that progress has accelerated in recent years.

One key finding that has made cancer progress possible has been an appreciation of the heterogeneity of cancer. There was a time when breast cancer was considered a single disease. Today we know that breast cancers are not all the same. There are distinct histologic and molecular subtypes of breast cancer, each with its own epidemiology and biology, each requiring different therapeutic approaches. This fractionation is present across all major cancer types and has fundamentally changed cancer science.

We have also learned that many cancers previously thought to be very different because they developed in different parts of the body have unsuspected molecular similarities and therefore can respond to similar treatments. This insight has led to the development of treatments that are indicated based on the molecular features of the cancer rather than the tissue of origin.

Modernization of Clinical Trials and More Drug Approvals

Our growing understanding of the molecular drivers of cancer also has implications for how we conduct clinical trials¹ and accelerates drug discovery. In the past, a typical randomized phase III treatment trial might have assigned hundreds or thousands of patients to slightly different therapies. Very minimal improvements in outcomes would have been considered a success. Today, we can discern a treatment’s effectiveness in a much smaller trial conducted in patients who share a particular genetic alteration. In the past few years, the FDA has approved a record number of cancer drugs, many of them for cancers that had previously been considered highly resistant to treatment, such as non-small cell lung cancer (NSCLC) and acute leukemia. A recent NCI analysis showed that mortality rates in NSCLC have been declining far more quickly than incidence rates because of new effective therapies.² In 2018 alone, eight new drugs for acute leukemia were introduced, contrasting the previous 18 years, in which no novel agents were approved.³ I predict 2020 set a record for the number of approvals of new cancer therapeutics in a single year, despite the global pandemic.

FDA Regulatory Paradigm Shifts

It is my belief that an important factor fueling recent progress against cancer has been the FDA’s willingness to adapt regulatory approaches for cancer therapeutics as our understanding of cancer biology evolves.

One such adaptation is the advent of “tissue agnostic” drug approvals, that is, based on the tumor’s molecular biology rather than its tissue of origin. Another is implementation of expedited programs that provide greater flexibility with regard to the data provided to demonstrate a drug’s safety and efficacy.⁴ These pathways have allowed for approval based on results from much smaller clinical trials than traditionally needed for approval. In addition, the FDA has begun using “real world evidence” as required by the 21st Century Cures Act to approve cancer drugs and devices based on outcomes outside of the traditional clinical trial setting.

A Virtuous Cycle

These developments have created a virtuous cycle. In other words, insights from basic science drive enthusiasm, innovation, and rapid advances in therapeutics. That progress allows for a more flexible regulatory posture toward cancer therapies, which, in turn, fuels further interest and investment in oncology by industry.⁴ Revenues from the sales of approved cancer drugs are then directed, in part, back into translational cancer research. Drug company investments complement federal investment, continuing the cycle of discovery to ultimately improve outcomes for people with cancer.

Reflecting on Progress in Cancer to Learn Lessons in Other Diseases

We still have a long way to go in defeating cancer, but not because we have failed. Rather, it is because cancer is a far more complex problem than was understood fifty years ago. The 50th anniversary of the National Cancer Act in 2021 is an important opportunity to reflect on our progress as well as on the long road still ahead. We must continue to ignite enthusiasm and sustain investment in cancer research to continue the virtuous cycle of research and progress.

The tremendous pace of advances in cancer research is absent from many other disease areas where progress over the last two decades has been more limited. I think the recent success of cancer progress offers a few lessons: first, we must focus on the foundational science. Large clinical trials that cost tens of millions of dollars and many years to complete are wasteful if not underpinned by solid basic science. Second, we must embrace the complexity that human biology presents. Cancer is not unique among human diseases in its heterogeneity. Other disease areas also exhibit tremendous variation, which may be unexplored or underappreciated. Finally, regulatory flexibility is essential to encourage industry participation.

To this last point, we should consider the effects of regulatory standards on drug discovery. Regulatory standards that are too low will hurt patients by allowing ineffective or unsafe drugs onto the market; we need not try too hard to think of such examples from the past. However, overly burdensome regulatory standards also stand to harm patients by slowing research and development. Without prospects for success, the virtuous cycle of drug discovery that includes resources from industry will slow or fail to start.

There are data purists who resist accepting less robust clinical evidence to support regulatory decisions, and many of them have complained about lower standards in the oncology space. They may not appreciate how these demands for “the perfect over the good” hurt patients. On the other hand, patient advocacy groups most certainly understand this risk as the cancer and HIV fields learned in the late 20th century.

Across other disease areas, the power of advocacy is just starting to be felt. As an example, when I was at the FDA, we significantly altered the regulatory guidance for trials in amyotrophic lateral sclerosis (ALS) to reflect a better scientific understanding of the disease but also in response to strong advocacy from the ALS community.⁴ The new guidance provided increased clinical trial flexibility for industry and will accelerate progress against this fatal neurologic disorder.

Striking progress against cancer in recent decades demonstrates how scientific understanding, industry investment, and regulatory flexibility can create the conditions for a virtuous cycle to continue fueling the engine of biomedical research. Herein lies a valuable model for the larger research enterprise seeking to accelerate progress in non-cancer fields.

About the Author

Norman E. Sharpless, M.D., has been director of the National Cancer Institute (NCI) since October 2017. Prior to this, he was director of the Lineberger Comprehensive Cancer. He served as Acting Commissioner for Food and Drugs at the U.S. Food and Drug Administration for 7 months in 2019, before returning to NCI.

References

1. Sharpless NE, Doroshow JH. Modernizing Clinical Trials for Patients With Cancer. JAMA. 2019;321(5):447-448.
2. Howlader N, Forjaz, G, Mooradian MJ, et al. The Effect of Advances in Lung-Cancer Treatment on Population Mortality. NEJM. 2020;383:640-649.
3. Lai, C., Doucette, K. & Norsworthy, K. Recent drug approvals for acute myeloid leukemia. J Hematol Oncol 12, 100 (2019). https://doi.org/10.1186/s13045-019-0774-x
4. Sharpless, N, Woodcock, J, Marks, P. Statement on final guidance to help advance development of novel treatments for ALS. U.S Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/statement-final-guidance-help-advance-development-novel-treatments-als. Published 23 September 2019. Accessed 7 December 2020.