Mark Ratain’s First Opinion piece of Feb. 4, 2025, implies that the oncologists in NCI’s Investigational Drug Branch (IDB) colluded with the drug company Exelixis to sponsor two Phase 3 studies of its drug cabozantinib. He claims these studies showed minimal benefit, yet the results were used to inflate the value of Exelixis stock. Ratain concludes by recommending that IDB be abolished.
The claims about the studies’ impact are incorrect, and the suggestion that Exelixis and NCI colluded to manipulated Exelixis stock price is patently false. Ratain misrepresented how these studies originated, argued for his retrospective judgment over the contemporaneous judgment of expert oncologists, misstated the results of both trials, and made a recommendation that ignores the history and value of the programs that IDB supports.
First, let’s clarify how NCI partners with drug companies to develop drugs in the public interest. A special review panel of external drug development experts, not NCI staff, selects the novel agent that becomes the focus of a public-private partnership with the NCI. Once an agent is selected, NCI develops research agreements with drug companies and becomes the Investigational New Drug (IND) sponsor for these agents in the trials that it funds, for the purpose of enabling promising clinical studies that are in the public interest and that would not otherwise be supported by the pharmaceutical industry. NCI runs its IND trials through its grant-funded networks that have sites throughout the United States and Canada.
Second, NCI-sponsored Phase 3 studies, such as CABOSUN and CABINET, are developed not by NCI staff but by oncologists working in NCI-funded clinical trial networks. Both CABOSUN and CABINET were developed by the Alliance for Clinical Trials in Oncology, which is part of the NCI’s National Clinical Trials Network (NCTN). Both CABOSUN and CABINET trials were considered by the extramural alliance investigators — academic oncologists who specialize in the care of these patients in our communities — to address the most important questions for these malignancies at that point in time. NCI helped to facilitate the wishes of these expert oncologists to test cabozantinib in these clinical settings by sponsoring both Phase 3 studies, funding the studies through the NCTN, securing the agents for these trials through its IND program, and using IDB medical officers to monitor the trials for safety.
Third, Ratain misstates both the design and outcomes of both the CABOSUN and CABINET studies. The bottom line is that both studies have led to FDA approval of new therapies for patients with renal cell carcinoma and neuroendocrine tumors, because these studies demonstrated that the therapies resulted in clinically important benefit, including quality of life and progression free survival for these patients.
Let’s also clarify the relation of pharmaceutical companies and NCI in the NCI-IND program. All drugs are owned and distributed by nongovernment entities; almost all are for-profit. Of course, companies develop drugs to create new markets for their products, and they all try to maximize their shareholder profit. When a Phase 3 study incorporating a new agent is successful, it simultaneously achieves its scientific objective by establishing a new and improved standard-of-care for patients, and it also increases the value of a company’s asset. However, this is not an argument that NCI should stop collaborating with industry to develop agents in indications that would not be pursued with industry resources alone.
In fact, the NCI-IND program helps to alleviate real conflicts between a pharmaceutical company’s profit motives and the public good. For example, a proposed clinical study may help to establish a new standard of care for a rare tumor (such as the neuroendocrine tumors studied in the CABINET trial) but does not have a favorable return-on-investment for a pharmaceutical company. A company may be willing to invest in clinical trials that could create a large customer base, but might not spend the same amount of money for developing an indication in a rare tumor, where the potential market may be one-tenth or even one-hundredth the size. These types of conflicts are one reason why NCI has, for decades, developed drugs in collaboration with industry with the NCI-IND program. The trusted NCI-IND platform also provides a safe haven for collaboration between pharmaceutical companies to conduct early phase drug combination studies.
Contrary to the impression left by Ratain’s article, the primary role of IDB in the CABOSUN and CABINET trials was to monitor them for safety. IDB medical officers act as liaisons between NCI and its industry partners. In NCTN trials where NCI is the IND sponsor, IDB medical officers are the medically responsible physicians who monitor the adverse events that occur on study, ensuring the trial’s safety. IDB medical officers were not co-investigators on these protocols and were not authors of their reports.
It was therefore very sad to read the conclusion of Ratain’s article, with his recommendation to abolish IDB and replace it with an entity that would study optimal drug dosing, an important issue that Ratain has championed for years. It is unfortunate because our society is already in the midst of so many assaults on trusted institutions by individuals using misinformation to advance personal agendas. One can only counter these assaults with the truth. In this case, the truth is that NCI’s historic IND program has been a successful public-private partnership and remains a trusted platform for collaboration between NCI, pharmaceutical companies and academic oncologists. This program provides a mechanism for cancer drug development that is in the public interest and that would not be performed with industry resources alone. The drugs that enter the NCI-IND program and large-scale NCI Phase 3 trials are reviewed and prioritized by academic oncologists and scientists who are experts in their fields. Both CABOSUN and CABINET trials helped to establish beneficial new therapies for cancer patients. The medical officers in IDB support the NCI-IND program by facilitating the collaboration — not collusion — between NCI, industry partners and extramural investigators for the public good.
Jeffrey A. Moscow, M.D., was formerly chief of the Investigational Drug Branch, NCI. He retired from federal service in 2023.
Correction: An earlier version of this letter misspelled Exelixis and cabozantinib. It also has been corrected to more accurately describe CABOSUN and CABINET trial outcomes
