Dr. Katherine Thornton
These issues were the topic of the June 6 Education Session “Drug Approval and Study Design: Regulatory Issues in the Drug-Approval Process for Sarcoma and Rare Disease.” The session featured three speakers bringing unique perspectives on U.S. and global drug regulation, the economics of drug development, and issues surrounding global health care policy.
This is an area that “too often falls to the wayside of drug development discussions,” said session chair Katherine Thornton, MD, of Dana-Farber Cancer Institute.
Regulatory Issues for Rare Disease Development
Dr. Thornton previously spent several years at the U.S. Food and Drug Administration (FDA), where she gained first-hand experience in the regulation of oncology drugs. She noted that there are many misconceptions and preconceived notions about the FDA and its drug approval process, and these can be detrimental to investigators, clinicians, and patients.
Dr. Thornton reviewed some of the common pitfalls in the drug development and approval process from a regulatory standpoint and informed attendees about resources available within the FDA to facilitate the pathway to drug approval for rare tumors. She explained that the Orphan Drug Act was signed into law in 1983 to promote the development of products that show promise for treatment of rare diseases, defined as those with a prevalence below 200,000 Americans. Although the act covers all disease types, oncology and hematology/immunology indications account for 43% of orphan drug designations.
Other laws and initiatives designed to refine the regulatory process include the FDA Modernization Act, signed in 1997, which led to the fast-track designation and accelerated approvals, and the development of priority reviews, which shorten the review time. In 2012, the FDA introduced the “breakthrough therapy” designation, which provides for intensive, real-time interaction with the FDA during the course of drug development as well as a high level of regulatory oversight.
Regardless of the regulatory path a drug takes, there are challenges investigators, regulators, and clinicians face regarding the approval and use of drugs in rare tumors. Dr. Thornton said that these challenges include the tension between providing access and adequately studying the drug, the practice of approving drugs based on small populations with short exposures, the need to weigh severe toxicities in the face of modest efficacy gains, and the decision to approve wide indications spanning a disease spectrum.
In the setting of clinical trials, Dr. Thornton commented that lack of dose optimization is an important issue. Although doses have historically been selected based on the maximum-tolerated dose, this may not be the most appropriate measure for non-cytotoxic drugs and may not align with the goals of treatment. Dr. Thornton suggested that dosing to modulate a target could be the gold standard for dosing, although this requires knowing, and having confidence in, the actual target.
Another issue in drug development relates to the distinction between drug activity and clinical benefit. Even if a drug shows statistically significant activity, this may not reflect a clinically relevant improvement, Dr. Thornton explained. Other challenges include registration trials not predicting real-world experience, the reliance on single-arm trials or on single trials, and the risk of overestimating the effect size of interim analyses. Finally, Dr. Thornton said that although subgroup analyses can be informative, they “should never be used to attempt to salvage a trial that has failed to meet its primary endpoint.”
Designing Clinical Trials for Rare Cancers
Antonio Tito Fojo, MD, PhD, of Columbia University, spoke about considerations for clinical trial design in rare cancers. Reviewing the three recent drug approvals in sarcoma, Dr. Fojo noted that for patients with metastatic soft tissue sarcoma, pazopanib received approval based on an improvement in progression-free survival (PFS) but not overall survival (OS). For patients with advanced liposarcoma or leiomyosarcoma, eribulin received approval based on a 2-month improvement in OS, but it showed no PFS benefit. Trabectedin was approved based on a PFS benefit.
Dr. Fojo added that although these therapies showed only marginal benefits, they were providing options for patients with few options. When considering the minimum trial design for cancer drug approvals, however, Dr. Fojo said that it is important not to “lower the bar,” as this can lead to marginal therapies rather than the development of more effective therapies that are really needed. However, acknowledging the difficulty in developing more effective therapies, he said, “realistically, then, what we need is guidance on what drugs to continue pursuing and how to pursue them.”
Dr. Antonio Tito Fojo
In 2015, ASCO defined clinically meaningful increases in OS in different cancer settings. These were generally OS increases of at least 3 or 4 months for most clinical scenarios. Dr. Fojo noted that recent sarcoma trials actually aimed for smaller OS improvements of 2.5 or 3.0 months and only met these lower goals in the eribulin trial. He cautioned against wasting resources by enrolling patients on trials evaluating “marginally effective therapies.”
To try to address these issues, Dr. Fojo and his colleagues undertook efforts to develop what he calls a more “resource-conscious” approach to drug development in rare cancers. The researchers developed a new way to analyze oncology trials based on rates of tumor growth and regression. He explained that the tool that they developed, “if not broadly applicable … should lead us to think about how we should go about this.” Dr. Fojo explained that benchmarking small datasets against established reference data sets allows calculation of tumor growth rates, which he said “can prove invaluable in guiding decision making.”
Subsequently, Dr. Fojo said, it is important to conduct the large trials needed to solidly determine efficacy; he concluded that international collaborative efforts can help make these trials a reality.
Global Health Care Policy and Drug Development
Richard Sullivan, MD, PhD, of Kings Health Partners Cancer Centre, London, discussed global health care policy as it relates to cancer drug development. Dr. Sullivan explained that around the world, there is “an extremely complex interface between cancer drug development and health care systems” that is affected by the political economy, regulatory and economic environments, history, and the structural of national health, education, and other systems.
Dr. Sullivan noted that what he called the “p-medicine drug development paradigm” is relatively new, having emerged in the past 15 years. Complex global patterns of cancer drug development research have arisen, with high-income countries focusing on breast, lung, colorectal, and hematologic cancers and emerging powers focusing on more rare cancers. Dr. Sullivan also described a rise in “nontraditional actors” around the world, in particular with regard to generics and repurposing of drugs.
Dr. Richard Sullivan
Despite their differences, one tenet that regulatory systems around the world have shown, Dr. Sullivan said, is a “greater willingness to embrace uncertainty in cancer drug development pipelines.” One challenge of this trend, he added, is a concomitant uncertainty about what constitutes clinically meaningful benefit and value.
In general, the changing nature of drug development and the various issues at play have created what Dr. Sullivan called “a complete disconnection between price, value, and health systems”; this has led to substantial heterogeneity in what countries spend for cancer medicines as a proportion of their budget.
Dr. Sullivan also discussed the effect of global structural and economic factors on cancer drug development. He explained that outside of high-income countries, there is a “massive shortfall” in health care funding that negatively affects both the ability to conduct drug development and to reap its benefits. Moreover, in an issue related to cancer care but aside from drug development, some countries have substantial deficits in their ability to effectively, safely, and affordably administer other key cancer treatment modalities such as surgery and radiation therapy. Without these other modalities in place, Dr. Sullivan said, cancer drug development becomes less important.
Finally, Dr. Sullivan said that equity and inequality make a difference for global cancer drug development. He added that economic downturns have been shown to have “enormous impacts” on cancer mortality in high- and middle-income countries. One strategy that has been shown to be protective against this effect, he explained, is universal health care coverage.
“Health care policy is changing rapidly,” Dr. Sullivan said, “and so too is cancer research.” He suggested that significant thought should be given to the design of cancer trials. “There is a very careful balance between how we design our trials and the speed at which we give marketing authorization to our medicines, and that balance needs to be adjusted,” he said. “Fast is not necessarily better.”