In a commentary published in The Lancet Oncology, Harpreet Singh, MD, and Richard Pazdur, MD, both of the Oncology Center of Excellence at the U.S. Food and Drug Administration (FDA), warned against the increasing number of oncology drug development programs based wholly or predominantly on data from China aimed at seeking approvals for use in the United States.
Their case in point was the ORIENT-11 trial, which was discussed by the FDA's Oncologic Drugs Advisory Committee on February 10 (see below). The trial compared chemotherapy plus the PD-1 inhibitor sintilimab vs chemotherapy alone in the initial treatment of metastatic non–small cell lung cancer (NSCLC) in an exclusively Chinese population; the Committee voted 14 to 1 that additional clinical trial(s) should be required to demonstrate applicability to the U.S. population and U.S. medical practice prior to a final regulatory decision.
Harpreet Singh, MD
Richard Pazdur, MD
The design, patient population, and statistical analysis of the trial closely resemble landmark NSCLC trials that established checkpoint inhibitors as part of initial treatment regimens in the United States several years ago. The authors noted that this trial is not an isolated case, noting that there are at least 25 applications from China in drug development phases planned to be submitted or that are currently under review by the FDA.
Generalizability to U.S. Population
The authors observed that the ORIENT-11 trial raises questions regarding the use of data from a single foreign country to support U.S. approval and their generalizability to the U.S. population. Asian countries have been historically underrepresented in multiregional clinical trials performed to support U.S. applications, with differences in intrinsic factors (eg, genetic and physiologic variables, including polymorphisms; lean body mass; organ dysfunction; differences in causes; histologically and molecularly defined disease subtypes; and known determinants of response to therapy) and extrinsic factors (eg, medical practice; available therapies, including supportive care medications as well as subsequent oncologic treatments; social and cultural determinants [such as diet]; and concomitant herbal medications), posing problems for generalizability to the U.S. population.
In the case of China, there is also the fact that many current applications are similar to previous multiregional clinical trials that led to U.S. approval and therefore do not fulfill an unmet need. Most of the drugs involved are checkpoint inhibitor antibodies; China’s Centre for Drug Evaluation cites more than 100 investigational new drug applications for this class.
As stated by the authors, “The degree of regulatory flexibility in establishing the acceptability of data from a single country and its generalizability to a new population should be balanced against the drug’s innovation.”
Call for Increased Reliance on Multiregional Clinical Trials
An antidote to the influx of applications based on trials in single countries may come in the form of the 2017 International Council for Harmonisation guidance document E17, which, building upon earlier guidance, reflects emerging consensus that trials requiring international collaboration are preferred over single-country trials. Multiregional clinical trials can support more efficient drug development, avoid duplication, allow earlier access to innovation, enhance infrastructure development, and establish new standards of care earlier that might affect subsequent drug development. E17 states that specific country concerns regarding intrinsic and extrinsic factors should be addressed preferentially in an exploratory phase before performance of multiregional clinical trials.
The authors further pointed out that many sponsors seeking U.S. registration based solely on data from China have not sought regulatory advice from established FDA milestone meetings. Trials in China have used comparators that are not representative of the current U.S. standard of care and would have difficulty in enrolling patients where advances have been approved and widely accepted by practitioners.
As stated by the authors, “Frequently, these advances have not yet been approved in China at the time of trial initiation; however, they might subsequently be approved during the trial’s enrollment. The [FDA’s] Oncology Center of Excellence’s Project Orbis, which allows for concurrent regulatory submissions to multiple nations, could assist in addressing this delay.”
The authors concluded, “The true bridge over so-called troubled waters for global drug development and regulatory harmonization will be multiregional clinical trials rather than single-country trials. Multiregional clinical trials can be strengthened by providing support and welcoming countries, such as those in Africa and Latin America, currently underrepresented in oncology multiregional clinical trials. This greater diversity might provide additional information to assist the U.S. in addressing the underrepresentation of racial and ethnic minorities in drug development. Participation of a greater number of countries in multiregional clinical trials will provide a framework to establish experience and trust in the evidence supporting applications and might create a long-lasting bridge between patients, health-care professionals, and regulatory agencies of different nations in expediting future advances.”
Commentary at the February 10 ODAC Meeting
In a briefing document released in light of the February 10 ODAC meeting focused on the biologics license application for sintilimab, the FDA briefed panel members by pointing out:
“The application is reflective of an increasing number of oncology development programs based solely or predominantly on clinical data from China. The applicant did not consult with the FDA regarding trial design or conduct, including selection of endpoint and control arm. This single-country trial closely resembles multiregional clinical trials in NSCLC that led to FDA approval prior to study initiation. The patient population in ORIENT-11, as a single-country trial, does not reflect the diversity of the American population, with both known and unknown differences in intrinsic and extrinsic factors. Acceptance of single-country foreign data that does not reflect the diversity of a U.S. population challenges the widespread industry commitment to patient equity and inclusion of underrepresented populations. While clinical site inspections may be performed, they cannot fully capture the heterogeneity of data quality and study conduct across numerous clinical sites.
"Investigators in ORIENT-11 have had limited prior interactions with the FDA and an unknown level of prior participation in multiregional clinical trials that led to FDA approvals. Importantly, the extent of past participation in multiregional clinical trials may provide added confidence in trial conduct and data integrity. The NSCLC treatment landscape includes many front-line immunotherapy options conferring advantages in overall survival, whereas ORIENT-11 was powered for progression-free survival….
“Sintilimab does not fulfill an unmet need for U.S. patients with NSCLC, limiting the degree of regulatory flexibility that is warranted regarding the acceptability of this data to support FDA approval.
“Rather than pursue a large number of duplicative development programs exclusively in China, patients in China should be participants in multiregional clinical trials. Multiregional clinical trials should be strategically conducted with global participation to ensure broad access for all patients in all regions of the world.”