The Foreign Data Problem: Implications of the FDA’s New Criteria for Foreign Data Submissions

Articles

Aug. 31

The Foreign Data Problem: Implications of the FDA’s New Criteria for Foreign Data Submissions

As the push for innovation and differentiation in the oncology space intensifies, manufacturers continue to look to streamline data generation to augment R&D approaches. One strategy that has come into focus recently is the use of foreign clinical data submissions to support FDA approval. The increasing interest in the commercial potential of Asian markets will continue to lead to a significant amount of data in markets like China and Japan, and stakeholders are grappling for the most appropriate way to consider this data when launch in Western markets.

In 2021, Eli Lilly and Innovent’s PD-1 inhibitor, Tyvyt (sintilimab), sought approval from the FDA’s Oncologic Drugs Advisory Committee (ODAC) based on the ORIENT-11 clinical trial in metastatic non-small cell lung cancer (NSCLC). The published Phase III study, exclusively in a Chinese patient population, demonstrated significant improvements in overall survival (OS) benefit and has already been approved in China [1].

In anticipation of its review of sintilimab, the FDA released a briefing document focused on standards for single-country foreign data submitted to the regulatory agency for authorization in the US. The briefing outlined and established several new “requirements for use of foreign data as the sole basis for marketing approval” [2]:

The foreign data are applicable to the U.S. population and U.S. medical practice
The studies have been performed by clinical investigators of recognized competence
FDA is able to validate the data through an onsite inspection or other appropriate means

With these requirements in mind, the Committee voted 14-1 to reject the bid for approval in February of 2022, citing a need for additional clinical trials to verify translatability of the ORIENT-11 results to the US population [3]. Despite the negative outcome for sintilimab, the use of foreign trials continues to proliferate as a strategic approach for supporting earlier Western launch.

The interest in data generation and launch in these markets is clear – a large recruitment pool [3], eager study particpants [4], and significant commercial opportunity. Due to this, trials in these markets are often already being conducted as part of an earlier foreign launch (oftentimes in partnership with companies based in these markets) and can help establish longer-term clinical outcomes than what would otherwise be available in Western population at the time of FDA submission.

Despite this, concerns around transferability and reliability continue to slow the acceptance of this foreign data in Western populations. Decision-makers are faced with questions around how genetics, lifestyles, environments (living, working, etc.), and the homogeneity of populations impact how individuals, let alone entire subpopulations, react to treatment. Furthermore, data from China has historically been deemed unreliable not only by Western entities, but by Chinese regulators themselves, and continues to be perceived as such by many in the West despite the tightening of regulations and infrastructure surrounding the Chinese clinical trial landscape. A Chinese government-led investigation in 2016 found that over 80% of clinical trials within China had reliability issues [5,6]. These factors, coupled with an increasingly complex geopolitical landscape, have created a very challenging environment for industry leaders to navigate.

Windrose Take:

As companies become more adept at harnessing data tools and an increasingly global workforce, we expect that requests to consider foreign data, as a primary and/or a supplementary source, in regulatory submission to continue. This creates a number of key questions which stakeholders in Western markets (more than just regulators in the US) will need to contend with, including:

Will other major regulatory agencies adopt similar criteria to the FDA’s recent decision, or will the acceptability of foreign data become a differentiating factor in market attractiveness?
When Western markets show interest in foreign data, how will they adapt their standards and expectations to deal with the challenges stated above? What type of data, validation, processes, and tools need to be put in place to increase confidence in this data?
What considerations will manufacturers need to account for when developing clinical trial programs globally? If certain Western markets begin accepting foreign data more frequently, could launching Asian trials explicitly to support initial Western launches become a winning R&D strategy?
If we’re able to address these challenges, could this create new opportunities to bring more potentially life-saving therapies to Western markets faster?

This is a complex issue, and its resolution is in part impacted by ever-changing political landscapes; therefore, the resolution is challenging to predict. Any solution will require carefully crafted data standards and policies, credible and accessible audit capabilities, and most of all, compromise by stakeholders across markets. In the meantime, the use of foreign data will continue to pose hurdles for industry, and should not be counted on to support benefits claims in lieu of Western data.