FDA’s treatment of China-developed drugs spurs demands for multiregional clinical trials

China’s emergence as an R&D powerhouse means that the country is quickly adding a number of drug candidates to the global pipeline. Despite more treatment options being a positive, Ben Hargreaves finds that this has raised issues over single-region clinical trials, leading to the FDA rejecting certain treatments and clarifying what is required for approval.

China’s ambition to become a leader in the biopharma industry has been clear in the last few years. The investment flowing into the sector is not limited to just the development of medicines, there has also been a focus on rapidly developing capability and capacity to manufacture both traditional pharmaceuticals and biologic medicines.

A representation of the country’s rapidly developing capability can be seen in the example of WuXi Biologics, which is a contract development and manufacturing organisation, that was created in 2015 and is now in the top five companies in terms of manufacturing capacity for biologics. Similar signs of growth can be seen in the amount of drugs, biologics and medical devices the country exports to the US. The US FDA notes that China ranks third among countries that export drugs and biologics to the country, with China also placing in first position for export of medical devices to the US.

The innovation that is happening within the Chinese biopharma ecosystem means that frequently Western pharma companies are looking to partner with Chinese firms to bring treatments to the US and Europe. Only last month, the US company Merck agreed to pay a potential $1.4 billion to partner on an immuno-oncology asset with Chinese firm, Sichuan Kelun Pharmaceutical. Merck is not alone, with a number of companies making deals to leverage the growing pipeline of therapeutic candidates developed in China, such as Bavarian Nordic’s agreement to progress a potential RSV vaccine developed by Nuance Pharma.

Evolving regulatory landscape

However, the developing commercial relationship between established pharma companies and China recently hit a snag: the US FDA has adopted a tougher approach to reviewing applications of treatments tested in China. Last month, the agency rejected two cancer therapies developed by Chinese pharma companies, after previously moving against Eli Lilly and Innovent Biologics’ immunotherapy, sintilimab.

The two treatments to be most recently rejected were Hutchmed’s surufatinib, and Coherus BioSciences and Shanghai Junshi Biosciences’ toripalimab. Coherus’ treatment was rejected on grounds related to the manufacturing process for the drug. More significant were the reasons for the rejection of sintilimab and surufatinib, as the FDA cited issues with the lack of clinical trial data gathered from outside of China.

Hutchmed had carried out two phase 3 trials in China and one bridging study in the US, but it was not enough to secure approval. Instead, in the complete response letter (CRL), the FDA requested a multi-region clinical trial to be completed for approval to be considered. Effectively, this will push back potential marketing approval for the treatment by years while the trial is completed. The FDA’s decision may not have been a surprise to Hutchmed, after the FDA also raised issue with Lilly’s application that relied on single-country clinical trials as the foundation for its request for approval.

Single-region concerns

The reasons behind the FDA’s decision to push back on single-country clinical trials were made explicit during the application process for Lilly’s sintilimab. Richard Pazdur, director of the FDA’s oncology centre of excellence, had an article published where he outlined concerns over drug applications being based on solely or predominantly data gathered from China-based clinical trials.

Underlining the importance of the FDA’s stance on the issue, Pazdur highlighted that there were at least 25 applications from China based on such data for treatments within oncology. As a senior member of the FDA, Pazdur’s comments can be taken as reflecting the position held by the FDA over similar applications and point towards the agency’s stance for future applications – later confirmed by the FDA’s rejection of Lilly’s and Hutchmed’s application.

Within the article, several key concerns were raised over the use of clinical trial data from a single foreign country. One significant factor centred on the generalisability of data gathered when applied to the US population, with intrinsic factors, such as genetic dissimilarity of populations, and extrinsic factors, such as difference in medical practice, raised as potential problems.

Pazdur noted, “The degree of regulatory flexibility in establishing the acceptability of data from a single country and its generalisability to a new population should be balanced against the drug’s innovation.”

Emphasising multiregional trials

The problem for Lilly’s sintilimab application is that there already exist a number of approved PD-1 treatments on the US market, making it difficult to suggest that the treatment represented an innovation. When asked, a spokesperson for Lilly refused a request for further information on the CRL it had received. However, the company had previously issued a statement on why it believed the treatment should have been approved: “We had hoped that sintilimab could have played a positive role for patients and the US healthcare system through an aggressive pricing strategy.”

The positioning of the treatment as one that could compete on pricing with existing treatments was enough to secure one vote when the treatment was put in front of the FDA’s oncology drug advisor committee, but was not enough to persuade the remaining 14 members to recommend the treatment for approval.

Within Pazdur’s piece, he pointed towards a pathway for future applications that focused on multiregional clinical trials, particularly hinting that those containing studies conducted in Africa and South America would be ‘strengthened.’ He explained that this was due to these regions being currently underrepresented in oncology multiregional clinical trials and would boost diversity thereby increasing the representation of racial and ethnic minorities.

After the rejection of Hutchmed’s treatment, despite the efforts to include a bridging trial, the FDA seems to have drawn a line in the sand, effectively requiring multiregional clinical trials unless the drug candidate is considered ground-breaking. With many treatments already progressing through towards an application the US, the question will be whether companies now pivot to establish multiregional trials, despite this adding time and expense to the drug development process.