Dr. Sean Xiao of 3D Medicines: Pathways for Chinese Biotech Innovation to Achieve a Win-Win-Win in Global Markets for Patients, Physicians, and Companies

Going global has become a hot topic in China’s biopharmaceutical industry. In the first half of 2023, several Chinese pharmaceutical companies established international partnerships with multinational corporations (MNCs), although some also encountered setbacks in their global expansion efforts. Amid the industry’s downturn, successful global expansion has become a key marker for biotech firms to establish their leading position within the sector. Nevertheless, companies still face numerous complex risk factors that must be addressed or mitigated, with regulatory challenges being an indispensable component.

Recently, at the 8th China Pharmaceutical Innovation and Investment Conference,Dr. Xiao Shen, Chief Medical Officer of 3D Medicines, delivered a keynote speech titled “Analysis of Key Factors and Pathway Selection for the Global Expansion of Innovative Drugs.” From a medical perspective, he analyzed the critical factors Chinese biotech companies should consider and the potential pathways they could pursue when deciding to expand into international markets.

Dr. Xiao Shen previously served as a Senior Clinical Reviewer at the U.S. Food and Drug Administration (FDA), where he was responsible for the clinical review of new drugs targeting cardiovascular, renal, and vascular diseases. During his nearly 20-year tenure at the FDA, Dr. Shen reviewed hundreds of new drug candidates across various stages of development. As a primary clinical reviewer and lead of the integrated review team, he oversaw the approval of multiple New Drug Applications (NDAs) for market authorization. Additionally, while at the FDA, he led and participated in the development of several guidelines related to new drug development.

The following are the key points of Dr. Xiao Shen's speech:

As is well known, BeiGene’s zanubrutinib successfully entered the global market in 2019. This international expansion was based on clinical data generated in China, and the drug received FDA marketing approval after conducting only a Phase I pharmacokinetic (PK) clinical trial in the United States. However, another example that has emerged in recent years is the challenges faced by PD-(L)1 inhibitors in their efforts to go global, leading to a widespread perception that international expansion is extremely difficult.

What is the difference between these two examples? One addressed the unmet clinical needs of patients, while the other lacked experience in clinical data quality, overall clinical trial design, and alignment with international standards.

The key question we need to consider today is, beyond collaborating with foreign partners, under what conditions will overseas markets welcome you? That is, youAddressing patients' unmet needs is the foundation and guarantee for global expansion.，Therefore, I would like to discuss with you from four aspects how these key factors safeguard our global expansion and achieve a win-win outcome for patients, physicians, and enterprises.

When discussing patient needs, the focus is often on unmet clinical needs. When designing clinical trials or planning to expand into overseas markets, companies should first consider whether the condition is a serious disease and second, whether it is a rare disease. In this context, it is important to note that the definition of rare diseases differs between China and other countries; some conditions that are rare in Europe and the United States may be common in the Asia-Pacific region.

Additionally,For products that are not first-in-class, it is even more critical to engage in frequent dialogue with frontline clinicians to determine whether these diseases represent unmet medical needs.Do not simply follow the crowd. Take diabetes as an example: initially, everyone focused on developing new drugs for diabetes, but the market is now nearly saturated. Meanwhile, weight-loss medications have gained significant traction, highlighting the market potential of obesity as a disease. In the realm of chronic diseases, consider targeting acute complications. Rather than focusing solely on diabetes itself, direct attention to diabetic nephropathy, diabetic cardiomyopathy and cardiovascular complications, ophthalmic complications, and other systemic disorders associated with diabetes.

Therefore, we should consider selecting a truly differentiated clinical trial design to address unmet clinical needs. Of course, if the chosen indication lacks any approved novel therapies, companies may achieve greater returns.

Therefore, I hope that Chinese pharmaceutical companies will not blindly follow foreign trends in clinical trials but should instead pursue differentiation.How can such differentiation be identified? By engaging in frequent communication with frontline clinical physicians to understand what patients in different regions currently lack, thereby addressing unmet needs.In particular, during my tenure at the FDA reviewing approvals, I encountered companies that had achieved differentiation. Although some were small, they were highly sought after and were quickly acquired by larger corporations. This was because they selected differentiated clinical endpoints that addressed the needs of clinical disease management.

In terms of clinical trial design, I will share insights from three perspectives: selection of clinical trial methodologies, determination of efficacy endpoints, and safety assessment.

Regarding the selection of clinical trial methodologies, it is well known that designs can range from simple single-arm open-label trials to single-blind and double-blind, double-dummy trials. The double-blind, double-dummy design may be less familiar to some; specifically, when comparing intravenous injection with oral administration, direct blinding is not feasible. In such cases, a double-dummy approach can be employed, wherein one control group receives an intravenous injection plus an oral placebo, while the other receives an oral medication plus an intravenous placebo.

Furthermore, we must consider whether a company should conduct early-stage or late-stage clinical trials. The choice of strategy hinges on whether the company pursues international expansion at an early or late stage. Early-stage and late-stage trials differ in design, and the selected clinical endpoints may also vary. Exploratory efficacy studies differ from definitive registration-enabling clinical trials. Therefore, when planning for global market entry, careful consideration must be given to clinical trial design.

There is also the design of clinical efficacy endpoints. A major reason for the failure of drugs in global expansion is the selection of clinical endpoints.For example, some drugs initially selected progression-free survival (PFS) as the clinical endpoint for lung cancer, whereas the FDA actually required overall survival (OS). This discrepancy became one of the key reasons for the failure of their new drug marketing applications. Therefore, the determination of clinical endpoints is critically important.It is also worth noting that there are differences in the selection of clinical endpoints between China and other countries; these differences stem from national circumstances rather than from any disparity in clinical significance.For example, in patients with heart failure, length of hospital stay can serve as a valid clinical endpoint in countries such as the United States, but may be less appropriate in China.

Furthermore, surrogate endpoints represent a highly meaningful choice, as clinical trials for most diseases are conducted using such endpoints. For instance, in conditions like hypertension, diabetes, and certain cancers, blood pressure, glycated hemoglobin (HbA1c), objective response rate (ORR), and progression-free survival (PFS) are all accepted surrogate endpoints. The selection of surrogate endpoints involves extensive considerations. Beyond statistical significance—whether the P-value is less than 0.05, 0.01, or 0.001—if the observed differences lack clinical meaningfulness, the product will not gain recognition or approval from foreign regulatory authorities.

The third issue concerns composite endpoints. Generally, a composite endpoint comprises at least two or three valid endpoints. Taking heart failure as an example, patient death and hospitalization duration are typically used as clinical endpoints; combining them constitutes a composite endpoint. In clinical trials, if the analysis yields positive results indicating that the outcome may be driven by reduced hospitalization duration while mortality cases also decrease, the overall clinical composite endpoint is considered achieved. However, if hospitalization duration is significantly shortened but mortality increases, although the overall results might appear acceptable, the FDA may reject the application because mortality carries substantially greater clinical significance than hospitalization duration.

Therefore, whether conducting clinical trials or tracking clinical data, composite endpoint trials in patients must be evaluated with sufficient caution and rigor; these are lessons I have accumulated through my long-term work at the FDA.

Next, let us discuss the determination of safety. Unlike efficacy, safety cannot be hypothesized through statistical sampling; instead, the design of safety trials must be established based on the frequency of signal occurrence and patient characteristics.

Taking diabetes as an example, the research and development of new drugs has undergone a complex evolution. Initially, regulatory approval could be granted based solely on the reduction of glycated hemoglobin (HbA1c). Later, the industry recognized that while lowering HbA1c reduces microvascular complications, it does not fully improve macrovascular complications and may even exacerbate them. Consequently, for certain new molecular entities, despite a decrease in HbA1c levels, there is a potential risk of increased mortality. After several years of such fluctuations, the FDA has adjusted its guidelines multiple times. To ensure drug safety, previous guidelines required cardiovascular safety trials lasting more than one year; this requirement has now been removed, but requirements for patient exposure have been introduced. Therefore, it is recommended that clinical trial designs be adjusted in accordance with the guidelines of international regulatory agencies. Additionally, post-marketing requirements and commitments (PMR/PMC), as well as Risk Evaluation and Mitigation Strategies (REMS), are critical factors to consider during clinical trial planning.

Here, I will further discuss certain regulatory requirements both domestically and internationally. For instance, what key considerations should be taken into account for domestic clinical trials and Multi-Regional Clinical Trials (MRCTs)? How can we fully leverage the facilitative measures provided by the FDA, including Fast Track designation, Breakthrough Therapy designation, and Priority Review?Recently, the FDA’s Oncology Center of Excellence issued a new guidance on RTOR (Real-Time Oncology Review).，Companies may submit data to regulatory authorities in advance; while this does not guarantee early approval, it helps regulators understand the product’s characteristics and accelerates the drug approval review process.

Furthermore, combination therapies are increasingly prevalent. Within the oncology sector, pharmaceutical companies must carefully consider numerous factors when developing combination regimens. For instance, scenarios may involve two unapproved drugs, one approved and one unapproved drug, or two already approved drugs. Clinical requirements, trial designs, and data submission standards vary significantly across these different situations.

Currently, there are numerous companies in the industry focused on oncology. Over the past two years, the FDA’s Oncology Center of Excellence has proposed four key concepts to facilitate drug approval:

First is Project Equity, referring to racial diversity, which requires that everyone receive the same assessment, rather than assessing only one race.

The second is Project Front RunnerThe FDA believes that it is unfair to both patients and pharmaceutical companies to administer new drugs after chemotherapy and second- to fourth-line treatments have failed. By this stage, patients’ conditions are typically deteriorated, leading to inevitably poor responses to the new medication. Thus, such an approach is unreasonable for both the drug and the patient. Therefore, the FDA encourages early-stage exploratory trials, such as first-line or early-line treatment studies. When patients are in relatively good physical condition and chemotherapy has demonstrated only modest efficacy, administering a highly effective new drug can yield maximal clinical benefit for the patient. This paradigm also significantly aids pharmaceutical companies in their new drug development efforts.

Third is Project Optimus, in the past, the FDA, clinicians, and pharmaceutical companies believed that cancer patients had a poor prognosis, and mere survival was considered a satisfactory outcome. Consequently, during new drug development, dose escalation typically proceeded to the highest possible level, with the maximum dose selected. Although this approach could improve patient survival, it also severely compromised patients’ quality of life. Therefore, the FDA is increasingly emphasizing this issue, requiring pharmaceutical companies to conduct dose-finding studies to identify the optimal dose rather than simply selecting the highest dose. The goal is not only to prolong patient survival but also to improve their quality of life.

Fourth is Project Orbis, this concept aims to enable patients worldwide to benefit from new medicines within the same timeframe. Project Orbis has currently been implemented to some extent in Australia, the United States, Canada, and New Zealand, where certain new drugs are approved for marketing simultaneously, allowing patients in these countries to benefit at the same time. However, there is still a long way to go in regions such as Japan, Europe, and China.

Having grasped these concepts, we encourage stakeholders to fully leverage these conditions to facilitate drug development and approval, and to optimize pathways for the global market entry of pharmaceutical products.