FDA Rejections of Roche's Columvi and GSK's Blenrep Highlight the Geopolitical Clinical Trial Dilemma for MNCs

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When Roche andGSKThe heavy-duty new drug received consecutively in the same weekFDARejection Letter: The Global Clinical Trial Strategy of Multinational Pharmaceutical Companies Faces Serious Questions. Two Star Therapies for Hematological Tumors——ColumviDouble Antibody andBlenrepTheADC, although it has shown promising efficacy in the overall population, the proportion of American patients is insufficient.5%The fatal shortcoming was blocked outside the door of listing. The iron rule of supervision is sending a clear signal: in the field of oncology with significant racial differences,“Global Data Homogenization”The illusion has already shattered, and localized evidence has become an insurmountable new threshold.

Record of Failure

First look GSK Of Blenrep, this targeted B Cell Maturation Antigen (BCMA) antibody-drug conjugate (ADC), aiming to overcome recurrence / Refractory Multiple Myeloma (R/R MM) This stubborn hematological malignancy. Its marketing application is mainly based on DREAMM - 7 And DREAMM - 8 Two global III Phase clinical trial.DREAMM - 7 Data shows,Blenrep In combination with bortezomib and dexamethasone (BVd), the median progression-free survival (PFS) From13.4 Months significantly extended to 36.6 Months, reduced risk of death 42%, with a three-year survival rate reaching 74%, the efficacy appears to be very impressive. However DREAMM - 8 The trial encountered setbacks,Blenrep Median in the monotherapy group PFS Not reaching the endpoint (12.7 Months vs Control Group 12.7 months), overall survival (OS) Data also did not improve significantly.

FDA Oncology Drug Advisory Committee (ODAC) raised sharp questions about this. On the one hand, the enrollment rate of American patients in the two trials was extremely low, both below 5% . This greatly reduces the applicability of the trial results to the U.S. population and fails to provide strong support. Blenrep In the United States, the approval has been granted. On the other hand, drug safety issues have also surfaced. In two studies,Blenrep The incidence of ocular toxicity caused by the drug is extremely high, with most patients experiencing keratopathy and vision loss, and even severe corneal ulcers. Additionally, there are flaws in the dose design of the trial; many patients struggle to maintain the initial planned dose by the third treatment cycle, and frequent dose adjustments significantly impact the evaluation of drug efficacy and tolerability.

Refocusing on Roche Columvi, as a targeted CD20/CD3 The bispecific antibody, it targets recurrence / Refractory Diffuse Large B Cellular Lymphoma (DLBCL). Its supplemental biologics license application (sBLA) Based on III PeriodSTARGLO Research results. The study was conducted globally 13 Country 62 Central inclusion 274 Example patients, with the proportion of Asian and Australian populations 59%, North American population accounts for only 9% . From the data, the median follow-up 11.3 Months later,Columvi Combined Chemotherapy Regimen GemOx Compared with Rituximab Combined GemOx Plan (R - GemOx), significantly extending the overall survival (OS)(Not yet reached vs 9 Months,HR = 0.59，P = 0.011); median follow-up 20.7 Months later,OS The benefits remain (25.5 Months vs 12.9 Months,HR = 0.62）。

But FDA The decision to reject approval was still made. The reason lies in the insufficient sample size of American patients in the trial, making it difficult to represent the American patient population. Moreover, subgroup analysis revealed significant regional differences: across the entire trial population,Columvi - GemOx Compared to Rituxan - GemOx Reduced 41% The risk of death can be in non-Asian countries,Columvi The mortality risk of the regimen was higher 6%. This makes FDA Questions remain about its safety and efficacy for American patients, even though Roche explained that it might be due to differences in subsequent treatments in Western countries and the pandemic causing slower enrollment of American patients, but doubts still persist. FDA Concerns.

It is not difficult to find that,GSK The common fatal flaw of Roche's new drug failure lies in the insufficient consideration of the particularity of the American population during the trial design, and the lack of a strong evidence chain targeting the American population. In global multi-regional clinical trials (MRCT), the severe lack of American patient samples creates a black hole in data representativeness, making it difficult for regulatory agencies to establish trust in the drug's efficacy and safety among the U.S. population, ultimately leading to approval failure.

Fatal Blind Spot

The failure of these two new drugs is not accidental, behind which lies a极易被忽视却又极其关键的问题 in global trials. ——Geobiological Trap. In the field of hematological oncology, racial differences have a significant impact on the occurrence, development, and drug response of diseases.

Take multiple myeloma as an example, the National Cancer Institute (NCI) in the United States (NCI) Data show obvious disparities between Black and White individuals in terms of incidence and survival rates. Black individuals have a relatively higher incidence of multiple myeloma, and their survival rates are often lower than those of White individuals after receiving the same treatment. This disparity involves complex genetic factors, with differences in genetic backgrounds among different racial populations contributing to the variation. BCMA The drug responses of targets vary.Blenrep As a BCMA Targeted drugs, in clinical trials, failed to adequately consider this racial difference, with too few American patients enrolled, making it difficult to accurately assess their efficacy and safety across different ethnic populations. This undoubtedly laid the groundwork for the approval failure.

Look at recurrence / Refractory Diffuse Large B Cell lymphoma,CD20/CD3 The efficacy of bispecific antibodies also varies among different ethnic groups. Studies have shown,DLBCL The distribution of subtypes is significantly different in Eurasian populations, and the treatment response to certain subtypes in Asian populations is vastly different from that in European and American populations.Columvi The STARGLO In the study, North American subjects accounted for only 9%, this imbalance in sample distribution makes “Global Data” Difficult to accurately reflect the real situation of the American population, leading to FDA Questions remain about its efficacy and safety for American patients.

From the regulatory logic,FDA Rejection is by no means so-called “Local Protection”, but is based on rigorous scientific considerations. Pharmacogenomics research reveals that differences exist among ethnic groups in the genetic polymorphisms of drug-metabolizing enzymes and drug targets, and these differences can significantly affect drug efficacy and toxicity. For example, cytochrome P450（CYP) Enzyme system is involved in the metabolic processes of numerous drugs, and there are differences among various ethnic populations. CYP The activity and expression levels of enzymes vary, leading to different metabolic rates and concentrations of drugs in the body, which in turn affect efficacy and safety. Human leukocyte antigen (HLA) The subtype also varies among different ethnic groups, which may influence the mechanism of action and risk of adverse reactions of immune-related drugs.

When Global Multi-Regional Clinical Trials (MRCT) When not stratified by ethnicity, the aggregated “Global Data” It is like a statistical illusion, masking the true differences in drug responses among different ethnic groups and failing to provide precise and reliable decision-making basis for regulatory authorities. This requires pharmaceutical companies to fully consider geopolitical biological factors when designing clinical trials, reasonably plan the sample sizes and trial groupings of different ethnic populations, and build a scientific and comprehensive evidence system to overcome this geopolitical biological pitfall.

Regulatory Fission

In GSK Behind the failure of Roche's new drug isFDA A profound transformation in the regulatory paradigm, with a greater emphasis on “Weight of Local Evidence” The era has already arrived.

In recent years,FDA In the process of new drug approval, the emphasis on domestic data is increasing. In the design of pivotal trials, the Oncology Drug Advisory Committee (ODAC) clearly requires that the trial must include “Can support benefits for the American population” The preset subgroup. The introduction of this hard indicator means that pharmaceutical companies must consider planning global multi-regional clinical trials (MRCT), it is necessary to fully consider the representation of the U.S. population from the beginning of the trial, reserve sufficient sample size for subgroup analysis of the U.S. population, to accurately evaluate the efficacy and safety of the drug in American patients.

In the process of transitioning from accelerated approval to full approval, the weight of local data has also significantly increased. After a new drug is launched in the U.S. through accelerated approval, in order to successfully transition to full approval, pharmaceutical companies need to provide more detailed and targeted local data to demonstrate that the benefit-risk ratio for American patients remains within an acceptable range during long-term use. This undoubtedly puts enormous pressure on pharmaceutical companies, requiring them to continuously focus on the American patient population in post-marketing studies and conduct supplementary research to collect local data.

By Roche's Columvi For example, Roche attempted to “Differences in Follow-up Therapies between Europe and the United States” As a defense argument, explain STARGLO The issue of the low proportion of American patients in the study, but this claim has been met with FDA The ruthless rejection. This incident profoundly reveals FDA For so-called “Accessibility Excuse” The zero-tolerance attitude also sends a strong signal to the entire industry: any attempt to ignore or downplay the importance of domestic data in new drug approvals will be difficult to accept.

In the future, multinational pharmaceutical companies in designing MRCT At the same time, it is necessary to integrate localization modules. This not only includes reasonably increasing the proportion of American patients in the trials but also involves optimizing the trial protocols, fully considering the impact of genetic background, lifestyle, and medical environment of the American population on drug efficacy and safety, and conducting targeted research to meet... FDA Strict requirements for local evidence increase the success rate of new drug approvals.

The Road to Breaking Barriers

Facing FDA The shift in regulatory paradigms and the geoclinical trial dilemma require multinational pharmaceutical companies to actively explore new tactics. “Regulatory Sandbox” Carefully plan to increase the success rate of new drug approvals.

In Global Multi-Regional Clinical Trials (MRCT), dynamic stratified recruitment is an effective strategy to address the insufficient sample size of American patients. Pharmaceutical companies can preset the minimum proportion of American patients during the trial design phase, for example, setting it as 20%, and adopt a real-time regional recruitment monitoring system to ensure that the recruitment progress meets expectations. In this way, it can guarantee that the trial data is sufficiently representative of the U.S. population, for FDA Approval provides a solid data foundation.

For high-risk targets,前置化桥接试验 is crucial. In the early stage of new drug development, initiating supplementary cohort studies in the U.S. in advance can rapidly obtain drug response data from the U.S. population. This way, when pivotal trials are conducted, the trial design can be optimized based on the results of prior supplementary cohort studies to better meet requirements. FDA Requirements for data from the U.S. population to reduce the risk of approval delays or failures due to insufficient data in later stages.

Real-world evidence (RWE) is gradually becoming an important lever in the approval of new drugs. Multinational pharmaceutical companies can collaborate with U.S.-based electronic medical record platforms, such as Flatiron Health Deep cooperation has been carried out to collect real-world data from patients during the actual treatment process. This data can reflect the efficacy and safety of drugs in real healthcare settings, complementing clinical trial data and providing... FDA Approval provides more comprehensive and authentic evidence support. In the continuous monitoring after drug marketing,RWE It can also help pharmaceutical companies promptly identify long-term safety and efficacy issues of drugs in different populations, providing a basis for the continuous optimization of products and market expansion.

Localization of drug dosage is also a crucial aspect that cannot be overlooked. With GSK The Blenrep For example, its ocular toxicity issues might be resolved by adjusting the dosing regimen based on the pharmacokinetic and pharmacodynamic characteristics of European and American populations. In clinical trials, conducting dose-finding studies targeting different ethnic groups to determine the most suitable drug dosage and administration frequency for the U.S. population can effectively reduce the incidence of adverse drug reactions, improve the safety and efficacy of the drug, and enhance its overall performance. FDA Confidence in the drug.

Multinational pharmaceutical companies in response to FDA When facing regulatory and geopolitical clinical trial challenges, it is necessary to implement comprehensive tactical innovations across multiple levels, including trial design, data collection, evidence supplementation, and dose optimization. Through these actionable solutions, there is hope to break the deadlock, stand out in the global competition for new drug development, and bring more effective treatment options to patients.

Conclusion

The failure of two star drugs heralds the end of the extensive era of global drug development. WhenFDAWill“Data Sovereignty in China”Reach an unprecedented height, multinational pharmaceutical companies must reconstruct the logic of evidence chain production: from pursuing“Statistical Significance”Turn to Build“Geobiology Credibility”The winners of the future will surely be those companies that can turn ethnic differences into precise development strategies.——Not filling Americans in trials, but letting American data tell the scientific story.

Source: Public information compilation

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