Bristol Myers Squibb's Opdivo Liver Cancer Trial Setback Due to Regulatory Violations in China

Source: China Business News Author: Yan Qiaoru

In recent years, incidents of illegal outflow of human genetic resources have occurred from time to time, and cross-border cooperation supervision involving human genetic resources has been increasingly strengthened.

Recently, renowned pharmaceutical company Bristol-Myers Squibb and prominent clinical research organization ICON were penalized by the Ministry of Science and Technology for violating regulations on the management of human genetic resources. As a result, their applications for international cooperation activities involving China’s human genetic resources have been suspended for six months and one year, respectively.

A reporter from China Business News learned through public records that the penalty stemmed from a study on the indication of Bristol-Myers Squibb’s PD-1 monoclonal antibody drug Opdivo (Opdivo) for liver cancer, which was commissioned to ICON. This drug, widely known as “O Drug,” is one of Bristol-Myers Squibb’s key products. An employee of ICON forged the official seal of an ethics review committee to expedite the project and obtain administrative approval from the Human Genetic Resources Administration of China (hereinafter referred to as the “Genetic Office”). The individual was ultimately sentenced for the crime of forging the seal of a public institution.

ICON stated to reporters that the employee’s actions were personal in nature. Upon learning of the incident, ICON promptly reported it to the relevant authorities and cooperated with the investigation, and has since terminated the employment relationship with the employee.

Regarding the potential impact of this penalty, Bristol-Myers Squibb stated to reporters that it has transferred the entire study back for internal conduct. Given that the study had not yet been initiated at any clinical research center in China and no Chinese patients had been enrolled, patient safety and data integrity for the study were not compromised. The clinical use of Opdivo in China and existing clinical trials remain unaffected. The penalty only restricts the submission of new applications related to international collaborative activities involving human genetic resources in China for a period of six months.

　　# Suspension of Application Acceptance

On December 20, 2020, the Ministry of Science and Technology publicly disclosed two Administrative Penalty Decisions, numbered Guo Ke Fa [2020] No. 1 and No. 2, imposing penalties on ICON Clinical Research (Beijing) Co., Ltd. and Bristol-Myers Squibb (China) Investment Co., Ltd., respectively, which are the operating entities of ICON and Bristol-Myers Squibb in China.

The two Administrative Penalty Decisions actually pertain to the same case. The Human Genetic Resources Administration of China (HGRAC) investigated the violation of human genetic resource management regulations by ICON and Bristol-Myers Squibb. The investigation revealed that Bristol-Myers Squibb, as the sponsor, entrusted ICON to apply for administrative licensing for international cooperative activities involving Chinese human genetic resources. ICON’s personnel responsible for handling the administrative licensing applications for human genetic resources forged official seals and legal representative signatures, submitting false application materials to HGRAC. Both parties were found to have obtained administrative licensing for the collection of Chinese human genetic resources (international cooperation) through non-compliant means.

In accordance with the relevant provisions of the Interim Measures for the Administration of Human Genetic Resources, the Administrative License Law of the People's Republic of China, and the Administrative Penalty Law of the People's Republic of China, the following penalties are hereby imposed: acceptance of applications submitted by ICON for international collaborative activities involving China’s human genetic resources shall be suspended for one year, and acceptance of applications submitted by Bristol-Myers Squibb for such activities shall be suspended for six months, effective from the date of service of this decision letter.

A reporter’s search of China Judgements Online revealed that a criminal judgment issued by the Shanghai Putuo District People’s Court had disclosed details of the case. According to the judgment, the court found that in June and July 2018, while working at ICON, the defendant, Lu Moumou, used online software to forge seals bearing the names “Zhongshan Hospital Fudan University” and “Medical Ethics Committee of Zhongshan Hospital Fudan University,” and affixed these seals to relevant documents. The aforementioned forged documents were used to obtain administrative approval from the Human Genetic Resources Administration of China for the research project numbered CA209-9DX, which was commissioned by Bristol-Myers Squibb and managed by ICON.

Upon appraisal, the seals of “Zhongshan Hospital Affiliated to Fudan University” and “Medical Ethics Committee of Zhongshan Hospital Affiliated to Fudan University” affixed on the relevant documents were all forged. The aforementioned conduct of the defendant Lu XX caused direct economic losses of more than RMB 14,000 to Bristol-Myers Squibb Company.

The victim entity, Bristol-Myers Squibb Company, alleged that Lu’s conduct caused losses to Bristol-Myers Squibb Company totaling more than RMB 118,000 in project management fees, had a negative impact on Bristol-Myers Squibb Company’s reputation, and also infringed upon the interests of the patients involved in the research project.

The court ultimately ruled that the defendant, Lu Moumou, was guilty of forging the seal of a public institution, sentencing him to two years of imprisonment with a two-year probation period, and imposing a fine of RMB 5,000. Meanwhile, the compensation paid by the defendant Lu Moumou was returned to the victim entity, Bristol-Myers Squibb.

ICON confirmed to reporters that the penalty in question pertains to the aforementioned case. ICON further stated that the actions of its former employee, Mr. Lu, were personal in nature and involved only a single batch of trial materials for one client. Upon learning of the incident, ICON promptly reported it to the Human Genetic Resources Administration of China (HGRAC) and terminated its employment relationship with Mr. Lu. As this clinical trial had not yet commenced and no patients had been enrolled, there was no risk posed to patients.

Following a comprehensive internal review, ICON immediately initiated process optimization efforts to prevent similar incidents in the future. Specific measures included enhancing supervision and training for staff in the clinical project initiation department, with particular focus on the material submission procedures to the Human Genetic Resources Administration of China (HGRAC), as well as implementing improvements to processes and quality control.

Bristol-Myers Squibb stated to reporters that the company attaches great importance to this matter. Upon discovering the incident, it immediately conducted a systematic and comprehensive in-depth investigation and maintained close and transparent communication with the Human Genetic Resources Administration of China and the Ministry of Science and Technology regarding this incident.

Regarding the potential impact of this penalty on the company’s operations, ICON stated that, as a global company, it conducts business in 40 countries and regions. This penalty only affects Phase II to IV clinical trials in China over the next year. The company is working with the Human Genetic Resources Administration of China (HGRAC) to mitigate the impact of this matter. ICON’s ongoing trials have not been substantially affected, nor have its central laboratory and DOCS businesses. ICON values its operations in China and has therefore taken corresponding measures to optimize processes and respond to the relevant authorities. At this stage, ICON will not change its business strategy in China, which remains an important growth area.

　　“O Drug” Indication Studies Affected

According to the Chinese Clinical Trial Registry, study CA209-9DX is a Phase III clinical trial currently listed as actively suspended. The sponsor, Bristol-Myers Squibb, voluntarily halted the conduct of the study in mainland China on July 3, 2020.

The investigational drug is Nivolumab Injection. The study title is “A Randomized, Double-Blind Study of Adjuvant Nivolumab versus Placebo in Subjects with Hepatocellular Carcinoma.” The objective is to evaluate the safety and efficacy of nivolumab monotherapy in subjects with hepatocellular carcinoma (HCC) at high risk of recurrence after curative resection or ablation, thereby addressing unmet medical needs in populations lacking effective treatment options.

Nivolumab, marketed under the brand name Opdivo (欧狄沃) and commonly known as “O drug” or nivolumab, is a PD-1 immune checkpoint inhibitor that exerts antitumor effects by relieving tumor-induced suppression of the immune system.

PD-1 monoclonal antibodies have been the “stars” of the anticancer drug field in recent years and once became the focus of attention during the negotiations for the 2020 National Reimbursement Drug List. However, after the negotiation results were announced, among the seven PD-1 monoclonal antibody products that participated in the negotiations, only three domestically produced drugs were successfully included, while products from four foreign companies, including Bristol-Myers Squibb, failed to be included.

Opdivo is the world’s first PD-1 monoclonal antibody and the first PD-1 monoclonal antibody marketed in China, approved in June 2018. Its currently approved indications in China include lung cancer, head and neck squamous cell carcinoma, and gastric cancer.

Following the successive approvals of several domestically produced PD-1 monoclonal antibodies, indications have become a key battleground for pharmaceutical companies amid fierce market competition. Globally, another major PD-1 monoclonal antibody drug, Keytruda, has currently been approved in China for five indications, including melanoma, lung cancer, and esophageal cancer.

Regarding whether the initiation timeline and progress of the clinical trials involving Opdivo would be affected, Bristol-Myers Squibb stated that it attaches great importance to this matter and is collaborating with the Ministry of Science and Technology to minimize the impact of the incident on clinical trials in China. Meanwhile, Bristol-Myers Squibb has brought the entire study back in-house. Given that the study has not yet been initiated at any clinical research centers in China and no Chinese patients have been enrolled, Bristol-Myers Squibb declined to provide further comments on the details.

As victims in the case, the joint penalty imposed on Bristol-Myers Squibb and ICON was actually in accordance with established regulations. In June 2003, the former State Food and Drug Administration reviewed and approved the Good Clinical Practice (GCP) for Drug Clinical Trials. Article 33 thereof clearly stipulates that sponsors delegating tasks to contract research organizations (CROs) must comply with the following requirements: A sponsor may delegate part or all of its clinical trial work and tasks to a CRO, but the sponsor remains ultimately responsible for the quality and reliability of the clinical trial data and shall supervise the various tasks undertaken by the CRO.

It is understood that, in accordance with relevant regulatory requirements, any clinical research project involving foreign-owned or joint-venture enterprises that engage in the processing or management of biological specimens, samples, or data must undergo approval for human genetic resource management. Consequently, this step has become a mandatory procedure for clinical studies involving foreign investment and represents one of the critical factors affecting project initiation timelines. Furthermore, obtaining the ethics committee’s approval letter is a prerequisite for submitting an application for human genetic resource management approval.

In recent years, the state has intensified its crackdown on crimes involving human genetic resources. In October 2020, the Biosecurity Law of the People's Republic of China was officially promulgated, dedicating a specific chapter to “the security of human genetic resources and biological resources.” This legislation strengthens the management and supervision of activities related to the collection, preservation, utilization, and external provision of China’s human genetic and biological resources, thereby safeguarding their security.