Since the outbreak of the covid-19 pandemic, five vaccines have been approved for conditional marketing in China, namely inactivated vaccines developed by Sinopharm’s Beijing Institute of Biological Products, Sinopharm’s Wuhan Institute of Biological Products and Sinovac Biotech, the adenovirus vector vaccine developed by CanSino Biologics, and recombinant protein vaccine by Chongqing Zhifei Biological Products. Two other vaccines have been authorised for emergency use – namely inactivated vaccines developed by BioKangtai and the Institute of Medical Biology of the Chinese Academy of Medical Sciences.
Rapid marketing of these vaccines would not have been possible without efficient promotion of phase III clinical trials.
However, while China leads the world in pandemic prevention and control, objective conditions for phase III clinical trials of covid-19 vaccines are basically unavailable in China. Thus Chinese companies have had to conduct clinical trials in overseas countries or regions (destination countries).
Since 2020, the authors’ team has been extensively involved in assisting Chinese companies conduct phase III clinical trials of covid-19 vaccines abroad. Drawing from this experience, key issues that Chinese companies need to pay attention to during overseas clinical trials of covid-19 vaccines are summarised here.
Chinese companies need to conduct complicated investigations in destination countries, which usually require consideration of the following localised factors: (1) covid-19 infection rate; (2) population; (3) local variant prevalence; (4) local vaccination rate; (5) types of locally marketed vaccines; (6) local competitive trials; (7) local laws, regulations and ethical requirements; (8) local political situation and local government’s relationship with China; (9) Chinese companies’ ties with local government and partner companies; and (10) experience in implementing clinical trials locally.
Since it is often the first time that Chinese companies are conducting clinical trials in these countries, their Chinese lawyers need to quickly help them understand the conditions and processes for clinical trial approval under local laws and regulations.
Many companies choose to conduct various clinical trials in African countries, where the pre-approval process is cumbersome, lengthy and varies widely – usually taking six to 12 months in a single country.
However, during exceptionally urgent circumstances of the covid-19 pandemic, the WHO African Vaccine Regulatory Forum (AVAREF) has opened an accelerated pathway for clinical trials of these vaccines – integrating approval of drug regulatory agencies and ethics committees in different African countries, so approvals can be granted within one month at the earliest.
In this process, engaging reliable local lawyers from top law firms in the pharmaceutical field in African countries and regions not only saves Chinese companies time in the preliminary investigation, but also facilitates rapid approval of their clinical trials.
As selecting a destination country depends on uncontrollable factors, such as local covid-19 infection rate, Chinese companies generally do not have established legal entities holding relevant qualifications where they determine to conduct clinical trials.
According to local legal requirements, the following co-operation modes are generally adopted:
(1) Co-operating with local government, research institutes or local enterprises (“destination country partner”); seeking assistance from a local government, research institutes or enterprise, known as a “local contract research organisation”(CRO); or managing the project independently, entrusting a Chinese clinical trial organisation to supervise the project as central CRO;
(2) Working directly with a global/regional CRO; or
(3) Co-operating directly with a local CRO.
However, these alternative modes are basically subject to different legal agreement frameworks.
Taking just the first co-operation mode as an example, the main framework includes:
(1) Agreement between the Chinese company and its destination country partner generally providing for identification of the sponsor (a domestic sponsor is the Chinese company, while a foreign sponsor is a joint sponsor or destination country partner, depending on local registration-related laws); the bearing of costs; and distribution of commercialisation benefits at a later stage. As a domestic sponsor, the Chinese company needs overseas data to support its new drug application (NDA) in China. If it also wants to initiate an NDA in the destination country, it needs to establish a local legal entity, or if there is no local legal entity, request its destination country partner to initiate an NDA, or submit a joint application;
(2) A clinical trial agreement between the Chinese company and its destination country partner and local CRO, detailing division of rights and obligations between the sponsor and local CRO, in accordance with the ICH guideline for good clinical practice (GCP), local GCP and Chinese GCP;
(3) Specific division of rights and obligations between local CROs and local research institutes and investigators regarding specific clinical trial tasks, under the provisions of the ICH GCP, local GCP and Chinese GCP; and
(4) Agreement between the Chinese enterprise and central CRO on communication with all parties and supervision over the entire clinical trial process on behalf of the Chinese enterprise, providing the Chinese enterprise should retain a clause stating that the central CRO represents the Chinese enterprise in all the agreements signed with the above parties.
In summary, the entire management process of a clinical trial project overseas is often intricate and involves the rights and obligations of different parties.
In addition, under ICH GCP and Chinese GCP, local CROs and research institutes/investigators have different roles, rights and obligations. These parties would usually develop a list of contractual obligations detailing performance, quantity, quality, timelines, acceptance criteria, transmission/shipment methods, etc.
Ultimately, the most important factor for a Chinese company is controling collection and feedback of serum samples and test data. Therefore, the agreement must clearly specify the time and method of serum sample transportation and test data transmission – stipulating clear, enforceable liabilities of breach. Otherwise, the project will veer beyond control.
April Zhao is a senior counsel at ZSK Attorneys-at-Law. She can be contacted on +86 176 0086 2819or by email at firstname.lastname@example.org
Benjamin Bai is a partner at ZSK Attorneys-at-Law. He can be contacted on +86 186 1073 1683 or by email at email@example.com