China Releases First Clinical Trial Guidelines for HPV Vaccines, Accelerating Domestic 9-Valent HPV Vaccine Development

Last week, the Center for Drug Evaluation (CDE) of the National Medical Products Administration released the Technical Guidelines for Clinical Trials of Human Papillomavirus Vaccines (Trial) (hereinafter referred to as the “Guidelines”), drawing significant attention from the industry.

As the first official directive issued by China’s regulatory authorities specifically addressing clinical trials of human papillomavirus (HPV) vaccines, this document specifies detailed requirements regarding indications, primary endpoints in clinical trials, research and development strategies, clinical trial design and evaluation, and post-marketing studies. The Guidelines provide clear responses to issues of significant industry interest, such as surrogate endpoints for clinical trials of next-generation HPV vaccines and requirements for immunobridging studies.

Human Papillomavirus Vaccine, commonly known as the HPV vaccine. Extensive research has demonstrated that HPV infection is associated with a variety of serious conditions, including cervical cancer, vaginal cancer, vulvar cancer, penile cancer, anal cancer, oropharyngeal and other head and neck cancers, and genital warts. For instance, in China, 99% of cervical cancer cases, 88% of anal cancer cases, and 77% of vaginal cancer cases have been found to be linked to HPV infection; whereas in the United States, HPV infection accounts for 99% of cervical cancer cases, 91% of anal cancer cases, and 75% of vaginal cancer cases. Consequently, the HPV vaccine has become one of the most widely recognized biological products globally.

GSK's previously launched bivalent HPV vaccine, CERVARIX^®Merck's Quadrivalent HPV Vaccine GARDASIL^®and the nine-valent HPV vaccine GARDASIL^®9. It became an instant best-seller upon launch, with demand outstripping supply.

As a rare blockbuster vaccine in history, the HPV vaccine faces a global market worth hundreds of billions.

According to Frost & Sullivan, the global HPV vaccine market size grew from $2.26 billion in 2016 to $4.22 billion in 2020, representing a compound annual growth rate (CAGR) of 16.2%. Driven by factors such as rising HPV vaccine penetration in low- and middle-income countries and the expansion of vaccination programs to include age-eligible males, the global HPV vaccine market size is projected to reach $10.52 billion in 2025 and $16.82 billion in 2031, respectively.

The substantial supply-demand gap and clear clinical value have attracted a large number of companies to join the surge in HPV vaccine research and development. As of June 2023, prior to the issuance of the Guidelines, dozens of HPV vaccines with different valencies had entered clinical trials in China. Among them, five leading HPV vaccine manufacturers, including Wantai BioPharm, Health Guard, and Walvax Biotechnology, have advanced their most highly anticipated domestically produced nine-valent HPV vaccines into pivotal Phase III clinical trials, signaling that intense market competition is imminent.

Industry practitioners told VCBeat that, prior to the issuance of the Guidelines, domestic HPV vaccine developers lacked uniform standards for the design and conduct of clinical trials. Consequently, these companies independently designed and conducted their trials by either referencing publicly disclosed clinical study protocols and reports of already marketed HPV vaccines, or by adhering to documents such as the Technical Guidelines for Clinical Trials of Vaccines, Good Clinical Practice for Drug Clinical Trials, Chinese Expert Consensus on the Clinical Application of Human Papillomavirus Vaccines, and Recommendations to assure the quality, safety and efficacy of recombinant human papillomavirus virus-like particle vaccines (WHO, Annex 4, TRS, No. 999).

“The Guidelines propose relatively stringent technical requirements, demonstrating strong scientific rigor and offering significant guidance,” said the industry practitioner. “At a time when domestic HPV vaccine R&D is experiencing an explosive surge, the issuance of this document will undoubtedly have far-reaching implications.”

For domestic manufacturers of nine-valent HPV vaccines whose pipelines have already entered Phase III clinical trials, competition in the “final stretch” is undoubtedly a race against time. VCBeat has noted that the provisions in the Guidelines regarding surrogate endpoints for clinical trials and immunobridging studies will help some domestic nine-valent HPV vaccine manufacturers accelerate their clinical trials, and may even shape the future competitive landscape of domestically produced nine-valent HPV vaccines.

On the one hand, the Guidelines clarify the requirements for setting differentiated surrogate endpoints in clinical trials, which will accelerate the iterative development of vaccine products.In the Guidelines, the screening and treatment indications for cervical cancer, CIN2+ and AIS, are still required as surrogate endpoints for HPV vaccines in the prevention of cervical cancer. However, the Guidelines further propose vaccine iterations and their corresponding surrogate endpoints.

The Guidelines state that, based on the presence or absence of an established HPV vaccine development platform, HPV vaccines can be broadly categorized into first-generation vaccines and iterative vaccines. First-generation vaccines are those initially developed by a vaccine manufacturer and typically cover a limited range of HPV types. In contrast, iterative vaccines are developed by manufacturers leveraging their first-generation vaccine platforms to expand the spectrum of covered HPV types, while maintaining production processes, quality standards, and other foundational conditions that are identical or highly similar to those of the first-generation vaccines.

For example, at the outset of its nine-valent HPV vaccine development, Health Guard strategically positioned its trivalent HPV vaccine, and both candidates have entered the 24-month visit phase of Phase III clinical trials. Should the trivalent HPV vaccine achieve a lead in development progress, it will serve as Health Guard’s first-generation HPV vaccine, while the nine-valent HPV vaccine will be classified as an iterative vaccine.For instance, for Wantai Bio and Walvax Biotech, which already have second-generation HPV vaccines on the market, the 9-valent HPV vaccine could also serve as an iterative vaccine. However, when previously asked whether their bivalent HPV vaccine production capacity could be utilized for the 9-valent HPV vaccine, Wantai Bio stated that it was currently unable to repurpose its bivalent HPV vaccine production lines for 9-valent HPV vaccine manufacturing. Meanwhile, Walvax Biotech’s 9-valent HPV vaccine has not yet initiated Phase III pivotal efficacy clinical trials, indicating relatively lagging R&D progress. Although several other companies’ 9-valent HPV vaccines have entered Phase III clinical trials, they either did not conduct or abandoned clinical trials for lower-valency vaccines. In accordance with the Guidelines, they are therefore ineligible to adopt persistent infection (PI12) as an endpoint for iterative vaccine approval, putting them behind Xiamen Wantai Bio and Health Guard in terms of the market launch of their 9-valent HPV vaccines.

According to the previously announced milestones for its Phase III clinical trials, Health Guard’s development of the nine-valent HPV vaccine ranks third among domestic companies. With the issuance of the Guidelines, Health Guard’s strategic layout and experimental protocols for its HPV vaccine are fully aligned with the requirements set forth in the Guidelines. As a result, Health Guard’s nine-valent HPV vaccine is poised to become one of the first two domestically produced nine-valent HPV vaccines approved for market launch.

The advantage of iterative vaccines lies in the ability to select 12-month persistent infection (PI12) as the clinical trial endpoint, rather than using histopathological CIN2+ as a surrogate endpoint for clinical trials.The Guidelines state that, considering the potential for further reduction in the incidence of diseases such as cervical cancer with the addition of new types, and given that persistent infection (PI) with high-risk types is the pathogenic and progressive mechanism leading to histopathological changes, if the first-generation vaccine has completed protective efficacy trials using recognized histopathological endpoints and met marketing authorization requirements, and is confirmed through pharmaceutical evaluation to be an iterated vaccine, it may be acceptable to apply for marketing authorization based on virological endpoints, namely 12-month persistent infection (PI 12), thereby shortening the time required for approval and market launch of iterated vaccines.

“HPV R&D companies in the industry are all eager to adopt virological persistent infection (PI) at 12 months as a surrogate endpoint, replacing histopathological cervical intraepithelial neoplasia grade 2 or worse (CIN2+), so as to shorten the development cycle,” an industry practitioner pointed out to VCBeat. Adopting a virological surrogate endpoint means that a nine-valent HPV vaccine entering Phase III clinical trials could potentially be launched as early as 12 months after vaccination of subjects, whereas the follow-up period for traditional histopathological surrogate endpoints often lasts several years. Previously, Merck’s quadrivalent HPV vaccine initiated its domestic Phase III clinical trial in China in 2009, but the trial was not completed until 2014, precisely because there was controversy over the “efficacy endpoint” for evaluating preventive vaccines.

On the other hand, the Guidelines’ provision allowing for immunobridging trials in specific populations has further reduced the clinical trial burden for certain domestically produced nine-valent HPV vaccines with expanded age indications, potentially accelerating their market launch.The Guidelines indicate that for populations in whom clinical efficacy trials cannot be conducted due to ethical or other considerations, protective efficacy may also be evaluated through confirmatory clinical trials using immunogenicity bridging. In other words, in clinical trials involving specific populations, other immunogenicity endpoints with established or partial correlation to protection may be used to support product registration, thereby simplifying clinical trial requirements.

Specifically, the Guidelines stipulate two types of immunobridging scenarios: between different age groups and between populations with different characteristics. Immunobridging across age groups primarily covers adolescent females who have not yet become sexually active, while immunobridging across populations with different characteristics allows female indications for relevant diseases to be bridged using specific clinical trial data from males. For domestic HPV vaccine manufacturers that have targeted younger age groups or male indications, this undoubtedly represents a highly valuable green channel.

Previously, Health Guard initiated an immunobridging clinical trial for its 9-valent HPV vaccine in younger age groups in March 2022. Currently, the company is conducting Phase III clinical trials for the 9-valent HPV vaccine (for female indications), has completed the three-dose vaccination regimen for all enrolled subjects, and is carrying out 24-month case monitoring and follow-up. The issuance of the Guidelines may accelerate the market launch of Health Guard’s 9-valent HPV vaccine for younger female indications. Furthermore, Health Guard launched Phase III clinical trials for male indications of its 9-valent HPV vaccine at the end of 2022, which is also expected to expedite its subsequent market entry.

With the implementation of the Guidelines, the domestic R&D ecosystem for HPV vaccines will become further standardized. We also hope to see Chinese enterprises that have long been deeply engaged in HPV vaccine research and development advance their product pipelines more smoothly and efficiently in the future.