By Meng Qian, Zhou Fang, Fu Jieying, Zuo Jun and Ning Yajuan
As China’s CDE seeks industry feedback on its policies to improve the regulatory regime for clinical trials and drug approval, Tigermed and PharmaDJ have been inviting regulatory experts since 2019 to discuss the policies and raise awareness of issues that are often overlooked. These valuable insights are presented in a report every year.
In the 2021 report (in Chinese), experts discussed IND and NDA review and approval, communication with the CDE, on-site inspections, the marketing authorization holder system, fast track approvals, the development of oncology drugs for use in combination, policies to support orphan drug development, regulation of cell and gene therapy, as well as the use of real-world data in a total of 12 chapters.
To offer a glimpse of the report, the chapter discussing the development of combination therapies for cancer patients in China has been translated into English. It suggests how regulatory pathways can be streamlined to help test combination therapies more efficiently in China.
The development of antineoplastic combinations
With the development of antineoplastic combinations being the current and future area of focus, regulatory authorities in various countries have formulated a relatively complete system of guidelines to encourage orderly and rational research and development (R&D) in the industry.
The development of antineoplastic drugs has become one of the hotspots for new drug R&D worldwide. Chemical drugs and biological products made up 42.1% and 47.3% of antineoplastic drug clinical trials respectively, according to the 2020 Annual Report on the Current Status of Clinical Trials for New Drug Registration in China. That is much higher than the clinical development of drugs in other therapeutic areas.
Since the pathogenesis of tumors is complicated, the development of combination therapy is the inevitable R&D direction to improve efficacy, overcome drug resistance and prolong patient survival. Taking the clinical trials of PD-1 and PD-L1 monoclonal antibodies for example, the proportion of clinical trials of combination therapy increased by 34% per year on average from 2015 to 2019. Meanwhile, the proportion of monotherapy trials decreased by 30% per year on average.
While rational combination therapy can provide cancer patients with better treatment options, it also carries certain risks and challenges compared to monotherapy. Regulatory authorities have issued relevant guidelines to guide and regulate the rational conduct of such clinical trials as well as to encourage value-oriented clinical development.
I. Overview of domestic and overseas regulations and technical guidelines for combination therapy development
The Center for Drug Evaluation (CDE) released the Technical Guidelines for Clinical Trials of Combinations of Antineoplastic Drugs in December 2020 to encourage the development of innovative antineoplastic drugs as well as further regulate and guide the clinical trial designs of antineoplastic combinations. The guidelines elaborate on the rationale for the development of combination therapy, considerations of monotherapy clinical data, dose finding and factorial analysis of the efficacy of combination therapy, as well as the design of confirmatory clinical trials under different combination methods.
Thereafter, the CDE has also issued a series of technical guidelines to provide advice and guidance on the combination of antineoplastic drugs at different stages of development and under different circumstances, including the Guidance for Clinical Development of Clinical Value-Oriented Antineoplastic Drugs, Technical Guideline for Statistical Analysis of Clinical Trials of Antineoplastic Drugs (for Trial Implementation), Technical Guidelines for Expansion Cohort Studies of First In Human Trials of Antineoplastic Drugs and the Technical Guidelines for the Preparation of Safety Summary Data of Innovative Antineoplastic Drugs for Marketing Applications. These documents further guide the applicants to conduct patient-centered, stepwise progressive, clinically valuable combination therapy trials in terms of R&D rationale, non-clinical studies supporting IND applications, clinical trial designs of combination therapy and data supporting registration.
In addition, the CDE has also published relevant literature in different professional journals, such as Considerations for Application of Early Clinical Trials of Anti-Tumor Drugs for Use in Combination and Common Types of Pivotal Registration Clinical Trial Designs for Combination Therapy of Two New Anti-Tumor Drugs, which has given more specific and practical suggestions and guidance on the content and design ideas of the submission package provided for the development of combination therapy under different circumstances.
The U.S. FDA’s guidance for combination therapy, Co-development of Two or More New Investigational Drugs for Use in Combination, was released back in 2013. It provides general guidance on the design and application pathways for the co-development clinical trials of two or more new investigational drugs for use in combinations. In 2018 and 2020, the U.S. FDA successively issued a draft for soliciting comments for several guidelines, including Expansion Cohorts: Use in FIH Clinical Trials to Expedite Development of Oncology Drugs and Biologics and Cross Labeling Oncology Drugs in Combination Regimens, which also addressed the co-development of drugs for use in combination and labeling instructions on combination medication.
Since the development of antineoplastic combinations has become the main focus for now and in the future, various regulatory authorities have formed a relatively complete system of guidelines to encourage orderly and rational R&D. Despite a late start, combination therapy of antineoplastic drugs has made substantial achievements in a short period of time in China. Regulators have rapidly established a guideline, which offers not only a wider scope of application but also strong practicality to provide more complete guidance on R&D for the domestic industry.
II. Suggestions for the development of antineoplastic drugs for use in combination
A review of the guidelines for co-development in China and the U.S. revealed that the regulatory and review considerations of both are very clear and consistent, as shown below 1) patient-centered; 2) with non-clinical data and/or data from clinical trials (with plausible biological rationale), supported by relatively adequate data of monotherapy studies; and 3) the factorial analysis will be conducted from early exploratory studies onwards, and a rational and clinically valuable confirmatory combination regimen should be formulated in a stepwise progressive and scientifically rigorous manner.
Furthermore, it is emphasized in the guidelines of both countries that the combination of antineoplastic drugs varies in practical situations and the development degree and registration status of each monotherapy is also very complicated. Therefore, it is difficult to simply standardize the submission requirements and application pathway based on the approval/investigational status of monotherapy. The drug regulators of both countries, therefore, encourage the sponsors to maintain close communication with the drug regulatory authorities throughout the development process and to fully discuss the protocol design and the application pathway of combination therapy.
The regulatory procedures for the development of combination therapy, including the application pathway, submission requirements, annual report submission, marketing application requirements and pathway, and how the combination therapy information is presented in the package insert of monotherapy, remain the most important concern for applicants because of its direct impact on the development of combination therapy.
1) Bridging monotherapy and combination therapy in early clinical trials of combination therapy
For the early development of combination therapy, the safety and pharmacokinetic data of monotherapy should be first obtained. But in order to improve the efficiency of combination therapy development, dose escalation and cohort expansion studies of monotherapy and combinations should be submitted at the same time for IND applications. If the relevant studies of monotherapy have been completed, the Safety Review Committee (SRC) or the Data Monitoring Committee (DMC) shall assess whether it can proceed to the study of combination therapy. If needed, the CDE may request the sponsor to submit clinical data after completing the monotherapy-related studies in the clinical approval, which serves as the basis for post hoc assessment.
2) Marketing application pathway for combination therapy development
From the standpoint of the industry, enterprises should be allowed to file for NDAs/BLAs after completing the clinical trials in accordance with Provisions for Drug Registration and other related guidelines. If one of the drugs for use in combination is already marketed but not yet approved for use in combination, we recommend applying for marketing authorization directly by using the clinical data of combination therapy under the premise that the benefits of other drugs are not infringed, i.e., “one application for one approval”. This can effectively eliminate unnecessary administrative processes, which accelerates the marketing approval of combination therapy and makes medication more accessible to patients.
III. Promising Future
There is still a high unmet medical need for antineoplastic therapy, which underscores the need to develop antineoplastic combinations in the future. Under the guidance of the patient-centered R&D concept, we believe that patients will benefit from better treatment options through joint efforts of all parties.