Since the industry and regulatory agencies have been accumulating innovative antibodies development and review experiences, applicants often lack sufficient reference to the production process and "original drugs", resulting in inadequate pharmaceutical research; reviewers may also make a request according to the "biosimilar drugs" review principles and standards as they are familiar with it. The two sides have obvious differences in understanding of some "focus issues" in pharmaceutical research, such as: clinical risk awareness of innovative drugs, necessary content of IND phase pharmaceutical research, process changes during clinical period, priority review and communication policies. The above-mentioned problems are also the main reason for the high rate of replenishment in the pharmaceutical review, and even multiple rounds of supplementation.
1. Risk control and phased requirements of pharmaceutical research
The pharmacological research of innovative drugs is mainly to meet the needs of clinical trials at different stages. IND phase pharmaceutical research should first control the “basic safety” of clinical drugs. At present, it is generally believed that the main risks that may cause clinical safety for innovative drugs include: unknown or impure components, chemical structure containing potentially toxic components, poor stability, and insufficient determination of impurities. The main risks involved in monoclonal antibody products are inadequate cell bank assays, biosafety risks of animal-derived components, and changes in biological activity caused by unstable production processes. Therefore, if there is a major defect in the pharmaceutical research that is not limited to the safety of clinical medication, the applicant must resolve it before conducting clinical trials.
According to the technical guidelines adopted internationally, before the clinical trial of innovative antibody drugs begin, the establishment and verification of the main cell bank that can support the clinical trial should be completed; the cell genetic stability test should support the pilot test of production scale process. The production process and scale should be stable and can meet the needs of clinical trial drugs, complete the study of product impurity removal that affects clinical safety; establish preliminary quality standards, biological activities can temporarily use immunological methods, product-related impurity content should be combined with toxicity research and the clinical maximum dose are evaluated, and the relevant project limit requirements can be reserved for tightening space; the preliminary stability study results supporting clinical trial drugs are available.
Before applying for product launch (or clinical trial period), it should be completed: establish a working cell bank that meets the requirements of commercial production and complete a comprehensive verification; determine the process, scale and location of the product to be listed and complete verification, such as: chromatographic medium service life, the entire purification process for the removal of retroviruses; quality studies should be related to the separation, identification and measurement of related substances (or impurities), quality standards should be used to simulate the clinical mechanism of cell activity, content, purity, and important indicators such as activity are not lower than the similar products already listed; the long-term stability data supports the proposed storage conditions and expiration date.
2. Process changes during clinical period
With the development of innovative monoclonal antibody clinical trials, the production process is usually further optimized. Major process changes include: rebuilding engineered cell lines, optimizing media components, changing fermentation equipment and scale, using new purification methods or media, and adjusting formulation and specifications. For example, the non-clinical and early clinical trials of anti-PD-1 antibody nivolumab adopt the A process; the B process is adopted after the process and the site change in the critical clinical period; the C process is adopted to improve the downstream process robustness before the application for the market.
Therefore, it is recommended that applicants use a list in the pharmacy data to clarify the batch, production scale and process information of the samples used in pre-clinical and different clinical trials. The time nodes of major process changes should be coordinated with clinical trials. Before critical clinical trials, it is recommended to clarify the production process, scale, and location to ensure that commercial products are consistent with the quality of clinical trial samples.
3. Priority review and communication
The long-term evaluation of innovative drugs has long been criticized in the industry. Among them, there are reasons for excessive anxiety caused by insufficient review ability, and there are also institutional reasons for the lack of effective communication and submission of innovative drugs. In order to promote the development of innovative drugs, the FDA adopts “fast track”, “breakthrough therapy” and “accelerated approval” for the treatment of major diseases (or clinically unmet needs). And the “priority review” and other means to speed up the review. For example, anti-PD-1 monoclonal antibody Keytruda® and Opdivo® are eligible for “breakthrough therapy” in the treatment of non-small cell lung cancer.
Communication can make up for the shortcomings of written materials and is an important safeguard for scientific evaluation of drugs. In recent years, the Drug Testing Center has also issued relevant regulations on “communication and exchange meetings” and “consultation on general technical issues”. For common problems in pharmaceutical research, applicants are advised to use the “general technical problem consultation” written communication. For pharmacy issues involving major decisions on specific varieties, it is recommended to apply for a “communication meeting” at the important node of the new drug development (pre-IND, end-of-phase 2, pre-NDA). The meeting notes can be used as an important basis for review and approval of drug development. It is important to point out that due to the limited content and time of discussion in communication, there may be changes in future policies, regulations and technical requirements. Therefore, applicants cannot treat “communication and meeting” as “pre-review”. Discuss with the regulators on the law and evaluation of new drug development.