A new batch of guidelines from the CDE covers the subjects, primary endpoints and design of clinical trials for COVID-19 drugs.
Chinese drug regulators are now turning their attention to COVID-19 treatments in addition to vaccines, laying out guidelines for clinical trials this month. On Feb. 17, the CDE released The technical guidelines of clinical trials for COVID-19 drugs (for pilot implementation).
The CDE said the guidelines will provide technical guidance and reference for the design, implementation and evaluation of clinical trials for chemical drugs and therapeutic biologics developed to prevent and treat COVID-19.
The move came six days after the NMPA granted conditional approval for Pfizer's Paxlovid (nirmatrelvir/ritonavir) via emergency review process, making it the second COVID-19 treatment in China after Brii Biosciences' ambacizumab/romlusevimab.
Three phases of clinical development covered
The guidelines cover three phases of clinical development: clinical pharmacology, exploratory, and confirmatory clinical trials.
Although early clinical pharmacology trials are generally conducted on healthy volunteers, the document states that multiple-dose trials may also be conducted on patients with COVID-19 infections, allowing for timely collection of in vivo pharmacodynamic data.
For multidrug combinations comprising antibodies or antivirals with different mechanisms of action, the guidelines recommend conducting a proof of concept study for each drug first to analyze potential interactions.
For exploratory clinical trials, the guidelines suggest that virological outcomes can be the primary endpoint, while clinical and imaging outcomes can be secondary endpoints. Early administration and exploration of optimal dosing regimens are recommended. The CDE encourages flexibility in the design of exploratory studies as well.
But it is the confirmatory trials that take center stage in the document, in which regulators specify guidelines for therapeutic and prophylactic drugs, respectively.
For confirmatory trials of therapeutic drugs, subjects must be a COVID-19 patient who exhibits mild-to-moderate or severe-to-critical stages of symptoms. Regulators also recommend enrolling patients who are at high risks of developing complications, such as the elderly, patients with cardiovascular, respiratory and chronic liver diseases and diabetes, and those immunocompromised.
The guidelines recognize no primary endpoints for confirmatory clinical studies, which means sponsors must therefore communicate closely with the CDE.
Placebos should be used when control drugs are absent. Once a drug is marketed as standard-of-care and shares a similar mechanism of action, it should be used as a control drug in the studies.
Sponsors are encouraged to set up an independent data monitoring committee or a data and safety monitoring board to evaluate safety data and key endpoints to decide whether the clinical trial should be ongoing, modified or terminated.
When it comes to multicenter phase III trials, sponsors should consider whether the trials in different countries would affect the trial design, as subjects might have been enrolled based on different criteria and clinical indicators could be different. They are reminded to pay attention to racial disparities and reach a consensus with regulators on the design of these trials.
Moreover, the guidelines call for confirmatory clinical studies of prophylactic treatments to be randomized, double-blind, placebo-controlled superiority trials. Both the treatment group and the placebo group must be combined with standard isolated observation measures, and COVID-19 incidence data should be collected during the observation period.
COVID-19 drugs currently under development in China
At present, several domestic and foreign companies are developing COVID-19 drugs in China:
· Brii Biosciences’ amubarvimab/romlusevimab, a SARS-CoV-2 virus-neutralizing monoclonal antibody combination therapy granted conditional approval in China on Dec. 8, 2021
· Pfizer’s Paxlovid (nirmatrevir/ritonavir), a SARS-CoV-2-3CL protease inhibitor for oral use granted conditional approval in China on Feb. 11, 2022
· Kintor Pharmaceuticals’ proxalutamide, an androgen receptor antagonist in phase III trials in China (NCT04869228)
· Eli Lilly and Junshi Biosciences’ bamlanivimab/etesevimab, a SARS-CoV-2 virus-neutralizing monoclonal antibody combination therapy in phase I clinical trials in China (NCT05167279)
· Frontier Biotechnologies’ FB2001, which is in phase I clinical trials in China (NCT05197179)
· Junshi Biosciences and Vigonvita Life Sciences’ VV116, an oral nucleoside drug candidate in phase II/III trials in China (NCT05242042)
· Hybio Pharmaceutical’s polypeptide nasal spray, which is in preclinical development
· Shenzhen Antaiwei and Kexing Biopharm’s SHEN26, an RdRp inhibitor in preclinical development
· Everest Medicines’ EDDC-2214, a coronavirus 3CL proteinase inhibitor licensed from A*CCELERATE on Jan. 13, 2022
· Huahui Health’s HH-120, a viral fusion protein inhibitor in phase I clinical trials in Australia (NCT05116865)