Another specific guidance for makers of copy biologicals has been published by China’s Center for Drug Evaluation (CDE). This time the guidance covers denosumab.
The CDE published draft guidance on clinical trials for the approval of denosumab on 10 April 2020. This guidance is the fourth specific guideline released by the CDE in April. The agency also released guidance on adalimumab on 1 April 2020  and on bevacizumab and trastuzumab on 7 April 2020 [2, 3].
The CDE, which is part of the National Medical Products Administration (NMPA), formerly the China Food and Drug Administration (CFDA, 国家食品药品监督管理局)– the Chinese authority that oversees all drug manufacturing, trade, and registration in the country – has released the draft guidance for a one-month consultation period.
Guiding Principles for Clinical Trials of Denosumab Copy Biologicals
Date: April 2020
The draft guidance follows the format of the adalimumab guidance  in outlining how companies should ‘according to the principle of gradual progress’ conduct pharmaceutical, non-clinical and clinical comparison trials in stages ‘. The draft guidance states that the first prerequisite for clinical R & D of denosumab copy biologicals is to prove that the drug is similar to the originator through pre-pharmaceutical and non-clinical comparison tests. Then, based on these results, pharmacokinetics (PK) comparison studies and clinical safety and effectiveness comparison studies can be carried out.
The draft guidance covers how comparison studies should start with PK comparisons in healthy subjects and then be followed by assessing clinical effectiveness in patients. The guidance refers back to the overarching guidance on the clinical study of copy biologicals in China ; but includes points specific to denosumab and bone tumour patients taking denosumab. The PK of denosumab is non-linear at doses below 60 mg, therefore it is recommended to use higher doses, where the denosumab exposure is roughly proportional to the dose.
For PK comparison studies the draft guidance recommends using a single-dose, randomized, double-blind, parallel-controlled trial design to evaluate the similarity of PK characteristics preferably in healthy male adults. Due to the influence of the clearance rate of denosumab and the weight of distribution volume receptors, it is recommended to try to control the weight of the subjects in a relatively narrow range. area under the curve (AUC)0-t and maximum concentration (Cmax) are recommended as the main research endpoints, with AUC0-∞, time at maximum concentration (tmax), volume of distribution (Vd), and t½ as secondary research endpoints for comparative analysis. The equivalence limit should be set at 80%‒125%.
For clinical effectiveness comparison studies the draft guidance recommends conducting a head-to-head equivalence study with the originator biological, Xgeva using the following criteria:
Population: adults with solid bone tumour metastasis
Trial design: equivalent design with imported originator drug as a control for randomized, double-blind, and parallel-controlled trials
Dosing regimen / dose: 120 mg/1.7 mL once every four weeks, subcutaneous injection
Primary endpoint: percentage of urinary N-telopeptide/urinary creatinine ratio uNTx/uCr change from baseline value at Week 13
In addition, it is also recommended to investigate immunogenicity throughout the R & D process by detecting the incidence of anti-drugs antibodies and neutralizing antibodies.
The draft guidance states that if a systematic comparison study is carried out in a certain population, then the candidate drug may also seek approval for extrapolation of other indications with the same mechanism of action for the originator drug based on the existing data and information.
The Chinese patent for denosumab will expire in 2022.
China’s NMPA has accepted a clinical trial application of denosumab copy biological HLX14 . The only other Chinese company known to be working on a trastuzumab copy biological is Qilu Pharmaceutical. The company reported in November 2019 that it is carrying out a phase III clinical trial for its copy biological, QL1206 .
The CDE deadline to accept feedback on the draft guidance was until 10 May 2020.
Copy biologicals approved in China
Biosimilars of trastuzumab
1. GaBI Online - Generics and Biosimilars Initiative. China publishes draft guideline for adalimumab copy biologicals [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 22]. Available from: www.gabionline.net/Guidelines/China-publishes-draft-guideline-for-adalimumab-copy-biologicals
2. GaBI Online - Generics and Biosimilars Initiative. China publishes draft guideline for bevacizumab copy biologicals [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 22]. Available from: www.gabionline.net/Guidelines/China-publishes-draft-guideline-for-bevacizumab-copy-biologicals
3. GaBI Online - Generics and Biosimilars Initiative. China publishes draft guideline for trastuzumab copy biologicals [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 22]. Available from: www.gabionline.net/Guidelines/China-publishes-draft-guideline-for-trastuzumab-copy-biologicals
4. GaBI Online - Generics and Biosimilars Initiative. Chinese guidelines for copy biologicals [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 22]. Available from: www.gabionline.net/Guidelines/Chinese-guidelines-for-copy-biologicals
5. GaBI Online - Generics and Biosimilars Initiative. Denosumab copy biological clinical trial application accepted in China [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 22]. Available from: www.gabionline.net/Biosimilars/News/Denosumab-copy-biological-clinical-trial-application-accepted-in-China
6. GaBI Online - Generics and Biosimilars Initiative. Qilu starts phase III trial for denosumab copy biological [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 22]. Available from: www.gabionline.net/Biosimilars/News/Qilu-starts-phase-III-trial-for-denosumab-copy-biological
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