The CDE published draft guidance on clinical trials for the approval of trastuzumab on 7 April 2020. This guidance is the third specific guideline released by the CDE in April. The agency also released guidance on adalimumab on 1 April 2020 [1] and on bevacizumab on 7 April 2020 [2].

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the Chinese authority that oversees all drug manufacturing, trade and registration in the country – has released the draft guidance for a one-month consultation period.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 Trastuzumab Copy Biologicals
Date: April 2020
http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315034

The draft guidance follows the format of the adalimumab guidance in outlining how companies should conduct pharmaceutical, non-clinical and clinical comparison trials in stages ‘using a step-by-step sequence’. The draft guidance also suggests that companies should ‘design follow-up comparison test research based on the results of the previous comparison test’.

The draft guidance covers how comparison studies should start with pharmacokinetic comparisons in healthy subjects and then be followed by assessing clinical effectiveness in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 [3]; but includes points specific to trastuzumab and breast cancer patients taking trastuzumab.

The draft guidance recommends following one of three strategies for the patient population and endpoint for assessing clinical effectiveness in patients when conducting a head-to-head equivalence study with the originator biological, Herceptin:

1. Population: human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer patients who have not received chemotherapy
   Primary endpoint: objective response rate (ORR) as a surrogate endpoint for sensitive efficacy indicators
2. Population: HER2+ early breast cancer pre-operative neoadjuvant therapy
   Primary endpoint: complete remission of pathology (pCR)
3. Population: HER2+ metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma that has not undergone chemotherapy
   Primary endpoint: ORR as a surrogate endpoint.

The draft guidance states that if the above path to complete the study of individual indications is followed, and after the technical review is passed, approval for extrapolation of other indications can be obtained.

Other trastuzumab-specific issues discussed in the guidance include the criteria for selecting study subjects, dose/dosing regimen and route of administration, endpoints/endpoint index and cut-off value, sample size and equivalence thresholds, as well as safety and immunogenicity studies for trastuzumab.

The draft guidance also states that products marketed in China should be selected as reference drugs as far as possible in the clinical research. If a reference drug that is not approved for import registration in China is selected, comparable evidence or development of originator drugs from different sources should be provided before the clinical trial begins.

Shanghai CP Guojian Pharmaceutical had its trastuzumab copy biological (Saiputing) approved by the NMPA in June 2014, however, this was later withdrawn [4]. The only other Chinese company known to be working on a trastuzumab copy biological is Shanghai Henlius Biotech. The company reported in June 2019 that its trastuzumab copy biological, HLX02, had been accepted for review by the NMPA, as well as by the European Medicines Agency [5].

Feedback on the draft guidance to CDC ended on 7 May 2020.

Related article
Biosimilars of trastuzumab

References
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 15]. 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 15]. Available from: www.gabionline.net/Guidelines/China-publishes-draft-guideline-for-bevacizumab-copy-biologicals
3. GaBI Online - Generics and Biosimilars Initiative. Chinese guidelines for copy biologicals [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 15]. Available from: www.gabionline.net/Guidelines/Chinese-guidelines-for-copy-biologicals
4. GaBI Online - Generics and Biosimilars Initiative. Copy biologicals approved in China [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 15]. Available from: www.gabionline.net/Biosimilars/General/Copy-biologicals-approved-in-China
5. GaBI Online - Generics and Biosimilars Initiative. EMA accepts first application for Chinese-made biosimilar HLX02 [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 15]. Available from: www.gabionline.net/Biosimilars/News/EMA-accepts-first-application-for-Chinese-made-biosimilar-HLX02

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