Asia-Pacific Roundup: Japan’s PMDA shares guidance on assessing the toxicity of monoclonal antibodies
The Pharmaceuticals and Medical Devices Agency (PMDA) published guidance on using a weight of evidence (WOE) approach to assessing the toxicity of monoclonal antibodies in Japan.
Part of PMDA’s early consideration series, the document is the agency’s response to changes in understanding of the risks of monoclonal antibodies. Monoclonal antibodies pose a low risk of off-target toxicity. Retrospective analyses of short- and long-term general toxicity studies of monoclonal antibodies in monkeys suggest three-month assessments can provide enough information to support clinical trials, PMDA said.
Considering the evidence, regulators in the European Union and United States have moved to rationalize monoclonal antibody toxicity testing and support the use of new approach methodologies (NAMs) rather than animal tests. The early consideration document outlines the current situation in Japan.
PMDA has provided a framework for determining whether a six-month toxicity study is needed in two scenarios. When monkeys are the only relevant species, drug developers should factor data on the drug candidate and other monoclonal antibodies targeting the same antigen into a WOE approach. Relevant evidence includes three-month monkey data on the molecule and clinical results for other treatments.
Companies are likely to need to run a six-month study when toxicity is seen that cannot be explained by the pharmacological or class effects, and for which the mechanism is unknown, PMDA said. The agency also expects companies to run six-month studies when toxicity findings cannot be appropriately monitored in humans, when the presence of the target in multiple organs and tissues creates a risk of diverse toxic effects, and when it is difficult to predict risks based on existing knowledge.
Outside of those situations, the additional value of conducting a six‑month repeated-dose toxicity study may be limited, PMDA said. Six-month studies may also offer limited value when immunogenicity makes it difficult to interpret toxicity findings linked to repeat dosing.
PMDA’s second scenario explains how companies should proceed when no appropriate animal species exists. Citing International Council for Harmonisation guidance, PMDA said transgenic animals expressing the human receptor or homologous proteins should be considered. When neither is available, 14-day repeated-dose toxicity studies in a single animal species should be considered. The 14-day study should evaluate critical functional endpoints, such as cardiovascular and respiratory systems.
In both scenarios, PMDA is encouraging drug developers to use its consultation services proactively to discuss their approaches to toxicity testing. PMDA plans to apply the “reduce, refine, replace” 3R animal testing ethos and consider WOE approaches and NAM data on a case-by-case basis.
China’s NMPA offers to expand WHO cooperation, reaffirms listed authority ambition
China’s National Medical Products Administration (NMPA) has discussed working with the World Health Organization (WHO) “to open up broader prospects for cooperation based on existing efforts.”
NMPA Commissioner Huang Guo recently met a delegation led by WHO’s Martin Taylor in Beijing. In the aftermath of the US leaving WHO, Huang said the body plays “a crucial leading and coordinating role in global public health governance” and discussed expanding NMPA’s cooperation with the organization. Taylor expressed his hope that China will make greater contributions to global public health.
The talks covered the WHO listed authority (WLA) assessment. China began working to become a WLA years ago — a WHO webpage from 2020 said the organization was continuing to work with NMPA on the process — but has yet to secure the status. WHO named the first WLAs in 2023.
NMPA is well-positioned to successfully complete the WLA assessment and other related tasks, Huang said. The confidence reflects a belief that China’s drug regulation and pharma industry have developed rapidly in recent years. NMPA will adhere to the principle of seeking progress while maintaining stability and firmly pursue development up to international standards, Huang said.
The WLA initiative facilitates reliance on the decisions of trusted agencies to optimize the use of regulatory resources. NMPA is one of 18 national regulatory authorities that WHO classed as transitional WLAs as of December.
Senior reviewers from NMPA recently met with Hong Kong’s Department of Health and briefed pharma companies in the Chinese special administrative region. NMPA’s Guangdong-Hong Kong-Macao Greater Bay Area Center for Drug Evaluation and Inspection has been supporting Hong Kong’s regulatory efforts.
Medsafe starts enforcing tighter controls on shipping nitrous oxide to New Zealand
Medsafe has begun enforcing a permit system designed to ensure nitrous oxide entering New Zealand has legitimate medical, catering, or industrial uses.
Nitrous oxide, commonly known as laughing gas, provides pain relief and relaxation during some medical procedures. The compound’s euphoric effects have led to recreational use. Seeking to reduce the risk of serious harm from recreational inhalation, New Zealand last week adopted tighter controls on imports of the gas.
Importers need approval to bring nitrous oxide into New Zealand. Medsafe is assessing applications for permits. To receive a permit, importers need to convince the regulator that they are buying nitrous oxide for a lawful purpose and have established safeguards to prevent misuse. The agency is engaging with importers and assessing early applications, with priority given to companies with imminent shipments.
“The new permit system provides a clear and robust mechanism to verify lawful imports of nitrous oxide, strengthening our ability to identify and intercept consignments that may be diverted for recreational misuse,” New Zealand Customs Service’s Craig Chitty said.
Malaysia’s MDA orders fixes for medical devices after uncovering causes of complaints
The Medical Device Authority (MDA) has ordered corrective and preventive actions for multiple products after identifying the causes of quality problems.
MDA ordered testing of six types of medical devices that were subject to a high volume of complaints. The complaints covered issues including scalpel blades that became blunt mid-procedure, eye drops that caused allergic reactions, and transfer sets that leaked during use. Working with ECRI Berhad, MDA evaluated multiple hypotheses for each complaint.
The tests provided at least one potential explanation for each complaint. The degradation of silicone tubing from prolonged exposure to povidone-iodine explained the transfer set leakage, while the lack of coating on blade surfaces may account for the blunt scalpels. MDA has asked the manufacturers to fix the problems identified through the testing.
TGA posts alert after influenza vaccine erroneously administered to infants in Australia
Reports that AstraZeneca’s FluMist nasal spray influenza vaccine has been used in children below the minimum age have triggered an alert by Australia’s Therapeutic Goods Administration (TGA).
Last month, TGA identified 116 reports of FluMist administration errors in children under two years of age. The vaccine is authorized for use in children and adolescents aged 2 to 18 years. The most common administration errors were “product administered to patient of inappropriate age” and “wrong product administered.”
Early clinical trial data linked the vaccine to increased rates of hospitalization in children aged 6 to 11 months and wheezing in children aged 6 to 23 months. None of the 161 adverse event reports linked to the vaccine, including the 116 infant administration errors, were classed as serious. TGA has advised healthcare professionals to confirm a child is 24 months or older before giving the vaccine.
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India’s Central Drugs Standard Control Organization (CDSCO) has told stakeholders to ensure they establish and maintain robust pharmacovigilance systems. CDSCO Notice
