UK MHRA Guidance: Use of Non-OECD MAD Non-Clinical Data in Support of UK Clinical Trial Authorisation
The Medicines and Healthcare products Regulatory Agency (MHRA) has published guidance on using non-clinical data generated outside the Organisation for Economic Co-operation and Development (OECD) Mutual Acceptance of Data (MAD) framework to support UK Clinical Trial Authorisation (CTA) applications.
OECD MAD (Mutual Acceptance of Data) is an international agreement under which participating countries accept data generated in accordance with OECD Test Guidelines and OECD Principles of Good Laboratory Practice (GLP) for regulatory purposes. This avoids unnecessary duplication of non-clinical testing and supports international regulatory cooperation.
The MHRA's framework provides a risk-proportionate approach to considering non-OECD MAD data while maintaining scientific integrity, regulatory confidence and clinical trial participant safety.
Introduction and Scope
Non-OECD MAD data refers to non-clinical data generated outside the OECD MAD framework. This may include studies conducted in countries that are not OECD members or full MAD adherents, as well as studies performed at facilities that are not covered by recognised national GLP compliance monitoring programmes.
The guidance applies to UK CTA applications relying on such data. OECD MAD-compliant studies remain the preferred standard for pivotal non-clinical safety studies. However, the MHRA may consider non-OECD MAD data based on study quality, inspection information, regulatory compliance and the totality of available evidence.
MHRA Framework for Non-OECD MAD Data
The MHRA has introduced three complementary assessment streams:
Inspection and Compliance Intelligence: Risk-based inspections and compliance information to improve confidence in testing facilities generating non-OECD MAD data.
Enhanced Non-Clinical Assessment: A dedicated assessment pathway for eligible CTA applications relying on non-OECD MAD data.
Weight-of-Evidence Use of Clinical Data: Consideration of relevant previous human experience alongside non-clinical evidence.
These streams support a proportionate assessment based on data reliability, scientific uncertainty and potential risks to clinical trial participants.
Inspection and Compliance Intelligence Stream
The UK Good Laboratory Practice Monitoring Authority (UK GLPMA) may conduct voluntary, risk-based inspections of facilities generating pivotal non-OECD MAD data.
Inspections may examine quality management systems, study records, data integrity, traceability and archiving arrangements.
Following inspection, facilities may be required to address findings through Corrective and Preventive Actions (CAPA). The UK GLPMA may issue a Statement of Inspection describing the inspection scope and outcome.
These inspections do not constitute statutory GLP compliance monitoring inspections and do not result in a UK GLP compliance certificate. The MHRA may also consider relevant inspection findings from other regulatory authorities.
Sponsors should undertake appropriate due diligence of testing facilities and provide available inspection information, GLP documentation and relevant compliance history.
Enhanced Non-Clinical Assessment Pathway
The enhanced assessment pathway initially focuses on eligible first-in-human (FIH) clinical trials involving:
Patients with advanced oncology indications.
Patients with life-threatening or severely debilitating conditions associated with substantial unmet medical need.
Patients with eligible rare diseases.
The MHRA considers disease severity, prognosis, available treatment options and unmet medical need when determining eligibility. Trials involving healthy volunteers will not normally qualify.
Sponsors must engage with the MHRA before submitting their CTA application and provide justification for pathway eligibility, details of the investigational product, proposed indication and information on the non-clinical study package.
The MHRA aims to communicate its eligibility view within 14 calendar days. Eligibility confirmation must be obtained before CTA submission.
Confirmation of eligibility does not guarantee acceptance of the non-clinical data or CTA approval, and the pathway does not change the applicable statutory assessment timelines.
Additional Information Requirements and Non-Clinical Assessment
Sponsors relying on non-OECD MAD data should provide sufficient supporting information, including:
Identification of pivotal non-clinical studies, testing facilities, study numbers and locations.
Full study reports and relevant supporting records.
Available GLP certificates, Statements of Inspection and regulatory inspection documentation.
Details of significant inspection findings and associated CAPA.
Scientific justification for using non-OECD MAD data, including relevant clinical experience, disease context and unmet medical need.
For mixed OECD MAD and non-OECD MAD study packages, additional information requirements will primarily focus on non-OECD MAD studies relevant to participant safety.
The MHRA will assess the reliability and relevance of the data, including dose selection, target organ toxicity, safety margins and proposed clinical trial safeguards.
Where necessary, risk mitigation measures may include conservative dose selection, sentinel dosing, staggered recruitment, predefined stopping rules and enhanced safety monitoring.
If the available evidence is insufficient, the MHRA may request additional information or studies, impose restrictions or conditions, or refuse the CTA application.
Weight-of-Evidence Use of Clinical Data
Relevant previous human experience may support the overall assessment of non-OECD MAD non-clinical data and help address remaining scientific uncertainties.
The MHRA will consider clinical data quality, GCP compliance, relevance to the proposed trial, dose and exposure levels, treatment duration and available safety information.
However, clinical data do not automatically replace pivotal non-clinical studies required to support human exposure, particularly where uncertainties involve cumulative toxicity, delayed adverse effects or other important safety endpoints.
Ethnic and Population Differences and Bridging Approach
Sponsors should evaluate whether clinical data generated in other populations are applicable to the intended UK clinical trial population.
The assessment should consider potential differences in pharmacokinetics, pharmacodynamics, safety, immunogenicity and efficacy.
Where uncertainties remain, a bridging approach may be required. This could include relevant external clinical evidence or bridging elements within the proposed UK trial, such as safety or pharmacokinetic assessments before wider participant enrolment.
Future Evolution of the Framework
The MHRA intends to develop the framework further based on experience from CTA assessments, inspection activities, compliance intelligence and stakeholder engagement.
Future developments may include increased regulatory confidence in specific testing facilities and potential expansion of the enhanced assessment pathway to additional clinical trial areas.
OECD MAD will continue to represent the preferred standard for generating pivotal non-clinical safety data.
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