Guidance

Use of non-OECD MAD non-clinical data in support of UK clinical trial authorisation applications

MHRA guidance on the use of non-clinical data generated outside the OECD MAD framework in support of UK Clinical Trial Authorisation applications.

• From: Medicines and Healthcare products Regulatory Agency
• Published: 4 November 2026

1. Introduction and scope

Introduction

The Organisation for Economic Co-operation and Development (OECD) Mutual Acceptance of Data (MAD) framework, underpinned by the principles of good laboratory practice (GLP), remains the internationally recognised standard for the generation and regulatory acceptance of pivotal non-clinical safety data. Data generated within the OECD MAD framework benefit from established compliance monitoring programmes and provide a high level of regulatory confidence for decision-making.

The MHRA recognises that the increasingly global nature of non-clinical drug development has led to greater use of specialist test facilities generating non-clinical data outside the OECD MAD framework. Many of these non-clinical development programmes support innovative medicines intended to address serious diseases, rare conditions, and areas of significant unmet patient need.

The MHRA is committed to supporting timely patient access to innovative medicines and enabling high-quality clinical research in the UK, while maintaining robust standards of participant protection and scientific integrity.  To support these objectives, the MHRA has established a risk-proportionate and patient-centred framework for the consideration of non-OECD MAD non-clinical data submitted in support of clinical trial authorisation (CTA) applications.

For the purposes of this guidance, “non-OECD MAD data” refers to non-clinical data that do not fall within the mandatory acceptance arrangements of the OECD mutual acceptance of data system. This includes:

• data generated in countries that are neither OECD members nor full adherents to OECD MAD
• data generated at test facilities or test sites that are not covered by, or whose GLP compliance status has not been verified through, a national GLP compliance monitoring programme recognised under the OECD MAD system

Under the OECD MAD system, mandatory acceptance of non-clinical safety data depends not only on the country in which the work was conducted but also on the GLP compliance status of the test facility and any relevant test sites.

Data generated at a laboratory located within an OECD member country or full MAD adherent country may still be considered non-OECD MAD data for the purposes of this guidance where the laboratory is not included within the scope of the relevant national GLP compliance monitoring programme, or where its GLP compliance status has not been verified by the relevant GLP monitoring authority.  Similarly, data generated at a laboratory located outside an OECD member country or full MAD adherent country are not considered to fall within the OECD MAD framework, irrespective of whether the laboratory has been inspected by another authority.

A study falling outside the OECD MAD framework may have been conducted in accordance with OECD GLP principles or applicable local GLP requirements. However, the regulatory assurance provided through the OECD MAD system relies on the study having been conducted at a test facility or test site that is subject to the national GLP compliance monitoring programme of the country in which it is located. Where this condition is not met, the assurances associated with OECD MAD do not apply. A statement or claim of GLP compliance does not provide equivalent assurance.

The framework is intended to facilitate the development of promising new medicines where appropriate, while ensuring that any uncertainty associated with non-OECD MAD data is identified, understood, and managed. This guidance sets out the MHRA’s initial approach. The framework will be kept under review and, where supported by emerging evidence and regulatory experience, may be expanded to encompass a broader range of therapeutic areas, trial phases or clinical development settings. The framework may also be refined as experience is gained through CTA assessments, inspection and compliance intelligence activities, stakeholder engagement and wider regulatory assurance activities. 

The MHRA approach comprises three complementary and interconnected streams that together support different aspects of regulatory decision-making. The streams provide different but mutually reinforcing sources of assurance and may be applied individually or in combination, depending on the nature of the data package and the level of regulatory uncertainty. Further details of each stream are provided below.

Scope

The scope of this guidance is to:

• describe the MHRA’s approach to the acceptance and use of non-clinical data generated outside the OECD MAD system in support of CTA applications
• provide transparency and guidance regarding the information sponsors should submit when relying on non-OECD MAD data
• describe how inspection and compliance intelligence activities may contribute to regulatory confidence in non-OECD MAD data over time
• explain the enhanced assessment pathway through which eligible applications may be considered for authorisation
• outline how clinical data may be considered within a weight-of-evidence framework where appropriate
• support consistent, transparent, and proportionate regulatory decision-making while maintaining participant safety

This guidance applies broadly to CTA applications that rely on non-clinical data generated outside the OECD MAD framework. However, eligibility for the Enhanced Non-Clinical Assessment Pathway is limited to applications meeting the criteria set out in Section 5.0.

Applications that do not meet those criteria may still be submitted through the standard CTA route, and non-OECD MAD data will be considered on a case-by-case basis. Other elements of the framework, including inspection and compliance intelligence activities and weight-of-evidence considerations, may apply more broadly depending on the circumstances of the application.

2. General principles

Sponsors should note that studies conducted in accordance with OECD GLP and covered by the OECD MAD system remain the primary and expected standard for pivotal non-clinical safety studies.

Assessment under this framework will be guided by the following principles:

• participant safety remains paramount
• decisions will be informed by the totality of evidence available
• the level of scrutiny applied will be proportionate to the degree of uncertainty and the importance of the data for regulatory decision-making
• the anticipated patient benefit and unmet medical need will be considered within the overall benefit-risk assessment

Participation in the OECD MAD framework represents an important source of assurance but is not the sole determinant of confidence. Confidence will also be informed by the available evidence relating to the relevant studies and test facilities, inspection and compliance intelligence, and accumulated regulatory experience.

3. MHRA Framework for non-OECD MAD data

The MHRA framework for the consideration of non-OECD MAD non-clinical data comprises three complementary and interconnected streams:  

• inspection and compliance intelligence
• enhanced non-clinical assessment
• weight-of-evidence use of clinical data

The streams are intended to operate as a coordinated framework rather than as independent regulatory pathways. Depending on the specific circumstances of an application, one or more streams may contribute to the overall regulatory assessment. The relative contribution of each stream will depend on factors including the nature of the investigational medicinal product (IMP), the extent of reliance on non-OECD MAD data, the level of uncertainty associated with the available evidence, and the potential implications for participant safety.

The inspection and compliance intelligence stream represents a longer-term strategic component of the framework. It supports the progressive development of regulatory confidence in selected test facilities generating non-clinical data outside the OECD MAD framework through inspection activities, compliance intelligence and accumulated regulatory experience. As confidence develops, this stream may support a more proportionate approach to the assessment of data generated at those facilities, including for applications that do not meet the eligibility criteria for the enhanced non-clinical assessment stream.

The enhanced non-clinical assessment stream provides an immediate route through which eligible applications may be considered while MHRA inspection and compliance intelligence capability continues to develop. The stream will also remain relevant over the longer term for eligible applications relying on data from facilities for which sufficient MHRA inspection and compliance intelligence has not been established. In such cases, uncertainty associated with the non-OECD MAD data will be appropriately characterised and managed.

The Weight-of-Evidence Use of Clinical Data Stream enables relevant prior human experience, where available and appropriate, to be considered, alongside non-clinical and other supporting evidence as part of the overall regulatory assessment.

Over time, inspection outcomes, compliance intelligence, and accumulated regulatory experience may increase regulatory confidence in study conduct, quality systems, and data integrity at specific facilities. Where sufficient confidence has been established, CTA applications supported by data generated at those facilities may be assessed through standard CTA processes without the additional information normally expected under the enhanced non-clinical assessment stream. Such applications will remain subject to the usual scientific and regulatory assessment requirements.

4. Inspection and compliance intelligence stream

Purpose

The Inspection and Compliance Intelligence Stream supports the development of regulatory confidence in non-OECD MAD facilities that generate non-clinical data submitted in support of UK CTA applications.

The objective of this stream is to enhance MHRA understanding of the systems, processes, and controls used by selected facilities and to support assessment of the reliability, integrity, and traceability of data generated outside the OECD MAD framework. Information obtained through this stream may contribute to both current and future regulatory decision-making.

This stream forms part of the broader MHRA framework for the consideration of non-OECD MAD data and complements the Enhanced Non-Clinical Assessment and Weight-of-Evidence streams.

Inspection and compliance intelligence activities

To support these objectives, the MHRA will undertake targeted, risk-based inspections of selected facilities and may consider other relevant sources of compliance intelligence.

Facilities will be selected for inspection primarily based on the frequency with which data generated at the facility are submitted in support of UK CTA applications. The scheduling and scope of inspections will also take account of the importance of those data to regulatory decision-making, any emerging compliance intelligence, and the nature and level of regulatory uncertainty. Facilities may be identified through review of CTA applications and associated regulatory information. Inspections form part of the MHRA’s broader compliance intelligence strategy and will not necessarily constitute a directed inspection of a particular CTA or study.

Any inspections will be undertaken by the UK Good Laboratory Practice Monitoring Authority (UK GLPMA). These activities will be conducted on a voluntary basis, do not constitute statutory GLP compliance monitoring inspections and will not result in the issuance of a UK GLPMA GLP compliance certificate. They may include review of:

• facilities generating pivotal non-OECD MAD non-clinical data
• quality management systems
• study data and supporting records
• data handling, traceability, and archiving arrangements

The scope and depth of each inspection will be determined using a risk-based approach and may include facility-level systems, relevant processes and selected studies, with the objective of evaluating whether the arrangements in place provide sufficient confidence in the reliability, integrity and traceability of data generated at the facility.

Following the inspection, the test facility will be expected to respond to any findings and provide appropriate corrective and preventive action plans. The UK GLPMA may request evidence of implementation or completion, taking account of the nature and significance of the findings.

A statement of inspection, rather than a GLP statement of compliance, will be issued once the inspection process has been closed. Closure is based on the UK GLP Monitoring Authority’s review and acceptance of the facility’s response to the inspection findings, including proposed corrective and preventive actions. Acceptance of the response does not necessarily require completion of all actions before closure. The Statement of Inspection will describe the scope and outcome of the inspection and indicate whether the facility’s response to the inspection findings was accepted by the UK GLPMA. The MHRA may also consider relevant inspection findings and other compliance information from regulatory authorities and trusted sources, where available and appropriate. The relevance and weight of such information will be considered in the context of its scope and applicability to the facility and studies concerned.

The MHRA will continue to consider whether, and in what form information about facilities inspected and the outcomes of inspection and compliance intelligence activities may be communicated to support transparency and regulatory confidence and appropriate confidentiality protections.

Sponsor responsibilities

Where sponsors directly commission studies, contractual arrangements with test facilities should include provisions permitting appropriate engagement with the MHRA, including the UK GLPMA where inspection or other compliance activities are required. These provisions should enable the test facility to respond to requests for information, provide access to relevant study data and supporting records and facilitate regulatory inspection activities where necessary.

Sponsors should request available information concerning the facility’s quality systems, regulatory oversight and relevant inspection history as part of their proportionate due diligence. Where an inspection statement is available, sponsors should request and review it, taking account of the scope, timing and outcome of the inspection and its relevance to the studies intended to support the CTA. Sponsors should consider whether the information available provides sufficient confidence in the reliability, integrity and traceability of the data generated, and describe in the submission any relevant limitations or residual uncertainties.

The MHRA recognises that sponsors may not always have direct contractual relationships with facilities that generated the original non-clinical data, particularly where products have been acquired or in-licensed. In such circumstances, sponsors should provide available information and explain any limitations on access to supporting documentation. Expectations will be applied proportionately and in the context of information reasonably available to the sponsor.

Contribution to regulatory confidence

Inspection outcomes and other relevant compliance intelligence may inform the MHRA’s level of confidence in a test facility and, where appropriate, support a more proportionate approach to the assessment of data generated at that facility. However, an MHRA inspection does not confer GLP compliance status or guarantee acceptance of data generated there. The acceptability of an individual study will remain subject to assessment of the study and the context of the relevant CTA application.

Sponsors are not expected to seek separate confirmation of acceptability for every CTA supported by data from an inspected facility. Available inspection and compliance intelligence will be considered when determining the applicable information requirements and assessment approach.

The MHRA recognises the importance of providing sponsors with sufficient regulatory predictability before pivotal studies are commissioned or UK clinical development is planned. Sponsors are encouraged to engage with the MHRA by sending an email to clintrialhelpline@mhra.gov.uk using the heading “Non-OECD MAD Compliance – Enquiry – Laboratories” where there is uncertainty about the appropriate assessment route or the relevance of available inspection and compliance intelligence. Any such indication will reflect the information available at that time and will not constitute advance acceptance of an individual study or CTA application.

5. Enhanced non-clinical assessment pathway

Purpose

The enhanced non-clinical assessment stream is the primary mechanism through which eligible CTA applications supported by non-OECD MAD data may be considered for authorisation where the totality of evidence is sufficient to support participant safety and a favourable benefit-risk assessment. It provides an immediate route for eligible applications, including those relying on data from facilities for which sufficient facility-specific inspection and compliance intelligence has not been established, and will remain relevant as the MHRA’s longer-term inspection and compliance intelligence programme develops.

Initial scope

The initial scope of the enhanced assessment pathway is focused on first-in-human (FIH) clinical trials in patients with advanced oncology indications or other life-threatening or severely debilitating conditions associated with substantial unmet medical need, including rare diseases where those criteria are met. This initial scope reflects the MHRA’s intention to facilitate development of innovative medicines in areas where patient need is greatest whilst gaining regulatory experience in a controlled and proportionate manner.

The scope of the pathway will be kept under review and may be expanded or refined considering experience from CTA assessments, inspection and compliance intelligence activities, and stakeholder feedback on the clarity, proportionality and practical operation of the pathway.

Eligibility for consideration for enhanced non-clinical assessment

The following sets out the MHRA’s current position on when non-OECD MAD data may be considered eligible for enhanced non-clinical assessment in support of a CTA application.

Inclusion criteria

Eligibility is restricted to CTA applications that meet all the following criteria:

• FIH clinical trials
• trials in patients with advanced oncology or other life‑threatening or severely debilitating conditions associated with a substantial unmet medical need

For the purposes of this guidance, the MHRA will consider:

• advanced oncology indications as those involving relapsed, refractory, metastatic, or otherwise advanced disease where existing treatment options are limited or prognosis remains poor despite current standards of care
• life-threatening conditions as those in which death is reasonably likely without effective therapeutic intervention
• severely debilitating conditions as those associated with substantial, persistent impairment of functioning, quality of life, or progressive irreversible disability

The disease needs to be associated with a substantial unmet medical need, such that the anticipated benefit-risk balance may justify accepting additional uncertainty associated with the use of non-OECD MAD non-clinical data.

Exclusion criteria

The following will not normally be eligible for consideration under this pathway:

• trials in healthy volunteers
• trials in conditions where effective treatment options are available and the anticipated benefit–risk balance does not justify residual uncertainty

In determining eligibility, the MHRA will consider the severity and prognosis of the condition, the availability and effectiveness of current treatment options, the degree of unmet medical need, and the patient population proposed for enrolment. Eligibility will also depend on whether the residual uncertainty is considered justifiable within the context of the proposed clinical trial and its anticipated benefit–risk profile.

Eligibility for the enhanced non-clinical assessment pathway must be confirmed by the MHRA following early engagement and prior to CTA submission.

Following confirmation of eligibility by the MHRA, sponsors should provide, at the time of CTA submission, the supporting information described in this guidance to facilitate assessment and minimise the need for requests for further information. Sponsors should also include confirmation of eligibility for the enhanced assessment pathway within the CTA submission package (refer to the details below).

A determination that an application is not eligible for the enhanced non-clinical assessment stream does not constitute a decision on the acceptability of the non-OECD MAD data or the CTA application. Sponsors may still submit such applications through the standard CTA route.

Applications submitted through the standard CTA route will be assessed on a case-by-case basis, taking account of the overall evidence package, the importance of the non-OECD MAD data to the proposed trial, the degree of associated uncertainty, and any measures proposed to mitigate risk to trial participants. The MHRA may request additional information where necessary to support assessment and participant safety.

Subsequent applications and substantial modifications

Where non-OECD MAD data have previously been assessed in support of a UK CTA, that assessment may inform subsequent CTA applications or substantial modifications relying on the same data. Full reassessment will not necessarily be required. However, the continued relevance and adequacy of the data will be considered in the context of the proposed trial and any new non-clinical, clinical, inspection or compliance information. Further assessment or additional information may be required where the proposed exposure, treatment duration, participant population or overall risk profile differs materially from that previously assessed.

Early engagement for trials relying on non-OECD MAD non-clinical data

Early engagement with the MHRA is intended to identify the appropriate assessment route and provide sponsors with clarity on eligibility and information requirements before CTA submission. For eligible applications, the enhanced non-clinical assessment stream provides a structured route through which non-OECD MAD data may be considered, with the additional scientific justification and supporting information needed to characterise and manage the associated uncertainty. Therefore, sponsors intending to rely on non-OECD MAD non-clinical data should engage with the MHRA prior to CTA submission. Sponsors submitting through the standard CTA route are not required to seek eligibility confirmation but should provide sufficient information at submission to explain the relevance of and reliance on any pivotal non-OECD MAD studies.

Sponsors should notify the MHRA via email to clintrialhelpline@mhra.gov.uk with ‘URGENT-NON-OECD MAD NON-CLINICAL DATA SUBMISSION’.

Early notification should include:

• a brief description of the investigational medicinal product and indication

• a detailed justification demonstrating how the proposed application meets the eligibility criteria for enhanced non-clinical assessment. Sponsors should address the severity and prognosis of the condition, available treatment options and their limitations, the extent of unmet medical need, and the proposed patient population
• an outline of the non-clinical package, including identification of pivotal studies generated outside the OECD MAD framework
• anticipated timelines for CTA submission

The MHRA will review the information provided and determine whether the proposed application is eligible for consideration under the enhanced non-clinical assessment pathway and aim to provide a view on eligibility within 14 calendar days. Eligibility must be confirmed by the MHRA prior to CTA submission.

Eligibility confirmation relates solely to entry into the enhanced assessment pathway and does not predetermine the outcome of the subsequent CTA assessment, nor the acceptability of the submitted non-clinical data.

The pathway is not an accelerated CTA assessment route and does not alter the applicable CTA assessment timeline. Early engagement is intended to confirm the appropriate assessment route and information requirements, facilitate efficient assessment and reduce avoidable requests for further information.

Sponsors are encouraged to use existing MHRA scientific advice or regulatory enquiry routes, where appropriate, to support early discussion of complex or borderline cases. Relevant previous MHRA Scientific Advice will be considered but does not, by itself, constitute confirmation of eligibility for the enhanced non-clinical assessment stream. Sponsors should reference the advice and need only provide additional or updated information necessary to support the eligibility determination.

Where eligibility is not confirmed, the MHRA will provide a brief explanation of the basis for its determination. Non-eligibility does not mean that the non-OECD MAD data cannot be included in a CTA. The sponsor may submit the application through the standard CTA route where appropriate, although the applicability of the framework and any additional information requirements will be determined on a case-by-case basis.

Additional information requirements for inclusion with CTA submission

For CTAs eligible for the enhanced non-clinical assessment stream, sponsors must provide the information necessary for the MHRA to assess the reliability, regulatory relevance and suitability of the pivotal non-OECD MAD data. Requirements will be proportionate to the extent of reliance on each study, its importance to participant safety and regulatory decision-making, and any residual uncertainty not addressed by other non-clinical or clinical evidence.

Where a non-clinical package includes studies generated both within and outside the OECD MAD framework, the additional information requirements will focus on non-OECD MAD studies on which the application relies to support participant safety or the proposed clinical trial. Where studies covered by the OECD MAD system adequately support the proposed clinical exposure, treatment duration and relevant safety endpoints, earlier or supplementary non-OECD MAD studies may be treated as supportive and will not, solely by their inclusion in the package, trigger enhanced non-clinical assessment. Any relevant findings from those studies must nevertheless be identified and considered as part of the totality of evidence.

Where an application is not eligible for the enhanced non-clinical assessment stream but is submitted through the standard CTA route, non-OECD MAD studies may still be included. Sponsors should provide sufficient information at submission to explain the relevance of those studies, the extent to which the application relies on them and any associated uncertainty. The additional information requirements below will not necessarily apply in full and will be determined case by case. The MHRA may request further information during the assessment where necessary.

For applications eligible for the enhanced non-clinical assessment stream, the following core information must be provided at the time of CTA submission.

Study identification and traceability

This includes:

• a list of all pivotal non-clinical safety studies
• study numbers, dates of conduct, and test facility names and locations
• identification of studies generated outside the OECD MAD framework

Study reports

Applicants should be aware that:

• full study reports must be provided for pivotal studies generated outside the OECD MAD framework
• relevant study data and supporting records should be made available to the MHRA upon request where necessary to assess data reliability, traceability or interpretation
• the extent of any request will be proportionate to the concerns identified

Regulatory and inspection status

Applications must include any available:

• information relating to the facility’s regulatory oversight, inspection history, or GLP status
• GLP certificates, inspection statements, inspection reports, or equivalent regulatory documentation relevant to the submitted studies. Documents issued in a language other than English should be accompanied by an accurate English translation. The original document should also be provided. Sponsors should identify the date, scope and outcome of the inspection and explain its relevance to the facility, systems and studies concerned
• where known, details of any critical or major inspection findings or equivalent classifications, that relate to the submitted studies or concern facility systems or processes that could affect their reliability, integrity or traceability, together with any corrective and preventive actions taken.

Inspection information should be sufficiently current and relevant to inform the assessment. There is no automatic three-year cut-off; the weight placed on an inspection will depend on its timing relative to study conduct, its scope, any subsequent changes at the facility and any more recent compliance information.

Scientific justification

A clear justification for reliance on non-OECD MAD data, including:

• disease context, patient population and unmet medical need;
• any supporting evidence relied upon, which may include mechanistic understanding, class knowledge, related products, clinical experience, inspection history, or other relevant information

The MHRA does not expect sponsors to duplicate information already contained within submitted study reports. Where relevant information is adequately described in study reports or other submitted documentation, sponsors may cross-reference the relevant sections rather than provide separate summaries.

Provision of this information at submission is intended to facilitate efficient assessment and minimise the need for requests for further information.

Assessment approach

The MHRA will apply a structured, risk-proportionate assessment to determine whether the totality of evidence submitted is sufficient to support the safe conduct of the proposed clinical trial and a favourable benefit-risk assessment.

Enhanced non-clinical assessment may be undertaken prospectively for applications confirmed as eligible through early engagement. It may also be undertaken during the assessment of a CTA submitted through the standard route where the MHRA identifies that additional assessment of pivotal non-OECD MAD data is necessary to determine whether the residual uncertainty is acceptable.

The assessment is described as enhanced because, in addition to the standard CTA assessment, the MHRA will consider supplementary information submitted in support of non-OECD MAD data. The extent of review will be proportionate to the importance of the data for regulatory decision-making and the level of uncertainty identified.

The assessment will consider the reliability of the submitted data and the level of confidence that can be placed in critical studies supporting key regulatory decisions, including FIH dose selection, identification of target organs of toxicity, establishment of safety margins, and the adequacy of measures proposed to protect clinical trial participants.

The MHRA will also consider the broader clinical context, including disease severity, prognosis, the intended patient population, the availability and limitations of existing treatment options, and the extent of unmet medical need. The assessment will evaluate the degree to which any residual uncertainty affects confidence in risk characterisation and whether the proposed risk mitigation measures are sufficient to support safe trial conduct.

Where justified by the level of uncertainty, additional safeguards may be required, including conservative dose selection, sentinel dosing, staggered recruitment, stopping rules, and enhanced safety monitoring. Such safeguards may be implemented through protocol provisions, including UK-specific measures, where considered necessary to support protection of UK clinical trial participants.

Where the overall level of uncertainty is considered too high, or where the available information does not provide sufficient confidence in the reliability or suitability of the data for their intended regulatory purpose, the MHRA may request additional information or data, impose restrictions or conditions on the proposed clinical trial, or refuse the CTA.

Applications assessed under this stream will remain subject to the applicable statutory clinical trial assessment timelines. Sponsors should ensure that all information and supporting documentation described in this guidance are provided at the time of submission to facilitate assessment and minimise the need for requests for further information. Such a conclusion applies to the application and evidence assessed at that time and does not prejudice a future CTA. A subsequent application may be considered where new evidence materially reduces the uncertainty, including relevant clinical data, additional studies covered by the OECD MAD system, further inspection or compliance information, or other supporting evidence.

6. Weight-of-evidence use of clinical data

Purpose

This section applies where a CTA is supported by non-clinical data generated outside the OECD MAD framework and relevant prior human experience is available. It describes the circumstances in which that clinical experience may contribute to the overall weight-of-evidence assessment. 

Where relevant clinical data provide sufficient evidence to address the uncertainty associated with the non-OECD MAD studies and support the proposed exposure, dosing regimen and trial population, the application may be assessed through the standard CTA route. Enhanced non-clinical assessment is intended for circumstances in which additional assessment of the non-clinical evidence is necessary to determine whether the residual uncertainty is acceptable.

Clinical data may be particularly informative where prior human experience helps characterise the risks associated with the proposed trial. To contribute meaningfully to the weight-of-evidence assessment, such clinical experience should be sufficiently mature and relevant to the proposed UK study, including the intended trial population, dose level, dosing regimen, frequency and duration of exposure. For example, clinical experience limited to single-dose administration may not adequately address uncertainties associated with a proposed multiple-dose regimen. Limited data from ongoing early-phase development programmes would not normally be expected to provide adequate reassurance in this context. Their contribution will be considered case by case within the overall benefit-risk assessment.

Clinical data do not generally replace pivotal non-clinical studies required to support human exposure. However, where appropriate, they may contribute to the assessment of residual uncertainty associated with non-OECD MAD data. The weight placed on the clinical data will depend on their quality, relevance, completeness and ability to address the uncertainty identified.

Sponsors intending to rely on clinical data as part of a weight-of-evidence approach should provide the relevant data, supporting analyses, and scientific justification as part of the CTA submission package. The relevance and weight of the clinical data will be determined as part of the CTA assessment. Separate pre-submission confirmation of their acceptability is not required. Sponsors may seek MHRA scientific advice or use existing regulatory enquiry routes for complex or novel product development questions where appropriate.

Clinical data have inherent limitations in their ability to characterise risk, particularly during early development. Early-phase studies are typically small, involve limited exposure durations, and may not identify cumulative toxicity, delayed adverse effects, or fully characterise target organ toxicity. Certain hazards, including genotoxicity and reproductive toxicity, cannot generally be adequately assessed through clinical data alone.

Therefore, the use of clinical data within this framework will generally be considered only where there is a serious or life-threatening condition, substantial unmet medical need, or other circumstances in which prior human experience may meaningfully inform the assessment of participant risk. Examples of such circumstances may include situations where a GLP-compliant OECD MAD generated genotoxicity package is available together with relevant prior clinical experience, or certain biological products for which genotoxicity testing is not generally expected and where available clinical experience substantially informs the assessment of residual uncertainty. However, the availability of clinical data alone would not necessarily justify acceptance of residual uncertainty associated with non-OECD MAD data. The acceptability of such uncertainty will also depend on the anticipated benefit to participants and the overall benefit-risk balance of the proposed study, which may differ between studies in serious or life-threatening conditions, studies in conditions for which effective treatment options are available, and healthy volunteer studies. Such considerations will be evaluated on a case-by-case basis within the overall benefit-risk assessment.

Where clinical data are submitted, the MHRA will consider the following factors:

Data quality and reliability

Sponsors should demonstrate that the clinical data are robust, reliable, and suitable for regulatory decision-making. This should include evidence that:

• the data are sufficiently complete, consistent and reliable for their intended regulatory use;
• studies were conducted in accordance with the principles of good clinical practice (GCP) as set out in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice, as amended from time to time (ICH E6)
• appropriate oversight, monitoring, and safety reporting arrangements were in place
• the observed safety profile is consistent with available non-clinical findings and, where relevant, with products sharing a similar mechanism of action

For clinical studies conducted in accordance with ICH GCP in countries or regions where this guideline has been implemented by the relevant regulatory authority, the MHRA would not normally expect extensive additional evidence of routine GCP oversight arrangements beyond that contained within the submitted supporting clinical documentation.

Relevance to the proposed clinical trial

Where clinical data are relied upon to support the proposed dosing regimen, the data should be directly relevant to the intended clinical use. Sponsors should demonstrate that the proposed dose, dosing frequency, and treatment duration are supported by prior clinical experience at comparable exposure levels.

Data derived from incomplete or ongoing studies, such as dose-escalation programmes that have not yet achieved the proposed exposure, will generally provide limited support for dose justification. Similarly, single-dose clinical studies cannot be assumed to adequately characterise risks associated with repeated administration, accumulation, or delayed toxicity.

Where relevant clinical experience is insufficient to support the proposed dosing strategy, the MHRA will consider whether the available non-clinical evidence provides sufficient support for the proposed dose, exposure and treatment duration. Where both the clinical evidence and the non-OECD MAD non-clinical data are subject to significant uncertainty, the overall evidence package may not be sufficient to support the proposed trial.

Risk mitigation measures

Where residual uncertainty remains, the MHRA may consider whether appropriate risk mitigation measures have been incorporated into the trial design. These may include:

• sentinel dosing;
• staggered enrolment;
• safety run-in cohorts;
• conservative dose selection and escalation strategies; and
• enhanced safety monitoring and predefined stopping criteria.

The nature and extent of any mitigation measures should be proportionate to the identified risks and uncertainties. Sponsors should incorporate appropriate measures into the proposed trial design taking account of the considerations outlined above. The MHRA may require further measures where, having considered the totality of evidence and any residual uncertainty, the proposed approach is not considered sufficient to support participant safety.

Population applicability and ethnic considerations

Where clinical data have been generated in populations that may not be representative of the proposed UK trial population, additional considerations may apply. Sponsors should provide an assessment of the applicability of the available data, including consideration of potential differences affecting pharmacokinetics (PK), pharmacodynamics (PD), safety, immunogenicity, or efficacy.

Where available, supporting data from populations relevant to the proposed UK clinical trial should be provided. Where such data are unavailable, additional scientific justification and, where appropriate, risk mitigation measures may be required.

Assertions that ethnic differences are unlikely should be supported by relevant evidence where available. Whilst scientific justification may contribute to the assessment, theoretical considerations based solely on product characteristics, mechanism of action, pharmacology, or disease considerations may not, in isolation, be sufficient to demonstrate the applicability of clinical data to the proposed UK population.

In some situations, a bridging approach may be necessary to support extrapolation of the available data to the intended UK population. This may include:

• external bridging evidence from relevant clinical studies demonstrating comparable exposure, safety, PK, or tolerability; or
• incorporation of bridging elements within the proposed UK study, such as a safety or PK run-in phase designed to confirm key assumptions before wider participant enrolment

Therefore, where uncertainty regarding the applicability of non-UK clinical data remains, incorporation of appropriately designed bridging elements within the proposed UK study is generally preferred. Alternative external bridging evidence may also be acceptable where it sufficiently addresses the identified uncertainty.

Overall weight-of-evidence assessment

Clinical data will be considered within the context of the totality of evidence and will not normally be sufficient, in isolation, to compensate for significant deficiencies in the non-clinical package.

The MHRA will consider the combined contribution of the non-clinical data, available clinical experience, mechanistic understanding, external evidence, and proposed risk mitigation measures when determining whether the overall level of uncertainty is acceptable to support the safe conduct of the proposed clinical trial.

7. Future evolution of the framework

The MHRA’s approach to non-OECD MAD non-clinical data will continue to evolve as experience is gained through CTA assessments, inspection and compliance intelligence activities, and engagement with stakeholders and international regulators.

Future developments may include:

• increased confidence in data generated at specific facilities following inspection outcomes and accumulated regulatory experience
• a more proportionate assessment approach for data generated at such facilities
• expansion of the enhanced non-clinical assessment stream to a wider range of trials, supported by corresponding refinement of the eligibility criteria as experience and evidence develop

Any future developments will remain evidence-based, risk-proportionate, and focused on maintaining participant safety. The OECD MAD framework will continue to represent the preferred standard for the generation and regulatory acceptance of pivotal non-clinical safety data.

Annex A: key concepts and assessment principles

1. Why the MHRA has introduced this framework

The MHRA recognises the increasingly global nature of medicines development and the growing use of non-clinical data generated outside the OECD MAD framework. This framework is intended to support timely development of innovative medicines, particularly in areas of substantial unmet medical need, whilst maintaining robust standards of participant protection, scientific integrity, and regulatory oversight.

2. Definition of non-OECD MAD data

For the purposes of this guidance, “non-OECD MAD data” refers to non-clinical data that do not fall within the mandatory acceptance arrangements of the OECD Mutual Acceptance of Data system. This includes:

• data generated in countries that are neither OECD members nor full adherents to OECD MAD
• data generated at test facilities or test sites that are not covered by, or whose GLP compliance status has not been verified through, a national GLP compliance monitoring programme recognised under the OECD MAD system

Under the OECD MAD system, mandatory acceptance of non-clinical safety data depends not only on the country in which the work was conducted but also on the GLP compliance status of the test facility and any relevant test sites.

Data generated at a laboratory located within an OECD member country or full MAD adherent country may still be considered non-OECD MAD data for the purposes of this guidance where the laboratory is not included within the scope of the relevant national GLP compliance monitoring programme, or where its GLP compliance status has not been verified by the relevant GLP monitoring authority. Similarly, data generated at a laboratory located outside an OECD member country or full MAD adherent country are not considered to fall within the OECD MAD framework, irrespective of whether the laboratory has been inspected by another authority.

A study falling outside the OECD MAD framework may have been conducted in accordance with OECD GLP principles or applicable local GLP requirements. However, the regulatory assurance provided through the OECD MAD system relies on the study having been conducted at a test facility or test site that is subject to the national GLP compliance monitoring programme of the country in which it is located.

3. Use of inspection information outside the enhanced non-clinical assessment stream

Inspection outcomes, compliance intelligence and accumulated regulatory experience may, where sufficient confidence in a test facility is established, support a more proportionate assessment of data generated at that facility, including through the standard CTA route.

An inspection does not confer GLP compliance status or guarantee acceptance of the data. Each study and CTA will be assessed on its own merits, taking account of the scope and outcome of the inspection, the studies concerned, the proposed trial population and any residual uncertainty.

4. MHRA inspections and GLP compliance status

Inspection activity undertaken by the MHRA in connection with this guidance does not constitute a statutory GLP compliance monitoring inspection and will not result in the issue of a UK GLPMA GLP compliance certificate or confer GLP compliance status on the test facility.

A statement of inspection will be issued to the test facility following closure of the inspection. This will indicate the inspection dates, any deficiency areas classified as critical or major, and whether the test facility’s response has been accepted or rejected.

Sponsors considering using the facility should request the statement directly from the facility as part of their due diligence and review its scope, date, outcome and relevance to the studies concerned.

The statement may contribute to confidence in the facility but does not guarantee acceptance of data generated there. The acceptability of individual studies will remain subject to assessment in the context of the relevant CTA.

The MHRA will continue to consider how sponsors may be informed that relevant facility-level inspection information exists and how such information may appropriately be communicated, subject to confidentiality protections.

5. Obtaining and using statements of inspection

Sponsors considering using a facility should request any available UK GLPMA statement of inspection directly from the facility as part of their due diligence.

Sponsors should consider:

• the date and scope of the inspection
• the systems, processes and study types reviewed
• the inspection outcome
• any material findings
• the status of relevant corrective and preventive actions
• the relevance of the inspection to the studies intended to support the CTA

An inspection statement is one source of information and should be considered alongside the facility’s experience, capabilities, quality systems, regulatory history and relevant study information.

6. Use of inspection findings from other regulatory authorities

The MHRA may consider inspection findings and other compliance information from regulatory authorities and trusted sources. The weight placed on that information will depend on:

• the date and scope of the inspection
• the systems, processes and studies reviewed
• its relevance to the facility and submitted studies
• the outcome and status of any material findings
• any subsequent compliance information or changes at the facility

Information from another authority does not automatically confer GLP compliance status or guarantee acceptance of the submitted data.

7. Additional information requirements for non-OECD MAD data

Data generated within the OECD MAD framework are subject to independent compliance monitoring programmes, including inspections and, where appropriate, study audits. These activities provide regulatory assurance regarding study conduct, data integrity, traceability, and reliability.

Where non-clinical data are generated outside the OECD MAD framework, this assurance may not be available. Additional information is therefore required to enable the MHRA to assess the reliability of the data and determine whether any residual uncertainty can be appropriately managed.

8. Acceptability of non-OECD MAD data

Data generated outside the OECD MAD framework can still be considered for regulatory purposes.

Data generated in compliance with OECD MAD remain the preferred standard for regulatory confidence. However, non-OECD MAD data may be considered in defined circumstances where sufficient information is available to support an assessment of data reliability and where the overall benefit–risk balance justifies any remaining uncertainty.

Acceptance is determined on a case-by-case basis.

9. Eligibility of oncology trials for the enhanced non-clinical assessment stream

Not all oncology research will qualify for the enhanced non-clinical assessment stream.

Eligibility is not based solely on the therapeutic area. The MHRA will consider factors such as:

• disease stage
• prognosis
• availability of existing treatment options
• unmet medical need
• the extent to which additional uncertainty can be justified in the proposed clinical context

For example, advanced, relapsed, refractory, or metastatic malignancies may be more likely to satisfy the eligibility criteria than malignancies for which effective treatments are widely available and prognosis is favourable.

10. Definition of advanced oncology

For the purposes of this guidance, advanced oncology generally refers to:

• relapsed disease
• refractory disease
• metastatic disease; or
• disease where prognosis remains poor despite current standards of care

The MHRA will consider the specific clinical context and available treatment options when determining eligibility.

11. Definitions of life-threatening and severely debilitating conditions

A life-threatening condition is one in which death is reasonably likely without effective therapeutic intervention or where available treatment options are inadequate to substantially alter prognosis.

No fixed timeframe is specified. The MHRA will consider the likelihood and timing of mortality in the context of the condition, its expected progression, available treatments and the prognosis of the proposed trial population.

A severely debilitating condition is one associated with substantial and sustained impairment of physical or cognitive function, quality of life or progressive irreversible disability.

Examples may include certain advanced malignancies, severe neuromuscular disorders, progressive neurodegenerative diseases and serious genetic conditions. These examples are illustrative and not exhaustive.

12. Definition of substantial unmet medical need

When considering unmet medical need, the MHRA may consider:

• whether satisfactory treatment options are available
• the effectiveness and limitations of existing therapies
• disease prognosis despite treatment
• whether patients have exhausted available treatment options
• the potential clinical benefit offered by the investigational medicinal product

No single factor is determinative, and decisions will be made in the context of the overall benefit–risk assessment.

13. Eligibility for the enhanced non-clinical assessment stream

Eligibility is currently restricted to first-in-human trials in patients with advanced oncology or other life-threatening or severely debilitating conditions associated with substantial unmet medical need.

The MHRA will consider:

• disease severity and prognosis
• the intended patient population
• availability and effectiveness of existing treatments
• degree of unmet medical need
• the importance of the non-clinical data to key safety decisions
• whether the additional uncertainty associated with non-OECD MAD data is justified in the context of the proposed clinical trial

Eligibility will be determined on a case-by-case basis following early engagement with the MHRA.

14. Pre-submission advice on eligibility

Sponsors intending to rely on non-OECD MAD data are expected to engage with the MHRA before CTA submission and provide the information outlined in this guidance.

The MHRA will aim to provide a view on eligibility within 14 calendar days. Eligibility must be confirmed before the CTA is submitted.

Confirmation of eligibility:

• permits the application to use the enhanced non-clinical assessment stream
• identifies the applicable information requirements
• does not confirm that the non-clinical data are acceptable
• does not predetermine the CTA outcome
• does not provide an accelerated CTA assessment timeline

Where eligibility is not confirmed, the MHRA will provide a brief explanation of the basis for its determination.

15. Use of previous MHRA scientific advice

Relevant previous MHRA scientific advice may support early engagement. Sponsors should reference and provide any relevant MHRA scientific advice letter that considered the non-OECD MAD data or the proposed assessment route.

The MHRA will take this advice into account, and sponsors need not repeat information that remains current. However, unless the advice expressly confirmed eligibility for the enhanced non-clinical assessment stream, eligibility must still be confirmed through the early-engagement process.

Sponsors should identify any material changes since the advice was provided.

16. Where eligibility for the enhanced non-clinical assessment stream is not confirmed

Non-eligibility does not mean that non-OECD MAD data cannot be included in a CTA.

The application may be submitted through the standard CTA route where appropriate. Sponsors should explain:

• the relevance of the non-OECD MAD studies
• whether and to what extent the application relies on them
• any associated uncertainty

The enhanced information requirements will not necessarily apply in full and will be determined case by case. The MHRA may request further information or undertake additional assessment during the CTA review where necessary.

17. Eligibility confirmation and acceptance of non-clinical data

Confirmation of eligibility for the enhanced non-clinical assessment stream does not mean that the non-clinical data have been accepted.

Eligibility confirms only that the application may be assessed under this framework. Acceptance of the non-OECD MAD non-clinical data will be determined during the CTA assessment and will depend on:

• the reliability and regulatory relevance of the data
• their suitability for their intended use
• the extent of any residual uncertainty
• the totality of supporting evidence
• whether the proposed trial adequately protects participants

18. Assessment of mixed OECD MAD and non-OECD MAD non-clinical study packages

The presence of non-OECD MAD studies does not automatically trigger enhanced assessment.

The relevant consideration is whether the CTA relies on those studies to support participant safety or the proposed clinical trial. Where studies covered by the OECD MAD system adequately support the proposed exposure, treatment duration and relevant safety endpoints, earlier or supplementary non-OECD MAD studies may be treated as supportive.

Relevant adverse or discordant findings from all studies must nevertheless be identified and considered as part of the totality of evidence.

19. Role of clinical data in addressing deficiencies in the non-clinical package

Clinical data will not normally replace the need for an adequate and reliable non-clinical safety package.

Clinical data may, however, be considered supportive as part of the totality of evidence. In exceptional circumstances, relevant clinical data may contribute to the overall assessment of uncertainty as part of a weight-of-evidence approach, provided the data are robust, sufficiently mature, applicable to the proposed UK trial population, dose level, dosing regimen, frequency and duration of exposure, and supported by an appropriate scientific justification.

Examples may include situations where a GLP-compliant OECD MAD generated genotoxicity package is available together with relevant prior clinical experience, or certain biological products for which genotoxicity testing is not generally expected and where available clinical experience substantially informs the assessment of residual uncertainty.

The availability of clinical data alone would not necessarily justify acceptance of residual uncertainty associated with non-OECD MAD data. The acceptability of such uncertainty will depend on the overall benefit-risk balance of the proposed study. Limited clinical experience from ongoing early-phase development programmes would not normally be expected to provide adequate reassurance in this context.

The MHRA will consider the relevance, quality, completeness, and applicability of any clinical data submitted.

20. Additional and UK-specific clinical trial safeguards

Where residual uncertainty remains, the MHRA may require additional safeguards to support participant safety, including:

• conservative dose selection
• sentinel dosing
• staggered enrolment
• safety run-in cohorts
• enhanced safety monitoring
• predefined stopping criteria

Where a trial is already recruiting outside the UK, additional UK-specific measures will not necessarily be required. However, the MHRA may require such measures where the arrangements used elsewhere do not adequately address the risks or residual uncertainty relevant to UK participants.

21. Use of previously accepted non-OECD MAD data in future applications

Each application will be assessed on its own merits and the nature of the CTA. While previous experience, inspection outcomes, and other regulatory information may contribute to the MHRA’s overall confidence in a facility or dataset, acceptance is not automatic and will depend on the totality of evidence available for the specific application.

22. Definition of a bridging approach

A bridging approach is a strategy used to extrapolate existing clinical data to the proposed UK trial population and to understand and reduce uncertainty regarding the applicability.

The purpose of bridging is to confirm key assumptions regarding safety, tolerability, PK, PD, and population applicability before exposing larger numbers of UK participants.

A bridging approach may take different forms, including:

• external bridging evidence, such as completed clinical studies conducted in populations relevant to the proposed UK trial population
• physiologically based PK-PD models
• considerations of possible differences in the safety profile in the two populations
• consideration of possible disease differences in the two populations
• embedded bridging within the proposed UK trial, such as a safety run‑in phase involving a limited number of participants before wider recruitment is permitted

Bridging approaches may be particularly relevant where: clinical data have been generated predominantly in a single geographic region; uncertainty exists regarding population applicability, and limited data may be available at the proposed dose, dosing schedule, or treatment duration; or additional confirmation is required before broader participant exposure.

Bridging approaches are intended to reduce uncertainty and support participant safety. They do not replace the need for an adequate non-clinical data package.

23. Relevance of ethnic and population differences to CTA assessment

Clinical trial data generated in one population may not always be directly applicable to another population.

Intrinsic and extrinsic factors may influence PK, PD, safety, immunogenicity or efficacy.

Examples of relevant factors include body weight and body composition; genetic variability/polymorphisms; disease characteristics; co-medications; environmental and dietary factors; clinical practice patterns.

Where such differences exist, the safety profile, exposure levels, or treatment response observed in one population may not accurately predict outcomes in another population.

For this reason, sponsors should provide sufficient evidence to demonstrate that the available clinical data and models, if used, are applicable to the proposed UK trial population.

24. Evidence requirements for assessing ethnic and population differences

ICH E5 provides a framework for considering potential ethnic differences, but it does not remove the need for supporting evidence.

Arguments based solely on theoretical considerations, class effects, mechanism of action, or assumptions that ethnic differences are unlikely are generally not sufficient in isolation.

An expectation that clinically meaningful differences are not expected does not demonstrate that they are absent for a specific investigational medicinal product.

The MHRA therefore expects sponsors to support such assumptions with product-specific evidence wherever possible. This is particularly important where:

• clinical data have been generated predominantly in a single population
• the proposed UK trial involves a different population
• the product is novel or has limited clinical experience
• uncertainty remains regarding PK, safety, immunogenicity, or efficacy

The extent of supporting evidence required will depend on the overall level of uncertainty and the importance of the clinical data in supporting the CTA.

25. Evidence supporting the applicability of clinical data to the UK trial population

The MHRA may consider a range of evidence to support the applicability of clinical data generated outside the UK population.

Examples include:

• clinical data from populations relevant to the proposed UK trial population
• comparative PK data from different populations
• population PK analyses
• exposure–response analyses
• covariate analyses examining the impact of ethnicity and other relevant factors
• integrated analyses from completed clinical studies
• bridging studies specifically designed to evaluate PK, safety, tolerability, immunogenicity, or efficacy in a relevant population
• physiologically based pharmacokinetic/pharmacodynamic models incorporating ethnic differences

The amount of evidence required will depend on the level of uncertainty and the importance of the proposed assumptions to the overall benefit–risk assessment.

Where significant uncertainty remains, the MHRA may require additional mitigation measures, including bridging approaches within the proposed UK trial, such as a safety run‑in cohort or staged recruitment strategy.

Annex B: case studies

To support implementation of this guidance, case studies demonstrating practical examples and regulatory considerations are intended to be developed and included in future revisions.