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Part 2 of Schedule 1 to the amended Clinical Trials Regulations requires that the鈥�鈥�(and any individual or organisation that the sponsor听or investigator听delegates trial-related activities to) have regard to all relevant guidance with respect to听commencing听and conducting a clinical trial.

Investigators and sponsors must, therefore, ensure that they are fully aware of the information within this guidance and act accordingly to achieve and听maintain听regulatory compliance.听

In addition, the following guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) are also considered relevant guidance and should be consulted:听

• 听

• 听

Scope听

This guidance should be read in conjunction with ICH E8 (R1)听General Considerations for Clinical Studies. ICH E8 (R1)听establishes听the overarching scientific and quality principles for clinical study design and conduct, including the application of quality by design approaches.

These principles form the basis for the more detailed operational expectations explained in ICH E6 (R3), and organisations are expected to apply ICH E8听(R1) and E6听(R3) together when planning,听conducting听and overseeing clinical trials.听

ICH E6 (R3)听provides听principles听and detailed guidance听which听are听intended听to support sponsors听and investigators听in听delivering听high-quality clinical trials.

This guidance听serves to provide an听explanation of the interconnected quality concepts embedded within ICH E6 (R3);听quality by design (QbD), risk-based quality management (RBQM), and risk proportionality,听and outlines the practical implications for trial听conduct,听oversight听and compliance.听

Schedule 1, Part 2听paragraph听1 of the听Clinical Trials听Regulations adopts the principles of听good clinical practice听as听set out听in ICH E6 making it a requirement to implement these听quality concepts听when conducting clinical trials in the UK.听听

This guidance applies to all UK clinical trials of IMPs.听听

It is not the intention of this document to rewrite the guidance contained in ICH E6 (R3) or ICH E8 (R1) and it is expected that organisations are conversant with these documents.听

Note that the concept of听type A, B and听C听trials听听as听introduced in the听MRC/DH/MHRA joint project paper Risk-adapted Approached to the听Management of Clinical Trials of Investigational Medicinal Products听(Oct 2011)听has been retired.听

ICH GCP E6 R3听and ICH E8听core quality concepts听

E8 (R1) introduces听critical to quality (CTQ) factors听in Section听3.2, describing them as trial attributes fundamental to participant safety and the听reliability and interpretability of trial听results.听听

ICH E6 (R3) Principle听6听reinforces the concept that听鈥檘uality should be built into the scientific and operational design and conduct of clinical trials鈥櫶齛nd more specifically听states:听

鈥淔actors critical to the quality of the trial should be听identified听prospectively.鈥�

These factors are attributes of a trial that are fundamental to the protection of participants, the reliability and interpretability of the trial results and the decisions made based on those trial results. Quality by design involves focusing on critical to quality factors of the trial听in order to听maximise the likelihood of the trial meeting its objectives.

QbD requires听sponsors to identify听the听CTQ factors,听which are the听trial attributes听essential to听clinical trial听participant protection and the reliability of听the听trial results,听early in trial planning.听Examples include (but are not limited to):听

• validity听of primary endpoint measurement

• integrity of randomisation and blinding

• fit-for-purpose听decision-making听(for example those which听impact听safety, dose-escalation听and/or stopping criteria)

• correct application of eligibility criteria

• collection and management of relevant clinical data听

• fit for purpose of validation of computerised systems that are used for clinical data or endpoints听

• informed consent of trial participants听

QbD also听requires听sponsors to:

• design trial processes intentionally to protect these听essential听factors

• ensure that scientific and operational feasibility听(including investigator听and participant burden)听are assessed from the outset

• establish metrics听or key risk indicators听(KRI)听related to the CTQ to听proactively听identify听risk realisation, including the use of quality tolerance limits (QTL)听of acceptable values of KRI听and those that听initiate听defined听escalation processes

ICH E6 (R3) Principle 7 states:

鈥淐linical trial processes, measures and approaches should be implemented in a way that is proportionate to the risks to participants and to the importance of the data collected and that avoids unnecessary burden on participants and investigators.鈥澨�听

This principle links听the听identified听CTQ听factors to the quality management activities undertaken to protect them.听Risk-based quality management听translates听QbD听into operational practice through:听

• systematic听hazard and听risk identification, evaluation, and prioritisation听

• focused risk听mitigation/acceptance,听control听measures听and monitoring aligned with CTQ factors听and KRIs听

• ongoing, dynamic risk review throughout the trial lifecycle

ICH听E6 (R3)听Principle听7.1 states:听

鈥淭rial processes should be proportionate to the risks inherent in the trial and the importance of the information collected. Risks in this context include risks to听the rights,听safety听and well-being of trial participants as well as risks to the reliability of the trial results.鈥�

This听directly reflects the E8 (R1) concept that听conduct and reporting of clinical studies听should听be tailored听to what is critical.听听

These both听emphasise听that听risk听proportionality听should be applied to听ensure that:听

• oversight, data controls, and monitoring reflect the likelihood,听detectability听and impact of听identified听risks

• effort and resources are听allocated听where they protect participant safety and the reliability of key data.听

ICH E6 (R3) Principle 9 states that 鈥淐linical trials should generate reliable results鈥�.听听

This principle underlines the fundamental expectation that trial outcomes can be trusted, interpreted appropriately, and used confidently in regulatory and scientific听decision听making.听

Principle 9.1听builds on this by听stating:听

鈥淭he quality and amount of the information generated in a clinical trial should be听fit for purpose听and sufficient to provide confidence in the trial鈥檚 results and support good decision making.鈥澨�

This means the data collected should be sufficient, relevant, and proportionate to support robust conclusions about the safety and efficacy of the investigational product.

It encourages sponsors and investigators to focus on critical data and processes,听those that directly support听fit-for-purpose decision making during the trial,听participant safety, data integrity, and the credibility of trial results.听

ICH GCP E6 (R3) 3.10听states:

鈥淭he sponsor should adopt a proportionate and risk-based approach to quality management, which involves incorporating quality into the design of the clinical trial (i.e., quality by design) and identifying those factors that are likely to have a meaningful impact on participants鈥� rights, safety and well-being and the reliability of the results (i.e., critical to quality factors as described in ICH E8听(R1)).鈥澨�

Sponsors should therefore move away from a 鈥渙ne size fits all鈥� model of听quality management听as was previously common, and adopt trial-specific proportionate measures based on the intended design of the trial听in order to:听听

鈥⑩�僺afeguard听participant safety and rights

鈥⑩�僲aintain听scientific validity and reliability of trial results听

鈥⑩�僡void unnecessary complexity or burden

It is essential to recognise that the risks associated with a clinical trial may evolve as planned modifications are executed and as practical experience accumulates during the听trial.

Therefore, systems and processes should allow for the continued assessment of听CTQ听factors and related risks with听appropriate risk听control and mitigation applied where听indicated.听

QbD听and RBQM work together to ensure that clinical trials focus on what truly matters: protecting participants and generating reliable, fit听for听purpose results. By听identifying听and safeguarding听CTQ听factors from the outset and adapting controls as risks evolve, sponsors can direct oversight and resources to the areas that have the greatest impact on participant safety,听data听integrity听and results reliability.

Risk proportionality is therefore not about reducing effort but about applying it intelligently,听reducing听oversight where risk is low and strengthening it where aspects of the trial are critical to听trial听success.

This approach replaces听鈥檕ne听size听fits听all鈥櫶齫uality models with a responsive,听evidence听driven framework that supports efficient, credible, and听participant听centred trial conduct.听

The MHRA鈥檚 expectations听

Critical to quality factors听听

These should be defined prior to/alongside protocol development.听

These should be听integrated into the trial protocol, risk assessments,听quality听plans, data management plans听etc.听so that they are transparent and considered听cross-functionally.听

A factor that is critical to quality rarely affects only a single area, so cross鈥慺unctional involvement is essential to ensure broad input and holistic assessment. Establishing a common definition and consistent nomenclature for听CTQ听factors听across functions helps ensure shared understanding, even when each department鈥檚 specific risks or level of interest may differ.听

CTQ听factors should be reconsidered听routinely听as part of听the evolution of the trial as听protocols are听modified听and changes听are听made听to trial听processes听and听learning from听experience听of听conducting the trial are听integrated.听

Risks听identified听through the assessment of听CTQ听factors should be transparent and communicated as听appropriate to听Investigators and delegated service providers.听

To ensure that CTQ factors are appropriately protected, sponsors should also听establish听meaningful metrics, including key risk indicators (KRIs) and quality tolerance limits (QTLs).

KRIs act as early warning indicators of emerging issues that may affect participant safety or the reliability of critical data, while QTLs define the acceptable boundaries of variation for critical parameters.

Exceeding a QTL should trigger predefined review and escalation processes. Together, KRIs and QTLs provide a measurable and proactive mechanism to detect risk realisation and ensure听timely听oversight of what matters most.听

Quality听management听

ICH E6听(R3)听provides guidance on the identification of听risks generally, as well as听on how sponsors should听determine听which risks significantly听impact听CTQ听factors. The MHRA does not prescribe a specific听methodology听for risk听management听but听expects听the following:听

• the establishment and maintenance of a transparent, documented risk听management framework听from protocol development through to trial close-out听and reporting听

• assurance听that risk management听remains听dynamic and embedded within ongoing trial processes, recognising that risks may change as information accumulates. Previously听identified听risks may reduce in significance, new risks may听emerge, and certain events,听such as protocol amendments, accumulating data trends, deviations from expected recruitment or safety patterns, or a SUSAR that听warrants听reconsideration of study conduct,听may require听a听re-evaluation of CTQ factors and associated controls. The risk management system should therefore support continuous review and听timely听adjustment of mitigation measures throughout the trial

• regular review and updating of risk assessments throughout the course of the trial.听

• cross-functional engagement in both risk听identification听and review processes to ensure comprehensive input and holistic evaluation听

• sponsor oversight of the trial,听including quality management,听should听be clearly听demonstrated

Finalisation of the protocol should only take place after all听initial听risk听assessments involving relevant stakeholders are completed听in order to听encompass听required risk听control听and mitigation.听

For example, some risk mitigations may require inclusion in the clinical trial protocol such as how听eligibility听of trial participants is听determined听and confirmed.听

These assessments听should听aim to minimise risks to participants and ensure data integrity, while also reducing burden and inefficiencies for听Investigators听and participants.听听

It is expected that sponsors utilise all relevant stakeholders to听identify听and manage听risks to听CTQ听factors听with an emphasis on cross-functional, open,听and听proactive dialogue.听听

Stakeholders should also include representatives from听quality assurance听(QA)听to听facilitate听exchange of knowledge from this function.听

QA听staff hold significant knowledge of issues associated with the conduct of clinical trials, often across听many听functional areas/teams,听and this information should be considered during the identification and management of听CTQ听factors.听Care, however,听should be taken to ensure the independence of audit activities conducted by the QA function.听

Differing incentives among trial team functions can pose significant challenges to conducting听trials听in a risk听proportionate manner, with priorities often placed on speed or financial milestones, such as activation of听the first site or enrolment of听the听first听participant, rather than on quality objectives that support听participant听safety听and scientific rigour.

It is听suggested that听sponsors implement performance goals that emphasise quality, thereby promoting cross-functional alignment, enhancing risk proportionality, safeguarding participant safety, and ensuring the reliability of trial outcomes.听

It should be ensured that risk-based quality management which focuses on participant safety, data integrity听and听results听reliability is not confused with operational risk assessments which often focus on trial milestones, timing, or cost.听

Once听CTQ听factors and any risks to those are听identified, it is important that sponsors employ a听structured approach to management of听those during听the lifecycle of the trial听ensuring continuous reassessment of the听CTQ听factors and RBQM.听

Organisations should ensure that听timely听proactive actions are taken when issues associated with听CTQ听factors are听identified.听听

Essential record requirements听

Essential records should align with the essentiality criteria described in听ICH E6 (R3)听Appendix C3.1, and sponsors may use structured听trial master file (TMF)听content lists to prospectively听identify听essential records.听

The TMF consists of repositories, usually with a principle or key repository that contains the majority of essential records. The TMF should be used to retain documentation to demonstrate proactive, prospective quality planning; QbD decision making, identification of CTQ factors and RBQM activities.

Documentation should describe the critical to quality (CTQ) factors identified for the trial, the associated risks, and the strategies implemented to mitigate those risks. This information should be readily accessible and may be documented within the protocol, or in the TMF as described in ICH GCP E6 (R3) B.12.1.听听

Retained evidence听should enable听effective evaluation听of key discussions and decision making but avoid excessive or unnecessary record-keeping.听听

The focus should be on capturing what is necessary to听demonstrate听that the sponsor听identified听key risks in the trial听and any processes put in place to听control and听mitigate those risks.听听

Certain decisions may be taken at the programme听or product level rather than at the trial level. Appropriate consideration should be given to how these decisions are referenced, documented, and presented within the TMF.听听

Evidence should be听retained听to demonstrate the structured risk management process implemented:听

• initial risk assessment听identifying听risks to CTQ factors听

• risk evaluation outputs (likelihood, detectability, impact)听听

• rationale for听prioritising or deprioritising听risks听considered听as 鈥榠mportant鈥�

• version history of risk assessments (updated as needed during听trial听conduct)

• personnel听and听functions involved in the risk management process听

• evidence that听the听risk controls听developed are听proportionate to risk severity听

Evidence should also be retained to听demonstrate听that听the听risk听controls听were implemented听and听monitored, including:

• retained documentation that should clearly听demonstrate听completion of activities put in place to detected and mitigate risks.听For听example,听evidence of central monitoring outputs and necessary escalations听听

• evidence to听demonstrate听continuous assessment of听CTQ听factors听and听RBQM activities听

• use of meeting minutes, oversight logs, key risk indicator (KRI) review and quality听tolerance听limit (QTL) assessments to show continuous oversight and听decision-making

It should be clear that risks听highlighted are communicated to stakeholders, such as听investigators or delegated service providers.听

Records听should allow a reader to clearly trace each CTQ factor to associated risks, corresponding controls, and evidence of lifecycle oversight听thereby听presenting a coherent narrative and听demonstrating听effective safeguarding of the听CTQ听factor.听

For instance, a single CTQ factor can be exposed to several types of risk, each听possibly requiring听different controls. Risks A, B, and C have been听identified听for CTQ听factor听1; these are managed by processes X, Y, and Z, detected听via听KRIs听i, ii, and ii听and where a听KRI听exceeds听the QTL, action 伪 is听taken.听

Regular reviews, audits, and oversight logs are essential, and sponsor oversight should be clear, especially when third parties are involved. The emphasis is on efficient, effective, and proportionate documentation that supports compliance throughout the trial lifecycle.听

Records related to听the risk management process听may be听requested and听reviewed during inspections.听Inspections are likely to include review of听听 such records听and听interviews听with relevant personnel听related to, but not limited to:听

• the process听for identification of CTQ factors听

• established risk management framework activities, such as听the听risk assessment process听

• review of any mitigations or controls implemented to safeguard CTQs听

• effectiveness of mitigations and controls听

• review and updates to the above听

• associated record-keeping听