The Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 (SI 2025/538) amend the 2004 Regulations rather than replace them; the amendments came into force on 28 April 2026 (MHRA guidance, GOV.UK). Combined MHRA + HRA review via IRAS becomes the standard legal pathway (combined-review pilot 2018-2023 now embedded). Single IRAS submission with protocol, IB/IMPD, ICF, patient-facing materials, GCP qualifications, insurance/indemnity, transparency plan, diversity plan; parallel MHRA CTA + HRA REC review; combined decision within ~30 days standard. Risk-proportional categorisation — Type A (drugs/uses no higher risk than standard medical care, typically licensed drugs near label) operates notification scheme; Type B (moderate risk, most Phase II/III on licensed drugs, off-label, comparator-controlled) operates expedited review; Type C (higher risk, first-in-human, novel mechanism, ATMPs, paediatric, vulnerable populations) operates full review. Sponsor proposes type with justification; MHRA confirms or recategorises. Mandatory transparency — public registry registration (ISRCTN, ClinicalTrials.gov, EU CTIS, EudraCT or recognised list) within 28 days of authorisation; summary results publication on registry within 12 months of last patient last visit including primary/secondary outcomes, adverse events and paediatric lay summary. Mandatory diversity-and-inclusion — sponsor considers participant diversity (ethnicity, sex, age, comorbidity, geography, socioeconomic) relative to target patient population with documented rationale; HRA inclusive-design guidance on recruitment, language accessibility (Welsh where applicable), inclusive consent. Divergence from EU CTR 536/2014 (CTIS) — separate submission systems (IRAS vs CTIS), different timelines and risk language, no UK-EU mutual recognition. Dual UK/EU trials run parallel submissions with shared protocol and adapted ICFs. Aligns with MHRA Innovative Licensing and Access Pathway (ILAP) and International Recognition Procedure (IRP).

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