Clinical Investigation Documents under ISO 14155:2026 (CIP/IB/ICF/SAP/CIR)

ISO 14155:2026 (fourth edition) was published on 23 March 2026 and replaces ISO 14155:2020 with immediate effect — ISO editions take effect on publication, and no transition period has been announced. It remains the backbone Good Clinical Practice (GCP) standard for the design, conduct, recording and reporting of clinical investigations of medical devices in human subjects, underpinning MDR Articles 62–82 and Annex XV.

Note on harmonisation status: at the time of writing, the harmonised European version cited in the Official Journal (per CID (EU) 2021/1182 and its amendments) is still EN ISO 14155:2020 + A11:2024. ISO 14155:2026 has been adopted at the European level as EN ISO 14155:2026, but its formal citation in the OJ for MDR conformity-assessment purposes should be tracked. In practice, notified bodies expect new clinical investigations to be designed against the current state of the art — i.e. the 2026 edition.

What Changed in the 2026 Edition

The fourth edition builds on established principles but introduces targeted enhancements that directly affect how clinical investigation documents are written:

• Risk management restructured (6.2, Annex H) — a clear distinction is now required between (a) risks related to the use of the investigational device and (b) risks related to procedures required by the Clinical Investigation Plan (CIP) that are not part of routine clinical practice. A documented assessment of residual risks (6.2.2) is required before the investigation starts, and management of CIP-procedure-related risks flows into adverse event handling (7.4.5).
• Estimands framework introduced (6.4, A.5–A.7, Annex K) — objectives can now be translated into one or more estimands with defined attributes (population, variable, intercurrent-event strategy, population-level summary), aligning device investigations with modern statistical practice from the pharmaceutical domain (ICH E9(R1)).
• Data Monitoring Committee justification (6.11, A.14) — sponsors must now justify the absence of DMC involvement, and the DMC must confirm the conditions for suspending or stopping the investigation.
• Clinical Events Committee formalised (3.8, 6.12, A.14) — a new dedicated section requires sponsors to consider establishing a CEC for consistent, unbiased adjudication of clinical events.
• Informed consent clarifications (5.8) — consent from the subject's legally designated representative where applicable, and the subject must be given the opportunity to discuss participation with others (e.g. family members).
• CIP content upgrades (Annex A) — methods and timing for assessing, recording and analysing variables, equipment calibration requirements (A.6.4), explicit requirements for non-inferiority margins and missing data handling (A.7), and subject follow-up / continued care that differs from normal practice (A.16).
• Investigator's Brochure additions (Annex B) — precautions (B.5), training on the use of the investigational device, and recognition of in-silico testing as pre-clinical evidence (B.3).
• Sponsor obligations (9.2) — clarified local-representative arrangements for harmonisation with national requirements and a new implant-card requirement (9.2.2).

The Five Core Documents

A pre-market or PMCF clinical investigation under ISO 14155:2026 revolves around five interlocking documents. Their required content is normatively defined in the annexes:

Clinical Investigation Plan — CIP (Annex A, normative)

The CIP is the master protocol. Annex A prescribes its full structure: identification and synopsis (A.1), investigational device description (A.2), justification of the design (A.3), benefits and risks of device and CIP procedures (A.4), objectives and hypotheses — with estimand translation where applicable (A.5), design including subjects, procedures, and monitoring plan (A.6), statistical design and analysis (A.7), data management (A.8), amendments (A.9), deviations (A.10), device accountability (A.11), statements of compliance (A.12), informed consent process (A.13), adverse events / device deficiencies and committee arrangements including DMC/CEC justification (A.14), vulnerable populations (A.15), and subject follow-up and continued care (A.16).

Investigator's Brochure — IB (Annex B, normative)

The device-IB compiles the pre-clinical and clinical evidence available before the investigation: device description and intended purpose, summary of pre-clinical testing — bench, animal, and now explicitly in-silico (B.3) — prior clinical experience, risk analysis summary, precautions (B.5), and instructions and training relevant to investigational use. The IB is the evidence bridge between the manufacturer's design dossier and the investigator's understanding of the device.

Informed Consent Form — ICF (Clause 5.8)

The ICF must present risks, benefits, alternatives and data-protection arrangements in language understandable to the subject, cover compensation and continued-care arrangements, and respect the 2026 clarifications on legally designated representatives and the subject's opportunity to consult others before consenting. Ethics committee expectations (Annex G) drive local adaptations.

Statistical Analysis Plan — SAP (Clause 6.4, A.7)

The SAP operationalises the statistical design: analysis populations, handling of intercurrent events per the estimand definitions, sample-size justification with scientific rationale for effect sizes / non-inferiority margins / equivalence limits, interim analyses and stopping rules (linked to DMC conditions), and pre-specified handling of missing data.

Clinical Investigation Report — CIR (Annex D, normative)

The CIR reports the investigation against the CIP: subject disposition and accountability, protocol deviations, safety results with adverse event categorisation per Annex F, performance/effectiveness results per the pre-specified analyses, risk-assessment conclusions (8.5), and the final benefit-risk statement. Under MDR Article 77 the CIR (with a lay summary) is submitted to the concerned member states, and it feeds directly into the Clinical Evaluation Report (CER) as the primary source of investigation-generated clinical evidence.

Clinical Development Stages (Annex I) and the CDP

Annex I (informative) describes clinical development staging that maps directly onto the Clinical Development Plan (CDP) chapter of a CEP under MDCG 2020-6 logic: exploratory vs confirmatory vs observational designs; pilot → pivotal → post-market progression; and first-in-human, early-feasibility, traditional-feasibility and pivotal study types. When a clinical evaluation identifies evidence gaps that cannot be closed by literature or equivalence data, the CDP should describe the planned investigation using these stage concepts, and the CIP/IB/ICF/SAP set then implements that plan.

Practical Notes for MDR Submissions

• Investigations designed against ISO 14155:2020 that are still in planning should be gap-checked against the 2026 requirements — especially the risk-analysis structure (device vs CIP-procedure risks), DMC/CEC governance, and estimand definitions, since these shape the CIP and SAP rather than just the surrounding paperwork.
• FDA recognises ISO 14155 as a consensus standard and accepts foreign clinical data collected under it (21 CFR 812.28); compliance with the 2026 edition continues to support multi-jurisdiction strategies.
• For PMCF investigations, the same document set applies "as far as relevant" (Annex I.2), proportionate to the investigation's nature and risk.

The Reguverse Assistant clinical investigation workflow generates the complete document set (study design rationale, CIP, device-IB, ICF, SAP and CIR) aligned to ISO 14155:2026 annex structures, and cross-references evidence gaps identified in the clinical evaluation workflow so that investigation objectives trace back to the claims they are designed to support.