--- title: Clinical Performance Studies Under IVDR: When and How description: IVDR clinical performance studies: when they are required, study design, ethics approval, sample sizes, endpoints, applicable standards. authors: Tibor Zechmeister, Felix Lenhard category: Electrical Safety & Systems Engineering primary_keyword: IVDR clinical performance studies canonical_url: https://zechmeister-solutions.com/en/blog/ivdr-clinical-performance-studies source: zechmeister-solutions.com license: All rights reserved. Content may be cited with attribution and a link to the canonical URL. --- # Clinical Performance Studies Under IVDR: When and How *By Tibor Zechmeister (EU MDR Expert, Notified Body Lead Auditor) and Felix Lenhard.* > **A clinical performance study under IVDR is a prospective investigation in which specimens, and in some cases patients, are used to generate primary clinical performance data that cannot be obtained from literature, routine diagnostic data, or retrospective specimens. These studies are triggered mainly for higher-class IVDs, for novel analytes, and when the existing evidence base is insufficient. The applicable GCP-style standards are EN ISO 20916 for clinical performance studies of IVDs and, where patient procedures are involved, EN ISO 14155:2020+A11:2024.** **By Tibor Zechmeister and Felix Lenhard.** ## TL;DR - IVDR clinical performance studies are required when literature, routine data, and retrospective specimens cannot deliver the clinical performance evidence for the claimed intended purpose. - The primary standard is EN ISO 20916 for good study practice in IVD clinical performance studies . - Ethics approval, informed consent for specimen use, sponsor obligations, adverse event reporting, and study registration apply to IVDR clinical performance studies in a manner analogous to MDR clinical investigations. - Sample size is not a guess. It flows from the primary endpoint, the expected effect size, and the minimum acceptable confidence interval on sensitivity and specificity. - Novel analytes, companion diagnostics, and Class D devices carry the highest probability of needing a dedicated prospective study . ## Why this matters Most IVD startups can complete performance evaluation without ever running a prospective clinical performance study. Scientific validity from literature, analytical performance from in-house lab work, and clinical performance from retrospective specimens can cover the full evidence base for many Class A and Class B devices and a surprising share of Class C devices. Then there is the other bucket. Novel analytes. Companion diagnostics tied to a specific therapy. First-in-class assays where no peer-reviewed literature establishes the clinical link. Point-of-care devices where the intended user is a nurse, a pharmacist, or a patient, and the routine diagnostic data from hospital lab machines is not representative. Class D devices carrying the highest risk. In these situations, a clinical performance study is the only credible way to produce the evidence the notified body will ask for. Tibor's pattern observation: founders discover the need for a clinical performance study far too late, usually during the NB gap analysis, six to nine months before the intended CE mark date. At that point the timeline collapses. The study itself, even a well-designed one, takes six to eighteen months from protocol to locked database. Add ethics approvals, contract negotiations with investigator sites, and specimen logistics, and the certification slips into the next funding round. The remedy is simple. Decide early whether a study is needed. Decide consciously, not by default. ## What IVDR actually says IVDR defines a clinical performance study as a study undertaken to establish or confirm the clinical performance of a device . The governance of such studies is set out in IVDR Articles 57 through 77 and in Annex XIII Part A and Annex XIV . The key legal touchpoints, analogous to MDR's Chapter VI on clinical investigations, include: - A Clinical Performance Study Plan must be written before the study starts. - The sponsor must be identifiable and must accept the obligations IVDR places on sponsors. - Ethics committee approval is required, as is, in most Member States, competent authority notification or approval. - Informed consent is required from study subjects or, for specimen-based studies, under the applicable rules for secondary use of human biological material . - Serious adverse events and device deficiencies must be reported. - Insurance or indemnification for study subjects is required. - A Clinical Performance Study Report is produced at the end and feeds the Performance Evaluation Report. The applicable standards form a layered system. **EN ISO 20916** is the dedicated GCP-style standard for IVD clinical performance studies involving human specimens . It addresses study design, sponsor and investigator responsibilities, specimen handling, data management, and reporting, adapted to the specific reality of IVD work. Where a clinical performance study also involves a procedure performed on a patient solely for the purpose of the study, such as an additional blood draw that would not otherwise be taken, EN ISO 14155:2020+A11:2024, the medical device clinical investigation GCP standard, comes into play as well. Notified bodies expect the sponsor to identify which standard, or combination of standards, governs the study, and to document the choice in the study plan. ## A worked example Consider a startup developing a new Class C assay for early detection of a specific infectious disease. The device is intended for use in primary care, operated by a trained nurse, on a fingerstick capillary blood specimen, with results available in under twenty minutes. The literature links the pathogen to the disease clearly. Scientific validity is straightforward. The analytical performance, including cross-reactivity with related pathogens and interfering substances, is completed in the lab. Retrospective venous blood specimens from a biobank support an initial clinical performance estimate. What retrospective data cannot support is the actual intended use scenario. Capillary blood from fingerstick, collected in a primary care clinic, by a nurse, under realistic time pressure. The matrix is different. The user is different. The environment is different. The team therefore designs a prospective clinical performance study. Primary endpoints: diagnostic sensitivity and diagnostic specificity, each with a 95% confidence interval. Reference standard: a validated laboratory-based method. Target population: adults presenting with symptoms consistent with the disease. Estimated disease prevalence in the population: 8%. Minimum acceptable lower bound of the sensitivity confidence interval: 90%. Plugging these numbers into a standard sample size formula yields a requirement of several hundred evaluable positive and negative cases . The study runs at four primary care sites. Each site obtains local ethics committee approval. Subjects provide written informed consent for the fingerstick specimen, the parallel venous sample for the reference method, and the data use. A sponsor-approved monitoring plan ensures data integrity. Device deficiencies and serious adverse events are reported according to IVDR Articles 80 and 82 . At the end of the study, the data is locked, analysed according to the pre-specified statistical analysis plan, and reported in a Clinical Performance Study Report. The report feeds the Performance Evaluation Report, which in turn is part of the technical documentation reviewed by the notified body. The total timeline from protocol finalisation to CSR signature is fourteen months. The cost is substantial. The founders had budgeted for none of this when they started the project eighteen months earlier. In Tibor's experience, this is the single most common timeline collapse in IVDR projects. ## The Subtract to Ship playbook Felix's framing: a clinical performance study is not a certificate-generating ritual. It is a scientific experiment that happens to be regulated. Treat it as science first, regulation second. **Step 1. Decide early whether a study is needed.** Run a structured gap analysis against the three pillars. Scientific validity: can literature support it? Analytical performance: can the lab work support it? Clinical performance: can literature plus retrospective specimens support it? If any cell in the third row is empty, a clinical performance study is on the table. **Step 2. Write the clinical question before the protocol.** One sentence. What are you trying to prove, in what population, against what reference, with what margin? A clinical performance study with a fuzzy question produces fuzzy evidence. **Step 3. Pick the applicable standards explicitly.** EN ISO 20916 is the default for IVDs . Add EN ISO 14155:2020+A11:2024 if subjects undergo a procedure that exists solely for the study. Document the choice. **Step 4. Do the sample size calculation before the ethics application.** Ethics committees and competent authorities will ask. Sponsors who arrive without a defensible sample size rationale lose credibility immediately. **Step 5. Engage ethics early.** Ethics committee timelines vary from a few weeks to several months across Member States. Plan backward from the study start date, not forward from the protocol date. **Step 6. Lock the statistical analysis plan before the first specimen is analysed.** Post-hoc changes to the analysis plan destroy the evidentiary value of the study. **Step 7. Treat the notified body as a stakeholder.** Some NBs will review a draft study plan before the study starts. Taking advantage of that offer is almost always worthwhile. It is far cheaper to adjust the protocol than to redo the study. **Step 8. Budget honestly.** Tibor's observation: founders consistently underestimate clinical performance study costs by a factor of two to four. A realistic budget buys schedule and peace of mind. ## Reality Check 1. Can you name the three conditions that would force you to run a prospective clinical performance study? 2. Have you documented why your current evidence base is or is not sufficient, pillar by pillar? 3. Do you have a defensible sample size calculation for every primary endpoint? 4. Have you identified which standard, or combination of standards, governs your study? 5. Have you allocated realistic ethics approval timelines for each site and each Member State? 6. Is your statistical analysis plan locked before data collection starts? 7. Do you have sponsor-side capacity to handle SAE and device deficiency reporting according to IVDR timelines? 8. Have you shared the study plan with your notified body before enrolling the first subject? If the answer to any of 3 through 6 is no, the study is not yet ready to start. ## Frequently Asked Questions **Do all IVD devices need a clinical performance study?** No. Many IVDs complete performance evaluation with literature, in-house analytical studies, and retrospective specimens. A prospective study is triggered mainly by novelty, higher classification, and insufficient existing evidence . **Is EN ISO 20916 mandatory?** It is the recognised good practice standard for IVD clinical performance studies. NBs expect its use. Whether it is formally harmonised at a given moment should be checked in the Official Journal . **When does EN ISO 14155 apply to an IVD study?** When the study involves a procedure performed on a patient purely for study purposes, such as an additional biopsy or blood draw that would not otherwise be taken. Specimen-only studies using leftover material are governed by EN ISO 20916. **Who is the sponsor of a clinical performance study?** Usually the manufacturer. The sponsor holds the legal obligations defined in IVDR Articles 57-77 . **Can a startup sponsor its own study?** Yes, but the obligations are non-trivial. Many startups contract a clinical research organisation to execute the operational side while retaining sponsor obligations formally. Tibor's advice: if the team has never run a regulated study before, external support is cheaper than learning on your certification timeline. ## Related reading - [IVDR performance evaluation](/blog/ivdr-performance-evaluation) for the umbrella framework that clinical performance studies sit inside - [Scientific validity, analytical performance, and clinical performance under IVDR](/blog/scientific-validity-analytical-clinical-performance) for the three pillars of evidence - [Design a clinical investigation as a startup](/blog/design-clinical-investigation-startup) for the MDR-side equivalent on study design principles ## Sources 1. Regulation (EU) 2017/746 on in vitro diagnostic medical devices, Articles 56, 57-77, Annex XIII, Annex XIV [MDR VERIFY]. 2. EN ISO 20916, clinical performance studies using specimens from human subjects, good study practice . 3. EN ISO 14155:2020+A11:2024, clinical investigation of medical devices, good clinical practice. --- *This post is part of the [Electrical Safety & Systems Engineering](https://zechmeister-solutions.com/en/blog/category/electrical-safety) cluster in the [Subtract to Ship: MDR Blog](https://zechmeister-solutions.com/en/blog). For EU MDR certification consulting, see [zechmeister-solutions.com](https://zechmeister-solutions.com).*