FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

June 4, 2026

Joana Martins

The United States is the world’s largest market for in vitro diagnostic devices. It is also one of the most complex to enter. FDA regulation of IVDs operates through a risk-based framework that determines how a device is classified, which approval or clearance pathway applies, what evidence is required before commercial distribution, and what obligations continue after authorization.

This guide covers the entire FDA regulatory landscape for IVD manufacturers, from initial device qualification through classification, premarket submission, investigational use, quality management system requirements, and post-market surveillance. It also addresses the specific considerations that apply to laboratory-developed tests, companion diagnostics, and manufacturers operating in both the US and EU markets simultaneously.

Key point: FDA regulation of IVDs sits within the same statutory framework as all medical devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act). However, IVDs have specific classification rules, dedicated guidances, and performance evidence requirements that differ materially from those applied to other device types.

What Counts as an IVD Under FDA Law

An in vitro diagnostic product is defined under 21 CFR 809.3(a) as a reagent, instrument, or system intended for use in the diagnosis of disease or other conditions, through the in vitro examination of specimens derived from the human body.

The definition is broad. It covers reagent kits, assay systems, instruments that process or read those assays, software that interprets results, and combinations of these elements. A product intended to generate medically actionable information from a human specimen will generally fall within the IVD framework regardless of the format in which it is supplied.

Two practical questions determine whether the FDA IVD regulatory framework applies:

Is the product intended to examine specimens taken from the human body?
Is that examination intended to support a medical decision, diagnosis, monitoring, patient selection, or treatment assignment?

If both are true, the product is an IVD and must comply with the applicable FDA requirements before commercial distribution in the United States. The intended use stated by the manufacturer, not the technology, the format, or the distribution channel, determines this status.

IVD vs. LDT: Laboratory-developed tests (LDTs), assays designed, manufactured, and used within a single laboratory, have historically operated under a different framework. FDA issued a final rule in 2024, but subsequent legal challenges (including a 2025 court decision) have created uncertainty, and the long-term regulatory framework for LDTs remains in flux. See the section on LDTs below.

FDA IVD regulation pathway tree diagram: classification (Class I, II, III), premarket routes (510k, De Novo, PMA), quality system (QMSR), and post-market obligations

IVD Classification: How FDA Assigns Risk Class

All FDA-regulated devices, including IVDs, are assigned to one of three risk classes. The class determines which controls apply and which premarket pathway is available.

Class	Risk Level	Controls Required	Typical Premarket Route
Class I	Low	General controls only	Exempt or 510(k)
Class II	Moderate	General + special controls	510(k) or De Novo
Class III	High	General + special controls + PMA	Premarket Approval (PMA)

For IVDs, classification is determined primarily by intended use and the clinical consequences of erroneous results, false positives, false negatives, or invalid results, rather than by the underlying technology. An assay with a low-risk intended use (for example, confirming a known condition in a low-risk population) may qualify as Class II even if it uses the same analytical technology as a Class III device with a high-risk intended use.

The FDA maintains a product classification database with assigned device codes, regulation numbers, and review panels. Before finalising a regulatory strategy, manufacturers should search this database for devices with a similar intended use to understand how FDA has previously classified comparable products.

FDA Premarket Pathways for IVDs: 510(k), De Novo, and PMA

The three main premarket pathways differ significantly in what they require, how long they take, and what outcome they produce. Selecting the wrong pathway, or failing to engage FDA early to confirm the right one, is one of the most common and costly mistakes in IVD regulatory strategy.

510(k) Premarket Notification

A 510(k) submission demonstrates that a new device is substantially equivalent to a legally marketed predicate device. For IVDs, this means identifying a predicate with the same intended use and similar technological characteristic, or, if the technology differs, demonstrating that the differences do not raise new safety or effectiveness questions.

The 510(k) route is appropriate when a suitable predicate exists. For IVD manufacturers, substantial equivalence must be established not just at the level of technology but at the level of the clinical claim. An assay using the same analytical platform as a predicate is not automatically equivalent if it is intended for a different patient population, a different decision point, or generates results that would be used differently in clinical practice.

Standard 510(k): most common; requires performance data and predicate comparison
Abbreviated 510(k): relies on FDA-recognised performance standards
Special 510(k): limited to device modifications by the original manufacturer

Timeline: FDA’s standard review target is 90 days. In practice, requests for additional information (AI letters) are common and extend the timeline. Manufacturers should plan for 4–8 months for a standard 510(k) with a well-prepared submission.

De Novo Risk-Based Classification for Novel Devices

The De Novo pathway applies to novel devices for which no legally marketed predicate exists, making the 510(k) pathway unsuitable, but the device is not high enough risk to require PMA. It creates a new device classification with specific controls appropriate to that device type.

For IVD manufacturers developing novel diagnostic technologies or applying known assay types to new clinical applications, De Novo is often the appropriate route. A successful De Novo classification becomes itself a predicate for future 510(k) submissions by other manufacturers.

The evidentiary requirements for De Novo are substantial and in practice often comparable to those for a PMA in terms of analytical and clinical evidence depth. The key difference is that De Novo does not presuppose Class III and gives FDA the ability to define special controls that make Class II regulation workable for the device type.

Timeline: FDA’s target is 150 days for De Novo review. With AI letters, 12–18 months is a realistic planning assumption for novel IVD applications.

PMA Premarket Approval

Premarket Approval is the most rigorous FDA pathway and applies to Class III devices, those for which general and special controls are insufficient to assure safety and effectiveness. PMA requires valid scientific evidence, typically from well-controlled clinical investigations, demonstrating that the device is safe and effective for its intended use.

For IVDs, PMA applies to:

Devices that determine eligibility for high-risk therapies where no predicate or De Novo classification exists
Companion diagnostics essential for the safe and effective use of a corresponding therapeutic, the majority of CDx devices proceed through PMA, though a November 2025 FDA proposal would reclassify certain NGS and NAAT-based oncology CDx to Class II
High-risk screening tests where a false negative or false positive result has severe clinical consequences

PMA submissions are organised in modules covering administrative information, device description, clinical performance data, analytical validation, manufacturing, software, and labeling. FDA offers a modular PMA submission option that allows review of completed modules before the full package is assembled, a significant strategic advantage in co-development programmes where evidence is generated progressively.

Criterion	510(k)	De Novo	PMA
Legal standard	Substantial equivalence	Safety & effectiveness via general/special controls	Safety & effectiveness
Predicate required	Yes	No	No
Device class outcome	Class I or II	New Class I or II	Class III
Review target	90 days	150 days	180 days (modular: staged)
Post-approval changes	Change assessment required	Change assessment required	PMA supplement required
Typical IVD use case	Known assay type, clear predicate	Novel technology, moderate risk	CDx, high-risk screening, no predicate

Investigational Use of IVDs: IDE Requirements and the Significant Risk Determination

When an IVD is used in a clinical investigation before it has received FDA premarket authorisation, the manufacturer and sponsor must comply with the investigational device provisions under 21 CFR Part 812. The applicable requirements depend on whether the device is classified as significant risk (SR) or non-significant risk (NSR).

Significant Risk vs. Non-Significant Risk

A significant risk device is one that presents a potential for serious risk to the health, safety, or welfare of a subject, including devices used in diagnosing, curing, mitigating, or treating disease where errors could have serious clinical consequences.

Investigational IVDs Used in Clinical Investigations of Therapeutic Products

For IVDs, the SR determination requires analysis of four specific questions defined in FDA’s 2024 draft guidance on investigational IVDs used in drug and biological product trials:

Will use of the IVD results lead some subjects to forgo or delay a treatment known to be effective?
Will use of the results expose subjects to safety risks exceeding those of the control arm or standard of care?
Is it likely that incorrect results would present a potential for serious risk, based on what is known about the biomarker-therapeutic relationship?
Does use of the IVD require invasive sampling that is not part of standard care?

Sponsors are responsible for the initial risk determination and must present it to the Institutional Review Board (IRB). If the device is classified as SR, an Investigational Device Exemption (IDE) application must be submitted to FDA (through CDRH) and FDA has 30 days to respond. If deemed NSR, IRB approval is sufficient, no IDE application is required, but abbreviated requirements under 21 CFR 812.2(b) still apply.

CDx in drug trials: When an IVD is used in a clinical investigation of a drug or biological product to determine patient eligibility or guide treatment decisions, the SR determination is critical. A misjudgement here, treating a device as NSR when it is SR, exposes the entire clinical programme to regulatory risk.

FDA Quality Management System Regulation (QMSR): What IVD Manufacturers Need to Know

Since 2 February 2026, the FDA Quality Management System Regulation (QMSR, 21 CFR Part 820) has replaced the former Quality System Regulation (QSR). QMSR incorporates ISO 13485:2016 by reference into US law, aligning US quality system requirements with the international standard for the first time.

For IVD manufacturers, QMSR introduces important practical changes. Several are particularly relevant to the IVD context:

What Changed for IVD Manufacturers Specifically

IVD quality systems under QMSR must go further than a standard ISO 13485-aligned QMS. The nature of IVD products, which generate results that directly inform clinical decisions, introduces additional complexity in several areas:

Design controls (ISO 13485 clause 7.3 / QMSR): design inputs must explicitly link intended use, specimen type, analyte definition, and performance claims to statistically robust analytical and clinical data. Design changes after clinical evidence generation may require bridging studies.
Risk management: for IVDs, risk management must account for false positive and false negative results, not just device failures. Diagnostic decision risks, interfering substances, and matrix effects must all be explicitly addressed.
Production and process control: lot-to-lot variability of biological materials requires validation against clinically relevant criteria, not just functional performance.
Post-market surveillance: systems must detect performance drift, shifts in sensitivity or specificity, which may not be visible through standard complaint handling alone.

The ISO 13485 Certification Gap

A persistent misconception in the IVD industry is that ISO 13485 certification means a manufacturer is QMSR-ready. It does not. While QMSR incorporates the standard by reference, FDA-specific requirements remain fully enforceable, and ISO certification does not address them.

The most consistently overlooked gaps include:

UDI traceability: the UDI must be recorded consistently across complaints, servicing records, and batch/history records, not just registered in GUDID
MDR linkage: complaint handling procedures must be explicitly connected to Medical Device Reporting obligations under 21 CFR Part 803
Internal audit and management review access: under QMSR, FDA inspectors can access these records, they were previously outside standard inspection scope
Labeling controls: FDA-specific label content requirements (UDI, expiry dates, handling instructions) require documented control procedures

Inspection change: Under QMSR and Compliance Program 7382.850, FDA inspections are now structured around six integrated quality system areas rather than the former QSIT subsystem model. Inspectors assess how quality processes function together across the product lifecycle, not whether each subsystem satisfies a checklist in isolation.

For manufacturers needing support with QMSR gap assessment, MDx CRO’s quality and regulatory affairs team provides structured readiness reviews specifically for IVD and CDx manufacturers. See the dedicated article: FDA QMSR: How the 2026 Regulation Shift Transforms MDSAP Audits and FDA Compliance Inspections.

Laboratory-Developed Tests (LDTs): FDA’s 2024 Rule and What It Means

Laboratory-developed tests are assays designed, manufactured, and used within a single CLIA-certified laboratory. Historically, the FDA exercised enforcement discretion over LDTs, meaning that while LDTs were technically subject to FDA device regulations, the agency generally did not enforce premarket submission or quality system requirements against them.

That changed with the FDA’s May 2024 final rule. The rule phases out the general enforcement discretion policy and progressively brings LDTs under the same regulatory framework as commercial IVDs. The phase-in timeline runs over four years, with higher-risk devices (Class III LDTs) subject to premarket requirements earlier and lower-risk devices later.

Phase	Timeline (from May 2024)	Requirement
1	Year 1	MDR, complaint handling, correction/removal reporting
2	Year 2	Registration, listing, labeling, investigational use
3	Year 3	Quality system (QMSR) requirements
4	Year 4	Premarket review — Class III LDTs
5	Year 5	Premarket review — Class II LDTs (most)

The practical implication for laboratories offering LDTs is significant. Tests that have operated without FDA premarket review for decades now face classification, potential 510(k) or PMA requirements, QMSR compliance, and post-market surveillance obligations. The transition is particularly complex for high-complexity molecular tests, NGS-based assays, and tests used to guide treatment decisions, the categories most likely to face substantive premarket requirements.

The IVD vs. LDT distinction has also created regulatory ambiguity for assays that are commercially distributed but described as ‘laboratory services’. FDA’s position is that the legal framework applies based on the nature of the product and its intended use, not the business model through which it is offered.

Companion Diagnostics: FDA’s Co-Development and Approval Framework

A companion diagnostic is an IVD that provides information essential for the safe and effective use of a corresponding therapeutic product. FDA’s CDx framework sits at the intersection of device and drug regulation, requiring coordination between CDRH (which reviews the diagnostic) and CDER or CBER (which reviews the drug or biologic).

Most companion diagnostics require PMA, though FDA’s November 2025 proposal to reclassify certain NGS and NAAT-based oncology CDx from Class III to Class II would, if finalised, make 510(k) available for a subset of these devices. Until that reclassification is confirmed, PMA should be treated as the working assumption for novel CDx programmes.

The Contemporaneous Approval Expectation

FDA’s CDx policy generally expects the companion diagnostic and the corresponding therapeutic product to receive marketing authorization simultaneously. This means that a deficiency in the diagnostic submission, a gap in analytical validation, an incomplete bridging study, or an unresolved labeling alignment issue, can delay drug approval, even though the drug is reviewed by a different FDA centre.

The most common causes of CDx-related drug approval delays are:

Assay version used in the clinical trial differs from the commercial assay proposed for marketing, requiring bridging studies that were not planned in advance
Clinical performance data collected in one population (for example, EU samples) not adequately bridged to the US population the labeling claim would cover
Intended use statement in the device submission misaligned with the indication in the drug label
Design controls documentation not adequately tracing the clinical trial assay to the commercial configuration

MDx CRO’s FDA Companion Diagnostics guide covers the full CDx regulatory pathway including PMA structure, IDE strategy, Q-submission programme, co-development governance, and assay lock considerations. A downloadable FDA Companion Diagnostic Roadmap is available on that page.

FDA Regulation vs. EU IVDR: Key Differences for IVD Manufacturers Targeting Both Markets

Many IVD manufacturers pursue US FDA authorisation and EU CE marking under the IVDR simultaneously. While the two frameworks share some structural principles, risk-based classification, performance evidence requirements, quality management system obligations, they diverge significantly in how those principles are applied.

Area	FDA (US)	EU IVDR
Classification basis	Intended use + clinical risk	Risk class A–D based on IVDR rules + MDCG guidance
Premarket route	510(k), De Novo, or PMA	Conformity assessment via Notified Body (Class B–D) or Self-certication (Class A)
Evidence standard	Valid scientific evidence (PMA) / substantial equivalence (510(k))	Scientific validity + analytical + clinical performance
Clinical evidence location	US population; bridging required for non-US data	EU population; bridging required for non-EU data
QMS standard	QMSR (incorporates ISO 13485:2016)	ISO 13485:2016 (harmonized under the IVDR)
Performance studies	IDE framework (21 CFR Part 812)	IVDR Articles 56-58 / Annex XIV
Post-market	MDR reporting, post-approval studies (PMA)	PSUR, PMPF, vigilance reporting
CDx specifics	CDRH/CDER/CBER coordination; PMA typical	Notified Body review; Annex IX section 5.2 procedure

The most significant practical challenge for dual-jurisdiction programmes is clinical evidence. A clinical performance study conducted exclusively with EU samples may not be acceptable to FDA without bridging evidence demonstrating equivalence to the US population. The reverse applies equally. Early engagement with both FDA (via Q-submission) and the Notified Body allows sponsors to design studies that generate evidence acceptable to both frameworks, reducing the need for duplicated studies.

Analytical validation can often be leveraged across jurisdictions if conducted to CLSI and CAP/CLIA standards, which both frameworks recognise. Intended use statements can be aligned between jurisdictions, though the labeling requirements differ. The most efficient approach is to map the two frameworks at programme inception and identify shared requirements before study design is finalised.

How MDx CRO Supports IVD Manufacturers Targeting the US Market

MDx CRO is a specialist contract research and regulatory organisation focused on IVDs, companion diagnostics, and medical devices. Our regulatory affairs and quality teams support IVD manufacturers entering or expanding in the US market across the full regulatory lifecycle.

Regulatory Strategy and Pathway Determination

We help manufacturers determine the appropriate FDA classification, premarket pathway, and investigational use strategy before resources are committed. For manufacturers also pursuing EU IVDR CE marking, we map the two frameworks in parallel to identify shared and divergent requirements early.

QMSR Gap Assessment

We conduct structured QMSR readiness assessments for IVD and CDx manufacturers, identifying gaps between current quality systems and FDA QMSR requirements, prioritising findings by inspection risk, and supporting remediation. Our quality team has specific IVD expertise, covering the additional complexity that performance claims, clinical evidence traceability, and analytical validation introduce into design controls and risk management under QMSR.

IDE and Investigational Use Support

We support the significant risk determination process, IDE application preparation, and coordination between the IVD and drug sponsors in combined studies. This includes IVDR performance study applications for EU clinical sites running in parallel with FDA IDE submissions for US sites.

Companion Diagnostic Co-Development

For pharma sponsors co-developing an IVD with their therapeutic programme, we provide IVD regulatory strategy, assay lock planning, bridging study design, and submission preparation, with the goal of achieving contemporaneous FDA authorization of the CDx alongside the drug or biologic.

Frequently Asked Questions

What is the difference between an IVD and a laboratory-developed test under FDA regulation?

A commercial IVD is a product manufactured and distributed to multiple laboratories or end users. An LDT is an assay designed, manufactured, and used within a single CLIA-certified laboratory. Historically FDA did not enforce premarket requirements against LDTs, but its 2024 final rule phases in the same regulatory framework for LDTs as for commercial IVDs over a four-year period beginning May 2024.

Does a 510(k) clearance mean an IVD is approved?

No. 510(k) results in FDA clearance, not approval. Clearance confirms substantial equivalence to a predicate device. FDA approval, issued through PMA, applies to Class III devices and requires independent demonstration of safety and effectiveness. The distinction matters clinically and commercially: the evidentiary standard and post-market obligations differ significantly.

Can clinical evidence generated in Europe be used to support an FDA submission?

It can be submitted, but FDA will assess whether the evidence is adequate for the US intended use and patient population. For devices where clinical validity depends on population-specific biomarker prevalence, disease incidence, or treatment patterns, bridging evidence may be required to establish that EU data is applicable to the US population. This should be discussed with FDA via Q-submission before the clinical study is designed.

What is the IDE pathway for IVDs used in drug trials?

When an IVD is used in a clinical investigation of a drug or biological product and classified as a significant risk device, the sponsor must submit an IDE application to FDA under 21 CFR Part 812. FDA has 30 days to approve or disapprove the application. If the device is non-significant risk, only IRB approval is required. The risk determination must be made by the sponsor and presented to the IRB before the study begins.

What does QMSR mean for IVD manufacturers who already have ISO 13485 certification?

ISO 13485 certification does not equal QMSR compliance. While QMSR incorporates ISO 13485:2016 by reference, FDA-specific requirements remain fully enforceable, including UDI integration across record types, MDR linkage to complaint handling, and specific labeling control documentation. Additionally, under QMSR, FDA inspectors can now access internal audit reports, management reviews, and supplier audits, which were previously outside inspection scope. A gap assessment against QMSR requirements is recommended even for certified manufacturers.

What is the FDA’s position on companion diagnostics and contemporaneous approval?

FDA’s policy for companion diagnostics that are essential for the safe and effective use of a therapeutic product generally expects simultaneous authorization of both products. A device deficiency can delay drug approval even when the therapeutic programme itself is ready. This makes early integration of the CDx regulatory programme into the drug development timeline, and coordination between CDRH and CDER or CBER, a practical necessity rather than an optional best practice.

The FDA IVD Regulatory Framework at a Glance

FDA regulation of IVDs operates through a risk-based classification system that assigns devices to three classes and directs them toward 510(k), De Novo, or PMA premarket pathways depending on risk level and the availability of a predicate. Investigational use of IVDs in clinical studies requires an IDE for significant risk devices. Commercial distribution requires compliance with QMSR quality management system requirements, which have been in force since February 2026 and now give FDA investigators access to records previously outside inspection scope.

Laboratory-developed tests are progressively subject to the same framework under FDA’s 2024 rule. Companion diagnostics follow the general device framework but require coordination with the drug regulatory review and are generally subject to PMA. Manufacturers pursuing both US FDA authorization and EU IVDR CE marking can leverage shared analytical validation data but must address population-specific clinical evidence requirements for each jurisdiction.

Services

Written by:

Joana Martins

QARA Specialist

QA/RA Specialist supporting teams in clinical evaluations and regulatory compliance with ISO 13485, MDR, and international medical device requirements (FDA, Health Canada, ANVISA).

Industry Insights & Regulatory Updates

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

MDCG 2021-24 Rev.1: What Changed in EU MDR Device Classification (April 2026)

ISO 10993-1:2025 From Checkbox Compliance to Risk-Based Biocompatibility

FDA Companion Diagnostics: A Complete Regulatory Guide to CDx Development, Approval, and Co-Development Strategy

ISO 20417:2026 You May Have a Gap Today: What Medical Device Manufacturers Shall Do Now

FDA Companion Diagnostics: A Complete Regulatory Guide to CDx Development, Approval, and Co-Development Strategy

May 7, 2026

Callum Pickett

The FDA companion diagnostic (CDx) regulatory framework is one of the most complex intersections in MedTech: a single device that must satisfy the standards of two regulators (CDRH and CDER or CBER), coordinate with a pharmaceutical development timeline measured in years, and carry clinical consequences that make a wrong result directly harmful to patients.

A misaligned CDx strategy does not just delays the diagnostic. It delays the drug.

Download the FDA Companion Diagnostic Roadmap

In tissue-agnostic oncology indications, the mean gap between drug approval and the corresponding CDx approval has historically approached two years. That is not a regulatory abstraction, those are patients waiting for access to an already-approved therapy because the diagnostic program was not adequately integrated from the outset.

This guide covers the complete FDA CDx regulatory pathway: what a companion diagnostic is under US law, how PMA and the modular submission process works in practice, how Q-submissions and pre-sub meetings should be structured, how FDA’s November 2025 proposed reclassification of NGS and NAAT-based oncology CDx from Class III to Class II will affect program planning, and what a realistic co-development timeline looks like when both a drug and a diagnostic are advancing in parallel.

What Is an FDA Companion Diagnostic? The Legal Definition and Its Practical Consequences

FDA’s 2014 final guidance on In Vitro Companion Diagnostic Devices established the foundational definition that governs every CDx program in the United States. An IVD companion diagnostic device provides information that is essential for the safe and effective use of a corresponding therapeutic product.

The word essential is not rhetorical. When FDA determines that a diagnostic result is necessary for any of the following functions, both the drug label and the device label must reflect that requirement:

Patient selection: identifying patients most likely to benefit from the therapy
Safety exclusion: identifying patients at elevated risk for serious adverse reactions
Dose optimisation: monitoring therapeutic or toxic effects to guide dose adjustment
*(note: not part of the core FDA 2014 definition, but an additional CDx function referenced in FDA co-development guidance)
Response monitoring: tracking treatment response after initiation (note: as above)

The applicable labeling regulations are 21 CFR 201.57 for therapeutic product labeling and 21 CFR 809.10 for IVD device labeling. Both labels must be aligned at time of approval. That requirement is the single most consequential structural feature of CDx regulation, and the one most often underestimated by sponsors approaching their first combined program.

The greatest value of experienced CDx support lies in anticipating cross-functional and regulatory risks early. Sponsors frequently overestimate their ability to manage these interfaces internally, particularly if they have limited prior experience with end-to-end companion diagnostic approvals. Intended use definition, analytical validation planning, clinical sample strategy, and regulatory positioning are highly interdependent, changes to one element consistently have material implications for the others.

Callum Pickett, Clinical Alliance Lead, MDx CRO

CDx vs. CDMO: An Important Distinction

Before addressing regulatory pathway, it is worth clarifying a distinction that frequently causes confusion in early-stage programs. A CDx development partner (such as a CRO with IVD regulatory expertise) is engaged to define what the diagnostic should be, guide R&D, manage analytical and clinical validation, ensure IVDR and FDA regulatory compliance throughout the development lifecycle, and advise on pathway strategy. A Contract Development and Manufacturing Organisation (CDMO) is engaged to manufacture a device that has already been defined. The CDMO can only produce what has already been designed and validated; it cannot assume responsibility for the regulatory fate of the product. Sponsors who engage a CDMO without first engaging a CDx development partner often discover, late in development, that their device lacks the analytical validation infrastructure or regulatory documentation to support an FDA submission.

How FDA Reviews a Companion Diagnostic: CDRH, CDER, and CBER Working in Parallel

Every IVD companion diagnostic program in the United States touches three FDA centres simultaneously. Regulatory affairs teams that approach CDx review as a single-centre process routinely encounter the coordination gap at the worst possible moment: during submission review.

FDA Centre	Full Name	Primary CDx Responsibility
CDRH	Center for Devices and Radiological Health	Reviews and approves the IVD companion diagnostic device; receives all PMA, Q-Submission, and IDE filings
CDER	Center for Drug Evaluation and Research	Reviews the NDA or BLA for associated small-molecule drugs; manages the IND; owns the therapeutic product label
CBER	Center for Biologics Evaluation and Research	Reviews biologics including monoclonal antibodies and gene therapies; handles HLA assays and certain blood-compatibility diagnostics

Two parallel submission tracks with different evidentiary standards, different review timelines, and different internal review divisions that must coordinate with each other. FDA’s codevelopment guidance makes clear that separate marketing applications are always required for the therapeutic product and the IVD companion diagnostic, even when a single sponsor is developing both.

Letters of Authorization allow each application to cross-reference the other’s proprietary data without duplicating confidential submissions. Setting up these agreements early, before either programme is well advanced, is a structural requirement, not a convenience.

Practical Implication

FDA strongly encourages sponsors to request early joint meetings involving all relevant centres before an IND is filed. Teams that wait until the NDA or BLA stage to engage CDRH consistently face longer review timelines and a higher volume of deficiency letters. The cost of a late start to FDA dialogue is not merely a delay, it is rework at a stage when rework is most expensive.

The PMA Pathway: How Premarket Approval Actually Works for a CDx

Premarket Approval under section 515 of the FD&C Act is the predominant regulatory route for companion diagnostics in the United States. FDA classifies most companion diagnostics as Class III devices on the basis that a misclassified result directly influences whether a patient receives or is withheld from a targeted therapy. Of the more than 80 drug-CDx combinations approved through early 2025, the overwhelming majority obtained marketing authorisation through the PMA pathway.

What a PMA Submission Must Contain

A PMA submission must demonstrate reasonable assurance of safety and effectiveness. The modular PMA format is available to sponsors and widely used for CDx programmes, in which sponsors sum¡bmit four sequential modules as data become available rather than waiting for a complete package.

Module	Content
Module 1	Device description and manufacturing information
Module 2	Non-clinical performance studies (analytical validation)
Module 3	Clinical studies and bridging data
Module 4	Proposed labeling

Engaging CDRH through a Pre-Submission (Q-Submission) before filing Module 1 is considered standard practice. That Pre-Submission should align the table of contents, content expectations for each module, and review timelines. Sponsors who skip this step and file directly tend to receive Module 1 deficiency letters that delay the entire sequence.

What the PMA Pathway Costs in Time and Fees

The PMA pathway is resource-intensive. User fees run into the hundreds of thousands of dollars. The statutory review clock is 180 days from acceptance under normal circumstances. Advisory panel meetings may be convened for novel device types or complex clinical performance questions, which can extend that timeline.

The modular format reduces total elapsed time by allowing CDRH to begin reviewing manufacturing and analytical data while clinical evidence is still being generated. However, the modular approach requires that Module 1, which includes the full device description and intended use, is sufficiently precise. Intended use ambiguity at the Module 1 stage tends to propagate into deficiencies across every subsequent module.

As Callum Explains, the earliest PMA modules should prioritise intended use definition, device architecture, analytical validation strategy, and clinical evidence planning. Intended use is the highest priority because it drives analytical requirements, specimen strategy, clinical study design, and labelling. Sponsors often attempt to preserve flexibility through broad or provisional language, but CDRH generally expects specificity. Ambiguity at this stage leads to downstream revisions and delays. The most common CDRH deficiencies relate to insufficiently precise intended use language, underdeveloped bridging strategies, weak cut-off justification, incomplete software documentation, and inadequate reconciliation of assay changes across modules.

When a Supplemental PMA (sPMA) Is the Right Mechanism

For a drug sponsor adding a companion diagnostic indication to an already-approved PMA device, the correct filing mechanism is a Supplemental PMA. The sPMA is a narrower submission focused on the analytical and clinical validation data supporting the specific new drug indication. It does not require re-justifying the device’s general safety profile, which substantially reduces the evidentiary package. This pathway is frequently used as the CDx landscape matures and new therapeutic indications are added to existing cleared platforms.

Q-Submissions and Pre-Sub Meetings: How to Use FDA’s Feedback Programme Effectively

A Pre-Submission under the FDA’s Q-Submission Programme is not optional for most novel or higher-risk CDx programmes, it is the mechanism by which sponsors and CDRH align on regulatory expectations before significant evidence generation has begun. Done well, a Pre-Submission meeting eliminates a class of avoidable deficiencies and establishes a shared framework for the entire submission strategy.

When to Submit a Pre-Submission

The first Pre-Submission interaction with FDA should occur once the following are reasonably defined: intended use statement, assay platform, specimen strategy, analytical validation concept, and clinical trial integration model.

Engaging too late with the FDA creates a risk of regulatory work being wasted. If a diagnostic partner is committed to the PMA route but FDA discussion suggests the 510(k) route, the organisation has over-invested in a more rigorous strategy than needed. Conversely, if they have embarked on a 510(k) strategy and FDA recommends PMA, they run the risk of having insufficient analytical and clinical evidence. Depending on how far into development the diagnostic partner is, unexpected requirements for additional studies can push back FDA submission and marketing by months to years.

Callum Pickett, Clinical Alliance Lead, MDx CRO

What to Cover in a CDx Pre-Submission Meeting

The questions posed to FDA should be specific and decision-oriented. A Pre-Submission is most effective when it provides sufficient background and preliminary data for CDRH to comment on a defined regulatory question rather than on the development programme in general. Topics should address:

Proposed regulatory pathway (PMA, 510(k), or De Novo) and rationale
Device description and intended use wording, the precise language FDA will accept
Investigational-use strategy and IDE status determination
Analytical validation pla, which studies FDA expects and in what format
Clinical validation plan, how clinical performance will be demonstrated
Assay lock-down and bridging approach, the most scrutinised area in CDx submissions
Labelling strategy and alignment with therapeutic product label
Coordination with therapeutic development timelines

Pre-IDE Q-Submissions

For programmes where an IDE may be required, a Pre-IDE Q-Submission allows for feedback from CDRH on approximately three to four topics prior to filing the IDE itself. The Pre-IDE ideally includes draft protocols or detailed summaries of proposed study designs. This step is particularly recommended when the significant risk determination is genuinely uncertain, FDA will provide a written position that prevents subsequent disagreement over IDE applicability.

Investigational Device Exemption (IDE): Significant Risk vs. Non-Significant Risk

When a CDx is used in a therapeutic clinical trial, particularly when the assay result influences patient enrolment, treatment assignment, or a clinical management decision, the sponsor must determine whether the study device is a significant risk (SR) or non-significant risk (NSR) device under 21 CFR 812.3(m).

This determination has material procedural consequences:

Risk Designation	Requirement	Consequence
Significant Risk (SR)	IDE application to FDA + IRB approval	Study cannot begin until both FDA and IRB approve. 30-day initial FDA review clock under 21 CFR 812.30(a); additional rounds of response to deficiencies will extend total time to IDE approval
Non-Significant Risk (NSR)	IRB approval only	Abbreviated requirements under 21 CFR 812.2(b). No IDE submission to FDA required.

The significant risk determination must answer four key questions drawn from FDA’s draft guidance on Investigational IVDs Used in Clinical Investigations of Therapeutic Products (December 2017, not yet finalised — the four factors below are drawn from a non-binding draft):

Will use of the IVD results lead subjects to forego or delay a treatment known to be effective?
Will IVD results expose subjects to safety risks exceeding those in the control arm?
Based on existing biomarker evidence, would incorrect IVD results present a serious risk to subjects?
Does the IVD require invasive sampling not part of standard care?

Sponsors are responsible for presenting the initial determination to the IRB. FDA and the IRB will review the assessment and may disagree with the sponsor’s position. If the IRB and FDA reach a different conclusion, the sponsor may appeal.

Important

For CDx devices used in oncology trials where the assay result determines treatment eligibility, a significant risk determination is generally expected. The consequential question is not whether IDE applies but how to structure the IDE submission and coordination between CDRH and the drug review centre.

FDA’s November 2025 Proposed Reclassification: What It Means for NGS and NAAT-Based Oncology CDx

In November 2025, FDA published a proposed order in the Federal Register that would materially change the submission pathway for a major category of companion diagnostics. Docketed as FDA-2025-N-4622, the proposed rule would create a new Class II device type under 21 CFR 866.6075. If finalised, NGS panels, PCR-based assays, and NAAT-based oncology companion diagnostics would move from the Class III PMA pathway to 510(k) clearance with defined special controls.

The Regulatory Logic Behind the Proposed Reclassification

FDA’s rationale is grounded in retrospective analysis of oncology CDx approvals over the past decade. The agency concluded that the risk profile of nucleic acid-based oncology tests is now sufficiently characterisable through defined special controls covering:

Analytical validity requirements (accuracy, precision, limit of detection, reportable range)
Clinical validity expectations linking the biomarker to the therapeutic indication
Design and labelling specifications consistent with the corresponding drug label
Post-market controls

The evidentiary bar remains rigorous. What changes is the submission architecture: substantial equivalence to a well-characterised archetype would, in principle, eliminate the need for a full clinical trial per new test when analytical comparability can be demonstrated.

What This Reclassification Does Not Cover

This proposed reclassification applies exclusively to nucleic acid-based oncology tests. IHC-based, FISH-based, imaging-based, and other modality companion diagnostics are not covered by the proposal. The comment period closed in January 2026. A final rule is anticipated but had not been published at the time of writing.

Programme Planning Implication

As Callum explains, the proposed reclassification is influencing planning conversations but very few sponsors are restructuring CDx regulatory roadmaps around it. The PMA route remains the most reliable assumption. If the reclassification is approved and the 510(k) route becomes available during development, the higher analytical and clinical rigour invested in a PMA programme can only offer an advantage when transitioning to a 510(k) pathway. The reverse, planning for 510(k) and then receiving FDA feedback requiring PMA, creates significant remediation cost.

Co-Development Timeline: What a Realistic Parallel Drug and CDx Programme Looks Like

For sponsors developing a drug and a companion diagnostic simultaneously, a realistic integrated programme is typically four to six years from biomarker confirmation to regulatory approval of both products. Aggressive programmes with mature biomarker readiness may compress to around three and a half years.

Development Phase	Typical Timeframe	CDx Programme Activity
Biomarker discovery and confirmation	Months 0–12	Define intended use concept; select assay technology; initiate pre-analytical controls
Prototype assay and fit-for-purpose validation	Months 12–24	Develop and validate CTA; initiate first FDA Pre-Submission
Clinical trial assay deployment	Months 18–36	IDE determination; IRB submission; analytical validation to GLP standards
Commercial assay lock and analytical validation	Months 24–42	Assay lock-down; design controls; assay bridging if needed; first PMA modules
Pivotal clinical performance study	Months 36–54	Clinical validation in the therapeutic trial; specimen banking; cross-referencing agreements
Regulatory submission, review, and approval	Months 48–72	Complete PMA submission; CDRH review; labelling alignment; contemporaneous approval target

The Critical Inflection Points Where CDx Programmes Fall Behind

Three structural failure modes recur across co-development programmes:

The drug programme evolves and the assay must evolve with it. Every major assay change after pivotal evidence generation has begun creates the potential for a bridging study, increasing the development burden and extending the timeline.Assay lock too late.
When the biomarker prevalence is low, common in rare disease and gene therapy indications, the pool of positive specimens available for analytical, bridging, and clinical studies is constrained. This limits statistical power and forces difficult decisions about study endpoints.Access to quality clinical samples.

Low enrolment due to unexpectedly low biomarker positivity rates collapses the statistical power of the pivotal trial, making it impossible to calculate meaningful sensitivity and specificity estimates within the planned timeline.Misestimation of biomarker prevalence.

The most common and expensive mistake is treating the IVDR performance study as the diagnostic manufacturer’s problem rather than a shared sponsor responsibility. The pharmaceutical team and the diagnostics team operate on disconnected timelines, and the CDx submission is not integrated into the master trial timeline from the outset. For US programmes, the equivalent failure is submitting the IND months before the PSA or IDE application is even drafted. The structural fix is identical in both jurisdictions: from Day 1 of trial design, the diagnostic regulatory workstream sits inside the integrated trial timeline, with a named owner, shared document management, and joint governance between pharmaceutical and diagnostic functions.

Callum Pickett, Clinical Alliance Lead, MDx CRO

Pharma-IVD Partnership Governance: What the Contractual Framework Must Address

When the drug sponsor and the diagnostic manufacturer are separate legal entities, the most common configuration in oncology CDx, the partnership must resolve several foundational questions before clinical trials begin. The governance gaps that create the most regulatory risk are the following:

Data Sharing and Letters of Authorization

The diagnostic sponsor needs access to clinical outcome data from the drug trial to support clinical validation. The drug sponsor needs the diagnostic sponsor’s performance data to complete the NDA or BLA. Neither can finalise its FDA submission without the other. Data sharing rights and the flow of clinical specimens between institutions require contractual agreements that anticipate FDA’s requirement for Letters of Authorisation, these letters allow each sponsor’s submission to cross-reference the other’s proprietary data without transferring confidential information directly.

Timing Alignment and Contemporaneous Approval

FDA’s preferred model is contemporaneous approval, the CDx PMA and the drug NDA or BLA approved on the same day. Achieving this requires joint regulatory strategy sessions from the pre-IND stage, coordinated Pre-Submission meetings with CDRH and the drug review centre, and contract provisions that prevent either party from advancing or withdrawing an FDA submission unilaterally.

The Bridging Study Decision

The choice of which assay to use in the clinical trial determines whether a bridging study will be required after the pivotal study closes. This is one of the most consequential and most frequently misunderstood decisions in CDx programme management.

Trial Assay Used	Bridging Study Required?	Timing Risk
Final CDx device (commercial version)	No: direct clinical validation	Lowest
Early-version CDx or LDT with central confirmatory lab	Possibly	Moderate
LDT only, no central confirmation	Yes	High: can delay PMA 12 to 24 months

Bridging studies must demonstrate that patients selected by the clinical trial assay show equivalent clinical outcomes when retested on the final CDx. Both biomarker-positive and biomarker-negative samples from all screened subjects must be banked with confirmed analyte stability, and patient consent for retesting must be obtained at enrolment. Retroactive consent collection is nearly impossible in practice.

Bridging strategy is particularly scrutinised by CDRH. As Callum explains, sponsors often underestimate the evidentiary burden required to demonstrate that assay modifications do not compromise clinical validity. Late recognition of the need for bridging often creates avoidable regulatory risk. It is therefore important to consider bridging scenarios prospectively, even where the expectation is that the assay will remain stable.

Class and Group Labelling: When a Single CDx Can Cover a Therapeutic Class

FDA’s 2020 guidance “Developing and Labeling In Vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products” opened the door to a single CDx covering a defined group of therapeutics rather than a named drug. Note that the 2014 CDx final guidance already contemplated multi-drug labelling to some degree; the 2020 guidance formalised and expanded this.

The appeal is clear: it reduces the need for repeated companion diagnostic label updates each time an additional therapy within the same class is approved. In practice, however, this strategy is viable in a narrower set of circumstances than sponsors initially anticipate.

Successful class labelling requires a high degree of mechanistic uniformity across the therapeutic class: the biomarker must predict response across all relevant agents through the same underlying biological mechanism, clinical effect must be consistent with no material variation in the biomarker-response relationship between therapies, and the clinical evidence package must be capable of supporting a common claim across products. FDA’s approach remains cautious, and appropriately so, because overly broad class labelling carries the risk of inappropriate treatment selection if mechanistic or clinical differences between therapies are not adequately characterised.

Class labelling is most successful in highly mechanistically homogeneous targeted therapy classes with analytically stable biomarkers and consistent treatment paradigms. It is far less effective in settings characterised by heterogeneous response biology, variable lines of therapy, or differing combination regimens.

Breakthrough Devices Designation: When to Pursue It for a CDx

The Breakthrough Devices Programme is an optional FDA designation intended to facilitate development and expedite review of medical devices meeting defined statutory criteria. It is important to note that the Breakthrough designation is not a separate premarket pathway, it operates within the existing PMA, 510(k), or De Novo framework and provides enhanced engagement rather than a reduced evidentiary standard.

Under section 515B of the FD&C Act, a device may be designated as a Breakthrough Device if it provides more effective treatment or diagnosis of a life-threatening or irreversibly debilitating disease or condition and meets at least one of the following: it represents a breakthrough technology, no approved or cleared alternatives exist, it offers significant advantages over existing alternatives, or availability is in the best interest of patients.

In the CDx context, Breakthrough designation is most relevant where the assay is linked to a novel therapeutic addressing a serious condition with limited treatment options, or where the diagnostic enables access to a targeted therapy in a population with previously unavailable options. However, designation should not be pursued as a default strategy. It should be considered only where the statutory criteria can be robustly justified and where the programme is expected to derive tangible benefit from more interactive FDA engagement during development.

Assay Technology Selection: IHC, NGS, PCR, and ELISA in a CDx Context

Assay technology selection for a companion diagnostic is not a pure technical decision, it is a regulatory and commercial one. The technology determines the scope of analytical validation, the plausibility of a 510(k) pathway (where applicable), the level of software and algorithm documentation required by CDRH, and the ease with which the assay can be standardised across clinical sites.

Expert input

When selecting a technology for the CDx assay, it is first important to consider the science. If the biomarker of interest is DNA- or RNA-based, NGS or PCR may be appropriate. If the biomarker is protein-based, IHC or ELISA should be considered. The current state-of-the-art for the detection of the analyte should be carefully reviewed to ensure the technology chosen reflects standard clinical practice. Analytically, the technology must be sufficiently sensitive and specific around the diagnostic cut-off, particularly for CDx devices, where the analytical performance around the cut-off directly influences patient management decisions.

FDA CDx in Rare Disease and Gene Therapy: Why These Programmes Are Harder

Rare disease and gene therapy CDx programmes present a specific set of structural challenges that generic CDx regulatory guidance does not adequately address. The challenges are not primarily regulatory, they are epidemiological.

The most common difficulty is sample availability. During analytical development, the limited patient population means that specimens positive for the biomarker of interest may be genuinely scarce. This constrains the options for bridging studies when the intended use needs to be extended to new sample types, and limits the ability to generate analytically sufficient datasets within normal development timelines.

In the clinical performance study, low enrolment numbers (a direct consequence of low disease prevalence) frequently mean there are too few samples to calculate diagnostic sensitivity and specificity with adequate statistical power. In these programmes, the objective and endpoints of the CDx performance evaluation must be carefully reconsidered. Rather than conventional accuracy metrics, the primary evidence may need to focus on clinical utility endpoints such as result turnaround time, quality control failure rate, or other parameters relevant to the specific clinical decision the device supports.

FDA and IVDR in Parallel: Structuring a Dual-Jurisdiction CDx Programme

When a sponsor wants to achieve both FDA approval and CE-IVDR marking for their CDx, the most important planning decision is identifying which parts of the development programme can be shared across the two frameworks, and which cannot. Making this determination at inception, not mid-programme, is what determines whether the parallel strategy is commercially viable within the intended timeline.

The intended use statement is the first element that can be aligned across jurisdictions. Both FDA and the IVDR require a clear, consistent intended use, and aligning this statement ensures that the development programme is synchronised so that data can be leveraged across both regulatory frameworks.

Analytical validation data can typically be leveraged across both, particularly if generated in accordance with CAP, CLIA, and CLSI guidelines. Both the IVDR and FDA’s 21 CFR Part 820 framework require comparable analytical parameters, sensitivity, specificity, accuracy, precision, interfering substances, and stability, before the device can be used in a clinical context.

The clinical performance study location introduces a jurisdiction-specific consideration. A study performed exclusively in the US or the EU may require justification of sample population equivalence for the other jurisdiction. Early dialogue with FDA through a Q-Submission, or with a Notified Body through pre-submission engagement, is the most efficient mechanism to establish whether the data from one population can support marketing in the other.

What a VP of Regulatory Affairs Should Ask When Evaluating a CDx Partner

Evaluating a CDx development partner requires questions that go beyond credentials and prior submission history.

The questions that most reliably separate capable partners from those that simply present well are the following:

Does the team assigned to the CDx project understand the science behind the device and the clinical setting, not just the regulatory requirements?

Does the partner have a regulatory intelligence system for continuous improvement and incorporating feedback from FDA to increase submission success rates?

Does the partner have tried-and-tested templates and procedures that can be deployed quickly?

What is the partner’s average number of RFIs received per submission and average time to resolution? If workload increases, can the partner scale the team with CDx-experienced personnel?

The RFI question is particularly diagnostic. The volume and complexity of requests for information during an FDA review directly reflects the quality of the initial submission. A partner that receives few RFIs or resolves them rapidly is demonstrating that its pre-submission preparation is calibrated to CDRH expectations, not merely producing technically complete documentation.

Summary: Key Decision Points in an FDA CDx Programme

Decision Point	Timing	Key Risk If Delayed
Intended use finalisation	Pre-IND / pre-trial design	All downstream validation, clinical, and labelling strategy misaligned
Significant risk determination	Before first clinical trial use	IDE applicability missed; study cannot proceed; IRB approval at risk
First Pre-Submission to CDRH	Once platform, specimen strategy, and analytical concept defined	Regulatory pathway misidentified; avoidable rework at submission
Assay lock	Before pivotal study enrolment	Bridging study required; 12–24 month delay; additional user fees
Letters of Authorisation between diagnostic and drug sponsors	Before pivotal study enrolment	Neither submission can be finalised; contemporaneous approval at risk
Pharmaceutical sponsor-CDx partner joint governance	Day 1 of programme	Disconnected timelines; IVDR/IDE workstream not integrated; delays at every stage

Frequently Asked Questions: FDA Companion Diagnostics

What is a companion diagnostic under FDA regulations?

An FDA companion diagnostic is an IVD device that provides information essential for the safe and effective use of a corresponding therapeutic product. Both the drug label and the device label must reflect this requirement at time of approval.

What is the primary FDA submission pathway for a companion diagnostic?

The primary pathway is Premarket Approval (PMA) under 21 CFR Part 814. Most CDx devices are classified as Class III due to the direct patient management consequences of their results. FDA’s preferred submission format is the modular PMA, in which four modules are submitted sequentially as data become available.

What changed with FDA’s November 2025 proposed reclassification of NGS-based oncology CDx?

FDA proposed moving NGS panels, PCR-based assays, and NAAT-based oncology CDx from Class III PMA to Class II 510(k) clearance with special controls. The comment period closed in January 2026. A final rule has not been published. Programmes currently in development should continue planning around the PMA pathway unless FDA provides specific direction otherwise.

When should a sponsor submit a Q-Submission or Pre-Submission to CDRH?

Once the intended use statement, assay platform, specimen strategy, analytical validation concept, and clinical trial integration model are reasonably defined, and before significant evidence generation has begun. Submitting earlier is more effective than submitting later. Late FDA engagement is one of the most common and most costly regulatory mistakes in CDx development.

Does an FDA companion diagnostic always require an IDE?

Only if the device is classified as a significant risk (SR) device under 21 CFR 812.3(m). If the assay result influences patient enrolment, treatment assignment, or another clinical management decision in a trial, an SR determination is generally expected. A Pre-IDE Q-Submission to CDRH is recommended when the determination is uncertain.

How long does FDA CDx co-development typically take?

From biomarker confirmation to regulatory approval of both the drug and the CDx, a typical programme takes four to six years. Aggressive programmes with mature biomarker readiness may compress to around three and a half years. The most common cause of delays is the CDx programme not being integrated into the master trial timeline from the outset.

About MDx CRO: FDA Companion Diagnostic Development Services

MDx CRO is a specialist CRO in MedTech with core expertise in IVD regulatory strategy, IVDR clinical performance studies, and FDA companion diagnostic development. Our regulatory team has supported more than 40 combined drug-diagnostic programmes across Phase 1 to Phase 3 trials, across the EU, US, and Asia-Pacific.

Our FDA CDx services cover: companion diagnostic regulatory strategy (PMA, De Novo, 510(k)); Q-Submission and Pre-Submission preparation; significant risk determination and IDE support; analytical and clinical validation planning; assay bridging strategy; co-development governance frameworks; and EU-US parallel submission strategy.

Download our FDA Companion Diagnostic Roadmap Template, a structured planning document covering the full regulatory pathway from intended use definition to post-market obligations. Available to download from this page.

Contact a CDx expert

Your Precision Medicine Partner for Companion Diagnostics

Industry Insights & Regulatory Updates

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

MDCG 2021-24 Rev.1: What Changed in EU MDR Device Classification (April 2026)

ISO 10993-1:2025 From Checkbox Compliance to Risk-Based Biocompatibility

ISO 20417:2026 You May Have a Gap Today: What Medical Device Manufacturers Shall Do Now

Making IVDR Work in Combined Studies: Scientific & Operational Lessons from 40+ Programs

April 13, 2026

Carlos Galamba

Combined studies, clinical trials that simultaneously investigate a medicinal product and an IVD under both the Clinical Trials Regulation (CTR) and the IVDR, are among the most complex regulatory challenges in precision medicine today. The lack of a coordinated EU assessment means sponsors face separate national submissions, divergent NCA interpretations, and timelines that can stretch 6-12 months beyond what was planned.

Last week, I presented at the 16th Clinical Biomarkers & Companion Diagnostics Summit Europe in London, sharing data and lessons from over 40 combined programs that MDx CRO has managed across 20+ EU countries. This article distils the key findings from that presentation: what triggers IVDR performance study requirements, why the same protocol can get three different answers from three NCAs, the top RFIs we see across programs, and how the regulatory landscape is evolving with MDCG 2025-5 and the December 2025 Health Services Pack.

Whether you are a pharmaceutical sponsor planning your first combined study, or a regulatory affairs professional navigating the dual-track CTR/IVDR submission process, this article gives you the operational intelligence that no guidance document provides.

Want the full CDx presentation slides?

Download the complete deck with case studies, the PSA approval timeline map, and the wave planning framework below.

Free download, presented at the 16th Clinical Biomarkers & CDx Summit Europe, London, March 2026

The Combined Studies Bottleneck: Why This Matters Now

The numbers tell the story. According to the EU COMBINE Analysis Report 2024, there were 402 combined study applications across the EU, of which 343 were CTR/IVDR combinations, and 86% of those were multinational. The mean approval time was 137 days, but the range was enormous: 45 to 267 days depending on the country, the submission pathway, and the quality of the initial dossier.

The root cause is structural. There is no coordinated IVDR assessment across Member States. Each country evaluates the performance study component independently, using national portals, national forms, and critically, national interpretations of the same regulation. For sponsors running multinational oncology trials with a companion diagnostic, this means multiplicative complexity: every additional country adds not just a submission, but a potentially different regulatory conclusion about whether a Performance Study Application (PSA) is even required.

And the volume is growing. Industry estimates project over 3,000 IVD submissions expected by 2029 as more CDx-driven oncology programs reach the EU. The system is already under strain.

This is the environment in which every combined study sponsor now operates. The question is not whether you will encounter divergent NCA opinions, it is how you prepare for them.

Same protocol, same device, three different answers.

The case presented at CDx Europe involved a pharmaceutical sponsor planning a multinational Phase 1b/2 oncology trial across France, Germany, and Spain. The study used a CE-marked companion diagnostic to run central testing retrospectively on leftover tumour samples, after enrolment was complete, purely as exploratory biomarker analysis. No additional invasive procedures. No impact on protocol-mandated treatment decisions. The sponsor sought pre-submission advice from three Member State competent authorities, presenting the same protocol and the same scientific rationale to each.

The three responses were incompatible.

NCA 1 concluded that no PSA was required, it accepted the sponsor’s argument that the activity was purely exploratory and non-interventional.

NCA 2 took the opposite position: because the assay was being used outside the scope of its CE-marked intended purpose, and because discrepant results would be communicated to investigators who could potentially act on them, it classified the study as interventional and required full PSA authorisation.

NCA 3 had not issued a definitive answer within the consultation period. This authority lacks a formal structured consultation procedure for performance studies and typically responds by email without fixed timelines.

When we presented this at the conference, there was an audible reaction in the room. Several attendees nodded immediately, this clearly resonated with their own experience. The most revealing question came from a regulatory affairs director at a mid-size pharmaceutical company who asked: “If the strictest authority changes its mind on appeal and agrees with the others, do we then need to explain to the permissive authority why we did something they told us we didn’t need to do?”

That question captures the operational absurdity of the current system perfectly. Sponsors are caught between harmonising upward, following the strictest requirement everywhere, which creates unnecessary burden in permissive jurisdictions, and harmonising downward, which creates compliance risk in the strictest one.

How Was It Resolved?

No harmonised consensus was reached between the three authorities. The sponsor appealed to the strictest authority in late 2025, providing additional justification and citing the fact that the most permissive authority had accepted the same protocol without any submission. By early 2026, the sponsor was cautiously optimistic that the appeal would succeed.

In parallel, they prepared contingency documentation for a dual-track approach: a full PSA in the country requiring it, a Performance Study Notification (PSN) in the country where the outcome remained uncertain, and no submission in the country that had cleared the protocol outright. Each country would effectively follow its own regulatory requirement.

Timeline impact: The divergent opinions introduced approximately 4–6 months of delay to the diagnostic component of the trial, encompassing multiple pre-submission consultation rounds, country-specific dossier preparation, appeal proceedings, and the need to compile and translate Annex XIV documentation for each jurisdiction independently.

There is currently no formal escalation or conflict-resolution pathway for performance study assessments. This is precisely the structural gap the COMBINE programme’s coordinated assessment pilot is intended to address.

What Triggers IVDR Performance Study Requirements?

Understanding the regulatory pathways is critical for any combined study. The IVDR establishes three routes, and the distinction between them determines everything: your timeline, your documentation burden, and whether your study can start at all.

Article 58.1 Authorisation Required

This applies to non-CE-marked devices or devices used outside their intended purpose. The process involves a 25-day validation phase followed by a 45-day review. You need full PSA authorisation when the study involves surgically invasive sample-taking for study purposes only, when it is an interventional clinical performance study, or when there are additional invasive procedures or risks beyond standard care.

Article 58.2 Notification Pathway

This applies to companion diagnostics using leftover samples only, where results do not influence treatment during the trial. The pathway is immediate or NCA-dependent after validation, depending on the Member State.

Article 70 CE-Marked Devices

This is a 30-day notification route for CE-marked devices used within their intended purpose but involving additional invasive or burdensome procedures beyond normal use. A critical nuance: if a CE-marked IVD is studied outside its intended purpose, the Article 70 notification route does not apply, it must be assessed under Article 58 instead.

The Key Decision Factors

From our experience across 40+ combined programs, the questions that determine which pathway applies and where NCAs diverge, are consistent:

CE mark status: for the specific trial use (intended purpose) not just whether the device has a CE mark, but whether the trial use falls within the marked scope
Whether results impact medical management: this is the most contested threshold, as “interventional” in the IVDR context carries a different meaning from “interventional” in clinical trial legislation
Study design: interventional vs observational
Sample type: fresh vs leftover, and the level of invasiveness required to collect them
Risk profile: additional procedures vs standard care
Whether device endpoints are clearly distinguished: from drug endpoints

Top 12 RFIs From 40+ Combined Programs

This is the data MDCG guidance documents do not provide. Over 40 combined programs, these are the most frequent Requests for Information (RFIs) we have received from NCAs and Ethics Committees across Europe:

1. Insufficient analytical validation (GSPR 9.1a). The test is a clinical trial assay, prototype, or lab-developed test (LDT) and was not developed under full design control. This may be accepted in US early-phase trials but is a common reason for rejection in the EU.

2. Insufficient data supporting the chosen cut-off. A small number of samples were used for cut-off validation. NCAs expect robust, data-driven rationales, not theoretical arguments.

3. Lacking or vague definitions of primary endpoints related to IVD performance, and the absence of a statistical analysis plan for the device component.

4. Informed Consent Form (ICF) lacks performance study-specific content. This is extremely common in combined CT/PS ICFs. Authorities regularly request revision in lay-user language that clearly distinguishes participation in the drug trial from participation in the diagnostic study.

5. Inconsistent objectives between the clinical trial application and performance study documentation. When the CPSP says one thing and the CTA says another, expect an RFI.

6. Incomplete risk plans and reports, with insufficient evaluation in the Investigator’s Brochure of how inaccurate test results could impact the clinical trial, especially for high-toxicity therapies.

7. Investigator and site documentation lacking PS references, required translations, or country-specific insurance certificates.

8. Lack of consideration towards monitoring the IVD study under ISO 20916, especially in sponsor-CRO or multicentre settings.

9. Divergent views between Ethics Committees and NCAs on risk, burden, or benefit, sometimes within the same country.

10. Use of leftover samples for future research without clear documentation on traceability, consent, or ethical approval.

11. Safety monitoring procedures in the CPSP not aligned with IVDR Article 74 and MDCG 2024-4.

12. Scientific inaccuracies in the CPSP, IB, and technical documentation, simple errors that erode credibility and trigger additional scrutiny.

What “Device-Specific Endpoints” Actually Means

One of the most common mistakes we see in combined studies is sponsors relying solely on drug efficacy endpoints (ORR, PFS, OS) as evidence of IVD performance. Under the IVDR and MDCG 2025-5, performance studies must generate data that establish or confirm device performance, not drug performance.

Analytical Endpoints (Often Used in Phase 1/2 Studies)

These include reportable rate, invalid-result rate, repeat-test rate, and assay failure rate; precision and reproducibility in the clinical setting; and accuracy at clinically relevant cut-offs.

Clinical Endpoints (CDx-Type, Often Used in Phase 3 and Bridging)

These include concordance with a clinically valid reference assay (PPA, NPA, OPA); diagnostic sensitivity and specificity vs clinical status; clinical outcomes studies in the IVD-selected group linked to drug endpoints; and clinical bridging studies.

What Is Not Sufficient as a Sole Endpoint

Turnaround time alone, and drug efficacy endpoints (ORR, PFS, OS) without device-specific performance measures.

Case Study: From Rejection to 8-Country Approval

One of the programs presented in detail involved an NGS-based CDx used to detect a specific mutation for targeted therapy patient eligibility in a rare tumour indication. It was a Phase 3 global trial with an interventional combined performance study across 30+ EU sites.

The Initial Rejection

The first EU submission was rejected. The reasons were typical of what we see repeatedly:

Incomplete analytical performance data vs GSPR 9.1(a) at the mutation cut-off
Weak linkage between biomarker, clinical condition, and treatment, a scientific validity gap
Under-developed risk management for false negatives in a high-toxicity therapy

What We Did

MDx CRO conducted a full gap analysis and remediation covering the Scientific Validity Report (SVR), Analytical Performance Report (APR), CPSP, and risk file versus Annex XIII requirements. We rewrote the CPSP with device-specific treatment-decision endpoints, strengthened the analytical data at the decision threshold, and quantified the false-negative impact in the risk management file.

The Outcome

Harmonised resubmission to 8 Member States. All RFIs resolved. Approvals in all 8 countries, within 4 months.

This case illustrates a pattern we see consistently: the initial submission fails not because the science is weak, but because the documentation does not speak the language the NCAs expect. The same data, presented differently, achieves a completely different result.

The Most Costly Mistake Sponsors Make

The single most expensive mistake we have seen sponsors make in the IVDR portion of a combined study is treating the performance study application as an afterthought, something to be “bolted on” after the clinical trial application is already in motion.

In one program, the sponsor had not engaged with IVDR requirements until approximately three months before planned first-patient-in. At that point they discovered that a PSA was required in multiple Member States, that documentation requirements were not harmonised across those countries, and that each required different local forms, different ethics committee interactions, and in some cases certified translations.

The result was a nine-month delay to the European portion of the trial and an estimated additional cost in the range of €800,000-€1.2 million when accounting for CRO renegotiation, site re-engagement fees, amended contracts, and the opportunity cost of delayed clinical data.

This is not an outlier. Industry survey data shows that a significant proportion of sponsors experience 6–12 months of IVDR-related delay in combined programs, with some reporting delays beyond 12 months. The structural cause is always the same: the pharmaceutical team and the diagnostics team are operating on disconnected timelines, and the IVDR submission is not integrated into the master trial timeline from the outset.

Wave Planning: The Operational Playbook

Not all EU Member States are equal when it comes to combined study submissions. One of the practical tools shared at the conference was our wave planning approach, a strategic framework for sequencing country activations based on regulatory architecture, not just commercial priority.

Wave 1: Speed, Parallel/Combined Processes

Spain offers parallel review, with submission to both AEMPS via the portal and the Ethics Committee (usually via email). Total timeline: approximately 85 days.

Belgium uses a consolidated review via CESP where the NCA and EC coordinate and issue a single opinion. Timeline: approximately 60 days.

These are faster because the EC and NCA review simultaneously, not sequentially.

Wave 2: Sequential Requirements

Germany, Austria, and Hungary all require EC approval first, followed by NCA submission. This adds the full EC timeline (46–166 days) before the NCA clock even starts. Total timelines: 135–267 days.

Wave 3: Administrative Complexity

Bulgaria requires notarised and apostilled Powers of Attorney, sworn translations, and physical courier submissions.

Poland requires paper copy submissions to both the EC and NCA, including wet-ink signed site documents, sworn translations, and stricter requirements demonstrating the Sponsor’s business registration and Power of Attorney.

Ireland has non-harmonised reviewers, causing inconsistent RFI rounds.

Why Wave Planning Matters

Typically, it is strategic to avoid submitting to high-administrative-burden countries in Wave 1. For example, Poland necessitates that the entire submission package is delivered to the EC and NCA via courier in printed form with wet-ink signatures. It is more efficient to submit first to countries with accessible pathways so that feedback from RFIs and lessons learned can be incorporated from the start for the more labour-intensive submissions.

The strategy: stagger activation by submission architecture and administrative burden, not just by regulator consolidation.

Illustration of European map showing estimated PSA approval timelines and submission complexities for MedTech products in the context of IVDR compliance. — Visual overview of European regions highlighting approval timelines and submission challenges for MedTech companies navigating IVDR requirements in combined studies.

How MDCG 2025-5 Is Changing the Landscape

MDCG 2025-5, published in June 2025, is the first dedicated Q&A guidance specifically addressing IVDR performance studies comprehensively. It covers 54 questions across topics that sponsors and NCAs have been debating since 2022, including:

A regulatory pathway decision tree (Appendix I) providing a structured framework for determining whether a planned activity requires a PSA, a PSN, or no submission at all
Clarification that “interventional” in the IVDR context meaning the results may influence patient management carries a different meaning from “interventional” as used in clinical trial legislation. This conflation has caused significant confusion
A working definition of “leftover samples” and the conditions under which they trigger notification rather than full application requirements
Guidance on combined studies including sponsor responsibilities, substantial modification handling across both the CTR and IVDR pathways, and the role of the performance study investigator

Are NCAs Following It?

Partially, and unevenly. Some authorities have begun aligning their pre-submission guidance with the decision-tree logic. Others continue applying their own interpretations, particularly on the definition of “interventional” which remains the most contested threshold.

The guidance is explicitly non-binding: MDCG 2025-5 itself states it cannot be regarded as reflecting the official position of the European Commission and that only the Court of Justice of the EU can give binding interpretations. In practice, guidance adoption across Member States typically lags publication by 12–18 months before a clear majority are operating consistently with it.

The Health Services Pack and the Biotech Act: Will It Actually Simplify Combined Studies?

In December 2025, the European Commission proposed two complementary pieces of legislation as part of a broader health services package. The first is a targeted revision of the MDR and IVDR, aimed at simplifying the existing regulatory framework. The second is the Biotech Act, which proposes amendments to the Clinical Trials Regulation that are directly relevant to combined studies.

What the Biotech Act Changes for Combined Studies

This is the more consequential development. The Biotech Act explicitly introduces a single integrated application for combined studies. Under the current framework, sponsors must seek authorisation of the clinical trial under the CTR and the performance study under the IVDR entirely independently separate portals, separate assessments, separate timelines, separate Member State interactions.

The Biotech Act proposes to eliminate that dual-track requirement. Instead, the sponsor would submit a single application covering both the investigational medicine and the IVD through a combined authorisation process managed under the CTR. That assessment would be led and coordinated by a Reporting Member State (RMS), with coordinated approvals across participating countries.

The proposal also accelerates CTR timelines generally, reducing the multinational CTA review from 106 days to 75 days, and as low as 47 days when no information request is issued.

My Assessment

This is not wishful thinking for the first time, there is a concrete legislative mechanism on the table that directly addresses the structural root cause of combined study delays. If adopted as proposed, it would be a genuine step-change.

However, three cautionary notes:

Legislative timeline. Even with political priority, realistic adoption and implementation timelines are 18–24 months from proposal. Do not expect sponsors to be able to use the single-application pathway before late 2027 at the earliest.

Implementation gap. CTIS will need to be updated to accept performance study documentation alongside the CTA, and Member State competent authorities will need to build assessment capacity for the IVD components within their CTR review teams.

The COMBINE pilot is the bridge. The COMBINE programme’s Project 1 pilot, launched on 13 June 2025, is already testing an “all-in-one” coordinated assessment approach. Sponsors who participate now are effectively rehearsing for the future framework.

The December 2025 package does have the potential to fundamentally simplify combined studies. But sponsors working in 2026 are still operating under the current framework. The practical advice remains: use the COMBINE pilot if you can, plan for Member State divergence if you can’t, and build your combined study submission strategy on the assumption that the current dual-track system will be in place until at least late 2027.

The #1 Mistake Sponsors Make in Their First Combined Study

They assume the IVDR performance study is the diagnostic manufacturer’s problem, not theirs.

The pharmaceutical sponsor designs the trial, defines the biomarker strategy, selects the assay, and writes the protocol. But when the conversation turns to the IVDR submission, they expect their diagnostic partner to handle it independently.

The reality is that under Article 2(57) of the IVDR, the “sponsor” is whichever entity takes responsibility for the initiation, management, and financing of the performance study and in a combined study, particularly in early-phase trials, that is often the pharmaceutical company itself.

This disconnect produces predictable failures:

The drug application is submitted through CTIS months before the PSA is even drafted
The diagnostic partner lacks access to the clinical trial protocol, site-level information, and country-specific documentation needed to complete the Annex XIV dossier
When an NCA issues an RFI at the interface between the two applications, neither team owns the response

MDCG 2022-10 is explicit: the clinical trial sponsor is responsible for overall compliance of products used in the trial, including the IVDR. Where a sponsor uses a CE-marked IVD outside its intended purpose, it assumes manufacturer responsibilities under Article 16(1).

The fix is straightforward: from Day 1 of trial design, the PSA workstream sits inside the integrated trial timeline, with a named owner, shared document management, and joint governance between pharmaceutical and diagnostics teams. Sponsors who do this avoid most problems. Sponsors who don’t are the ones calling us nine months before database lock.

How Much Time Does Expert Guidance Save?

Based on our experience across 40+ combined programs, working with a CRO that has specific IVDR and IVD regulatory expertise saves an average of 3 to 5 months compared to in-house teams or generalist CROs approaching combined studies for the first time.

The savings accumulate in three areas:

Pre-submission strategy (4–6 weeks saved). A specialist knows which Member States to sequence in Wave 1, what each authority actually expects beyond the statutory minimum, and which borderline classification questions need to be resolved before any dossier is submitted. Preventing a single misclassification avoids months of remediation.

Documentation preparation (4–8 weeks saved). Generalist CROs frequently prepare a single PSA dossier and submit it identically across all Member States. A specialist prepares country-adapted packages from the outset correct local forms, country-specific ethics committee requirements, certified translations, and portal-specific submission formats.

RFI management (2–4 weeks saved). When an NCA issues a request for information, a specialist drafts a response that also anticipates how the same question may be raised by other authorities whose reviews are still in progress preventing cascading delays across the wave.

Five Steps to De-Risk Your Next Combined Study

Based on the patterns from 40+ programs, these are the five actions that make the biggest difference:

1. Science first: do not underestimate analytical validation data. Analytical data should be traceable and robust, particularly around the cut-off. The APR and IB should be readable as standalone documents NCAs assess them that way.

2. Decide stakeholder ownership early. Sponsor vs Dx partner vs CRO for both the CTR and IVDR pathways. Ambiguous ownership is the single biggest source of delay.

3. Design device-specific endpoints upfront. Analytical and/or clinical, not just drug efficacy. If your performance study plan only lists ORR as an endpoint, expect a rejection.

4. Build the Annex XIII/XIV package early. SVR, APR, CPSP, risk management, GSPR logic evaluate internal capabilities and gaps before the submission clock starts.

5. Use structured tools for multi-country variation. Don’t rely on memory or email threads. Robust study design combined with an informed country strategy is what separates 60-day approvals from 267-day ones.

Looking Ahead: 2026–2027

From our experience, it will get slightly worse before it gets meaningfully better with the inflection point likely in late 2026 to early 2027.

The short-term pressure comes from volume. More sponsors are now aware of IVDR performance study requirements, which means more submissions entering the system. NCA capacity has not grown proportionally. Several smaller Member States still lack dedicated performance study reviewers.

The medium-term improvement will come from three converging developments: MDCG 2025-5 gradually reducing classification disputes, the COMBINE programme’s coordinated assessment pilot producing procedural lessons by mid-2026, and the December 2025 legislative revision proposal delivering structural changes by late 2027.

The biggest variable remains NCA behaviour. Regulatory guidance adoption is uneven and slow. It typically takes 12–18 months from MDCG publication before a clear majority of authorities are operating consistently with it.

For sponsors planning programs in 2026, the practical reality has not changed: plan for divergence between Member States, budget for country-specific regulatory strategies, engage the IVDR workstream at trial design not after the CTR is submitted and do not assume that what worked in one country will work in the next.

Download the Full Presentation

This article is based on my presentation at the 16th Clinical Biomarkers & Companion Diagnostics Summit Europe in London (March 30, April 1, 2026). The full slide deck includes additional data, the PSA approval timeline map across EU Member States, and detailed case studies that could not be covered in article format.

Need Help With Your Combined Study?

MDx CRO has managed 40+ combined programs across 20+ countries with a 100% approval rate and 90+ performance study submissions in the EU27. Our fastest program went from kick-off to full IVD Study Package Development and submission in 4 weeks.

If you are planning a combined study under the CTR and IVDR, talk to our team about how we can accelerate your path to first patient tested.

Frequently Asked Questions about IVDR Combined Studies

What triggers IVDR performance study requirements in a combined study?

IVDR performance study requirements are triggered through three pathways. Article 58.1 requires authorisation for non-CE-marked devices or devices used outside their intended purpose. Article 58.2 requires notification for companion diagnostics that use leftover samples only. Article 70 requires notification for CE-marked devices that involve additional burdensome procedures. Key decision factors include CE mark status for the specific trial use, whether results affect medical management, the study design, the sample type, and the risk profile.

How long does IVDR performance study approval take in a combined study?

Approval timelines vary by Member State. The EU COMBINE Analysis Report 2024 shows an average of 137 days, with a range of 45–267 days. Countries with parallel ethics committee and national authority review, such as Spain (~85 days) and Belgium (~60 days), are faster than those with sequential review, such as Germany, Austria, and Hungary (135–267 days).

What are the most common RFIs in IVDR combined studies?

Based on data from more than 40 combined programs, the most common RFIs include insufficient analytical validation under GSPR 9.1(a), insufficient data supporting the selected cut-off, missing device-specific endpoints in the CPSP, informed consent forms lacking performance study-specific content, and inconsistent objectives between the clinical trial application and performance study documentation.

What changed with MDCG 2025-5 for IVDR performance studies?

MDCG 2025-5, published in June 2025, is the first comprehensive Q&A guidance for IVDR performance studies. It introduces a regulatory pathway decision tree, clarifies that “interventional” in the IVDR context differs from the CTR definition, defines “leftover samples,” and addresses sponsor responsibilities in combined studies. Adoption by national authorities is uneven, and full alignment is expected within 12–18 months.

Will the December 2025 Health Services Pack simplify combined studies?

The Biotech Act proposed in December 2025 introduces a single integrated application for combined studies under the CTR framework. If adopted, it would remove the need for dual CTR and IVDR submissions. Realistic implementation is not expected before late 2027. The COMBINE programme pilot is currently testing coordinated assessment as a bridge to the future framework.

Written by:

Carlos Galamba

CEO & Head of IVD

Senior regulatory leader and former BSI IVDR reviewer with deep experience in CE marking high-risk IVDs, companion diagnostics, and IVDR implementation.

Industry Insights & Regulatory Updates

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

ISO 10993-1:2025 From Checkbox Compliance to Risk-Based Biocompatibility

ISO 14155:2026 What’s Changed and What It Means for Your Clinical Investigation

Portugal’s New Clinical Trials Law No. 9/2026: What Sponsors Need to Know

IMDRF Draft N91 2026: New Clinical Evidence Requirements for IVDs Explained

How to Run a CDx Performance Study Alongside a Drug Trial: Insights From 20+ Projects

March 20, 2026

Yaiza Benito

When a global pharma company runs a clinical trial for a new oncology drug that requires an NGS-based companion diagnostic to pre-screen patients, two regulatory worlds collide: the Clinical Trials Regulation governs the drug, while the IVDR governs the diagnostic. In Europe, these are legally separate submissions, with different portals, timelines and authorities. Operationally, however, they form one study, with shared patients, shared sites and shared deadlines.

At MDx CRO, we have supported over 20 companion diagnostic programmes in which the CDx clinical performance study runs in parallel with a pharma-sponsored drug trial. These combined studies, involving top-10 global pharmaceutical companies and IVD manufacturers across multiple EU Member States, have shown us what works, what fails and where regulatory friction most often arises.

This article reflects operational experience and interpretation of current regulatory frameworks under the CTR and IVDR. It shares what we have learned from supporting these studies in practice.

How to Run a CDx Performance Study Alongside a Drug Trial: Insights From 20+ Projects

When a global pharma company runs a clinical trial for a new oncology drug that requires an NGS-based companion diagnostic to pre-screen patients, two regulatory worlds collide. The Clinical Trials Regulation (CTR) governs the drug, while the IVDR governs the diagnostic. In Europe, these are legally separate submissions with different portals, different timelines, and different authorities, but operationally they are one study with shared patients, shared sites, and shared deadlines.

At MDx CRO, we have supported over 20 companion diagnostic programmes where the CDx clinical performance study runs in parallel with a pharma-sponsored drug trial. These combined studies, involving top-10 global pharmaceutical companies and IVD manufacturers across multiple EU Member States, have taught us what works, what fails, and where the regulatory friction points are.

This article shares what we have learned.

What is a combined study under IVDR and CTR?

A combined study is any study where two regulated product types, a medicinal product and an in vitro diagnostic, are investigated simultaneously. In practice, this is often referred to as a ‘combined study’. This typically means a Phase 2 or Phase 3 drug trial that uses a companion diagnostic to stratify or select patients based on a biomarker.

Under EU law, the drug trial falls under Regulation (EU) 536/2014 (the Clinical Trials Regulation, or CTR), and the CDx performance study falls under Regulation (EU) 2017/746 (the IVDR). There is currently no fully integrated EU submission pathway that covers both. Sponsors must file separate applications through separate systems: the drug trial via CTIS, and the performance study via national competent authority and ethics committee routes that vary by Member State.

The European Commission launched the COMBINE programme in 2023 to address this fragmentation, and a pilot coordinated assessment process began in mid-2025. However, for the foreseeable future, sponsors will need to manage dual submissions in parallel, and that is where complexity multiplies.

Why the CDx performance study gets underestimated

One of the most consistent patterns we see across combined studies is that the clinical performance study for the companion diagnostic is treated as secondary to the drug trial.

As Yaiza Benito, Clinical Project Manager at MDx CRO, explains:

“The clinical trial is always seen as the important one, and rightly so, there is enormous investment and pressure. But the companion diagnostic has to comply with IVDR on its own terms. Each product has its own requirements and each one has to meet them. You cannot undervalue the performance study.”

In our experience working with multinational pharma sponsors, this misalignment manifests in several ways. The IVD manufacturer and the pharma partner may not be fully coordinated on timelines, with the drug trial protocol advancing while the CDx documentation lags behind. Analytical validation, which must be completed before the CDx can be used in the trial, sometimes runs late because it was deprioritised in favour of the drug development programme. And the IVDR submission requirements, including the clinical performance study protocol, the investigator’s brochure for the IVD, and the risk management documentation, may not receive the same level of scrutiny as the CTR submission package.

The result is predictable: delays. Competent authorities and ethics committees issue Requests for Information (RFIs). Submissions stall. The drug trial start date slips, not because of the drug, but because of the diagnostic.

We have learned that the single most effective intervention in a combined study is treating the CDx performance study as an equal partner from day one, not an afterthought.

The regulatory landscape: two parallel submission tracks

Understanding the practical differences between the CTR and IVDR submission tracks is essential for anyone managing a combined study.

The drug trial (CTR track): Applications are submitted centrally via CTIS. The process is harmonised across the EU, with coordinated assessment between the reporting Member State and concerned Member States. Timelines are defined: validation within 10 days, assessment within 45 days (Part I), with extensions possible. The framework is mature and well-understood by sponsors.

The CDx performance study (IVDR track): Applications are submitted individually to each Member State’s competent authority and ethics committee, through national systems, which may include separate or partially coordinated submissions depending on the Member State. There is no central submission system yet, as EUDAMED’s performance study module is not expected before 2027-2028. Each country has its own templates, timelines, and review sequence. In some Member States, processes may be sequential (e.g., ethics review preceding competent authority assessment), while others allow parallel review.

This asymmetry creates a planning challenge. The drug trial submission is coordinated; the CDx submission is fragmented. When both need to be approved before the first patient can be enrolled at a given site, the slower of the two determines the timeline, and it is in many cases, the IVDR track becomes the critical path.

What MDx does in a combined study

Our involvement in combined studies focuses on the IVDR side of the equation. We support the CDx performance study across its full lifecycle, while the pharma sponsor or a drug-focused CRO manages the CTR clinical trial.

Review and development of technical documentation.

We review the IVD manufacturer’s technical documentation to ensure it meets IVDR requirements. In many cases, the CDx manufacturer is a US-based company whose documentation was initially built for FDA submission. We assess the documentation against IVDR General Safety and Performance Requirements (GSPRs) and identify the gaps that need to be addressed before European authorities will accept it. We can also develop documentation from scratch when the manufacturer provides the underlying data.

“Normally the bulk of the documentation is the same for FDA and IVDR, but IVDR tends to be more demanding on certain points. What we do is make sure it is 100% compliant with IVDR. That is our responsibility.”

Clinical performance study protocol development. We develop the Clinical Performance Study Protocol (CPSP) in accordance with ISO 20916 and IVDR Annex XIII requirements. The protocol defines study objectives, endpoints, specimen types, statistical methodology, site requirements, and monitoring plans. In a combined study, the CPSP must align with the drug trial protocol on key elements such as patient population, specimen collection procedures, and site selection, while remaining a standalone document for IVDR purposes.

Regulatory submissions to ethics committees and competent authorities. We manage the IVDR submission process across multiple EU Member States. This includes preparing country-specific documentation packages, managing communications with national authorities, and responding to RFIs. Each country has its own expectations, and our experience across 15+ EU Member States means we know what each authority prioritises before they ask.

Global sample monitoring under ISO 20916. We provide monitoring of testing sites, specifically the laboratories where the CDx is used to test patient samples. This includes site qualification (verifying the lab has the right equipment, QMS, and trained personnel), initiation visits, ongoing monitoring (on-site and remote), and close-out visits.

“For our current programmes with major pharma companies, we are monitoring all testing sites globally, not just the ones in Europe. We apply ISO 20916 across the board. This is where we are true experts.”

Clinical performance study reporting. At study close, we develop the Clinical Performance Study Report (CPSR), which feeds into the Performance Evaluation Report (PER) required for IVDR technical documentation and Notified Body review.

Five Lessons from 20+ CDx Programmes – MDx

.popup .popup-close{--wpr-bg-4cbf0c42-ba65-4f3d-ba1b-8752d5605d4e: url('https://mdxcro.com/wp-content/themes/mdx/assets/images/close_icon.svg');}.footer .newsletter{--wpr-bg-74874311-b5cc-4b21-9e40-544425300c48: url('https://mdxcro.com/wp-content/themes/mdx/assets/images/tmp/MDx-bg.svg');}.menu--sub):after{--wpr-bg-fd9f8604-8632-4a7f-9d35-5bdea90c87da: url('https://mdxcro.com/wp-content/themes/mdx/assets/images/arrow-down-black.svg');}.wpforms-container .wpforms-datepicker-wrap .wpforms-datepicker-clear{--wpr-bg-cd1d5b80-557a-4d06-97e7-9383b1fea1de: url('https://mdxcro.com/wp-content/plugins/wpforms/assets/pro/images/times-solid-white.svg');}

5 lessons from 20+ CDx programmes

Based on our experience managing the IVDR track of combined studies.

Strategy

Start IVDR strategy at the same time as CTR strategy

Develop the IVDR regulatory strategy in parallel with the CTR strategy from Phase 2 onwards — not after the drug trial protocol is finalised.

Validation

Complete analytical validation before the CDx enters the trial

Engage the validation team early — expertise in NGS, IHC, and qPCR is critical.

“When analytical validation is incomplete, competent authorities flag it immediately — RFIs can delay the study start by months.”

Submissions

Do not assume one submission package works for all countries

Cover letters, national forms, language and ethics requirements vary per EU Member State. Country-specific templates are essential.

Coordination

Align the CDx manufacturer and the pharma sponsor

Different regulatory obligations, timelines, priorities. Someone must coordinate protocol details, specimen handling & submission timelines.

“There are a lot of stakeholders involved. What we bring is agility, strong organisational capacity, and the ability to move fast.”

Monitoring

Risk-based monitoring must include CDx testing sites

CDx testing may happen at central labs, regional labs, or manufacturer facilities — these need qualification under ISO 20916 with remote monitoring capabilities.

Five lessons from 20+ CDx programmes

Based on our experience managing the IVDR track of combined studies, here are the five most important lessons we have learned.

1. Start the IVDR submission strategy at the same time as the CTR strategy, not after.

The most common mistake is treating the IVDR submission as something that can be figured out once the drug trial protocol is finalised. By that point, critical decisions have already been made about countries, sites, and specimen collection procedures that may not align with IVDR requirements. We recommend that the IVDR regulatory strategy is developed in parallel with the CTR strategy from Phase 2 onwards.

2. Analytical validation must be sufficiently established to support the safe and reliable use of the CDx in the clinical study

The CDx must be analytically validated before it is used to make patient selection decisions in a clinical trial. This seems obvious, but in practice we regularly see sponsors underestimate the time and resources required.

“Analytical validation is absolutely key. When it is incomplete or the documentation does not hold up, competent authorities flag it immediately, and the resulting RFIs can delay the study start by months.”

The analytical validation team, in our case a dedicated group with deep expertise in assay technologies including NGS, IHC, and qPCR, should be engaged early.

3. Do not assume one submission package works for all countries.

Each EU Member State has its own requirements for performance study applications. The core documentation may be the same, but cover letters, national forms, language requirements, and ethics committee expectations vary significantly. In some countries, you can submit in English; in others, key documents must be translated. Some authorities want the full Performance Evaluation Plan included; others do not. We maintain country-specific templates and relationship knowledge that allow us to submit with confidence across multiple markets simultaneously.

4. The CDx manufacturer and the pharma sponsor must be aligned, and someone needs to coordinate them.

In a combined study, the pharma company is typically the sponsor of the drug trial, and the IVD manufacturer is the sponsor (or legal manufacturer) of the CDx. These two entities have different regulatory obligations, different timelines, and sometimes different priorities. Someone needs to sit at the intersection and ensure alignment on protocol details, specimen handling procedures, site selection, and submission timelines.

“You have the pharma partner on one side and the IVD manufacturer on the other, and sometimes there is more than one CDx in the same study. There are a lot of stakeholders involved. What we bring is agility, strong organisational capacity, and the ability to move fast across all of them.”

5. Risk-based monitoring plans under ISO 20916 should include the CDx testing sites, not just the clinical trial sites.

Monitoring in a combined study often focuses on the clinical trial sites where patients are enrolled. But the CDx testing, where patient samples are analysed, may happen at different locations: central labs, regional labs, or the manufacturer’s own facilities. These testing sites need to be in line with ISO 20916 principles, including risk-based monitoring. We develop risk-based monitoring plans that cover both the clinical sites and the testing sites, with remote monitoring capabilities for global programmes.

The COMBINE programme and what it means for sponsors in 2026

The European Commission has initiated the COMBINE programme to explore and improve coordination between the Clinical Trials Regulation and the In Vitro Diagnostic Regulation for combined studies. The programme has identified several practical challenges, including misaligned timelines, fragmented national processes, limited coordination between competent authorities and ethics committees, and inconsistent documentation requirements.

In 2025, COMBINE activities included pilot work aimed at testing more coordinated approaches for multinational combined studies. These activities are intended to support better alignment between CTR and IVDR processes, including validation and assessment timelines, although the overall framework remains under development.

For sponsors planning combined studies in 2026 and beyond, the COMBINE programme is a positive signal. However, it is important to be realistic: the initiative is still evolving, and full harmonisation of IVDR submission processes is not expected until EUDAMED’s performance study module goes live, likely not before 2027–2028 at the earliest. In the meantime, sponsors should continue to plan for fragmented national submissions and invest in the country-specific expertise needed to manage them effectively.

Frequently asked questions

Are all companion diagnostic performance studies considered interventional?

Not necessarily. Under the IVDR, whether a CDx performance study is classified as interventional depends on whether the test results influence patient management decisions. In many combined studies, the CDx is used for patient selection (screening), and the results do directly affect care, making it interventional. However, if the CDx study uses only left-over samples and does not influence treatment, it may qualify as non-interventional, with reduced submission requirements. The classification has significant implications for the level of regulatory review required.

Can the CDx performance study use the same informed consent as the drug trial?

In some cases, yes. When the studies are fully integrated, with the same patients, the same sites, and the same specimen collection, it is possible to use a single Subject Information Sheet (SIS) that covers both the CTR and IVDR components. However, it must be very clear to participants that they are consenting to both studies. In practice, whether a single or dual consent approach is used depends on the specific study design and the requirements of the individual ethics committees involved.

Does MDx manage the drug trial side as well?

No. Our expertise is on the IVDR side: the CDx performance study, technical documentation review, regulatory submissions, and testing site monitoring. The drug trial is managed by the pharma sponsor or a drug-focused CRO. We work alongside them, ensuring the two tracks are coordinated and that the CDx programme does not become the bottleneck.

How long does it take to get IVDR approval for a CDx performance study?

Timelines vary significantly by country. In our experience, from initial submission to final approval, sponsors should plan for 3 to 6 months per country, accounting for validation, assessment, RFIs, and any required translations. Countries with sequential review processes (ethics first, then competent authority) tend to take longer. Starting the submission process early and in parallel with the CTR application is critical.

Planning a combined drug-diagnostic study in Europe?

MDx CRO manages the IVDR track of combined studies, from CDx documentation review and protocol development to multi-country submissions and ISO 20916 testing site monitoring. We work alongside your drug CRO to keep both tracks aligned and on schedule.

Talk to Our CDx Team

Written by:

Yaiza Benito

Clinical Development Lead | Precision Medicine

Senior Clinical Research Manager and biomedical engineer, expert in study design and clinical operations, MDR/IVDR regulatory compliance, GCP, CDx, and precision medicine.

Industry Insights & Regulatory Updates

Case Study: How MDx Enabled Argen’s Successful Transition to MDR CE Marking for Dental Alloys

Companion Diagnostic Clinical Trial Case Study

IVDR CE marking NGS: MDx Case Study with Fulgent

IVDR Transition for Precision Medicine: How MDx CRO Enabled a Seamless Portfolio Upgrade

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

FDA QMSR Gap Analysis: Compliance Guide for IVD and CDx Manufacturers

February 20, 2026

Joana Martins

On February 2, 2026, the U.S. Food and Drug Administration (FDA) implemented the new Quality Management System Regulation (QMSR), formally replacing the former Quality System Regulation (21 CFR Part 820). With this transition, the FDA incorporated ISO 13485:2016 by reference into U.S. law and introduced a new inspection model under Compliance Program 7382.850.

This article focuses on that second question. It explains how to structure a QMSR gap analysis, which areas almost always reveal gaps in practice, particularly for IVD and companion diagnostic manufacturers, and what FDA inspectors are finding in the first wave of QMSR inspections.

The insights below draw directly on MDx CRO’s quality and regulatory affairs experience supporting IVD manufacturers through QMSR readiness assessments.

Key point: ISO 13485 certification does not equal QMSR compliance. FDA-specific requirements remain fully enforceable, and under QMSR, inspectors now access records they previously could not.

Why the FDA QMSR Matters Beyond the February 2026 Deadline

The February deadline was the starting point, not the finish line. FDA’s Compliance Program 7382.850 is now the active inspection model. Manufacturers operating under the assumption that QMSR readiness was a one-time transition exercise are exposed to a different enforcement environment than the one they prepared for.

Under the former QSR model, inspections used QSIT subsystem checklists. Under QMSR, investigators evaluate how quality processes function as an integrated lifecycle framework, not whether each subsystem satisfies an individual checklist. That structural shift changes what inspectors look for and what they find.

Inspection change: FDA inspectors can now access internal audit reports, management reviews, and supplier audits. Under the previous QSR model, these records were largely outside inspection scope. Many manufacturers are unaware of this shift and have not reviewed the quality or completeness of these documents with inspection readiness in mind.

MDSAP Audit Approach 2026: How It Differs from FDA Inspections Under QMSR

MDSAP audits and FDA inspections serve fundamentally different regulatory functions and must not be conflated.

An MDSAP audit is conducted by an FDA-recognized Auditing Organization. It assesses conformity with harmonized quality management system requirements — ISO 13485 and the regulatory requirements of participating authorities including FDA. It is scheduled, structured, and conformity-focused. Participation remains voluntary.

An FDA inspection is a statutory enforcement activity conducted directly by FDA investigators. Its objective is not certification — it is the evaluation of compliance with US legal requirements and the identification of potential violations, systemic weaknesses, or public health risks.

MDSAP audit	FDA inspection (CP 7382.850)
Conformity-focused	Compliance-driven and enforceable
Scheduled and structured	Risk-based, for-cause, or routine
Bound by MDSAP task structure	Not limited by MDSAP scope or sampling
Outcome: certification report	Outcome: Form 483 / warning letter / no action
Internal records may not be reviewed	Internal audits, supplier audits, management reviews now in scope

Strong MDSAP performance may influence FDA surveillance planning. It does not eliminate the possibility of inspection, nor does it guarantee a favourable outcome when one occurs.

Common Assumptions That Increase Inspection Risk

Several structural misconceptions remain widespread. Under QMSR, these assumptions translate directly into inspection exposure.

“MDSAP replaces FDA inspections.” It informs surveillance planning. It does not limit FDA’s statutory authority.
“If the MDSAP auditor didn’t find it, FDA won’t pursue it.” FDA investigators are not constrained by MDSAP audit depth or task sequencing.
“ISO 13485 certification ensures FDA compliance.” ISO 13485 is incorporated by reference into QMSR, but FDA-specific requirements — UDI, MDR, device listing, labeling controls — remain fully enforceable and are not covered by ISO 13485 alone.
“QMSR was a documentation update.” For ISO-certified manufacturers, many gaps are substantive — missing FDA-required record content, incomplete UDI integration, absent MDR linkage — not cosmetic.

QMSR vs QSR vs ISO 13485: What Actually Changed

QMSR incorporates ISO 13485:2016 by reference into US law. That is a structural alignment, not a reduction in FDA enforcement authority. Obligations related to UDI, MDR, device listing, and labeling controls continue to apply in full.

Element	Former QSR (21 CFR 820)	FDA QMSR (2026)	ISO 13485:2016
Legal status	US regulation	US regulation (ISO 13485 incorporated by reference)	International standard
Inspection model	QSIT subsystem checklists	CP 7382.850 — lifecycle, risk-based	Certification audit
Internal audit access	Limited under §820.180(c)	Internal audits and management reviews reviewable	Auditor access at certification
CAPA focus	Procedural compliance	Demonstrated effectiveness + root cause verification	Effectiveness required
FDA-specific requirements	Fully embedded	UDI, MDR, labeling still fully enforceable	Not included

Takeaway: ISO 13485 alignment does not eliminate FDA-specific compliance obligations. A manufacturer can hold ISO 13485 certification and still have substantive QMSR gaps.

FDA Compliance Program 7382.850: How Inspections Work

As of 2 February 2026, FDA retired QSIT and implemented Compliance Program 7382.850. Inspections are now organised around six integrated QMS areas and four Other Applicable FDA Requirements (OAFRs).

Six QMS areas	Four OAFRs
Change Control	Unique Device Identification (UDI)
Design & Development	Medical Device Reporting (MDR)
Management Oversight	Corrections & Removals
Outsourcing & Purchasing	Tracking
Production & Service Provision
Measurement, Analysis & Improvement

Under this model, FDA evaluates how quality subsystems operate as an interconnected framework — not as isolated elements. Inspectors assess whether risk information, design decisions, post-market data, and management oversight are aligned throughout the product lifecycle.

The Four Areas That Almost Always Reveal Gaps

Across QMSR gap assessments conducted on IVD and medical device manufacturers, four areas surface as gaps with consistent regularity — even in organisations that have maintained ISO 13485 certification for years.

1. Complaint handling and servicing records

Many companies aligned with ISO 13485 underestimate the level of record detail FDA expects. Under QMSR, complaint and servicing records must include specific, enumerated data fields that ISO 13485 does not explicitly define. Records are often incomplete from an FDA perspective even when they satisfy the certification standard.

2. UDI traceability and record integration

UDI compliance is not simply a matter of having a UDI assigned and registered in GUDID. QMSR requires the UDI to be consistently recorded across multiple record types: complaints, servicing records, and batch or device history records. That level of cross-system integration is frequently missing — particularly in manufacturers who completed UDI registration without reviewing how UDI flows through their quality records.

3. Labeling and packaging controls

FDA maintains specific requirements for label content — including UDI, expiry dates, and handling instructions — and expects documented procedures designed to ensure accuracy and prevent mix-ups. These requirements are often handled informally or through processes that do not meet FDA’s explicit documentation expectations, even when the labels themselves are technically correct.

4. Linkage between ISO processes and FDA regulatory requirements

This is the gap that most consistently surprises ISO-certified organisations. A company may have complaint handling aligned with ISO 13485 clause 8.2.2 and consider that requirement closed — but fail to explicitly connect that process to Medical Device Reporting obligations under 21 CFR Part 803. FDA does not treat ISO conformity as a substitute for regulatory linkage. Each process must demonstrably connect to the applicable FDA requirement in the documentation.

“Companies often assume that having a robust ISO-aligned procedure is sufficient. What we find in practice is that the procedure exists — but there is no explicit documented connection between that procedure and the FDA-specific obligation it is meant to fulfil. That gap is invisible until an inspector asks for it.”

Joana Martins, QA/RA Specialist, MDx CRO

Why QMSR Gap Analysis Is More Complex for IVD and CDx Manufacturers

ISO 13485 and QMSR do not formally distinguish between device types. However, the nature of IVDs fundamentally changes which gaps are most consequential and how difficult they are to close.

Illustration of FDA inspection process emphasizing quality management systems, risk-based audits, and manufacturer readiness in MedTech industry.

A QMSR gap analysis for an IVD manufacturer must extend beyond traditional quality system elements. It needs to integrate scientific validity, analytical performance, and clinical evidence into the assessment framework. Where a general medical device gap analysis evaluates whether a product is designed, manufactured, and controlled to ensure safety and functional performance, an IVD-focused analysis must additionally verify that the product generates clinically reliable results under real-world biological variability.

Area	General medical device	IVD / CDx — additional complexity
Design controls	User needs, design inputs, outputs, V&V	Intended use, specimen type, analyte definition, performance claims must link to analytical and clinical data
Risk management	Device failure modes	Must also cover false positive and false negative results, diagnostic decision risks, interfering substances, matrix effects
Production controls	Process validation, specifications	Lot-to-lot variability of biological materials must be validated against clinically relevant performance criteria
Post-market surveillance	Complaint handling, MDR	Must detect performance drift — shifts in sensitivity or specificity — not just product failures
Purchasing controls	Supplier qualification	Supplier variability can directly affect assay performance outcomes

“For IVDs, failures may not manifest as product defects — they manifest as clinically incorrect results. That is a more insidious form of non-compliance, and it means the risk management and design control documentation needs to work harder than it does for a general medical device.”

Joana Martins, QA/RA Specialist, MDx CRO

What FDA Is Finding in QMSR Inspections: Warning Letter Patterns

Recent warning letters issued by CDRH following QMSR inspections show a consistent pattern. Deficiencies are not isolated — they are interconnected, reflecting a failure to operate an effective integrated quality system rather than individual documentation gaps.

Finding category	Most common deficiency pattern
CAPA	Procedures not defined or inadequate; failure to investigate root causes; CAPAs not verified for effectiveness
Complaint handling	Complaints not properly documented or evaluated; failure to assess whether complaints are reportable under MDR; no complaint trending or statistical analysis
Design controls	Lack of design verification and validation; poor documentation of design changes and their impact; no design and development plan or procedure
Supplier controls	Lack of defined quality requirements that suppliers must meet; no risk-based audit justification
Process validation	Manufacturing processes not validated; no revalidation after changes; validation protocols incomplete or not scientifically justified
Management responsibility	Management not actively involved in QMS; no effective management review with documented decisions and follow-up

Important: The FDA has clarified that if previous inspections were conducted under the QS Regulation (prior to 2 February 2026), any corrective actions proposed or implemented must now be pursued pursuant to QMSR requirements — not the former QSR standard.

What FDA Inspectors Scrutinize Most

Based on regulatory inspection support experience, three documentation areas present heightened exposure under QMSR.

1. Internal audits, supplier audits, and management review records

Under QMSR, FDA inspectors may review internal audit reports, supplier audit outcomes, and management review records. Investigators evaluate whether quality processes function effectively in practice — not merely whether procedures formally exist. Records must clearly demonstrate identified issues, root cause analysis, corrective actions, and documented closure. Incomplete or draft audit records increase inspection risk.

2. Design controls and traceability (ISO 13485 clause 7.3)

Manufacturers must demonstrate full traceability across user needs, design inputs, design outputs, verification and validation, and residual risks. Traceability weaknesses frequently arise at the interfaces between risk management files, labeling claims, UDI triggers, and MDR criteria. For companion diagnostics, this alignment is especially critical because intended use, biomarker claims, and clinical evidence directly impact regulatory risk classification.

3. CAPA and effectiveness verification

CAPA remains one of the most enforcement-sensitive areas under QMSR. The most common weakness is the absence of documented effectiveness verification following corrective actions. Closing a CAPA administratively — marking it complete without objective evidence that the root cause was eliminated — is insufficient. Investigators expect evidence demonstrating that actions prevented recurrence.

Inspection Risk Indicators

Risk area	Typical vulnerability
CAPA	Repeated issues without documented effectiveness verification
Design controls	Incomplete traceability between risk analysis and design inputs
Management review	Minutes lacking documented decisions, metrics, or follow-up actions
Supplier oversight	No risk-based justification for audit scope; missing quality requirements for suppliers
Post-market surveillance	Complaint trends not connected to CAPA or design updates
UDI	Not consistently recorded across complaints, servicing records, and device history records
MDR linkage	Complaint handling procedures not explicitly connected to MDR reporting obligations

How to Conduct a QMSR Gap Analysis: Process and Timeline

ISO 13485 certification does not automatically confirm FDA QMSR compliance. A structured gap analysis identifies the regulatory overlays and inspection exposure points that ISO conformity alone leaves unaddressed.

What a QMSR gap analysis covers

A thorough assessment works through four stages:

Clause mapping: Map ISO 13485 clauses to QMSR references. Confirm terminology alignment. Identify where the QMSR adds FDA-specific requirements beyond the ISO standard.
FDA-specific overlay identification: Verify explicit incorporation of UDI requirements across all applicable record types, MDR reporting triggers and their linkage to complaint handling, labeling obligations under 21 CFR Part 801, and device listing and registration controls.
Documentation exposure review: Assess internal audit completeness and whether records are inspection-ready, CAPA effectiveness evidence, management review decision traceability, and supplier risk classification and audit justification.
Risk prioritisation and remediation planning: Each gap is assessed for potential impact on quality, business continuity, and regulatory standing. Higher-risk gaps — those most likely to generate Form 483 observations or warning letters — are prioritised for remediation with assigned ownership and timelines.

How long does it take?

A gap analysis typically takes 4–6 weeks, provided documentation is made available at the outset. Implementation of corrective actions depends on the number and severity of findings and on the responsiveness of the internal team.

For manufacturers with both QMSR and ISO 13485 gaps, implementation may take 4–5 months. Where gaps are limited to QMSR-specific requirements in an otherwise ISO-aligned system, the timeline is typically shorter.

The ISO 13485 certification gap — what ‘compliant’ actually means

A persistent scenario in QMSR readiness work: a manufacturer holds ISO 13485 certification, has documented procedures that appear robust, and believes ISO alignment is sufficient. Gaps emerge in missing FDA-required data fields in records, incomplete UDI implementation, and failure to link ISO processes to FDA regulatory requirements.

They are structurally compliant with ISO but not fully aligned with FDA expectations. The distinction matters: an FDA inspector is not evaluating conformity to a certification standard. The inspector is evaluating compliance with US law and assessing whether the quality system actually functions as an integrated framework.

Medical device quality management and inspection process with team training, data-driven review, and inspection narratives for FDA compliance.

Download

QMSR Gap Assessment Checklist for IVD and CDx Manufacturers — A structured reference document developed by the MDx CRO quality team.

Download the FDA QMSR Gap Assessment Checklist

Practical Implications for Manufacturers

Inspection scope may be data-driven. FDA may use pre-inspection data reviews to target areas of concern, increasing scrutiny where trends or inconsistencies are identified.

FDA inspectors are evaluating how quality processes work together in practice — not whether each subsystem satisfies a checklist in isolation.

Previously internal records are now fair game. Internal audit reports, supplier audit outcomes, and management review records may be reviewed. These documents must reflect issues identified, decisions made, and actions taken.

Risk management must be continuous and demonstrable. FDA expects risk to be actively monitored and linked to CAPA, design changes, supplier controls, and post-market surveillance — not treated as a static exercise.

Post-market data is a primary inspection focus. Complaint trends, MDR, recalls, UDI, and tracking data are increasingly used to assess whether the quality system is effective and responsive.

How MDx Supports FDA QMSR Readiness: Expert Insight

Transitioning from QSR to FDA QMSR requires more than updating terminology. It demands structural alignment, inspection-oriented preparation.

Based on field experience supporting manufacturers through inspection preparation and regulatory alignment projects, Joana Martins, QA/RA Specialist at MDx, emphasizes that the most frequent vulnerabilities do not stem from missing procedures, but from insufficiently demonstrated system effectiveness.

According to Joana’s inspection readiness experience, organizations often underestimate three exposure points during FDA inspection preparation:

The depth of documentation review now permitted under QMSR
The need for traceability between risk management, design controls, and post-market data
The importance of documented effectiveness verification within CAPA systems

To address these exposure points, MDx supports medical device manufacturers through:

Independent QMSR-aligned readiness assessments focused on inspection exposure
Structured QMSR gap analysis incorporating FDA-specific regulatory overlays
Mock FDA inspections aligned with Compliance Program 7382.850
Strategic support for companies developing FDA companion diagnostics, where design traceability, labeling controls, and lifecycle data integration require heightened regulatory coherence

Rather than approaching FDA QMSR as a documentation update, MDx works with organizations to ensure their quality systems demonstrate operational integrity, risk-based decision-making, and inspection resilience.

Organizations preparing for FDA inspection or evaluating their QMSR alignment can benefit from early, structured assessment. Proactive evaluation reduces remediation timelines, minimizes inspection disruption, and strengthens regulatory confidence.

Frequently Asked Questions About FDA QMSR, MDSAP, and Inspections

What is the main difference between QSR and QMSR?

The main difference is structural alignment. Under QSR, FDA requirements were written directly into 21 CFR Part 820. Under QMSR, the FDA incorporates ISO 13485:2016 by reference into U.S. law while keeping FDA-specific obligations in force. In short, QMSR harmonizes structure with ISO 13485. However, it does not reduce FDA enforcement authority or eliminate U.S.-specific requirements such as MDR, UDI, or device listing.

Does ISO 13485 certification guarantee FDA compliance under QMSR?

No, it does not. Although ISO 13485 forms the backbone of QMSR, FDA-specific statutory requirements still apply. Manufacturers must comply with MDR, UDI, corrections and removals, and other U.S. obligations. Based on regulatory experience, companies often assume ISO certification closes all gaps. In practice, a targeted QMSR gap assessment is necessary to confirm full FDA alignment.

What replaced QSIT in FDA inspections?

FDA replaced QSIT with Compliance Program 7382.850, effective February 2, 2026. This new program aligns inspections with the QMSR framework. Instead of subsystem checklists, FDA now organizes inspections around six QMS areas and four Other Applicable FDA Requirements (OAFRs). As a result, inspections follow a more integrated, risk-based, lifecycle-focused approach.

Can FDA inspect internal audit reports under QMSR?

Yes. Under QMSR, FDA investigators may review internal audit reports, supplier audits, and management review records.
In practice, inspectors now verify whether issues were identified, documented, and effectively closed. They no longer focus only on whether procedures exist, they assess whether the system works as intended.
Incomplete or unverified audit actions may increase inspection risk.

What records are now receiving greater scrutiny during FDA inspections?

FDA now places greater scrutiny on:
– Internal and supplier audit reports
– Management review documentation
– Design control traceability records
– CAPA procedures and effectiveness checks
From inspection experience, CAPA effectiveness verification is a frequent weak point. Companies often implement corrective actions but fail to document objective evidence that the action resolved the root cause.
Under QMSR, effectiveness matters as much as documentation.

Why are companies that passed MDSAP still receiving FDA 483 observations?

Because MDSAP and FDA inspections serve different purposes. MDSAP evaluates conformity. FDA inspections assess legal compliance and public health risk. FDA investigators are not bound by MDSAP sampling methods or audit scope. If inspectors identify ineffective CAPA, weak traceability, or gaps between procedures and actual practice, they may issue Form 483 observations, even after a successful MDSAP audit.

How should manufacturers prepare for FDA inspections under QMSR?

Start early. Preparation often takes longer than expected. Then conduct a structured QMSR gap assessment. ISO 13485 compliance alone does not confirm full FDA alignment. Finally, train teams on Compliance Program 7382.850. Mock interviews and inspection simulations help identify weaknesses. Even documented remediation in progress demonstrates system control and reduces inspection risk.

When does FDA QMSR enforcement begin?

FDA QMSR enforcement began on February 2, 2026, when the new Quality Management System Regulation officially replaced the former Quality System Regulation (21 CFR Part 820). From that date, FDA inspections operate under Compliance Program 7382.850.

What are the FDA QMSR and ISO 13485 harmonization requirements for 2026?

Under the 2026 QMSR, ISO 13485:2016 is incorporated by reference into U.S. law. This means manufacturers must meet ISO 13485 requirements as part of FDA compliance. However, harmonization is not complete equivalence, FDA-specific obligations such as UDI, MDR reporting, device listing, and labeling controls remain fully enforceable and are not covered by ISO 13485 alone. See the QSR vs QMSR vs ISO 13485 comparison table above for a detailed breakdown.

Written by:

Joana Martins

QARA Specialist

QA/RA Specialist supporting teams in clinical evaluations and regulatory compliance with ISO 13485, MDR, and international medical device requirements (FDA, Health Canada, ANVISA).

Industry Insights & Regulatory Updates

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

MDCG 2021-24 Rev.1: What Changed in EU MDR Device Classification (April 2026)

ISO 10993-1:2025 From Checkbox Compliance to Risk-Based Biocompatibility

FDA Companion Diagnostics: A Complete Regulatory Guide to CDx Development, Approval, and Co-Development Strategy

IVDR Annex XIV Performance Studies for Companion Diagnostics: A Step-by-Step Guide 2026

February 19, 2026

This IVDR Annex XIV clinical performance study guide explains how you can plan and obtain authorisation for performance studies under Annex XIV of the IVDR when it involves a companion diagnostic. It aims to be practical and aligned with current expectations of ethics committees and competent authorities in the European Union.

If you require a structured checklist, you can download the Annex XIV Performance Study Authorisation (PSA) Toolkit, including an ISO 20916 monitoring checklist, templates, and a pre-submission workplan.

Cleared for Enrollment: A Practical Guide to IVDR Annex XIV Studies

Download the white paper here.

IVDR Annex XIV Clinical Performance Study: When PSA vs PSN Applies for Companion Diagnostics

Companion diagnostics (CDx) often require an IVDR Annex XIV clinical performance study because these tests directly influence patient management. Therefore, understanding when a Performance Study Authorisation (PSA) or a Performance Study Notification (PSN) applies is critical for effective regulatory planning and avoiding unnecessary delays.

Why Companion Diagnostics Often Fall Under Annex XIV

Companion diagnostics frequently fall under Annex XIV of the IVDR because the test result guides key treatment decisions, including:

Patient selection
Treatment allocation
Therapy continuation or discontinuation

If the study design allows test results to influence clinical decisions, regulators consider the study interventional, and this classification triggers the need for a Performance Study Authorisation (PSA). In addition, if you use the device outside its intended purpose as defined in the Instructions for Use (IFU), the IVDR framework also requires a PSA.

When Does a PSA Apply Under Article 58(1)?

For any IVDR Annex XIV clinical performance study, Article 58(1) serves as the key provision to determine whether a PSA is required. A PSA becomes mandatory if you meet any of the following three criteria:

You perform surgically invasive sample collection specifically for the clinical performance study (CPS).
You design the study as interventional in nature.
You introduce additional invasive procedures or other risks for participants.

If even one of these criteria applies, you must obtain a Performance Study Authorisation before starting the study.

When Does a PSN Apply Under Article 58(2)?

If you do not meet any of the Article 58(1) criteria, Article 58(2) may apply instead. In that case, you may submit a Performance Study Notification (PSN) when:

The study uses leftover samples only
The study includes no additional invasive procedures
Test results do not influence patient management
The design remains strictly non-interventional

However, even when these conditions apply, you must carefully evaluate national requirements and specific study design details to confirm that a PSN remains appropriate.

Combined Medicinal Product and Diagnostic Studies

An IVDR Annex XIV clinical performance study that involves both a companion diagnostic and a medicinal product requires structured coordination from the outset. When both regulatory frameworks apply, the Clinical Trials Regulation (CTR) governs the medicinal product, while the IVDR governs the diagnostic. Consequently, you must align timelines, documentation, and regulatory strategy under both frameworks to avoid inconsistencies and delays.

Step-by-Step: from planning to PSA approval

1. IB and CPSP Essentials, and the Link Between Endpoints, Intended Use, and Cut-off Strategy

Begin with a coherent Investigator’s Brochure (IB) and Clinical Performance Study Plan (CPSP). Every claim in the CPSP should trace to the intended purpose of the device and to analytical and clinical evidence that is sufficient for that claim. Endpoints must align with the intended clinical decision.

Based on our experience with more than 100 projects, the following two review findings occur repeatedly:

Analytical cut-off and validation. Authorities closely examine how the assay cut-off has been defined and supported. Sensitivity, precision, and accuracy should demonstrate that the device performs in a way that supports safe clinical decisions. Weak justification invites questions about patient misclassification risk, which frequently leads to requests for information.
Endpoints not aligned with intended use. Reviewers frequently question primary endpoints that are not clearly tied to clinical performance or to the intended use of the device. The endpoint should map directly to the decision being made for the patient.

Practical measures we have implemented in more than 100 projects:

Draft the statistical analysis plan early and show a clear line from intended use to endpoint to success criteria.
Map each analytical study (limit of detection, limit of quantitation, precision, interference, cut-off justification) to the clinical claim it supports.

2. Country Submissions: ethics committees, competent authorities, portals, translations, and fees

Plan both the ethics and competent authority pathways, including accounts for national portals, translation policies, and fee payments. Country-specific requirements can change timelines and logistics.

Some examples of country-specific requirements:

France requires an IDRCB registration code. The protocol, informed consent form, and insurance certificate must display this code. Missing or inconsistent use of the code commonly triggers requests for information.
Poland may require a physical submission package rather than a fully electronic file. Plan accordingly all documents that require original signatures. Courier time, notarised copies where applicable, and signature sequencing should also be built into the schedule.

A brief pre-submission checklist:

Identification of country EC-NCA submission approach (sequential, parallel, combined) and EC meeting schedules
Portal access verified and roles assigned for both ethics committees and competent authorities.
National identifiers obtained and propagated consistently across documents.
Translation scope defined and quality-controlled, particularly for patient-facing materials.
Insurance certificates aligned with the study footprint and national expectations.
Fee tables confirmed and purchase orders in place.

3. Timelines, Clock-Stops, and Expert Consultations

Validation and assessment phases of review often include clock-stops for clarification, where the reviewing authority can ask for further information, known as Request for Informations (RFIs). You should define internal service levels for responses in advance, and topic ownership should be clear across analytical, clinical, and biostatistics contributors. A master cross-reference that links CPSP, IB, risk management, and statistical sections reduces the risk of inconsistent responses. In Pickett’s assessment, assigning topic ownership for analytical, clinical, and statistical responses before submission helps keep clock-stops short and prevents inconsistent answers across documents.

IVDR Annex XIV Clinical Performance Study: How to Build a Robust Dossier?

A strong IVDR Annex XIV clinical performance study dossier reduces the risk of Requests for Information (RFIs), clock-stops, and approval delays.

Analytical Validation and Cut-Off Justification

For an IVDR Annex XIV clinical performance study, cut-off justification must go beyond presenting a single threshold value or ROC curve.

A robust dossier should:

Explain the clinical consequences of the selected cut-off
Describe how sensitivity and specificity change if the threshold shifts
Address false positives and false negatives at clinically relevant prevalence
Link analytical performance directly to the primary endpoint
Demonstrate how the device supports a safe clinical decision

Authorities frequently focus on misclassification risk. If the cut-off rationale does not clearly support safe decision-making, this section becomes a major driver of RFIs.

Best practice according to Callum Pickett Clinical Alliance Lead at MDx
Treat cut-off justification with the same rigor as a safety argument. Provide both statistical evidence and a clear clinical narrative.

Informed Consent Strategy Aligned With the CPSP

Misalignment between the Clinical Performance Study Plan (CPSP) and the informed consent form is a common cause of delay in an IVDR Annex XIV clinical performance study.

To reduce risk:

Finalize the CPSP first.
Draft the informed consent to mirror procedures, visit schedules, and risks.
Use clear, plain language that accurately reflects the protocol.

Reviewers assess whether participants are properly informed. If the consent document does not reflect the study design, an RFI is likely.

We recommend to include the following in the Informed Consent:

Clear summary of procedures and assessment schedule
Device-specific risks, including sample handling and possible retesting
Explanation of invalid or indeterminate results and participant implications

Consistency between the CPSP and consent documentation strengthens credibility during assessment.

Cross-Referencing: CPSP, IB, GSPR, and Study Reports

A cross-reference matrix improves both internal quality control and external review efficiency.

Your matrix should demonstrate:

Where each General Safety and Performance Requirement (GSPR) is addressed
How CPSP procedures are monitored and documented
Where statistical commitments are supported by analysis
How risk management links to study controls

For a successful IVDR Annex XIV clinical performance study submission, document traceability is critical.

Frequent RFI Drivers in IVDR Annex XIV Clinical Performance Studies

Below are common deficiencies and practical mitigation strategies:

RFI Driver	How to Address It
Primary endpoint not aligned with intended use	Redefine or restate the endpoint so it directly supports the clinical decision
Cut-off justification insufficient	Provide complete analytical data and explain clinical impact
Sample representativeness unclear	Justify matrix type, disease stage, prior therapy, and relevant variables
Misclassification of study type (leftover samples)	Clarify whether the design remains non-interventional and whether PSN is appropriate
Monitoring plan not aligned with ISO 20916	Define adverse event categories, roles, and timelines
Informed consent inconsistent with CPSP	Align language and procedural details precisely
Statistical assumptions not clinically justified	Link alpha and power to meaningful clinical differences
Device deficiency reporting unclear	Define detection, escalation, and reporting mechanisms
Risk management not connected to study controls	Trace risks to mitigation and monitoring activities
Combined CTR–IVDR governance unclear	Define roles, responsibilities, and decision pathways
Incomplete or low-quality translations	Plan professional review and back-translation
National identifiers or insurance mismatched	Ensure consistent codes and appropriate coverage limits

Country Playbook: How to plan Performance Study Applications to EU Member States

1. Identify the PSA submission approach adopted by the EU member state.

There are three models adopted by EU countries which will impact your submission strategy:

Sequential – the EC is submitted to first and NCA submission can only occur once an EC approval has been issued.
Parallel – the EC and NCA submissions can be submitted around or at the same time allowing for a “parallel” review process. However, the NCA will only approve the study once a positive EC opinion has been granted
Combined – a single PSA submission is sent to one authority which serves as the EC and NCA, a single positive opinion will be issued.

2. Choose your Ethics Committee:

It is highly recommended to submit the PSA to the same EC reviewing the associated Clinical Trial Application
Identify any EC specific templates, this may include EC-specific application forms and site document templates
Identify the EC meeting schedule and the deadlines for PSA submission to achieve review at the EC meeting date
Use the EC meeting schedule to inform your submission strategy, different ECs will meet at different frequencies.

3. Identify any specific requirements set by the National Competent Authority:

Are there any NCA specific templates to be filed with the PSA?
Is there anything that can gate submission to this country? For example, does the NCA mandate that the final Clinical Trial protocol is submitted with the submission.

4. Identify any specific laws and requirements for the EU member state being submitted to:

The EU is governed by GDPR laws, but national laws on data protection add an additional layer of requirements. Ensure that your study is developed with the national data protection requirements in mind.
EU member states have different requirements for the insurance documentation, this may include reference to national laws, inclusion of national study codes, and extra details on the number of participants.

5. Use all these points to create your submission strategy, informed by the following:

Submission approach: countries with sequential review approaches take longer on average than countries with parallel and combined review approaches.
Clinical Priority: what countries are priority for enrolment? Which countries will have the most sites and therefore need to be activated earlier?
- How often do the chosen ECs meet according to their meeting schedule?
- Are there any NCA or EC document requirements which aren’t yet available, and might delay submission?

Monitoring in Line with ISO 20916

ISO 20916 introduces additional classification categories for adverse events compared with the base IVDR text. Sites need clear training on event taxonomy, responsibilities for classification, and reporting timelines.

Content to include in the monitoring plan and site training:

Definitions and examples for adverse events and serious adverse events as used in the study.
Roles for initial classification, medical review, and final assessment.
Specific clocks for reporting from site to sponsor and from sponsor to authorities.
How to capture assess and report device deficiencies.

As our clinical team has observed under Annex XIV submissions, early training on adverse event taxonomy and reporting timelines is essential. Misclassification in the first reported case often leads to corrective actions and schedule impact.

IVDR Annex XIV clinical performance study Advanced MedTech Performance Study Workflow.

Scientific Validity within Annex XIV Performance Evaluation

From PSA to Market: coordination with the notified body and medicines regulators

For a true companion diagnostic approval, align analytical validity, clinical performance, and scientific validity with post-market plans. Label language and evidence expectations should be coordinated with the Notified Body and, where applicable, medicines regulators. Plan the handover from study evidence to post-market performance follow-up.

According to Callum Pickett, maintaining a single evidence map that links analytical validity, clinical performance, and scientific validity to the eventual label language streamlines Notified Body review and reduces post-submission clarification rounds.

Resources

Guidance from the Medical Device Coordination Group (MDCG) and the European Commission on performance studies, including Q&A on Article 58 pathways.
National guidance such as the Belgian Federal Agency for Medicines and Health Products (FAMHP) on dossier structure, timelines, and fees for performance studies.
Consultancy overviews such as DLRC Group (DLRC Group) for pan-EU context.
Standards published by the International Organization for Standardization (ISO), notably ISO 20916 for clinical performance studies of in vitro diagnostic medical devices.

Cleared for Enrollment: A Practical Guide to IVDR Annex XIV Studies

Download the white paper here.

Expert insight by Callum Pickett

Success with Annex XIV studies for companion diagnostics depends on alignment. Intended use, endpoints, analytical validation and cut-off, consent, and monitoring must be consistent and mutually supportive. Careful attention to country-specific requirements and early planning for CTR-IVDR coordination reduces the likelihood of clock-stops and requests for information. A structured checklist and disciplined cross-referencing improve dossier quality and assessment efficiency.

Read more about IVD clinical studies services.

Frequently Asked Questions (FAQ)

Performance Study Authorisation (PSA) is required for an IVDR Annex XIV clinical performance study?

A PSA is required under Article 58(1) if the study includes surgically invasive sample collection specifically for the study, uses an interventional design where test results influence patient management, or introduces additional invasive procedures or risks. In practice, companion diagnostics often trigger a PSA because their results guide treatment decisions. Therefore, as soon as one of these criteria applies, you must obtain a PSA before starting the study. For broader context on running studies under IVDR, read the following article on Running Clinical Studies Under IVDR

When can a Performance Study Notification (PSN) be used instead of a PSA?

You can use a PSN under Article 58(2) when the study remains strictly non-interventional. For example, the study may rely only on leftover samples, avoid additional invasive procedures, and ensure that test results do not influence clinical decisions. However, you must assess the design carefully, because misclassifying a study as non-interventional frequently leads to delays and reclassification requests.

How do IVDR and the Clinical Trials Regulation (CTR) interact in combined CDx–medicinal product studies?

In combined studies, you must comply with both frameworks simultaneously: the CTR governs the medicinal product, while the IVDR governs the companion diagnostic. As a result, you should align endpoints, intended use, and patient population across both submissions from the outset. Otherwise, inconsistencies between the CTR and IVDR dossiers often trigger Requests for Information and clock-stops. A structured gap analysis can help you identify and resolve these risks early. Read the article about pre submission assessment here.

What are the most common reasons authorities issue RFIs in Annex XIV studies?

Authorities typically issue RFIs when sponsors fail to align primary endpoints with the intended use, provide insufficient analytical validation or cut-off justification, or clearly explain misclassification risk. In addition, inconsistencies between the CPSP and informed consent, or weak traceability between risk management and statistical assumptions, often raise concerns. Therefore, you should build a clear cross-reference structure across all documents to reduce review friction.
For more detail on documentation expectations, read IVD technical documentation.

How can sponsors reduce approval timelines for IVDR Annex XIV performance studies?

To reduce timelines, you should define endpoints early and link them directly to intended use, justify analytical cut-offs with both statistical evidence and clinical rationale, and align the informed consent precisely with the CPSP. At the same time, confirm national submission models, ethics committee schedules, translation scope, and insurance requirements before submission. By assigning clear internal ownership for analytical, clinical, and statistical responses, you can also shorten clock-stops and maintain consistency during review.

Written by:

Callum Pickett

Clinical Alliance Lead | Precision Medicine

Experienced clinical affairs professional specialising in performance study submissions and management under IVDR, with a focus on CDx and Precision Medicine.

Industry Insights & Regulatory Updates

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

ISO 10993-1:2025 From Checkbox Compliance to Risk-Based Biocompatibility

FDA Companion Diagnostics: A Complete Regulatory Guide to CDx Development, Approval, and Co-Development Strategy

Making IVDR Work in Combined Studies: Scientific & Operational Lessons from 40+ Programs

ISO 14155:2026 What’s Changed and What It Means for Your Clinical Investigation

Navigating the IVDR CDx Certification Pathway

February 3, 2026

Carlos Galamba

The evolving landscape of Companion Diagnostics (CDx) introduces complexities in regulatory and certification processes. Engaging in IVDR Companion Diagnostic Consulting is essential to ensure a streamlined and compliant journey.

Deciphering Regulatory Nuances: US vs. EU

Historically, CDx devices in the EU were self-certified under the IVDD. A CDx manufacturer may have had experience with the FDA but the regulatory process in the EU is only now emerging.

The EU IVDR defines a CDx as a device which is essential for the safe and effective use of a corresponding medicinal product to identify, before and/or during treatment:

Patients who are most likely to benefit from the corresponding medicinal product
Patients likely to be at increased risk of serious adverse reaction as a result of treatment with a corresponding medicinal product

The FDA’s definition is similar but extends to devices used for “monitoring treatment responses with a particular therapeutic product”. Unlike in the US such devices are not considered companion diagnostics in the EU. Furthermore, the FDA acknowledges a category of devices termed complementary diagnostics. These diagnostics are characterized as tests that pinpoint a group of patients, identified by specific biomarkers, who respond well to a drug. While they assist in evaluating the risk-benefit ratio for individual patients, they aren’t mandatory for drug administration. Within the IVDR framework, complementary diagnostics aren’t explicitly detailed, nor do they have specific prerequisites for CE certification

These nuances are key for any CDx regulatory strategy and for the planning of CDx clinical trials. A specialized IVDR CDx consulting company like MDx CRO can help diagnostic companies and their pharma partners navigate global differences and ensure CDx regulatory compliance.

The EMA Consultation Process

EMA’s guidance stands as a pivotal component in IVDR Companion Diagnostic Consulting. The EMA CDx Assessment Report Template, publicly available, provides a comprehensive blueprint. It is a great source of information for the expectations in CDx submission content, particularly useful for when drafting SSPs and IFUs.

MDx CRO published a comprehensive guide to the CDx consultation process.

The process encompasses:

Declaration of intent.
EMA Rapporteur appointment.
Optional, but highly recommended, pre-submission meeting.
Application submission.
Interactive Q&A phases.
EMA’s final verdict.

Crafting of SSP & IFU with Detail

For successful IVDR CDx certification, the SSP and IFU documents should be meticulously detailed as they are the 2 key documents used during the EMA consultation process.

Diagnostic manufacturers should ensure they include:

Emphasis on scientific validity of the biomarker
Comprehensive detail on performance evaluation, study design descriptions, encompassing both analytical and clinical performance.
Insight into clinical data, detail on device modifications during or after the clinical performance study, and associated impacts, rationale for cut-off point selection and more.

A deep dive into the risk-benefit analysis is pivotal, concentrating on major residual risks and device limitations.

Time Considerations for IVDR CDx Certification

The certification process for CDx under IVDR is extensive. From the initial 3-month EMA notification to the concluding recommendation, the timeline can span 8-18 months. Such extended durations underline the criticality of early preparations. Engaging early with a specialized CDx consulting company can help avoid surprises and streamline the CDx certification journey.

The expertise offered by the notified body can significantly enrich IVDR Companion Diagnostic certification. Early engagements, prior to document submissions, can provide clarity, ensuring alignment with EMA requirements.

Selecting your IVDR CDx Consulting partner

MDx CRO has published a deep dive into the crucial factors to bear in mind when picking an IVD consultant.

In the dynamic realm of CDx, efficient navigation is paramount. If you’re seeking specialized insights into IVDR certification, explore our IVD services. At MDx CRO, our experts offers tailored IVDR Companion Diagnostic Consulting, ensuring optimal integration of CDx within the regulatory framework.

Contact our team today to discuss your CDx product needs!

Written by:

Carlos Galamba

CEO & Head of IVD

Senior regulatory leader and former BSI IVDR reviewer with deep experience in CE marking high-risk IVDs, companion diagnostics, and IVDR implementation.

Industry Insights & Regulatory Updates

A CRO’s Guide to IVD Analytical Validation: Best Practices & Common Pitfalls

AI & SaMD: Driving a New Era in Medical Innovation

Carlos Galamba: Your Trusted IVD Consultant and IVDR Expert

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

ISO 20916:2024 What You Need to Know for Clinical Performance Studies in 2026

February 2, 2026

Carlos Galamba

Planning a clinical performance study under IVDR in 2026 requires more than regulatory awareness, it requires strategic alignment with ISO 20916:2024.

This article breaks down what ISO 20916:2024 means in practice, how it interacts with IVDR, the key differences you must consider before designing your study, and how to position your project for regulatory success.

What changed with ISO 20916:2024 and how it affects your study strategy

ISO 20916:2024, Clinical performance studies using specimens from human subjects: Good study practice, was first introduced in 2019. In March 2024, it was published as EN ISO 20916:2024, marking a major step in ISO 20916 2024 IVDR harmonization IVD studies across Europe. This update aligns clinical performance study requirements directly with the IVDR.

In today’s rapidly evolving IVD landscape, safety and performance remain top priorities. ISO 20916 provides a solid framework to ensure clinical performance studies are planned, executed, recorded, and reported with scientific rigor. Its goal is simple: ensure IVD studies are ethical, reliable, and aligned with regulatory expectations.

This standard supports robust study design, promotes high‑quality data generation, and strengthens compliance for IVD manufacturers navigating the IVDR.

Planning a clinical performance study in 2026?

Request access to our expert session on preparing a GDD clinical performance study under ISO 20916:2024.

Contact us to watch the replay

The Role of Annex ZA in IVDR Performance Studies

The March 2024 revision introduced a key milestone: Annex ZA, which formally harmonizes ISO 20916 with the IVDR. While the IVDR already referenced ISO 20916, the addition of Annex ZA creates a unified regulatory pathway for clinical performance studies.

Annex ZA bridges the remaining gaps between the standard and the regulation. As a result, manufacturers benefit from clearer expectations and a more predictable approval process.

EN ISO 20916:2024 was approved by CEN without modification, reinforcing its relevance for EU regulatory compliance. However, at the time of writing, official recognition of ISO 20916:2024 as an IVDR harmonized standard in the EU Official Journal is still pending.

Note: As of the date this article was written, the official recognition of ISO 20916:2024 as an IVDR harmonized standard for clinical performance studies in theEuropean Union’s Official Journal was awaiting confirmation.

How Annex ZA Connects ISO 20916:2024 with IVDR Requirements

1. Presumption of Conformity

Compliance with the ISO 20916 clauses listed in Table ZA.1 gives manufacturers a presumption of conformity with IVDR GSPRs. This presumption simplifies regulatory alignment across IVD clinical performance studies.

2. Definition Alignment

When definitions differ between ISO 20916 and the IVDR, Annex ZA prioritizes IVDR terminology. This ensures consistency across regulatory submissions.

3. Risk‑Management Updates

Annex ZA strengthens risk‑management expectations. It requires alignment with IVDR principles such as “reducing risks as far as possible.” It also notes that ISO 20916 does not include foreseeable misuse, while the IVDR does—requiring sponsors to bridge this gap.

4. Acceptable Risk Policies

Manufacturers must align acceptable risk decisions with specific GSPRs. Annex ZA also clarifies that while ISO 20916 excludes training as a risk‑reduction measure, the IVDR allows it.

ISO 20916 vs IVDR: A Practical Comparison for Study Design

Topic	ISO 20916	IVDR
Annex XIV studies	No specific terminology for surgically invasive sample taking	Recognizes surgically invasive sampling as Annex XIV study
Adverse events	Structured categorization (device-related / non-device-related, serious, anticipated)	Less prescriptive
CPSP	Detailed specimen requirements	Requires reference to state of the art
Monitoring	Prescriptive; allows rationale for remote monitoring	Requires independent monitor
Informed consent	Highly detailed framework	Less detailed

Where ISO 20916 and IVDR Align

Despite some differences, the ISO and IVDR frameworks remain closely aligned in key areas:
Clinical performance parameters: Nearly identical, except ISO 20916 omits expected values for normal and affected populations.
Ethical considerations: ISO 20916 provides more detail, defining responsibilities for sponsors and investigators.
Bias mitigation: ISO 20916 offers explicit direction on preventing population, protocol, and reference‑method bias.
Site qualification: More detailed under ISO 20916, specifying resources, equipment validation, and QMS expectations.
CPSR content: ISO 20916 includes additional requirements, especially for interventional studies.
Comparator devices: The standard requires clear listing with commercial name, manufacturer, and catalog number.
Investigator’s Brochure: Both the IVDR and ISO 20916 are aligned, though ISO adds more detail on risk‑benefit documentation.

Who Should Apply EN ISO 20916:2024 in 2026?

Manufacturers of in vitro diagnostic medical devices
In vitro diagnostic clinics and laboratories
Test centres for in vitro diagnostic medical devices
Regulatory authorities
IVDR Notified Bodies
IVD Clinical research organizations (CROs)
Investigators and sponsors

Advantages of Applying EN ISO 20916 in IVD Performance Studies

Robust Results: It ensures high-quality, accurate, and reliable data generation, pivotal for safe healthcare decisions.
Ethical Standards: It upholds the rights, safety, dignity, and well-being of study subjects.
Study Planning and Conduct: It facilitates the meticulous planning and execution of IVD performance studies, ensuring regulatory and ethical compliance alongside scientific validity.
Compliance and Clarity: It provides a framework for compliance with IVDR, clarifying roles and responsibilities of all parties involved.
Risk Management: It emphasizes subject safety, especially regarding specimen collection risks, and ensures data integrity.

Implications for Sponsors and CROs Conducting IVD Performance Studies

The integration of ISO 20916 with the IVDR, highlighted by the inclusion of Annex ZA, significantly transforms IVD clinical performance studies and CRO operations. This crucial alignment demands a comprehensive revision in study design, execution, and reporting methodologies, highlighting the importance of compliance with the unified ISO 20916 and IVDR standards. It emphasizes the need for robust quality and risk management systems and ethically responsible study development.

This evolution signifies more than standard adherence; it represents a commitment to elevating IVD performance and efficacy in line with the highest EU regulatory standards. It requires IVD stakeholders, including CROs, sponsors and manufacturers, to deeply understand and agilely apply these standards, not only for compliance but to set new quality and safety benchmarks in diagnostics.

This commitment is fundamental to advancing patient care and public health, marking a significant step forward in regulatory compliance and industry excellence.

Since its foundation, MDx CRO has consistently used ISO 20916 as the benchmark for all our IVD clinical performance studies. The release of Annex ZA and its harmonization with IVDR reinforces our status as the leading CRO for IVD clinical performance studies.

Achieving Success in IVD Clinical Performance Studies

At MDx CRO, we navigate the complexities of IVDR and the latest ISO 20916 revision for in vitro diagnostic (IVD) studies with unmatched expertise. Our commitment to rigorous clinical operations ensures that every clinical performance study meets all regulatory standards, incorporating strategic risk management and adaptability for maximum compliance and integrity.

Partnering with us offers manufacturers a significant advantage, rigorously evaluating IVDs to ensure adequate performance and safety, a critical component of regulatory approvals.

Choose MDx CRO for excellence in IVD clinical performance studies, driving success and enhancing patient outcomes. Contact us for a discussion today!

Frequently Asked Questions about ISO 20916:2024 in 2026

Does ISO 20916:2024 apply to all IVD performance studies under IVDR?

ISO 20916:2024 provides a structured framework for the design, conduct, recording, and reporting of clinical performance studies involving IVD medical devices. While IVDR sets the legal requirements, ISO 20916 supports sponsors in demonstrating compliance through a harmonized and internationally recognized standard. Not all studies are identical in scope or risk level, but for interventional and other performance studies involving risk to subjects, alignment with ISO 20916 is strongly recommended to ensure methodological and documentation consistency.

What is the practical relevance of Annex ZA in ISO 20916:2024?

Annex ZA explains the relationship between ISO 20916:2024 and the requirements of IVDR. It maps the clauses of the standard to the corresponding IVDR provisions, helping sponsors understand how applying the standard supports regulatory compliance. In practice, Annex ZA serves as a bridge between operational study conduct and regulatory expectations under IVDR.

Why is ISO 20916:2024 strategically important for sponsors in 2026?

In 2026, regulatory scrutiny around clinical evidence and performance data continues to increase. ISO 20916:2024 offers a structured and prescriptive framework that reduces ambiguity in study design, monitoring, and documentation. For sponsors, early alignment with ISO 20916 can help minimize deficiencies during review, improve study robustness, and support smoother interactions with Notified Bodies.

Is ISO 20916:2024 mandatory under IVDR?

ISO 20916:2024 is not a regulation. IVDR is legally binding, whereas ISO 20916 is a standard. However, when recognized as harmonized, applying the standard provides a presumption of conformity with relevant IVDR requirements. Even where not mandatory, it is widely considered best practice for structuring clinical performance studies.

Request a free consultation with Carlos

Written by:

Carlos Galamba

CEO & Head of IVD

Senior regulatory leader and former BSI IVDR reviewer with deep experience in CE marking high-risk IVDs, companion diagnostics, and IVDR implementation.

Industry Insights & Regulatory Updates

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

Scientific Validity Report (SVR) Under EU IVDR: From Literature Review to Defensible Scientific Argument

MDCG 2021-24 Rev.1: What Changed in EU MDR Device Classification (April 2026)

FDA Companion Diagnostics: A Complete Regulatory Guide to CDx Development, Approval, and Co-Development Strategy

Impact of the Health Services Pack on IVD manufacturers, labs/health institutions and sponsors of combined studies

January 13, 2026

Carlos Galamba

In this article, we analyze the Health Services Pack IVDR impact and its role in shaping future health regulations.

On 16 December 2025, the European Commission published a proposal to amend the EU Medical Devices Regulation (MDR) and the In Vitro Diagnostic Regulation (IVDR) with targeted measures intended to reduce regulatory complexity, cost, and unpredictability while maintaining high safety standards.

This article focuses on IVDs under IVDR and the combined-study interface (drug–diagnostic and multi-legislation studies). It explains what the proposal says today, what it could change in practice, and how different stakeholders can prepare. It also recognizes that the text is still a proposal and may change during the ordinary legislative procedure in the European Parliament and Council.

Executive summary

What matters most for IVDR stakeholders.

If adopted largely as proposed, the package could materially affect how IVD stakeholders plan certification lifecycles, evidence generation, post-market obligations, in-house testing, and combined-study authorisations:

PRRC organisational burden would ease for SMEs relying on external PRRC support (availability requirement would soften; detailed qualification rules would be removed).
Certificate validity would shift from a fixed 5-year maximum to risk-based periodic reviews during the certificate lifecycle.
The proposal would support a broader evidence toolbox, including wider “clinical data” recognition and explicit promotion of New Approach Methodologies (including in silico testing).
Administrative burden would reduce via a narrower scope for summary documents and lower PSUR update frequency, plus longer timelines for certain vigilance reporting.
In-house testing under IVDR Article 5(5) would become more flexible, including (under IVDR) removing the “no equivalent device on the market” condition and explicitly bringing certain central laboratories supporting clinical trials into scope.
For combined studies, sponsors could submit a single application triggering a coordinated assessment aligned with the Clinical Trials Regulation framework.
Digitalisation would expand: digital EU Declarations of Conformity, more electronic submission, and electronic IFU for near-patient tests (among other measures).

The Commission frames these changes as a way to keep safety standards high while improving predictability, competitiveness, and innovation support; it cites €3–5 billion/year in cost savings at conservative estimates.

Key regulatory updates

PRRC flexibility for SMEs

Risk-based certificate validity

Broader clinical evidence

Reduced administrative burden

Flexible in-house testing (IVDR)

Streamlined combined studies

Expanded digitalisation

1) Context: why the Commission proposed a targeted IVDR/MDR revision

The Commission’s Q&A states that evaluation work identified shortcomings that negatively affect competitiveness, innovation, and patient care—pointing to inefficient coordination, divergent application of requirements, and procedures that are overly complex and costly.

The Commission describes the reform’s core objectives as:

Reduced administrative burden and stronger coordination
More proportionate requirements, especially for lower/medium risk devices and small patient populations
Support for innovation, including early expert advice and regulatory sandboxes
Greater predictability and cost-efficiency of certification, including enabling real-world evidence
Increased digitalisation across compliance tools and conformity assessment procedures

For IVDR stakeholders, the significance is not only the “what” but also the “how”: the proposal aims to make the system more predictable and less duplicative while leveraging EU-level expertise (including expert panels and EMA support).

2) Understanding Health Services Pack IVDR Impact: what it means for IVD manufacturers

2.1 PRRC: reduced organisational friction (especially for SMEs)

The proposal would:

Remove detailed qualification requirements for the Person Responsible for Regulatory Compliance (PRRC), and

Remove the requirement that SMEs using an external PRRC must have the PRRC “permanently and continuously” available; the PRRC would need to be available (without the “permanently and continuously” standard).

Why it matters: This could reduce structural overhead for smaller IVD manufacturers and for non-EU manufacturers using EU-based regulatory operating models. It may also reshape how manufacturers design PRRC coverage (internal vs external, shared services, outsourcing structures).

2.2 Certificates: from 5-year re-certification to risk-based periodic review

The proposal would remove the current maximum 5-year certificate validity and replace it with periodic reviews proportionate to device risk during the certificate’s validity period.

In addition, the proposal’s summary of certification changes includes:

Reduced systematic technical documentation assessment during surveillance activities (as summarised for certain IVD classes),
The ability for notified bodies to replace on-site audits with remote audits, and
Surveillance audits “only every two years” where justified by the absence of safety issues, plus unannounced audits “for-cause”.

Why it matters:
This is a structural shift in compliance planning—from a calendar-driven re-certification event to an ongoing lifecycle model that could be more data-driven. IVD manufacturers will likely need stronger “always audit-ready” systems and clearer change-control strategies.

Before and after comparison of IVDR requirements versus the Health Services Pack proposal, highlighting changes in PRRC availability, certificate validity, clinical evidence, PSUR, vigilance timelines, in-house testing, combined studies, and digitalisation.

2.3 Evidence toolbox: broader clinical data concepts and explicit support for in silico approaches

The proposal summarises multiple evidence-related changes, including:

A wider range of data qualifying as clinical data,
More flexible conditions for relying on clinical data from an equivalent device, and
Promotion of New Approach Methodologies such as in silico testing.

Why it matters for IVDs:
IVDR evidence expectations are often the pacing item for certification and market access—particularly for novel biomarkers, decentralised testing, and CDx. A broader toolbox could let manufacturers structure performance evaluation more efficiently, but it also puts more emphasis on robust justification: the proposal supports flexibility, not a “free pass.”

2.4 Summary documents and PSUR: targeted burden reduction

The proposal would:

Reduce the scope of devices that must have a summary of safety and (clinical) performance (SS(C)P) to those where the notified body must conduct technical documentation assessment—and remove the need for separate notified body validation of the draft summary.
Reduce the required PSUR update frequency, with notified body PSUR review integrated into surveillance.

For IVDR specifically, the proposal text also states that:

Manufacturers of class C and D devices would update the PSUR in the first year after the certificate is issued and every two years thereafter (or earlier in defined change situations).

Why it matters:
This change could reduce recurring workload—yet it will likely increase expectations that PSUR content is meaningful, well-argued, and operationally integrated into surveillance interactions.

2.5 Vigilance and cybersecurity: longer timelines for certain incidents, plus cyber reporting alignment

The proposal would extend the reporting timeline for certain serious incidents (those not linked to public health threats, death, or serious deterioration) to 30 days instead of 15.

It would also introduce a cybersecurity linkage:

Certain MDR/IVDR vigilance reports that also qualify as actively exploited vulnerabilities or severe incidents under the cyberresilience framework would be made available to national CSIRTs and ENISA; and
Manufacturers would have to report actively exploited vulnerabilities and severe incidents that do not qualify as “serious incidents” under MDR/IVDR to CSIRTs and ENISA through Eudamed;
Cybersecurity would be explicitly mentioned in Annex I general safety and performance requirements.

Why it matters for IVD manufacturers:
Cybersecurity is not only an “IT topic.” It increasingly affects performance, safety, vigilance, and field actions—especially for connected IVD instruments, software-driven diagnostics, and laboratory information system integration.

2.6 Digitalisation: eDoC, electronic submissions, eIFU for near-patient tests, and online sales information

The proposal includes:

Digital EU Declarations of Conformity,
More electronic submission of MDR/IVDR information,
Economic operators providing digital contacts in Eudamed,
Digital technical documentation and conformity assessment documentation, and
For IVDs, the ability for manufacturers of near-patient tests to provide electronic instructions for use.

It also introduces online-sales transparency requirements: essential device identification information and IFU information must be provided for online sales.

Why it matters:
This points toward a compliance ecosystem where document control, traceability, and market surveillance become more data-centric. Manufacturers will need disciplined digital governance to prevent inconsistency across channels.

3) What the proposal could change for labs and health institutions (IVDR Article 5(5) in-house)

The proposal would make in-house conditions more flexible, including:

Allowing the transfer of in-house devices when justified by patient safety or public health interests, and
Under IVDR, removing the condition that no equivalent device exists on the market.

It also explicitly adds central laboratories manufacturing and using tests exclusively for clinical trials into the scope of the in-house device exemption.

Why Health Services Pack IVDR matters
If adopted, this could significantly affect:

The role of hospital laboratories in innovation and continuity-of-care testing,
How health systems respond to unmet needs, niche populations, and rapidly evolving clinical practice, and
The operational models used to support clinical trials (including biomarker-driven trials and decentralised sample workflows).

What labs should plan
Recognising the proposal may change

Governance and documentation systems that can withstand scrutiny as “in-house” use expands in scope and visibility.
Contracting and quality interfaces between health institutions, trial sponsors, and central labs—especially where a lab’s “in-house” position interacts with trial requirements and sponsor expectations.

4) What the proposal could change for sponsors of combined studies (drug–diagnostic interface)

4.1 A single application with coordinated assessment (CTR-aligned pathway)

For combined studies involving medicinal products, medical devices, and/or IVDs, the proposal states that a sponsor may submit a single application triggering a coordinated assessment in accordance with the Clinical Trials Regulation (CTR), noting alignment with amendments anticipated via the Biotech Act.

Why it matters:
Sponsors running biomarker-driven programmes often experience friction at the interface between medicinal product trial authorisation processes and IVDR performance study requirements. A coordinated model—if implemented in a practical, predictable way—could materially improve planning across Member States.

4.2 Performance study burden reduction in defined scenarios

The proposal also states that:

Performance studies involving only routine blood draws would not require prior authorisation; and
Notification of performance studies on companion diagnostics using left-over specimens would be removed.

Why it matters:
This could affect study-start timelines, especially in multi-country settings where administrative sequencing often drives critical path. For sponsors, it may also change how they design sample strategies, feasibility, and site activation planning.

5) Practical implications of Health Services Pack IVDR Impact: how stakeholders can prepare while the text remains a proposal

Because the proposal may change during negotiations, stakeholders should avoid “over-implementing” assumptions. At the same time, most organisations can act now in ways that remain valuable under multiple legislative outcomes.

5.1 For IVD manufacturers (RA/QA and clinical/performance teams)

Focus now on “no-regret” preparedness:

Map your portfolio to where the proposal signals the biggest change: certificate lifecycle management, audit model (remote/on-site), and surveillance cadence.
Re-evaluate your evidence strategy so it can flex across clinical studies, literature, equivalence, and (where applicable) in silico methodologies—while keeping scientific validity and traceability strong.
Strengthen change control to align with the proposal’s intent to distinguish changes that require different levels of notified body interaction (including predetermined change control planning).
Upgrade vigilance and cybersecurity workflows so reporting pathways align with both vigilance obligations and the proposed cyber reporting linkages (CSIRTs/ENISA/Eudamed).
Digitise with discipline: ensure eDoC, digital IFU strategies, and online-sales content controls remain consistent and auditable.

5.2 For labs and health institutions

Review how in-house governance could evolve if the “no equivalent device” condition disappears and trial-supporting central labs fall clearly within scope.
Align in-house test lifecycle controls with quality expectations likely to increase as in-house scope expands in visibility and operational relevance.

5.3 For sponsors of combined studies

Build study-start strategies around the proposal’s direction of travel: a coordinated route for combined studies and reduced administrative hurdles for defined performance study scenarios.
Stress-test protocols for evidence coherence: regulators will still expect sponsor claims and IVD performance claims to align, even if administrative routes simplify.

6) Health Services Pack IVDR Impact and its potential global reach: what this could mean outside Europe

The Commission positions the EU as a global leader in medical device regulation and indicates the reform aims to make the sector more competitive globally.
It also explicitly links the proposal to reinforcing international cooperation, including participation in high-standard international cooperation and information-sharing mechanisms with reliable partners and strengthened uptake of international guidance.

For global manufacturers, that matters because EU compliance strategies often influence:

Global clinical evidence planning and dossier structuring, and
How manufacturers operationalise post-market surveillance and cybersecurity controls across regions.

(How much convergence happens in practice will depend on implementation and on how reliance mechanisms are used over time.)

FAQs

Is the Health Services Pack already law?

No. The Commission published a proposal on 16 December 2025. The text must go through the ordinary legislative procedure in the European Parliament and Council before any final legal changes take effect.

Will the proposal change IVDR certificate validity?

The proposal would remove the maximum 5-year certificate validity and replace it with risk-based periodic reviews while the certificate remains valid.

Does the proposal reduce PSUR update frequency under IVDR?

Yes. The proposal would reduce PSUR update frequency and integrate notified body PSUR review into surveillance. It also states class C and D PSUR updates would occur in the first year after certification and every two years thereafter (or earlier in defined cases).

Does the proposal change serious incident reporting timelines under IVDR?

Yes. For serious incidents not related to public health threats, death, or serious deterioration, the proposal would extend reporting timelines to 30 days instead of 15.

Does the proposal change IVDR in-house testing rules?

Yes. The proposal would make in-house conditions more flexible and, under IVDR, would remove the condition requiring “no equivalent device on the market.” It would also add certain central laboratories supporting clinical trials into scope.

How would the proposal affect combined studies?

The proposal states that sponsors could submit a single application for combined studies, triggering a coordinated assessment aligned with the Clinical Trials Regulation framework.

How can MDx CRO help you navigate Health Services Pack IVDR Impact effectively?

If you manufacture IVDs, run laboratory services, or sponsor combined studies, you will likely need to translate the proposal into:

A portfolio-level impact assessment (technical documentation, evidence strategy, and certification lifecycle planning), and
An operational plan for performance studies and combined-study submissions that remains robust even if the final text changes.

MDx CRO supports IVD manufacturers and sponsors across IVDR technical documentation, performance evaluation strategy, and combined study operational delivery (clinical operations + RA/QA alignment). The most effective next step is usually a short, structured gap-and-opportunity review tied to your portfolio and pipeline.

Need support?

We can assist you translating the Health Services Pack proposal into practical IVDR actions for your portfolio, studies, or lab activities.

Request a Free consultation

Written by:

Carlos Galamba

CEO & Head of IVD

Senior regulatory leader and former BSI IVDR reviewer with deep experience in CE marking high-risk IVDs, companion diagnostics, and IVDR implementation.

Industry Insights & Regulatory Updates

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

MDCG 2021-24 Rev.1: What Changed in EU MDR Device Classification (April 2026)

FDA Companion Diagnostics: A Complete Regulatory Guide to CDx Development, Approval, and Co-Development Strategy

ISO 20417:2026 You May Have a Gap Today: What Medical Device Manufacturers Shall Do Now