Category: Blog & Insights

Performance studies in gene therapy trials: from assay cut-offs to clinical impact

October 31, 2025

In gene therapy, your in-vitro diagnostic (IVD) doesn’t sit on the sidelines—it drives clinical decisions. If a result screens a participant in/out, times dosing, or informs safety management, you’re in IVDR performance study territory with ISO 20916 as the operational backbone. Treat the IVD like a product under evaluation, not a lab tool, and design a study that proves it’s fit for the exact decision your trial needs.

What actually triggers a performance study in gene therapy?

Use the simplest rule of thumb: does the assay influence patient management? If yes, plan for an IVDR Article 58 performance study in parallel with your clinical trial authorization. Typical triggers:

  • Eligibility/stratification: AAV neutralizing antibody (NAb) or total-antibody (ELISA) results that gate inclusion/exclusion or set a dosing window.
  • Patient monitoring: Assays that guide timing or continuation (e.g., changes in humoral markers relevant to vector readiness).
  • CDx trajectory: When the test is essential for safe and effective use, your evidence should be built to scale toward CDx—even if you’re not filing as CDx yet.

Treat these as combined trials (IMP + IVD). Align the performance study application with the drug CTA so approvals move together.

Build the right “assay stack” for AAV programs

Design your assay plan around the decisions your trial must make. In combined trials (IMP + IVD), that usually means separating screening, decision-making, and context/supporting activities—and documenting exactly which assay output drives which action in the CPSP and APR.

1) Screening assays

  • Purpose: Identify participants who may be eligible for dosing or further evaluation.
  • Typical methods: Total antibody (ELISA) and/or neutralizing antibody (NAb) assays.
  • Predefine: intended purpose, the output used for screening, cut-off, QC/controls, and invalid/repeat handling.
  • Regulatory note: If screening impacts enrollment/timing, it’s within IVDR performance study scope—reflect this in the protocol and dossier.

2) Decision-making assays

  • Purpose: Provide the result that directly guides patient management (e.g., eligibility for AAV dosing or readiness after a waiting/intervention period).
  • Typical method: Cell-based NAb assay when the decision depends on functional inhibition of transduction.
  • Predefine: a validated cut-off and how it’s applied at the decision point; acceptance criteria (controls/repeats), handling of invalid/borderline results, and any repeat-testing logic.

3) Context/supporting assays

  • Purpose: Provide supporting information (e.g., PCR/NGS for inclusion criteria or other exploratory markers) without driving patient management unless explicitly pre-specified.
  • Governance: These may be exploratory assays; do not let them influence decisions unless pre-declared.

Designing the CPSP: endpoints that matter (and survive small-N)

Tie endpoints to the decision you must defend. In rare diseases, power is constrained—precision and transparency carry weight.

Primary, decision-linked endpoints (illustrative):

  • Proportion below cut-off at the dosing/decision point.
  • Time-to-negativity (post-intervention or natural decline).
  • Duration of sustained negativity.
  • Change from baseline in NAb titers.

Key secondaries (analytical + feasibility + safety):

  • Analytical performance in operations: run-level QC pass rate, invalid/repeat rate, assay deficiencies/deviations.
  • Feasibility: turnaround time from collection to result, pre-analytical robustness (freeze–thaw, transport windows, matrix effects), stability.
  • Safety: AEs from sample collection/device use as per IVDR performance study reporting.

Correlative (pre-specified, descriptive):
Relate NAb kinetics to other humoral markers (e.g., total IgG, capsid-specific antibodies) where it clarifies the biology without over-claiming.

When your IVD sample size is constrained by the gene therapy protocol, say so. Set precision targets for agreement or proportions and specify how you’ll treat indeterminates/missing—regulators prefer realistic clarity over decorative p-values.

From LDT to IVDR: documentation that actually wins

Many gene therapy assays start as lab-developed tests or adapted RUO methods. Under IVDR you need an Analytical Performance Report (APR), not just a conventional validation report. The APR:

  • Maps analytics to intended purpose and clinical decision.
  • Uses a structured narrative per characteristic: Purpose → Study design → Statistics → Acceptance criteria → Results → Conclusion.
  • References applicable frameworks (IVDR, ISO, MDCG) and integrates ICH Q2(R2)/Q14 principles within the IVDR lens.
  • Justifies non-applicable GSPR requirements explicitly instead of hiding them.

What reviewers expect to “see on the page”

  • Analytical sensitivity: LoD/LoQ with methods, not just point estimates.
  • Analytical specificity: cross-reactivity, interference, matrix effects—demonstrated, not assumed.
  • Accuracy (trueness/bias): vs. reference materials/known concentrations across the measuring range.
  • Precision: repeatability, reproducibility and intermediate precision (operators, days, instruments).
  • Measuring interval/reportable range: tied to clinical decisions.
  • Robustness & stability: small-parameter changes; specimen/reagent stability across the actual logistics.
  • Traceability: metrological traceability to reference materials or SI units wherever feasible.

Bridging without back-tracking

If you migrate platforms or laboratories, pre-declare equivalence boundaries, commutable panels, and the statistical approach before you switch. Link the APR to the Design History File and ultimately to the Performance Evaluation Report to keep evidence audit-ready.

Operational blueprint: lab-centric, ISO 20916–aligned execution

Programs that run smoothly accept a basic truth: lab operations are clinical operations when an assay drives decisions.

  • Risk-based monitoring (ISO 20916): Prioritize calibration records, control runs, instrument logs, sample accountability, LIMS audit trails, and lab-critical SDV.
  • Clear RACI across stakeholders: pharma sponsor, diagnostic partner, central lab, CRO(s). Assign a single “owner of truth” for eligibility calls and a documented adjudication path for gray-zone results.
  • Sample governance: pre-analytical controls (shipping, temperature, freeze–thaw limits), redraw/retest SLAs, and chain-of-custody that survives inspection.
  • Safety integration: define device-side AE/device-deficiency flows and their handshakes with the IMP SAE process—who reports what, where, when—and hold joint drills before FPI.

Common pitfalls (and the fix)

Copy-pasting a validation report into IVDR—without showing how analytics support the clinical decision.

  • Fix: Rewrite into an APR aligned to the intended purpose; connect every analytic claim to the use case.

Pretending power exists in tiny cohorts.

  • Fix: Pre-specify precision not power; make QC-forward primary endpoints; keep clinical associations descriptive.

Letting exploratory assays creep into decision-making ad hoc.

  • Fix: Lock the assay stack and decision logic in the CPSP; label everything else exploratory.

Underplaying pre-analytical risk.

  • Fix: Measure it (transport windows, freeze–thaw), set acceptance criteria, and track at run-level.

Ambiguity in roles and safety.

  • Fix: Publish a RACI and an integrated safety matrix early; rehearse escalations.

Sponsor checklist

  • Decide early if the assay changes patient management → if yes, plan an IVDR performance study.
  • Lock claims, cut-offs, and gray zones; write the CPSP to those decisions.
  • Choose your study model (prospective/retrospective/bridging) to match real sample access and clinical trial needs.
  • Produce an APR with complete traceability and justified non-applicable requirements.
  • Stand up lab-centric monitoring (ISO 20916), eTMF rigor, and LIMS auditability.
  • Align device and drug safety reporting—on paper and in practice.
  • Embrace small-N: set precision goals, prioritize QC endpoints, and keep associations descriptive.
  • Think CDx-ready: structure today’s evidence so tomorrow’s filing doesn’t start from zero.

How MDx CRO accelerates combined gene therapy studies

We run the device side of your combined trial end-to-end: strategy, CPSP/APR/PER authorship, submissions, ISO 20916-aligned operations, lab-centric monitoring and SDV, data/biostats, and inspection-ready traceability. We design performance studies that mirror real clinical decisions, so approvals and operations move in lockstep.

Let’s co-design your performance study

Speak with our IVD & gene therapy team

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Spanish IVD Regulation 2025 – New Royal Decree Updates for IVD Manufacturers, Sponsors, and Labs

October 21, 2025

On 21 October 2025, the Council of Ministers approved Spain’s new Royal Decree for in vitro diagnostic devices. AEMPS confirmed the approval and explained that the decree complements IVDR (EU) 2017/746, strengthens patient protection, and adds national rules on language, in-house manufacturing, performance studies, and vigilance. This development anchors the Spanish IVD Regulation 2025 and sets clear obligations for manufacturers, sponsors, and laboratories. (Official announcement: AEMPS)

Spanish IVD Regulation 2025: What Changed and Why It Matters

The Spanish IVD Regulation 2025 replaces Royal Decree 1662/2000. It clarifies how IVDR applies in Spain and fills Member-State choices, including competent authority, language regime, Article 5(5) in-house devices, genetic testing and counseling, a national marketing register, performance study authorization, and vigilance and market control.

The regulation aims to raise quality, ensure traceability, and speed up corrective actions. It also improves access to certain self-tests through pharmacy channels.

Quick Guide for Busy Teams (Manufacturers, Sponsors, Labs)

  • Confirm what the Spanish IVD Regulation 2025 changes for your role.
  • Map licensing, registration, language, Article 5(5), ISO 15189, performance studies, and vigilance to owners and deadlines.
  • Prepare Spanish-language materials and set up traceability and incident reporting workflows.
  • Labs should plan ISO 15189 and Article 5(5) notifications to AEMPS.

Competent Authority and Language Rules under the Spanish IVD Regulation 2025

AEMPS is the competent authority for IVDs in Spain. Under the Spanish IVD Regulation 2025, user-facing materials for devices marketed in Spain must appear in Spanish. That includes labels, IFU, and safety notices. Regulatory submissions to AEMPS should include Spanish content. Co-official languages may be added, but Spanish is mandatory.

Action: Audit labeling, IFU, FSNs, PMS templates, and performance study files. Plan translations and version control.

Facility Licensing: Manufacturers, Sterilizers, and Importers

The Spanish IVD Regulation 2025 requires operating licenses for manufacturers, sterilizers, and importers before they place devices on the market. AEMPS evaluates facilities, personnel, and quality systems.

Each site must appoint a Technical Responsible Person (national role) and meet IVDR oversight led by a PRRC. One qualified person can cover both if they meet the criteria.

Transitional rule: Existing third-party manufacturers get up to one year from entry into force to secure the new license. Existing licenses remain valid until renewal or change, which then follow the new procedure.

Action: Confirm license status, designate the responsible person, and prepare for renewal under the new framework.

Marketing Register and Traceability

The decree creates a Spanish marketing register for devices placed on the market. Manufacturers, authorized representatives, and importers must notify product information to support traceability and market surveillance. The register complements EUDAMED and UDI.

Transitional rule: Spain will activate notifications when the register is operational. Until then, use existing national channels.

Action: Build a clean data set for device identifiers, certificates, and supply chains. Prepare to submit once AEMPS opens the register.

In-House Devices (Article 5(5) IVDR): What Labs Must Do Now

Scope and intent

The Spanish IVD Regulation 2025 regulates in-house IVDs made and used within the same health institution. Labs must justify need: a commercial CE-marked device cannot meet the specific clinical need. No industrial-scale production. No commercial supply to third parties.

Quality and documentation

In-house devices must meet IVDR GSPRs. Labs should keep a technical file (intended purpose, risk management, analytical and clinical performance, V&V, SOPs, and labeling for internal use).

ISO 15189 accreditation

Labs that manufacture in-house devices must obtain ISO 15189 accreditation for the manufacturing scope. Spain ties this to the transitional schedule.

Notification to AEMPS

Before starting in-house manufacture, labs must notify AEMPS and submit the Article 5(5) declaration. They must designate a responsible person for the in-house manufacturing process.

Action for labs: Launch ISO 15189 projects, finalize Article 5(5) templates, and prepare the AEMPS notification package.

Genetic Testing: Information and Counseling

The Spanish IVD Regulation 2025 requires clear information and appropriate counseling for genetic testing. Health professionals must explain limits, implications, and result interpretation. This duty applies before and after testing.

Health professionals and centers must obtain explicit informed consent from individuals before performing a genetic test. The patient must be made aware of the nature and purpose of the test and consent in writing (except where law may exempt certain public health screening). This goes beyond standard consent, recognizing the personal and familial implications of genetic data.

Before the test, patients should be informed about what the test can and cannot tell them, and after the test, a qualified professional should explain the results and any recommended follow-up. This requirement ensures genetic tests (such as those for hereditary disease risk) are not delivered without context or support, helping patients make informed decisions.

These obligations apply to genetic IVDs regardless of whether they are done in-house or as commercial tests. For example, a direct-to-consumer genetic test kit (if allowed on the market) would need to be accompanied by processes that ensure the purchaser gets necessary information and counseling. However, most genetic tests are administered in clinical settings; the decree effectively standardizes the practice of genetic counseling as part of testing.

Action: Update consent forms, patient information sheets, and SOPs for genetic counseling, including training for staff.

Performance Studies in Spain

All performance studies in Spain must first obtain a favorable opinion from an accredited Research Ethics Committee (REC) and authorization from the health center’s management where the study will be conducted. This applies to any study using human specimens or data for evaluating an IVD’s performance, ensuring ethical considerations (informed consent, data protection, etc.) are addressed early.

When you need authorization

Interventional clinical performance studies and other studies involving risks require AEMPS authorization before first participant. Ethics approval remains mandatory.

What sponsors must prepare

  • Spanish protocol (CPSP), Investigator’s Brochure, and informed consent.
  • Insurance/indemnity for participants and a clear liability framework. The decree explicitly requires compensation for damages and defines the liability regime for sponsors. Sponsors should budget for a clinical trial insurance policy and follow the decree’s rules on coverage minimums and conditions (similar to drug trial insurance requirements in Spain).
  • Monitoring, data management, and safety reporting plans aligned with IVDR. Upon study completion, results (whether positive, negative, or inconclusive) should be documented and may need to be reported in the public database or to AEMPS.

Studies with CE-marked devices

If the study adds invasive or burdensome procedures or goes outside intended use, sponsors should request authorization and notify AEMPS.

Action for sponsors: Build a Spain-ready dossier, confirm insurance, and align timelines with AEMPS and ethics reviews.

Vigilance and Market Control

The Spanish IVD Regulation 2025 reinforces vigilance. Manufacturers must report serious incidents and FSCAs to AEMPS. Healthcare professionals and institutions should also report incidents. Authorities will coordinate inspections and market control actions.

For instance, if an IVD test yields false results that lead to patient harm, the manufacturer has to notify AEMPS and submit a Spanish-language safety notice so that users in Spain can be adequately informed. This ensures critical safety information is effectively communicated and mitigated in the local context.

The decree emphasizes that healthcare professionals, health institutions, and even patients/users have a responsibility to report any suspected serious incidents to AEMPS. Spain is thus bolstering a culture of vigilance: a lab that encounters a device malfunction or a clinician who notices a pattern of erroneous results should alert the authorities. The more comprehensive the reporting, the better AEMPS can intervene to prevent harm.

Action: Maintain robust PMS plans, trend analysis, Spanish FSNs, and clear internal reporting lines. Hospitals should assign a vigilance lead and train teams.

Self-Test Access and Pharmacy Channels

Notably, the new rules remove the prescription requirement for at-home self-testing kits (e.g. self-tests for glucose, pregnancy, COVID-19, etc.), making them more accessible. However, even without needing a prescription, these self-diagnostic products can only be sold through pharmacies (in-store or via an official pharmacy website) to ensure proper guidance on use. High-risk tests or those used for critical decisions may still require a prescription or professional administration.

Action: Manufacturers should confirm packaging, leaflets, and e-commerce pharmacy guidance in Spanish.

Transitional Timelines You Should Track

  • Entry into force: The decree takes effect after BOE publication.
  • Licensing: Existing third-party manufacturers have up to one year to obtain the new operating license.
  • Marketing register: Notification duties start when the register goes live.
  • In-house devices: Spain applies the IVDR timelines. Labs must meet Article 5(5) conditions and ISO 15189 by the dates set in the transitional provisions and related guidance.
  • Legacy devices: Spain honors the IVDR transition for legacy IVDs and preserves specific old-rule processes until systems fully switch over.

Action: Put a dated compliance tracker in place for licensing, Article 5(5), ISO 15189, registry readiness, and vigilance.

Implications by Stakeholder

IVD manufacturers

  • Secure or update operating licenses.
  • Localize labels/IFU into Spanish.
  • Prepare marketing register data.
  • Strengthen PMS and vigilance interfaces with AEMPS.

Sponsors

  • Plan authorization for risk-involving performance studies.
  • Build Spain-ready dossiers and insurance.
  • Prepare Spanish IB, consent forms, and patient materials. Note: AEMPS may allow an english version of the IB if no objection is raised by the Ethics Committee.

Hospital and private labs

  • Confirm Article 5(5) eligibility and prepare technical documentation for the in-house test.
  • Achieve ISO 15189 for manufacturing scope.
  • Notify AEMPS and assign the in-house responsible person.
  • Update genetic testing consent and counseling SOPs.

How MDx CRO Helps You Execute

Regulatory strategy and submissions

We align IVDR with the Spanish IVD Regulation 2025 and prepare AEMPS submissions (licenses, notifications, marketing register onboarding when live).

ISO 15189 and Article 5(5)

We run gap assessments, build SOPs, and guide labs to ISO 15189 accreditation for in-house manufacture. We prepare the Article 5(5) declaration and AEMPS notification package.

Performance studies

We plan and manage interventional and risk-involving performance studies in Spain. We handle AEMPS authorization, ethics submissions, monitoring, and safety reporting. MDx can also act your IVD performance study legal representative in the EU.

Vigilance and PMS

We design Spanish-compliant PMS frameworks, incident workflows, and FSNs. We help you interface with AEMPS and prepare for inspections.

Contact MDx CRO

Written by:
David Tomé

David Tomé

President

Clinical research leader and MedTech entrepreneur with deep expertise in medical devices, IVDs & precision medicine, with global study experience.
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TGA guidance (Oct 2025): IVD Companion Diagnostics (CDx) Requirements in Australia

October 16, 2025

What’s new

TGA IVD companion diagnostics requirements are now clearly explained in the Therapeutic Goods Administration’s guidance on IVD companion diagnostics (CDx) in Australia (updated 16 October 2025). Their revised companion diagnostics framework, adds process diagrams, a companion testing plan concept for medicine/biological sponsors, clearer clinical performance expectations, and case studies showing how the pathway works in practice.

This blog post summarises the definition of a CDx, Class 3 IVD classification, ARTG inclusion, companion testing plans, and the TGA CDx List.

What is a CDx under Australian law?

A companion diagnostic is an IVD (commercial or in‑house) that provides information essential for the safe and effective use of a corresponding medicine or biological—for patient selection, risk of serious adverse reactions, or treatment monitoring. To qualify, the test must be referenced in the Product Information (PI) for the medicine or in the Instructions for Use (IFU) of the biological. Tests used only for cell/tissue compatibility are excluded from the CDx definition.

This definition underpins the TGA IVD companion diagnostics requirements for medicines and biologicals that rely on patient selection testing.

Note: The term “a particular medicine or biological” can also cover a class of products with a similar mechanism of action, not only a single named product.

When does an indication require CDx testing?

An indication requires CDx testing when both:

  1. the medicine’s PI (or biological IFU) states that CDx testing is essential, and
  2. the CDx claims it is intended for that testing to enable use of the medicine/biological.
    This may apply to some (not all) indications of a medicine.

To aid transparency, the TGA recommends a PI “flag phrase” indicating that testing is essential and that clinical practice testing should be adequately comparable to the pivotal trial testing; the TGA also publishes a CDx List of approved tests.

How the TGA applies CDx requirements: Class 3 IVDs and ARTG inclusion

  • Classification: Under TGA IVD companion diagnostics requirements, all CDx—commercial and in-house—are Class 3 IVDs (including in‑house CDx).
  • Separate ARTG entries: Each CDx requires its own ARTG inclusion with a Unique Product Identifier (UPI) defined by the manufacturer.
  • Application audit: CDx applications are subject to a mandatory application audit unless supported by specified comparable overseas regulator documentation (e.g., EU IVDR, FDA PMA, PMDA, HSA, Health Canada).
  • Concurrent submissions: While encouraged, concurrent medicine/CDx submissions are not mandatory; however, a CDx application should only be submitted if the corresponding indication is approved or under concurrent review.

From companion testing plans to ARTG submissions, MDx CRO streamlines the end-to-end CDx pathway in Australia, aligning clinical, regulatory, and quality workstreams to the TGA’s expectations.

Request a CDx consultation

The companion testing plan (for medicine/biological sponsors)

Every new indication that requires CDx testing must include a companion testing plan (dated and version‑controlled) describing how Australian patients will access at least one adequate test. This is central to meeting TGA IVD companion diagnostics requirements. Four options are available:

  1. Option 1: A commercial CDx ARTG application is planned/underway (provide device submission details and sponsor contact).
  2. Option 2: An in‑house IVD CDx will be accredited under the National Pathology Accreditation Scheme (provide lab details, accreditation timeline, and quality/access reassurances).
  3. Option 3: Standard Australian testing is expected to deliver comparable clinical outcomes to the pivotal trials (provide detailed justification).
  4. Option 4: None of the above—TGA reviews full device data within the medicine dossier (appropriate when no onshore testing is expected).

If Option 4 is used, TGA may add a condition of registration requiring the sponsor to maintain and update the plan (e.g., in case of supply interruption, regulatory action, or material changes to test methodology). Approval of an indication can proceed even when no ARTG‑listed or accredited CDx is available, provided an adequate plan exists; however, a commercial CDx must be in the ARTG (or an in‑house CDx accredited) before supply in Australia.

Clinical trial assay evaluation & comparability

When an indication requires CDx testing, TGA evaluates the clinical trial assay used in the pivotal studies—reviewing scientific validity, analytical performance, clinical performance, and clinical utility. Subsequent CDx must show clinical comparability to the trial assay, typically via concordance and/or bridging studies (or other appropriate evidence) aligned to the trial assay’s core characteristics.

Responsibilities at a glance

Medicine/Biological sponsors must:

  • Use the TGA CDx identification guide to determine if CDx testing is essential.
  • Consider consequences of false positives/negatives, test failures or no result.
  • Include: (a) evidence to support evaluation of the clinical trial assay, and (b) a companion testing plan nominating at least one adequate test.
  • Note: The framework does not require a one‑to‑one link between an indication and a single proprietary CDx; it focuses on the core characteristics of testing.

Device sponsors must:

  • Submit an IVD medical device application for ARTG inclusion of the CDx (indicating the application is for a CDx and providing the UPI).
  • Demonstrate comparability to pivotal trial testing and meet Essential Principles; applications may undergo audit as above.
  • Ensure the corresponding indication is approved or under concurrent review.

In-house IVD CDx, NATA accreditation and NPAAC obligations

Pathology laboratories may develop/modify in‑house tests for use as CDx. Class 1–3 in‑house IVDs are not included in the ARTG, but require NATA accreditation, identification of CDx in the TGA notification test list, and compliance with the NPAAC standard. Under a NATA–TGA MoU, NATA can request TGA technical assistance during evaluation of in‑house CDx performance; TGA is not otherwise involved in the accreditation decision.

TGA CDx List

The TGA publishes a CDx List showing approved commercial CDx linked to corresponding indications (with in‑house CDx to be added). The list is informational (not a regulatory instrument) and may lag recent approvals by up to one month.

Transitional arrangements and change control

  • Transition: CDx previously included in the ARTG as Class 2 or 3 before 1 Feb 2020 (and certain in‑house IVDs) may continue supply until 31 Dec 2028; a new compliant application is required to continue supply thereafter.
  • Changes: Sponsors manage post‑market device changes via the TGA Device Change Request process.

Key takeaways (quick reference)

  • All CDx are Class 3 IVDs and require separate ARTG inclusion (commercial) or NATA accreditation (in‑house).
  • Every relevant medicine/biological indication must include a companion testing plan (Options 1–4).
  • TGA assesses the clinical trial assay and expects comparability evidence for subsequent CDx.
  • Approval can proceed without on‑shore CDx if a robust plan exists, but supply requires ARTG inclusion or in‑house accreditation.

FAQs

Are all CDx Class 3 IVDs in Australia?

Yes. The regulations specify all CDx (commercial and in‑house) are Class 3 IVDs.

Can an indication be approved if no Australian CDx is available yet?

Yes—if a suitable companion testing plan is in place; however, a commercial CDx must be in the ARTG (or an in‑house CDx accredited) before legal supply.

What goes into a companion testing plan?

Identify at least one adequate test and choose Option 1–4 with supporting details (e.g., ARTG application in progress, in‑house accreditation, justification that standard testing is adequate, or full device data reviewed within the medicine dossier).

Will the PI show that CDx testing is essential?

The TGA recommends a PI “flag phrase” indicating testing is essential and should be comparable to trial testing; approved tests appear on the TGA CDx List.

Written by:
Carlos Galamba

Carlos Galamba

CEO

Senior regulatory leader and advisor to top 10 global precision medicine companies with deep experience in high-risk IVDs including companion diagnostics.
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IVDR CE marking NGS: MDx Case Study with Fulgent

IVDR CE marking NGS: MDx Case Study with Fulgent

October 7, 2025

At a glance

Case Study: How MDx Helped Fulgent Genetics Achieve CE Marking for One of the World’s Largest Germline NGS Panels under IVDR

  • Outcome: CE mark granted by TÜV SÜD for an end-to-end Class C germline NGS solution (wet lab + bioinformatics).
  • Scope: Furthermore, panel covering 4,600+ clinically relevant genes with a validated PLM (Pipeline Manager) software component; later expanded to >7,000 genes using a new probe set.
  • What we did: Specifically, we built an ISO 13485 QMS from the ground up, prepared full Annex II + III technical documentation, validated bioinformatics under IEC 62304/82304, split documentation into two Basic UDI-DIs (wet lab vs. software), and guided Stage I/II audits.
  • Why it matters: Ultimately, this demonstrates a repeatable pathway to IVDR certification for large NGS services and software—something that had no clear precedent.

Read the announcements: For details, read the Fulgent press release and Citeline case study.

The challenge: certifying a service-based, large-scale NGS system under IVDR

To begin with, FulgentExome is a service-based NGS solution that integrates wet-lab workflows with the Fulgent PLM bioinformatics pipeline. As a result, pursuing IVDR certification meant converting a mature CLIA/CAP testing service into a CE-marked IVD system with robust evidence across scientific validity, analytical performance, and clinical performance—for thousands of genes. In particular, key hurdles included: defining intended use at scale; validating third-party components; proving scientific validity across 4,600+ genes; above all fully validating the bioinformatics pipeline under medical device software standards.

MDx approach: a playbook for complex NGS + software

1) Build the right QMS, fast

First, we performed an IVDR GAP assessment. Next, we designed and implemented an ISO 13485-compliant QMS with risk management, supplier control, document control, internal audits, and management review—migrating from a CLIA/CAP model to IVDR-ready operations.

2) Engineer a defensible intended use

Meanwhile, the intended-use statement evolved iteratively—from an initial ~300-gene scope to whole-exome, finally landing on 4,600+ genes aligned to available clinical and analytical evidence. In the end, the final language was future-proofed to support rapid updates as evidence expands.

3) Split wet lab and software into two regulated products

Afterward, following round 1 review feedback, we separated the documentation into two Basic UDI-DIs—FulgentExome (wet lab) and Fulgent PLM (software)—to align with IVDR expectations for traceability and lifecycle control. Consequently, this restructuring sharpened conformity assessment and accelerated subsequent approvals.

4) Validate the informatics stack like a medical device

In parallel, we validated PLM under IEC 62304/82304, including architecture, version control, cybersecurity, verification/validation, and integration with external databases. Therefore, the result was a fully evidence-backed bioinformatics pipeline capable of reproducible, high-confidence variant calling and reporting.

5) Make “evidence at scale” practical

  • First, Scientific validity: Three-tier strategy combining validation of exome sequencing as an approach, reliance on curated public databases, and deep exemplars for a large subset of genes.
  • Second, Clinical performance: Leveraged routine testing experience (thousands of positives) to focus clinical evidence on high-prevalence genes, and instituted a robust PMPF strategy to continuously strengthen low-prevalence areas.

6) Orchestrate TÜV SÜD audits to success

  • Initially, Stage I confirmed documentation readiness, scope, Basic UDI-DIs and integration of IVDR processes into daily practice.
  • Subsequently, Stage II verified on-the-floor implementation of SOPs, training, competence, CAPA and change control—closing findings on short cycles to hit NB timelines.

Results that move the market

  • CE mark granted for FulgentExome & Fulgent PLM—among the first end-to-end Class C germline NGS solutions under IVDR.
  • Certified scope covers 4,600+ genes, positioning Fulgent as a reference lab for comprehensive hereditary disease testing serving European patients.
  • Post-certification, the platform scaled to >7,000 genes using a new probe set—demonstrating the inherent scalability built into the certified system (process, documentation, and change control).
  • Strengthened competitive standing in the EU diagnostics market; public communications highlight the magnitude of this achievement for large NGS panels.

Read more in the Fulgent press release and Citeline’s in-depth article.

What this means for labs and IVD developers planning large NGS submissions

If you operate an LDT today: you’ll need to translate CLIA/15189 practices into an ISO 13485 framework, document design controls, and produce a full PER (PEP/PER), APR, SVR, PMS/PMPF, SSP, and labeling/IFU aligned to GSPR. Expect to validate any bioinformatics pipeline as SaMD with IEC 62304/82304 and cybersecurity controls.

If your panel is “large”: you likely won’t have uniform clinical data across every gene. A structured tiered evidence model + PMPF can satisfy Notified Bodies while keeping your roadmap scalable.

If you combine wet lab + software: plan for separate Basic UDI-DIs and documentation sets. Treat the pipeline as a product with its own requirements, verification, and risk controls.

Why MDx

  • End-to-end IVDR expertise: From regulatory strategy & classification to Annex II/III technical files, PER/SVR/APR, training, and mock NB reviews.
  • Clinical performance studies: We design, run, and report ISO 20916 studies (protocols, eTMF, monitoring, biostats, PER alignment), and we can act as delegated sponsor for multi-country submissions—100% submission success rate to date.
  • Operational scale: ISO 9001 clinical QMS, EU/US partner network, multilingual CRAs, and a repeatable process honed on 60+ performance study submissions for top IVD and pharma clients.

Project timeline

Our joint project with Fulgent spanned July 2023–July 2025, with overlapping tracks for QMS creation, technical documentation, NB review, and Stage I/II audits—a coordinated plan that allowed rapid closure of findings and post-certification scaling.

Client perspective

The program demanded evening/weekend execution across regulatory, documentation, and project management to meet Notified Body timelines—effort that, in the client’s words, “made all the difference” in achieving what initially “seemed almost impossible.”

Planning IVDR for your NGS panel? Here’s a quick readiness checklist

  • Intended use aligned to evidence (and future updates)
  • ISO 13485 QMS with software lifecycle integration
  • PER (PEP/PER), SVR, APR mapped to gene-level strategy
  • PLM/DR pipeline validated per IEC 62304/82304 (+cybersecurity)
  • Separate documentation/UDI for wet lab vs. software (if applicable)
  • PMS/PMPF plan to mature low-prevalence evidence post-market
  • Mock NB review + Stage I/II audit readiness

(Our team can lead or co-author each artifact above.)

Talk to us

Whether you’re certifying a focused oncology panel or pushing the limits with exome-scale content, MDx brings the cross-functional regulatory, clinical, quality, and software depth to make it possible—on a timeline that keeps your business competitive.

Let’s discuss your IVDR roadmap

Written by:
Carlos Galamba

Carlos Galamba

CEO

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

October 3, 2025

The future of in vitro diagnostics is being written at the intersection of tighter regulation, workforce pressure, and data‑driven innovation. Under the EU In Vitro Diagnostic Regulation (IVDR), evidence expectations and lifecycle obligations have risen sharply, changing how products are designed, validated, and maintained in the market. For manufacturers, success now depends on pairing scientific advances with stronger clinical evidence strategies, interoperable data flows, and operational resilience across supply, quality, and post‑market systems.

Demand is rising while systems are stretched

Backlogs from the pandemic have converged with long‑standing workforce shortages, particularly in diagnostic specialties, delaying access and lengthening diagnostic pathways. The OECD’s Health at a Glance: Europe 2024 highlights these shortages as a structural risk to access, quality, and system resilience—evidence that the pressure to do more with fewer people is not easing soon. For diagnostics leaders, that reality elevates the value case for automation, near‑patient testing, and real‑world evidence that proves earlier, faster decisions.

Market momentum is real—if evidence and access align

IVDs remain a cornerstone of Europe’s medtech economy and the largest segment globally by sector share, signaling robust demand for better, earlier diagnostics. But translating that momentum into market access requires credible performance evaluation, clear intended‑purpose claims, and a plan for post‑market performance follow‑up that stands up to Notified Body scrutiny. (MedTech Europe DataHub – Market). 

IVDR is raising the bar—and capacity is still normalizing

IVDR’s higher evidence threshold is now a constant, but Notified Body (NB) capacity and throughput continue to shape time‑to‑market. The European Commission’s latest Notified Bodies Survey shows progress on designations and certifications under MDR/IVDR while acknowledging persistent bottlenecks—practical context for planning dossier quality, NB engagement, and transition timelines. Manufacturers that front‑load clinical evidence planning and close gaps against GSPR, PER, and PMPF requirements are better positioned to move through review without costly rework. 

What the next decade looks like for IVD innovators

Expect faster iteration cycles powered by cloud connectivity and AI‑assisted analytics, paired with stronger governance of data provenance, cybersecurity, and change control. Procurement and HTA bodies will demand interoperable outputs that feed clinical systems and population analytics. In practice, this means designing for the 4P future—predictive, preventive, personalized, and participatory—while proving clinical performance and patient‑management claims under IVDR. Aligning technical files, labeling, and performance evaluation with clinical utility (not just analytical superiority) will increasingly differentiate winners.

What leaders should do now

Treat clinical evidence as a product pillar from day one—map intended purpose, target population, and clinical benefit to a coherent performance evaluation plan that integrates literature, device‑generated data, and targeted clinical performance studies. Build for integration and reuse of data across care settings to ease adoption and payer evaluation. Engage NBs early with complete, audit‑ready files. And make post‑market performance follow‑up a source of competitive insight, not a compliance afterthought.

How MDx CRO accelerates IVD market readiness

MDx CRO helps IVD manufacturers compress time‑to‑evidence and navigate IVDR with confidence—from regulatory strategy and technical documentation to clinical performance studies and post‑market performance follow‑up. We translate regulatory expectations into practical study designs and submission‑ready deliverables, then stay with you through NB interactions and lifecycle monitoring. Explore our IVD regulatory services and clinical research support, or contact us to scope a market‑access plan tailored to your portfolio.

Written by:
Carlos Galamba

Carlos Galamba

CEO

Senior regulatory leader and former BSI IVDR reviewer with deep experience in CE marking high-risk IVDs, companion diagnostics, and IVDR implementation.
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How many MedTech companies are there in Europe?

How many MedTech companies are there in Europe?

October 2, 2025

Europe’s MedTech Landscape in 2025: 38,000+ Companies Driving Innovation

Europe is home to one of the world’s most dynamic and diverse medical technology ecosystems, with more than 38,000 MedTech companies operating across the continent. The vast majority—over 90%—are small and medium-sized enterprises (SMEs), playing a critical role in driving innovation, improving healthcare outcomes, and fueling economic growth .

What Defines Europe’s MedTech Industry?

According to MedTech Europe, the sector includes manufacturers of medical devices, in vitro diagnostics (IVDs), and digital health solutions, spanning everything from surgical tools to AI-powered diagnostic platforms. In total, the industry employs over 930,000 people directly, making it one of the largest employers in Europe’s life sciences space .

Why It Matters for Clinical and Regulatory Success

With the growing complexity of EU MDR and IVDR regulations, these companies—especially SMEs—face increasing pressure to:

  • Prove clinical evidence and safety of their technologies
  • Navigate Notified Body reviews and CE Marking
  • Manage post-market surveillance (PMS) and performance evaluations

That’s where MDx CRO steps in.

Supporting Europe’s MedTech Growth

At MDx CRO, we specialize in helping MedTech innovators—from start-ups to established manufacturers—successfully plan, execute, and submit their clinical and regulatory strategies across the EU and global markets. With proven expertise in:

We partner with both large diagnostic leaders and agile SMEs to deliver compliant, high-quality, and market-ready solutions.

A Pan-European Presence

With offices in Barcelona, Madrid, Lisbon, and London, and a network of CRAs and regulatory experts across Europe, MDx provides localized insight with global reach—helping MedTech companies meet requirements faster and smarter.

The Bottom Line

The European MedTech sector is growing—but so are its regulatory challenges. Whether you’re launching a new diagnostic product or preparing for a Notified Body audit, MDx CRO is here to support your success every step of the way.

Let’s talk about your next clinical or regulatory challenge.

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High-tech laboratory technician handling test tubes in a medical research lab for advanced medical device development and accelerated MedTech innovation.

The future of in vitro diagnostics
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