--- title: "Your CDx Submission Has Two Authors. Does It Read Like One?" description: "Learn why CDx clinical trial and IVDR performance study submissions must align while remaining independently complete for different regulatory reviewers." url: https://qbdgroup.com/en/blog/cdx-submission-ctr-ivdr-alignment type: "Blog post" language: en published: 2026-09-02 author: "Kirsten Van Garsse" category: "Regulatory Affairs" publisher: "QbD Group" citation: "QbD Group, \"Your CDx Submission Has Two Authors. Does It Read Like One?\", https://qbdgroup.com/en/blog/cdx-submission-ctr-ivdr-alignment" --- # Your CDx Submission Has Two Authors. Does It Read Like One? > Learn why CDx clinical trial and IVDR performance study submissions must align while remaining independently complete for different regulatory reviewers. When a combined CDx programme is submitted, it does not travel to reviewers as a single package. On the ethics side, many countries do try to bring the two protocols together, with the same committee looking at the clinical trial and performance study side by side because both concern the same patients and the same consent process. On the Competent Authority side, that coordination is far rarer. The clinical trial application and the IVDR performance study application are, in most countries, assessed by different teams, working from different legal bases and on different timelines. The Medical Device Coordination Group has said as much directly. For trials combining a CTR-regulated product with an IVDR-regulated diagnostic, **"there is no dedicated procedure foreseen in the Regulations and therefore, currently, no harmonised procedure is in place"** (MDCG 2022-10, Q10). That split changes what "consistency" actually requires. It is not enough for the two documents to agree with each other if the reviewer assessing one of them is only ever going to see that one. ## In This Blog Post - Why CDx submissions are often assessed separately - What different reviewers actually see - Why cross-referencing between CTR and IVDR documents creates gaps - Why consistency checklists alone are not enough - How to make both submissions independently complete - Why amendments require the same cross-functional approach ## What CDx Reviewers Actually See, and What They Don't Consider the endpoints. The pharma CTA describes the primary endpoint as overall survival at 24 months. The IVDR performance study protocol describes the primary endpoint as concordance with the reference standard at the time of treatment allocation. Read together, these are not contradictory. They describe the same patient journey from two different frames of reference. But the reviewer assessing the performance study application very often does not have the CTA in front of them and has no reason to go looking for it. If the performance study protocol's own account of that relationship is thin, or simply cross-references "the clinical trial protocol", that reviewer is being asked to trust a document they cannot see. ## Small Differences Can Become Regulatory Questions The same logic runs in reverse. Where an Ethics Committee does review both protocols together, an inconsistency between them is at least visible and can be raised as a direct question. For example, the pharma team may describe the population as: **HER2-positive advanced gastric cancer** while the IVD documentation describes the intended use population as: **locally advanced or metastatic gastric adenocarcinoma with IHC 3+ or ISH-amplified HER2 status** The wording is close. But a joint reviewer may still query the difference. Where the two documents go to separate reviewers, which on the Competent Authority side is the more common outcome, that kind of inconsistency is not necessarily "caught" at all. Instead, it simply reads as a gap. The performance study protocol fails to explain something the reviewer needed explained because the explanation was assumed to live in a document from another regulatory framework that this reviewer may never open. ## Safety Reporting Makes the Problem Even Clearer Safety terminology makes the point clearest. SAE definitions, reporting timelines, and the division of responsibility for device-related adverse events are sometimes written into the performance study documentation as a cross-reference to the main trial's safety management plan. Where the two are reviewed together, that shortcut might survive. The reviewer can go and check. Where they are reviewed separately, the cross-reference may effectively resolve to nothing. The Competent Authority can then raise a request for information asking the sponsor to explain the safety framework in the document actually being assessed. Under IVDR Article 66, that RFI suspends the assessment clock until it is answered. And it happens at a point when both teams are already focused on other priorities. ## A Cross-Reference Checklist Is Not the Solution The standard response to this problem is a cross-reference checklist. The pharma Regulatory Affairs team reviews the IVD sections. The IVD Regulatory Affairs team reviews the pharma sections. Both confirm that the two documents agree with each other before submission. That catches genuine contradictions. **It does not catch the deeper issue.** Two documents agreeing with each other is not the same as either document being complete on its own. A checklist reviewer sitting inside the organisation has both documents open at once. That is exactly the position most external reviewers will not be in. ## Each CDx Submission Needs to Stand on Its Own The fix is not better cross-referencing. It is writing the performance study protocol and the CTA so that each stands on its own, detailed enough to be assessed by a reviewer with no access to the other document at all. The shared substance should be worked out once, jointly, by pharma RA and IVD RA. That includes elements such as: - patient population definitions - endpoint structures - site lists - safety reporting frameworks That shared substance should then be written into both documents in full, using language appropriate to each regulatory framework, rather than settled in one document and pointed to from the other. Not reviewed by both. **Written by both, and written out in full, twice.** The distinction matters. It shifts the solution upstream, to a point where duplicating a few paragraphs is cheap, instead of downstream, where a reviewer's request for information is not. ## CDx Amendment Management Creates the Same Problem Amendment management is the same problem, compounded. A protocol amendment on the pharma side may be classified as substantial or non-substantial under the CTR. The same change may trigger a separate notification obligation under IVDR Article 71 that is categorised differently. Pharma RA may not know about the IVDR obligation. The diagnostic partner's team may not know the amendment is coming until it has already been approved. And a notification filed as a cross-reference to "see the CTR amendment" fails for exactly the same reason as a cross-referenced protocol section. The IVDR reviewer assessing the change very often cannot see what the CTR amendment actually said. Without a cross-organisational amendment management process, these gaps can accumulate quietly until a Competent Authority identifies a hole in the regulatory record. ## Building a Joint CTR-IVDR Amendment Process Building a joint amendment triage process does not need to be complicated. It requires: - agreement on what constitutes a notifiable change under each regulatory framework - a shared calendar for submission windows - a named contact on each side responsible for cross-notification - a process for assessing the impact of changes across both frameworks - a standing rule that any notification affecting the other framework is written out in full for that framework's reviewer, rather than cross-referenced to a document they may never see The underlying principle is the same one that should guide the original submission. **Coordinate the content once. Write it for each reviewer separately.** ## One CDx Programme, Two Regulatory Frameworks A combined CDx programme may be one development programme internally, but regulators do not necessarily see it that way. Different reviewers may assess different documents, under different legislation and on different timelines. That means regulatory alignment cannot stop at ensuring that the CTA and IVDR performance study application do not contradict each other. Each needs to tell a complete and coherent story on its own. The strongest CDx submission strategy therefore starts before document review. It brings pharma RA and IVD RA together while the shared substance is still being defined, ensuring that both applications are aligned from the outset without making either dependent on the other. **Your CDx submission has two authors. The reviewer should never have to notice.** --- Source: https://qbdgroup.com/en/blog/cdx-submission-ctr-ivdr-alignment — © QbD Group. Quote freely with attribution and a link back.