Companion Diagnostics: Planning CDx Trials Alongside Drug Development

Why Clinical Trial Design Matters for IVD Companion Diagnostics
Sample Collection Requirements: Getting the Basics Right
Prospective Versus Retrospective Validation Strategies
Common Pitfalls and How to Avoid Them
Making Clinical Trial Planning Work

Careful planning is essential when developing companion diagnostics, to avoid costly sample collection mistakes and regulatory delays. Abingdon Health’s Chief Delivery Officer, Candice Vendettuoli, shares her insights on the importance of planning IVD companion diagnostics (CDx) clinical trials alongside therapeutic development.

One of the most consequential – and most frequently underestimated – aspects of companion diagnostic development is ensuring your clinical trial design supports both drug approval and diagnostic validation. Whether developing a lateral flow companion diagnostic assay or another in vitro diagnostic (IVD) applications, companies often discover too late that therapeutic trials optimised solely for drug endpoints didn’t collect samples in the right format, at the right timepoints, or with appropriate consent for IVD diagnostic development. These oversights can delay CDx approval significantly and add millions in costs for supplementary studies.

The challenge isn’t necessarily technical complexity – it’s coordination. Drug development teams and IVD contract development and manufacturing organisation (CDMO) teams operate under different timelines, have different validation requirements, and often don’t communicate adequately during early trial planning. Successful companion diagnostics programs integrate diagnostic requirements into therapeutic trial design from the outset, ensuring clinical studies generate data supporting both products simultaneously.

Why Clinical Trial Design Matters for IVD Companion Diagnostics

Unlike standalone IVD products that can design clinical validation studies specifically for their requirements, companion diagnostics must derive validation data from trials whose primary purpose is demonstrating drug efficacy and safety. This creates inherent constraints and coordination challenges.

The therapeutic trial determines patient enrolment, treatment protocols, outcome measures, and timeline. The diagnostic must validate within these constraints while meeting distinct requirements (e.g. from the FDA) for demonstrating that the test accurately identifies patients who will or won’t benefit from therapy.

When trials aren’t designed with diagnostic needs in mind, several predictable problems emerge: insufficient sample volumes for all required validation studies, samples collected at timepoints that don’t align with clinical decision-making, inadequate sample quality due to pre-analytical variable control issues, and missing consent permissions for future diagnostic use.

Each of these issues requires expensive remediation—either supplementary sample collection, additional validation studies, or compromised diagnostic claims that limit commercial utility.  It’s also crucial to synchronise analytical performance and clinical evaluation for IVDs.

Sample Collection Requirements: Getting the Basics Right

The foundation of successful CDx clinical validation is collecting appropriate samples during therapeutic trials. This sounds straightforward but involves numerous details that must be specified explicitly in trial protocols.

Sample Type Specification

Companion diagnostic assays must validate using the sample type that will be used clinically. This is particularly important for lateral flow and point-of-care IVD companion diagnostic devices, which may be designed to run on whole blood or fingerstick samples rather than processed laboratory specimens. If your diagnostic runs on plasma but the therapeutic trial only collected serum, you cannot use that trial data for validation without bridging studies demonstrating serum and plasma equivalence—studies that cost time and money while delaying submissions.

Specify exact sample requirements early: whole blood versus plasma versus serum, anticoagulant type for plasma collection (EDTA versus heparin versus citrate can all affect assay performance), collection tube specifications including any additives, and acceptable sample age and storage conditions before testing.

These details seem minor but create major issues when ignored. Don’t assume “blood samples” will suffice – specify precisely what you need.

Sample Volume Requirements

Diagnostic validation requires substantially more sample than preliminary feasibility testing might suggest. You’ll need sufficient volume for analytical validation studies testing precision and accuracy, clinical validation across the intended-use population, manufacturing bridging studies showing development-scale and commercial-scale comparability, and reserve samples for troubleshooting and potential additional testing.

A common mistake is calculating minimum volume for immediate needs without accounting for the complete validation program. Therapeutic trials typically collect samples sized for drug PK/PD analysis, not diagnostic validation. Explicitly specify diagnostic volume requirements in trial protocols, ensuring collection tubes and procedures accommodate both therapeutic and diagnostic needs.

Collection Timepoint Alignment

Companion diagnostics inform treatment decisions at specific points in the patient journey—typically before treatment initiation or at early response assessment timepoints. Clinical validation must demonstrate diagnostic performance at these clinically relevant timepoints.

If your diagnostic predicts initial treatment response but the therapeutic trial only collected samples at later disease progression timepoints, you lack data demonstrating the test works when clinical decisions actually get made. This requires supplementary studies collecting samples at appropriate timepoints which are expensive and time-consuming.

Work with clinical teams to ensure sample collection protocols include timepoints that matter for diagnostic use: baseline before treatment initiation, early response assessment timepoints aligned with treatment decision windows, and progression timepoints if the diagnostic has monitoring applications.

Pre-Analytical Variable Control

In vitro companion diagnostic device performance can be significantly affected by how samples are collected, processed, and stored before testing. Variables like time from collection to processing, storage temperature, freeze-thaw cycles, and shipping conditions all potentially impact results. For lateral flow companion diagnostic assays in particular, sample matrix effects and analyte stability can be especially sensitive to pre-analytical variation.

Therapeutic trials often have less stringent pre-analytical protocols than diagnostic validation requires because drug concentration measurements may be less sensitive to these variables. Ensure trial protocols specify pre-analytical requirements that enable diagnostic validation: maximum time limits from collection to processing, specific temperature requirements for storage and shipping, restrictions on freeze-thaw cycles, and documentation of pre-analytical conditions for each sample.

Without this control and documentation, you cannot determine whether performance variations result from biological variation versus pre-analytical handling issues.

Consent and Regulatory Considerations

I recently wrote an article explaining how the complex world of companion diagnostics development and CDx regulatory strategy is as complex as playing 5D chess.

For example, clinical samples collected during therapeutic trials can only be used for companion diagnostics if patient consent specifically permits diagnostic development and validation use. This seems obvious but creates problems when overlooked.

Consent Language Specificity

Generic consent for “research use” may not adequately cover commercial diagnostic development. FDA expects clear documentation that patients understood their samples would be used for developing a commercial diagnostic test potentially required for treatment access decisions.

Work with regulatory and legal teams to ensure consent forms explicitly address diagnostic development, explain how sample data will contribute to diagnostic validation, and clarify that diagnostic results may be included in regulatory submissions and potentially publication.

For retrospective samples from previously completed trials, carefully review original consent language to confirm diagnostic use is permitted. If consent was ambiguous, you may need to re-consent patients or conduct entirely new studies—significant timeline and cost implications.

International Considerations

If therapeutic trials enrol internationally but diagnostic approval will be sought in specific markets, ensure consent complies with relevant jurisdictions. European GDPR requirements, for example, impose specific constraints on sample use and data sharing that may differ from US requirements.

Address these regulatory variations during trial planning rather than discovering them when trying to use samples for validation.

Integrating Diagnostic Requirements into Trial Protocols

The practical challenge is ensuring diagnostic needs are explicitly captured in therapeutic trial protocols and that clinical operations teams understand and execute these requirements. This requires early collaboration between drug development and diagnostic teams.

Early Engagement Timing

Engage diagnostic teams during Phase 2 trial planning at minimum, ideally during Phase 1 protocol development. By the time Phase 3 trials launch, changing protocols to accommodate diagnostic needs becomes increasingly difficult due to regulatory submissions and site agreements already in place.

Early engagement allows diagnostic requirements to be built into initial protocol design rather than retrofitted through amendments that delay timelines and complicate execution.

As an important aside, when evaluating and selecting a development partner, consider their overall experience and expertise in navigating these complex requirements. The real – and often hidden – costs of switching lateral flow CDMO partner, as outlined by my colleague Mark Jones, can set your project back significantly.

Protocol Amendment Strategy

If diagnostic planning starts after therapeutic trials have begun, protocol amendments can add diagnostic-specific requirements. However, amendments create complexity: they require regulatory authority approval, ethics committee review, site retraining, and potentially patient re-consent.

Balance the value of perfect diagnostic sample collection against the delays and costs of protocol amendments. Sometimes accepting slightly suboptimal sample collection that still supports validation is preferable to delays from amendment processes.

Clinical Operations Training

Even with clear protocols, clinical site staff must understand diagnostic requirements and execute them correctly. Site personnel focused on therapeutic endpoints may not appreciate diagnostic sample handling importance.

Ensure site training specifically addresses diagnostic sample requirements, monitoring visits verify compliance with diagnostic-specific procedures, and sample quality issues are identified and corrected early in enrolment rather than discovered during validation when samples are already compromised.

Prospective Versus Retrospective Validation Strategies

Companion diagnostics can pursue either prospective validation using samples from ongoing trials or retrospective validation using archived samples from completed trials. Each approach has distinct planning implications:

Prospective Validation

Prospective validation – where the diagnostic is used to select or stratify patients in the therapeutic trial – provides the strongest clinical utility evidence. The FDA generally favours prospective designs because they most closely reflect intended clinical use.

However, prospective validation requires the companion diagnostic assay to be sufficiently mature for trial use, meaning development and analytical validation must complete before trial enrolment begins. For lateral flow and other IVD companion diagnostic formats, this means the assay design, manufacturing process, and reader integration must all be locked down before clinical deployment. This demands early diagnostic development investment and creates risk if the diagnostic performs poorly in the trial.

Planning for prospective validation requires tight coordination between diagnostic and drug timelines and clear decision criteria for when the diagnostic is ready for trial deployment.

Retrospective Validation

Retrospective validation uses archived samples from completed or ongoing therapeutic trials to validate the diagnostic after trial results are known. This approach allows diagnostic development to proceed in parallel with drug development without gating trial initiation.

Retrospective validation requires that trials collected appropriate samples with suitable consent and pre-analytical controls, even though the diagnostic wasn’t being actively used during the trial. This demands foresight during trial planning to collect diagnostic-suitable samples “just in case.”

Common Pitfalls and How to Avoid Them

Several patterns consistently cause problems in companion diagnostics clinical trial planning:

Pitfall 1: Late Diagnostic Program Initiation

Starting diagnostic development too late in drug development leaves insufficient time to influence therapeutic trial design. Protocols are locked, samples are already being collected under suboptimal conditions, and the diagnostic team must work with whatever samples are available.

Solution: Initiate diagnostic planning during Phase 1, even if full development doesn’t start until Phase 2. Early planning ensures Phase 2 and Phase 3 trials accommodate diagnostic needs.

Pitfall 2: Assuming Therapeutic Samples Work for Diagnostics

Drug development teams often assume samples collected for PK/PD analysis automatically suit diagnostic validation. Sample types, volumes, timepoints, and handling that work for drug measurements may not meet diagnostic requirements.

Solution: Explicitly compare therapeutic sample collection protocols against diagnostic validation requirements. Don’t assume compatibility – verify and specify differences in protocols.

Pitfall 3: Inadequate Sample Banking

Trials may collect diagnostic samples but fail to establish proper banking infrastructure for long-term storage and retrieval. When validation teams request samples years later, they discover poor storage conditions compromised quality or documentation gaps prevent identifying appropriate samples.

Solution: Establish dedicated biobanking procedures for diagnostic samples with appropriate quality controls, documentation, and retrieval systems from trial initiation.

Making Clinical Trial Planning Work

Successful companion diagnostics programs treat clinical trial planning as a critical collaboration between drug development and diagnostic CDMO development teams. This requires organisational commitment to integrated planning, clear communication channels between teams, adequate resources for diagnostic sample collection and banking, and willingness to accommodate diagnostic requirements in therapeutic trial designs.

The investment in proper clinical trial planning pays off through faster diagnostic validation, lower total development costs from avoiding supplementary studies, stronger regulatory submissions supported by robust clinical data, and commercial diagnostics that reliably support treatment decision-making.

Clinical trial design is one of the few aspects of IVD companion diagnostics development where getting it right the first time is dramatically easier and cheaper than fixing problems later. Companies pursuing precision medicine companion diagnostics – whether lateral flow, point-of-care, or other in vitro diagnostic formats – that recognise this and plan accordingly consistently deliver more companion diagnostics on time and on budget.

At Abingdon Health, our fully integrated CDMO and CRO teams support pharmaceutical and biotech companies in the development, scale-up, manufacturing and regulatory approval of IVD companion diagnostic devices, including lateral flow and point-of-care assay formats. We understand the challenges you’re navigating and the confidence you need in your development, manufacturing and regulatory partner. As a fully integrated CDMO and CRO with ISO 13485 and ISO 9001 certifications and dual UK/US manufacturing capabilities, our team brings extensive experience in companion diagnostic assay development, analytical performance studies, clinical trial management, and regulatory strategy. Get in touch with Abingdon Health to explore how our integrated approach can accelerate your path to market access.