The Companion Diagnostic Strategy That Combination Product Leaders Need

By Marcelo Trevino, independent expert

Drugs and diagnostics now move care from one size fits all to precise treatment. In oncology, rare disease, immunology, and neurology, an in vitro diagnostic increasingly determines who should be treated and when These are true combination products that sit where discovery, regulatory science, and commercial execution meet.

The mandate for leaders is simple: Elevate the diagnostic to the same strategic level as the therapy from the first protocol. Doing so aligns evidence, compresses timelines, lowers regulatory risk, and speeds access.

Regulatory Landscape

What Qualifies as a Companion Diagnostic

A combination product brings together a drug, a device, or a biologic as a single product or as interdependent components that must be used together. In the companion diagnostic setting, the diagnostic identifies patients who are most likely to benefit from or be at risk from a specific therapy. When the diagnostic controls use of the therapy, its analytical and clinical validity become central to the total benefit-risk profile.

Who Leads the Review

The Office of Combination Products assigns primary jurisdiction. CDER, CBER, or CDRH may lead with cross center consultation as needed. Assignment clarifies ownership of the review, but it does not remove the need to satisfy requirements on both the therapeutic and diagnostic sides. Sponsors earn credibility when they present an integrated plan and a single source of truth for evidence, risk, and change control.

Integrated Evidence Architecture

A coherent plan links the therapy and the test from first principles through analysis and launch. Use this checklist to keep teams aligned.

1. Define the biomarker context of use and the clinical question the test must answer.
2. Set the analytical validation plan covering sensitivity, specificity, limit of detection, linearity, precision, reproducibility, and guard band studies.
3. Anchor clinical validation to outcomes and decision impact, not only to correlation. Describe how the test changes treatment selection and timing.
4. Control the specimen life cycle. Lock preanalytical variables such as collection method, transport, storage, and stability and tie them to acceptance criteria.
5. Validate software and bioinformatics. Maintain version control, traceability from requirements to tests, and real-time performance monitoring.
6. Run one risk management file that addresses therapy and test hazards, patient impact, and mitigations and connect it to design and labeling.
7. Plan change management for reagents, algorithms, instruments, and suppliers with clear triggers for global notifications or supplements.
8. Preserve data provenance so every clinical conclusion can be traced back to raw data, processing steps, and quality gates.

Pathways You Will Use

1. Device-led with a linked therapeutic submission through PMA, De Novo, or 510(k) when the diagnostic controls the use of the drug or biologic
2. Therapeutic-led through NDA or BLA that cross references the diagnostic file and includes analytical and clinical validation of the test
3. Joint development aligned to companion diagnostic policy that encourages parallel planning of protocols, endpoints, and sample handling, with early meetings that include both drug and device experts

Global Alignment

The United States often sets the initial pace, but success requires global planning from the start. In the European Union, the drug may follow centralized review while the diagnostic must meet IVDR requirements that raise expectations for analytical validation and clinical evidence. PMDA in Japan and NMPA in China maintain their own co-approval expectations and frequently require local data. Programs that build modular technical documentation and plan for regional evidence avoid last-minute redesigns and launch delays.

Coordination blueprint:

1. Run one global evidence matrix that lists each claim, the supporting data, and the planned filing in each region.
2. Lock a single chain of custody for biospecimens and bioinformatics so regional studies are comparable.
3. Use a common change control narrative that aligns risk management, verification, and regulatory notifications across markets.

Policy Watch

Regulatory signals in 2025 favor practical execution over formal rulemaking. Read the landscape as a set of near-term operating constraints and opportunities for well-prepared programs.

1. FDA’s Unified Agenda and regulatory shifts: The spring 2025 agenda is shorter and now tags each item as regulatory, deregulatory, or not subject to Executive Order 14192. Several longstanding items were moved to long-term status or dropped. Expect fewer new rules and more guidance, workshops, and use of existing authorities.

2. Rare disease evidence principles: FDA clarified that for very rare conditions a single adequate and well controlled study may be supported by strong confirmatory evidence. This codifies flexibility already used in practice and gives sponsors clearer footing when patient numbers are small.

3. Plausible mechanism pathway: Leaders previewed an approach for rare diseases grounded in a scientifically plausible mechanism with conditional approvals and stronger post-market obligations. Plan now for real-world follow up, analytical reverification, and clear triggers for label and algorithm updates.

4. Complete Response Letter transparency: The FDA is posting redacted letters for non-approvals. Recurring themes include analytical validation gaps, unclear clinical cutoffs, and misalignment between drug claims and test performance. Treat CRLs as a living lessons library.

5. User fee programs and budget: The Over-the-Counter Monograph User Fee Program (OMUFA) faces a 2025 reauthorization milestone and continuing resolutions are possible. Time critical meetings and submissions to avoid transition windows and protect staffing continuity across centers.

6. Digital health and device regulation: CDRH’s emphasis on software and algorithms continues. Maintain traceability from the clinical protocol to the software life cycle and keep public facing summaries that explain meaningful algorithm changes.

7. Adverse event management consolidation: The FDA is integrating safety systems across centers to improve analytics and transparency. Combination product sponsors should unify drug and device signal management with shared taxonomies and joint governance.

8. Guidance agendas: Midyear agendas signal where staff attention is going even as items shift. Assign owners, update evidence plans, and move changes into meeting questions and files without delay.

Practical Moves To Take Now

1. Map agenda tags to your milestones and create alternatives that rely on current authorities.
2. For rare and ultra rare programs, specify confirmatory evidence streams and specimen controls early.
3. Build a post-market playbook that couples therapeutic safety with test performance monitoring.
4. Review new CRLs quarterly and adjust analytical acceptance criteria and cutoff strategies.
5. Stage presubmissions and pivotal filings around fee and budget transitions.
6. Document algorithm stewardship, version control, and provider communications.
7. Operate one safety governance model for pharmacovigilance and device vigilance.
8. Track guidance changes with a live gap assessment and due dates for protocol updates.

Life Cycle Management

Development And Approval

The drug and diagnostic must move in lockstep. Enrichment designs concentrate on biomarker positive patients. When large trials are unrealistic, use bridging and analytical concordance. The test must show sensitivity, specificity, reproducibility, and lot to lot control with clear cutoffs. Many late problems trace to early misses such as specimen handling, software validation, and traceability from protocol to analytical plan.

Use one evidence plan that maps therapeutic endpoints to diagnostic performance. Connect sample acquisition, handling, bioinformatics, quality metrics, and statistics. Define rules for cutoff setting, reflex testing, and invalids so reviewers see one integrated program.

Statistical And Analytical Design Anchors

1. Size studies with prevalence and spectrum bias in mind so performance estimates are reliable across intended use populations.
2. Choose cutoffs using training and locked validation sets and show clinical utility through outcome-based analyses in addition to receiver operating characteristic (ROC) curve metrics.
3. Control type one errors across biomarker subgroups, endpoints, and interim looks. State multiplicity adjustments in protocols.
4. Design bridging and equivalence studies that anticipate future instruments, reagent lots, and software updates, including guard band verification.
5. Plan concordance studies between central laboratories and any distributed use to quantify transfer risk and operator effects.
6. Define how missing data and invalid runs will be handled and avoid imputation for primary diagnostic calls.
7. Classify software changes as minor or major in advance with thresholds that determine verification only, notification, or a supplement.

After Approval

1. Label and indication alignment: Update test materials when a therapy changes to avoid patient risk.
2. Integrated safety: Run joint safety reviews across pharmacovigilance, device vigilance, clinical, quality, and regulatory.
3. Change control with global awareness: Manage reagent changes, software updates, lot release, and bioinformatics tuning through global templates linked to risk and verification.
4. Inspection readiness as a practice: Use mock inspections and digital dashboards to keep evidence inspection ready across sites.

What Has Worked Repeatedly

1. Engage both drug and device reviewers early through presubmissions and Type C meetings.
2. Embed regulatory and quality in design reviews and vendor selection to avoid late fixes.
3. Build for modification with version control, performance monitoring, and clear paths for notifications or supplements.
4. Align teams on one life cycle playbook with shared templates and metrics.

Innovation And Commercialization

Where the Market Stands Today

Companion diagnostics anchor many targeted therapies such as EGFR in non-small cell lung cancer and HER2 in breast cancer. Outside oncology, immunology and neurology are advancing, and rare disease programs are using the rare disease principles to make best use of limited samples. Integration of the therapy and the test accelerates adoption, supports payer decisions, and improves the patient experience.

Where Innovation Is Going Next

1. Artificial intelligence and machine learning will interpret complex signatures across sequencing, imaging, and multimodal data. This requires strict version control, continuous validation, and transparent communication.
2. Digital health integration through remote monitoring, applications, and wearables will generate real-world evidence on adherence, safety, and outcomes. Design data integrity, privacy, and security into requirements.
3. Rare and ultra-rare programs will combine creative designs with high-quality analytical validation and early dialogue with regulators.

Evidence That Moves Payers

1. Tie diagnostic cutoffs to outcomes that matter to clinicians and payers, not only to analytical thresholds.
2. Build early real-world evidence plans that capture adherence, turnaround time, and test effect on treatment selection.
3. Include provider workflow studies that quantify how the test reduces uncertainty and improves speed to therapy.

Coverage And Reimbursement Playbook

1. Plan codes early. Evaluate CPT and PLA pathways for laboratory tests and consider HCPCS where appropriate.
2. Map coverage routes. Prepare for national or local coverage and align with technology assessment expectations in major regions.
3. Quantify value. Build budget impact and cost offset models that link to clinical endpoints and diagnostic yield.
4. Reduce friction. Set provider support and turnaround time service levels that meet payer expectations and reduce prior authorization hurdles.

Commercial Moves That Create Advantage

1. Build true partnership with joint governance, shared milestones, and one risk register. Decide tissue banking, testing sites, and specimen logistics early.
2. Negotiate clear contracts that cover data ownership, commercialization rights, field support, and post-approval obligations before pivotal trials.
3. Prepare payer evidence in parallel with regulatory evidence through real-world plans and education for providers.
4. Plan for global scale with modular files for United States, European Union, Japan, and China, and integrate local data needs into pivotal planning.

Cross-Industry Collaboration

Align Incentives and Timelines

Pharmaceutical programs are large and long. Diagnostic cycles are lean and fast. Resolve the asymmetry through shared governance, aligned milestones, and risk sharing. Define one plan for analytical validation, clinical evidence, and market rollout with joint accountability.

Use Integrated Interactions with Regulators

Bring drug and device reviewers together. Present one evidence plan, one risk file, and a change control approach. Candid discussion of constraints and mitigations reduces late requests.

Governance essentials for joint programs:

1. Establish a joint scientific leadership board with clear decision rights on evidence, labeling, and change control.
2. Maintain a shared risk register with owners across clinical, regulatory, quality, and commercial.
3. Run one inspection readiness plan with common document maps and audit response templates.
4. Use a single message house for regulators, payers, investigators, and providers so claims remain consistent across channels.

Strategic Guidance For Leaders

Common Pitfalls

1. Treating the diagnostic as secondary
2. Underestimating post-market complexity
3. Waiting for late-stage feedback

Build the Right System

1. Run a regulatory intelligence function that translates requirements into design inputs and study plans.
2. Use digital oversight that links quality, risk, clinical data, and submission artifacts.
3. Train research, development, and commercial leaders on companion diagnostic requirements.

Earn and Keep Credibility

Present an integrated strategy, acknowledge risks early, document mitigations, and deliver on commitments.

Leadership Scorecard

Track these indicators monthly to keep the program on course.

1. Time from protocol lock to first patient screened with the test available.
2. Specimen failure rate and top three causes with corrective actions closed.
3. Turnaround time from specimen receipt to report and percent on time.
4. Percent of algorithm changes released with complete verification and validation and provider communication executed.
5. Median days from signal detection to risk decision across drug and device.
6. Global file readiness measured as percent of modules that are inspection ready.
7. On-time responses to agency questions and commitments met after meetings.

Outlook

Three forces will shape the next decade.

1. Greater transparency in review outcomes: Public summaries of reasons for nonapproval will raise the floor for validation quality and program discipline.
2. Modern safety analytics and integrated surveillance: Cross product signals will surface earlier, which will require tighter coordination between pharmacovigilance and device vigilance and faster decision-making on corrective action.
3. Expansion beyond oncology: Programs in immunology, neurology, and rare disease will increasingly pair targeted therapies with validated diagnostics that direct treatment with precision.

Leaders who integrate regulatory intelligence into daily decisions, invest in digital-first quality and evidence systems, and partner across industries with clarity will set the pace.

Conclusion

Combination products in companion diagnostics are redefining precision medicine today. Success belongs to sponsors that elevate the diagnostic to the same strategic level as the therapy, align global evidence from the start, and manage the full life cycle with rigor and speed. The path is clear. Treat the diagnostic as a strategic asset. Build regulatory science into the culture. Engage reviewers early with integrated plans. Invest in the digital backbone that keeps evidence current and inspections smooth. When you do these consistently, patients, clinicians, and payers see the benefit and your teams deliver with confidence.

About The Author:

Marcelo Trevino has more than 25 years of experience in global regulatory affairs, quality, and compliance, serving in senior leadership roles while managing a variety of medical devices: surgical heart valves, patient monitoring devices, insulin pump therapies, surgical instruments, orthopedics, medical imaging/surgical navigation, in vitro diagnostic devices, and medical device sterilization and disinfection products. He has an extensive knowledge of medical device management systems and medical device regulations worldwide (ISO 13485:2016, ISO 14971:2019, EU MDR/IVDR, MDSAP). He holds a BS in industrial and systems engineering and an MBA in supply chain management from the W.P. Carey School of Business at Arizona State University. Trevino is also a certified Medical Device Master Auditor and Master Auditor in Quality Management Systems by Exemplar Global. He has experience working on Lean Six Sigma Projects and many quality/regulatory affairs initiatives in the U.S. and around the world, including third-party auditing through Notified Bodies, supplier audits, risk management, process validation, and remediation. He can be reached at marcelotrevino@outlook.com or on LinkedIn.