(2014, updated 2020)

Example: The cobas® EGFR Mutation Test v2 received PMA approval as a companion diagnostic for osimertinib.

Step 2: Early Engagement – Q-Submissions and Pre-Submission Meetings

The Q-submission program allows developers to seek FDA feedback before submitting a formal application. Pre-submission meetings help clarify regulatory expectations, analytical validation needs, and labeling considerations.

• Types of Q-Subs: Pre-Sub, IDE, PMA, IND, Breakthrough Designation
• Key Content: Intended use, proposed indication, study design, predicate devices, risk analysis

Tip: Submit questions 60–75 days prior to your proposed meeting date. Expect written feedback within 70–90 days.

Visit FDA’s Q-submission program page for details.

Step 3: Analytical and Clinical Validation

Analytical validation ensures the CDx consistently and accurately detects the biomarker of interest. FDA expects robust performance metrics, including:

• Limit of Detection (LOD) and Limit of Quantification (LOQ)
• Precision (inter- and intra-assay CVs)
• Specificity and cross-reactivity testing
• Stability (sample and reagent)
• Reproducibility across sites/operators

For clinical validation, developers often conduct a bridging study alongside the therapeutic trial. The goal is to demonstrate that the diagnostic accurately identifies populations benefiting from the drug.

Example: PD-L1 IHC 22C3 pharmDx was validated using tumor samples from the KEYNOTE-010 and KEYNOTE-024 studies for pembrolizumab indication.

Step 4: IDE Submission for Trials Using Investigational CDx

If a CDx is used in a clinical trial to determine patient eligibility, and it is not yet FDA-approved, an Investigational Device Exemption (IDE) may be required. IDEs apply if:

• The CDx is used to make therapeutic decisions (i.e., significant risk)
• The diagnostic data supports the therapeutic’s efficacy or safety

IDE approval is essential when the CDx is pivotal to trial enrollment. Otherwise, retrospective testing with stored samples may be used to support submission.

Step 5: Premarket Approval (PMA) Submission Requirements

PMA submissions are comprehensive and include:

• Device description and manufacturing details
• Analytical and clinical performance data
• Labeling and instructions for use (IFU)
• Human factors testing
• Quality system and design controls (21 CFR 820)

PMA review timeline: ~180 days (excluding clock stops). The review includes potential Advisory Committee meetings for high-profile CDx.

Step 6: Labeling and Therapeutic Drug Coordination

CDx labeling must clearly specify the intended use population, biomarker criteria, and compatible platforms. FDA expects harmonized labeling between the drug and its CDx.

Key Labeling Elements:

• Intended Use Statement: “The [device] is intended to identify patients with [biomarker] for treatment with [drug name]”
• Performance Characteristics: Sensitivity, specificity, precision
• Platform compatibility and limitations
• Sample type and handling

Co-approval of CDx and therapeutic product ensures aligned launch strategies, especially under NDA or BLA submissions. CDx labeling must be cross-referenced in the drug’s package insert.

Step 7: FDA Approval and Post-Market Responsibilities

Once approved, the CDx manufacturer must adhere to post-market surveillance and compliance obligations, including:

• Medical Device Reporting (MDR) of adverse events
• Design change controls
• Annual reports to FDA
• Post-approval studies (if required)
• Lot release and product traceability

Real-world performance data may also be requested to confirm continued effectiveness in diverse populations.

Bridging Studies and Retrospective Validation Approaches

When simultaneous therapeutic and CDx development isn’t feasible, retrospective analysis is acceptable under FDA’s bridging guidance. Stored tissue samples can be tested with the proposed CDx after the drug trial concludes.

Bridging Study Elements:

• Sample selection and integrity verification
• Parallel testing with new and reference assay
• Positive and negative percent agreement (PPA/NPA)

This strategy has been used effectively in oncology where fresh samples are often limited.

Case Study: CDx Approval for Osimertinib

In 2015, the FDA approved osimertinib (Tagrisso) along with the cobas EGFR Mutation Test v2. Key points:

• Drug: Osimertinib for T790M-positive NSCLC
• CDx: cobas EGFR Mutation Test v2
• Sample type: Plasma ctDNA and FFPE tissue
• PMA submitted: with clinical trial data from AURA3 study
• Turnaround time: ~10 months

This marked the first approval of a liquid biopsy CDx for a targeted therapy.

Tips for Successful FDA CDx Submission

• Engage early with the FDA via Q-submissions
• Align clinical and diagnostic development timelines
• Ensure rigorous analytical validation across sample types
• Pre-plan co-labeling language and drug-CDx launch strategies
• Use checklists from FDA’s CDRH Device Advice portal

Refer to CDx co-development framework at ICH Q14 for international alignment.

Conclusion

Obtaining FDA approval for a companion diagnostic is a structured but complex process. It requires scientific rigor, early regulatory engagement, and precise coordination with therapeutic product development. From analytical validation to PMA submission and post-market vigilance, each step ensures that the CDx is reliable, reproducible, and critical for patient safety. A well-executed FDA approval strategy positions both the diagnostic and the drug for commercial success and clinical impact.