Companion diagnostic (CDx) development is a complex journey requiring detailed planning. In a previous article, we explored strategies for biomarker development and key considerations for early phase biomarker-guided studies, including the regulatory submissions required. Here we take a closer look at the later phases of CDx development, focusing on key considerations for registrational studies to achieve contemporaneous approval of the CDx and its associated therapeutic.
Key Considerations for Registrational Studies
The registrational study that will support the marketing authorization of the CDx and therapeutic will be with a biomarker-selected patient population. In the registrational study, the clinical trial assay (CTA), the assay used to identify which patients will respond best to the therapeutic, could be either a laboratory developed test (LDT) or the final CDx assay. An LDT an assay that is designed, manufactured, and used within a single laboratory, and often preferred by the drug sponsor due to the ease and speed of obtaining LDT test results to enable enrollment. From the perspective of CDx development, it is preferable to use the final CDx assay for patient enrollment in the registrational study, if possible, to avoid the need for a bridging study to the final CDx assay. Table 1 outlines the pros and cons of these two enrollment strategies when considered for the registrational study.
Table 1. Local testing vs final CDx testing
If LDTs are used to enroll patients, FDA recommends that the following information be collected:
- Test name, location of testing, and methodology
- Specimen types, collection, processing, and storage before and after testing
- Analytical performance characteristics of the test, such as limit of detection, analytical sensitivity, cutoffs, and accuracy
- DNA extraction methodology/kit name and instrumentation utilized by each site per sample
- Hard copy of local test reports
- Confirmation that assay is locked prior to testing
- Prevalence of targeted biomarker in that lab
Will a Bridging Study be Required?
A bridging study is required when the CTA used for enrollment is different from the final CDx assay. The purpose of this study is to demonstrate that the clinical efficacy observed by selection with the CTA is maintained with the final CDx assay, demonstrating clinical utility in the CDx selected patient population. If a bridging study is required, it is critical to bank both biomarker-positive and biomarker-negative samples from all screened subjects and to plan sufficient time to test the samples on the final validated CDx assay. This data will be needed for both the CDx and therapeutic submissions.
Critical considerations for bridging studies include:
- Biomarker prevalence and harmonization of biomarker rules
- Concordance between CTA(s) and final CDx
- Potential for missing samples from the registrational trial due to lack of specimen material or because the lab running the LDTs did not provide it
- Missing clinical outcome data in CTA-negative population
Occasionally, developers may source biomarker-negative samples from other trials or from biorepositories to be tested using the final CDx. If non-study samples are used, orthogonal testing may be required because these new samples would not have been tested previously with the CTA.
When planning for a bridging study, developers should remember that the analytical and clinical validation studies in compliance with the Clinical Laboratory Standards Institute (CLSI) Guidelines for the final CDx must be completed prior to testing the banked clinical samples as part of the bridging study. A CLSI-level validation is required for the marketing authorization of a CDx assay. Since there may be a time lag between the registrational study and the bridging study, it is also crucial to obtain both stability data on the samples and consent from patients for retesting.
Another important consideration is that it may not be possible to begin the bridging study until the phase 3 or registrational study has completed, thus delaying CDx submission completion, FDA review, and potentially, approval of the corresponding drug. While FDA prefers a modular premarket approval (PMA) submission, delays or complications with a bridging study may require a sponsor to submit a traditional PMA instead, meaning all sections of the PMA (Quality, Software, Analytical, and Clinical) are submitted at once.
Regulatory Submissions for CDx
In the US, FDA considers CDx to be high risk devices that usually require PMA. The modular PMA is preferred by FDA and typically includes four modules as outlined in Table 2 as an example. It is recommended that developers use the pre-submission program with CDRH to align on the table of contents for the modular PMA, content for each module, and review timelines prior to the submission of the first module.
Table 2. Modular PMA format
For developers who are adding a CDx indication to an already approved PMA, the appropriate regulatory submission mechanism is a supplemental PMA (sPMA). The sPMA is a streamlined submission focused on supporting analytical and clinical validation for the CDx indication of interest.
CDx and Therapeutic Co-Development
Ideally, a CDx and its corresponding therapeutic follow a parallel development pathway that includes use of the CTA in the drug trials and a CLSI-level validation prior to the registrational study to ensure contemporaneous approval (see Figure 1).
Figure 1. Ideal parallel development pathway for a targeted drug and CDx
Using the final CDx assay in the phase 3 trial maximizes the likelihood of drug/CDx co-approval since both can be clinically validated by the results of that study. Often, however, LDTs are used either in the registrational study or for patient inclusion or exclusion.
When using local testing for enrollment, there are options for minimizing regulatory requirements for CDx commercialization:
- Implementation of confirmatory testing by a central lab prior to enrollment
- Utilization of one of the local sites used for screening patients as the central confirmatory lab
Both options allow for bridging to the final CDx from a central lab. In these scenarios, it is extremely important to select a diagnostic vendor early so that analytical validation of the final CDx in the intended use population can be completed prior to starting the bridging study.
Conclusion
CDx are indispensable tools in modern medicine. However, developing and getting them approved can be a complex process. Effective development must follow a strategically sound pathway from biomarker identification to regulatory approval. By following best practices, developers can achieve contemporaneous approval of the CDx and corresponding therapeutic to deliver the right treatment to the right individuals at the right time.
At Precision for Medicine, we bring together new technologies, regulatory and scientific expertise, and operational scale to accelerate companion diagnostic and therapeutic timelines. Our global footprint includes seven specialty laboratories in the US and Europe; six sample processing sites in Europe, Africa, and Asia Pacific, and a biorepository with millions of high quality, deeply annotated specimens. We provide comprehensive CDx solutions, from biomarker assay development, clinical trial enabling regulatory approvals, and clinical trial testing to data management services, regulatory strategy and submission development, liaison with regulatory bodies, and parallel therapeutic support.
To learn more about effective co-development of companion diagnostics and therapeutics, view our on-demand webinar.
