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Vice President, Companion Diagnostics & Oncology
Q2 Solutions
Oncology clinical development programs are now typically using patient selection strategies to identify likely responders/non responders for efficacy and/or safety outcomes. Solid tumor lymphoma and leukemia indications increasingly have biomarker analysis built into their clinical development plans, and many of those biomarker plans include the provision for a companion diagnostic assay.
Since the approval of the first companion diagnostic (CDx), HER2 in 1998, precision medicine has embraced companion diagnostics as one way to ensure that targeted therapies can be appropriately administered to the right patient with some degree of assurance following clinical validity within clinical trials.
However, before a companion diagnostic can be delivered as an approved tool for patient care, it requires a vigorous level of analytical validation and testing within clinical trials before submission to the regulatory authorities, typically alongside the companion therapeutic.
There are several paths to that end goal that are available to pharmaceutical and IVD developers. These differently available routes should consider business, regulatory, science/technology, and commercialization elements. No two companion diagnostic projects are the same, and each relies on a balance and consideration of those four elements.
The majority of companion diagnostics approved by the FDA, and indeed, the majority of CDx assays evaluated in clinical trials, rely upon the submission of the assay by the IVD company for clearance/approval. The IVD company is responsible for the validation of that assay, the training and proficiency of the central laboratory to enable a verification of assay performance, and a pre-market approval (PMA) package to the FDA for approval. Typically, the IVD company will provide investigational use only (IUO) reagents and in Europe, under a performance evaluation only (PEO) designation. The pharmaceutical company and the IVD company typically enter into an agreement for the development and validation of the assay using GMP grade materials. This pathway has been successful for companion diagnostic assays that include PD-L1, EGFR, ALK, and BRAF. These assays have been successfully commercialized globally and are available in many labs as diagnostic tools to enable precision medicine treatment decisions.
A second model has been successful on a limited number of occasions but does offer an alternative path to a companion diagnostic approval—the so-called single-site PMA model. The laboratory develops and validates the assay and provides the testing for the clinical trials and is responsible for the submission to the FDA. In essence, these are laboratory developed tests (LDT’s) and therefore cannot be transferred to additional laboratories. Accordingly, the initial commercial testing can only occur in the laboratory developing the assay. This has limitations as samples would need to be routed from global clinical sites to the one testing laboratory.
A hybrid model is gaining traction in which the central laboratory develops and validates an IVD to CAP/CLIA standards. It utilizes IVD company reagents and instruments to perform the validation and, accordingly, defines the performance characteristics of the assay. This can provide a platform to manage risk, for example, when IUO reagents are not available, or when there is a hesitancy to make an investment in an IVD product early in clinical development. At some point, however, a bridging study would be required in order for the IVD company to continue the development of the CDx assay from the laboratory.
For oncology, different technologies are available dependent on the biomarker(s) that are being considered for precision medicine. These include IHC, FISH, NGS, and PCR. Before testing can begin, pathology review (typically confirmation of diagnosis and assessment for tissue containing cells of sufficient quantity and quality) is required, it’s imperative that pathologists are integral within the global central laboratory set up. Often, these pathologists will serve as principal investigators for the companion diagnostic assay.
Providing biomarker results to clinical trial sites within fast turnaround times is almost a ubiquitous requirement given that the screening period to get patients enrolled is short. The typical industry expectation is to provide results back to clinical sites within five business days of sample receipt.
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