Illumina’s Plans for Clinical Trials

As part of its move into the clinical market, Illumina has formed a collaboration with pharmaceutical companies AstraZeneca, Janssen Biotech and Sanofi to develop a companion-diagnostic test for oncology based on next-generation sequencing (NGS) (see page 2). Intending to extend the partnership to additional companies, Illumina plans to develop the Universal Oncology Test System, to be used in clinical trials. The system is based on the MiSeqDx sequencer, which received CE marking and FDA clearance (class II device) in June (see IBO 9/30/13) and November 2013 (see IBO 1/31/14), respectively. This collaboration will address several of the challenges of next-generation sequencing (NGS) in clinical trials listed by the 2014 article, “Navigating the Rapids: The Development of Regulated Next-Generation Sequencing-Based Clinical Trial Assays and Companion Diagnostics,” by Saumya Pant, PhD, et al., published in Frontiers in Oncology. These include a lack of standardization in decentralized testing, limited specimen quantity and the type of sample tested.

A companion-diagnostic typically tests for variants of just one gene in order to determine if a given drug is appropriate for treating a patient, and can also be applied to clinical trials. In many cases, the target of a drug is a particular mutation. However, tumors are complex and heterogeneous in their makeups and can be a result of many genetic and epigenetic factors. They can include multiple somatic mutations, genome rearrangements and changes in gene expression. Conducting multiple diagnostic tests to determine effective and individualized therapies for patients is expensive and time consuming, and is limited by the quantity of sample available, which is often a challenge in running multiple tests.

“Evaluating the genomic variation of a tumor through a multigene sequencing test can maximize the data available from limited tissues and provides a more comprehensive survey of variation thereby leading to more personalized decision making,” Naomi O’Grady, senior product manager, Oncology Product Development at Illumina, told IBO. With the Universal Oncology Test System, Illumina seeks to shift to a multigene approach to companion diagnostics, facilitating optimization of patient treatment or enrollment in clinical trials. With the input of its pharmaceutical partners, the company will develop assays to simultaneously test multiple analytes. The companies will identify genes and gene fusions of interest, 60–70 of which will be included in the assay.

The type of specimen can provide additional challenges. According to Ms. O’Grady, “[o]ne of the key developments of the Universal Oncology Test System will be to establish NGS claims for DNA and RNA extracted from formalin fixed paraffin embedded (FFPE) tissues.” FFPE specimens often have degraded, low-quality nucleic acids, restricting the length of the sequence amplified from them that can be considered reliable, and the fixation process can also alter the DNA. To account for these factors, it is necessary to carefully optimize the number of amplicons in a reaction. The amount of sample required for sequencing can also be a limiting factor.

Another challenge the assay would address is the lack of standardization in NGS across labs. According to Dr. Pant’s article, the majority of clinical NGS work is spread across multiple academic and hospital labs rather than in central labs and CROs, and there is thus a range of conditions in NGS assays and in their interpretation. This may result in patients incorrectly being included or excluded from clinical trials, potentially biasing their results. The Universal Oncology Test System assay would provide standardization of analysis across genes. This standardization would apply across the genes tested in the assay and across labs. This would facilitate the testing of new biomarkers, the expansion of candidate patients for clinical trials and the ability to combine the clinical trials of different companies.

Illumina’s recent acquisition of Myraqa (see IBO 7/31/14), a regulatory and quality consulting company, will be an asset to its preparing the system for regulatory approval. “We expect much of the work will be similar to other companion-diagnostic products in that both analytical and clinical data will be required,” explained Mya Thomae, vice president of Regulatory Affairs. “For the analytical data, we will be proposing approaches based on guidance [the] FDA has provided for other highly multiplexed products as well as our experience during the MiSeqDx clearance.” Illumina has not revealed a timeline for submission of the system to the FDA.

< | >