Next-generation sequencing (NGS) is rapidly evolving from research tool to diagnostic platform. As this novel technology moves from discovery into patient care, regulatory bodies including the U.S. Food and Drug Administration (FDA) are tasked with establishing new requirements for accuracy, reliability and clinical relevance. On January 30, President Obama specifically addressed the need for new requirements when announcing his new Precision Medicine Initiative. Illumina’s VP of Regulatory Affairs, Mya Thomae, talks about the company’s strategy for this evolution.
Where do you see regulation of next-generation sequencing (NGS) heading?
As we recently heard directly from the White House, regulatory modernization is a key priority for FDA. They are currently working on a framework for optimizing how NGS becomes regulated. This is because FDA sees NGS as fundamentally different than previous technologies. FDA stated it well in their recent discussion paper issued ahead of their public workshop on February 20 [on optimizing oversight of NGS diagnostic tests]:
"Most IVDs [in vitro diagnostics] detect only a single or a defined number of substances to diagnose one or several specified conditions. In contrast, NGS tests are capable of detecting the over 3 billion bases in the human genome, and in doing so identify the approximately 3 million genetic variants an individual may have. A single use of an NGS test could enable the diagnosis of any one, or more, diseases or conditions a patient presents with. NGS tests can also help to predict a patient’s risk for developing certain conditions. Because it is possible to sequence the whole genome, it is not necessary to know what variant one wishes to identify prior to running and successfully interpreting an NGS test—a concept which is very different from how traditional IVDs are used.”
FDA is suggesting novel regulatory approaches that are suitable to the “complexity and data richness” of NGS technology, while assuring analytical and clinical performance standards.
The discussion paper cites Illumina’s MiSeqDx instrument clearance as an example of a new approach to regulation. For the MiSeqDx 510(k), three analytical studies were performed. Two were traditional reproducibility/precision studies. The accuracy study, however, was unique in that the data provided included a representative subset of the variants rather than every possible variant.
More specifically, the accuracy study used a representative assay designed to query a variety of genes covering 24,434 bases across 19 different chromosomes, and containing potentially clinically relevant exons. The 13 unique samples used in this study are from two parents and 11 children that have been frequently sequenced by multiple laboratories and sequencing methodologies. There are six samples from females and seven from males. Accuracy was determined for single nucleotide variants (SNVs) by comparing the study data to well-characterized composite reference information.
The reference database sequence was derived from the combination of multiple sequencing methodologies, publicly available data, and hereditary information. With this subset we were able to demonstrate the required performance standards, which in turn provided FDA with reasonable assurance that the test would be able to successfully identify relevant variants across the genome without requiring us to submit data for every possible variant the test could identify.
Earlier this month, Illumina announced an evolution of its regulatory strategy. What is the thinking behind the shift?
As background, FDA classified Illumina’s MiSeqDx instrument as a Class II 510(k) exempt medical device. This was the first sequencer ever cleared by FDA, and it received clearance as an “open platform” with a Class II 510(k) exempt status [in addition to two tests that were cleared for use for cystic fibrosis and the Universal Reagent Kit 1.0]. This means that future sequencers do not need to go through the 510(k) process, and we do not need to develop specific assays in order to move them through the regulatory system. Instead, after having the data set, they only need to be ‘registered’ with FDA as new products. This significantly cuts the time to the IVD market in the U.S. for instruments. Building on this success, we expect to release a subsequent system, the NextSeqDx, as an open platform in the U.S. and in the European Union as a CE-marked product.
We are now building on our approach with the MiSeqDx instrument, which already has an indicated use for blood samples. We are also expecting to update our intended use (via a 510(k)) to include formalin-fixed, paraffin-embedded (FFPE) samples. Once this is in place, we will have the appropriate intended use to support our current oncology projects, and when we register the NextSeqDx, we will be able to register for both blood and FFPE at the same time.
Next, specific to non-invasive prenatal testing (NIPT), our updated strategy is to submit the NextSeqDx and take advantage of paired end sequencing, which will enable laboratories to run 48 samples at a time. The full solution, called VeriSeq NIPT, will be performed on the NextSeqDx, which we will register as an open platform prior to our NIPT submission. An assay based on paired end sequencing, and software, will be submitted to FDA as a Class III PMA device with appropriate clinical trials and analytical studies.
Part of the thinking behind this strategy is that NIPT is really starting to migrate into the average risk population. In our most recent conversations with FDA, it was really clear they want us to have at least some data that represents the average risk population. We are assessing current sample cohorts to determine the type of claim these existing cohorts can support. We will then work with FDA to reach agreement on the intended use prior to beginning our clinical work.
Outside of the United States, how does the regulatory strategy change?
In Europe, also specific to NIPT, we are currently working with customers who are using the HiSeq System as part of a technology transfer program. We want to support these customers and will be applying to CE mark the software that accompanies the HiSeq. By using a version of the software that is CE marked, these customers can subsequently submit the data from their laboratory developed tests for their own CE mark applications. We want to facilitate the work they’ve already done.
Our next step will be to CE mark the paired end sequencing version of the assay [for the NextSeqDx], and a version of the software that goes along with that. This will be ahead of our application for the NextSeqDx sequencer itself. In Europe, unlike in the U.S., it is acceptable to CE-IVD ‘portions’ of assays rather than an entire system, which is typically required by FDA. Once the NextSeqDx is also available, we will move forward to CE mark it and its associated chemistry.
In China, regulators have recently introduced new standards for NIPT, and we are taking the process there one step at a time. We are also pursuing numerous applications globally, including in Canada, Russia, non-EU countries, and Australia. Each locale may ask for different data, so we’re working on the comprehensive worldwide plan.