NEW YORK (GenomeWeb) – The US Food and Drug Administration today finalized two guidances on the design, development, and validation of next-generation sequencing tests.
The agency also released a third draft guidance describing a voluntary, streamlined submission process to determine whether an investigational in vitro diagnostic being codeveloped alongside a cancer drug in a trial confers significant risk and may require an investigational device exemption submission, or confers non-significant risk and is exempt.
The two final guidances focus on using public genetic variant databases to support the clinical validity of genetic and genomic based tests; and the design, development, and analytical validation of NGS tests in diagnosing germline diseases. According to an FDA spokesperson, the agency received 350 comments from 38 organizations and individuals on the draft versions of these guidelines.
The agency hopes that the principles outlined in these documents will make the development of these NGS technologies more efficient as they are increasingly used in precision medicine approaches. "As disease detection technologies rapidly evolve, so too must the FDA’s approach to reviewing these new innovations," FDA Commissioner Scott Gottlieb said in a statement. "The new policies issued today provide a modern and flexible framework to generate data needed to support the FDA’s review of NGS-based tests, and give developers new tools to support the efficient development and validation of these technologies."
The final guidances are part of FDA's overarching efforts to streamline the regulation and review of NGS tests. In this regard, the agency highlighted its authorization of a third-party review option for NGS tumor profiling tests with the clearance of Memorial Sloan Kettering Cancer Center's MSK-IMPACT test last year.
Efficient NGS test development
The guidance titled, "Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics," discusses how test developers can rely on FDA-recognized public variant repositories to support the accuracy of their tests, as well the claims they are making on these diagnostics.
The FDA spokesperson noted that stakeholders commenting on the draft version of this guidance, asked for technical clarifications and further explanation of what the agency considers "publicly accessible."
"These public databases may include resources like ClinGen, which is maintained by the National Institutes of Health," the FDA stated. The agency noted that databases that use licensing models and charge fees for commercial use may also be used for this purpose.
Although proprietary databases or those that charge fees for public access are out of the scope of the guidance, the agency said those types of databases "may also be sources of valid scientific evidence" and "could be used to support the clinical validity of genetic or genomic-based tests."
The FDA spokesperson also noted that stakeholders commenting on the draft version asked that the scope of the guidance be expanded to allow public genetic variant databases to be used not just for NGS but other types of genetic and genomic tests as well. As such, in the final document, the FDA specified that "a genetic variant database is a source of valid scientific evidence that could support the clinical validity of genetic and genomic-based tests in a premarket submission, regardless of the type of technology for the test (e.g., NGS, Sanger sequencing, PCR)."
The agency also included recommendations related to somatic variant databases and clarified that they are considered within the scope of the guidance, the spokesperson added.
"Information about genetic variants is generally stored in a manner that is not publicly accessible," said Jeff Shuren, director of FDA's Center for Devices and Radiological Health. "Today’s release of the FDA’s final guidance on genetic variant databases will help change this paradigm by encouraging data sharing and the accumulation in public databases of evidence supporting the clinical validity of genomic tests to help provide an even more efficient path to market."
The other guidance finalized by the agency entitled, "Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS)–Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases," lays out recommendations that test developers can use to inform the types of data FDA would look for in premarket submissions.
The FDA spokesperson said that the agency recognized in the guidance that standards for NGS testing can rapidly evolve and therefore supports the use of standards developing organizations (SDOs) to establish specific performance thresholds. The FDA will approve and formally recognize SDO-developed standards that test developers can use in regulatory submissions.
Some commenters to the draft version of this guidance did not favor the agency providing specific thresholds for test performance. In the final version, the FDA removed specific numeric thresholds for performance metrics and instead recommended that test developers predefine, justify, and report minimum acceptable overall and target threshold metrics, such as accuracy, precision, and coverage.
"These thresholds will depend on a number of factors, such as the indications for use of the test and the types of variants detected and reported," the FDA spokesperson explained. "Specific numeric thresholds could be defined in future consensus standards or special controls for specific tests or indications for use."
Determining risk of investigational IVDs
In the draft guidance on the use of investigational IVDs in oncology drug trials, the FDA said it would like sponsors to use the described streamlined process "to reduce administrative burden" on themselves and the agency, "and to maintain the current level of regulatory review."
The FDA said its device division would make the risk determination for the investigational IVD alongside the drug division's evaluation of the investigational new drug application. The sponsor should submit information on how the results from the test will be used in the clinical trial, discuss the prevalence of the biomarker in the patient population, and any risks the biopsy collection process has on study subjects.
The agency noted that if an invasive biopsy procedure presents serious health risk to study participants, the trial will not be eligible for this streamlined submission process. This draft guidance follows an earlier draft guidance issued last year, entitled "Investigation IVD Used in Clinical Investigations of Therapeutic Products," expressing concern that sponsors and investigational review boards may not appreciate that investigational IVDs used in clinical trials can pose significant risk to patients by affecting important aspects of the treatment they are receiving within the study.
In the streamlined risk determination pathway articulated today, the agency also recommends sponsors provide assurance that the institutional review board has reviewed the risks associated with an investigational drug and test, particularly the risks associated with incorrect test results.
If FDA's drug and device divisions determine that an investigational IVD in a particular study confers non-significant risk, the FDA will issue a letter that tells them to proceed with the trial ensuring that biopsy procedures don't carry significant risks, and to report any unanticipated adverse events. If the test is found to carry significant risks, then the FDA will tell the sponsor to submit an investigational device exemption application and wait to start the trial until that is approved.
The public has 60 days to comment on this draft guidance.