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NIH Language in RFAs Tells Researchers to Prepare to Discuss Study Protocols with FDA

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NEW YORK (GenomeWeb) – The US Food and Drug Administration's regulations on lab tests and devices used in clinical investigations are impacting federally funded study protocols involving advanced sequencing tests.

The National Institutes of Health has been adding language to certain requests for applications (RFAs) informing researchers that when they use results from new sequencing tests to guide clinical care of patients, they should be prepared to discuss their study designs with the FDA and may need to submit for an investigational device exemption (IDE).

According to FDA guidelines, in order for labs to be able to assess the safety and effectiveness of an investigational diagnostic on human subjects – usually as part of their efforts to receive premarket approval for the test – they need to garner an IDE before starting the study.

The NIH's National Human Genome Research Institute (NHGRI) and the National Institute of Child Health and Human Development (NICHD) posted RFAs in July to provide funding opportunities to groups involved in or interested in joining the Electronic Medical Records and Genomics Network (eMERGE). The RFAs included the following language:

"Due to regulatory requirements for using research results in clinical care, some sequencing data will be expected to be in compliance with the Clinical Laboratory Improvement Amendments (CLIA). In addition, FDA Investigational Device Exemption (IDE) may be needed for new sequencing methods used in clinical care, separate to the requirement for the test to have been conducted within a CLIA-certified environment. Investigators must be prepared to discuss the need for an IDE with their [institutional review boards] and document the outcome of those discussions, and to engage in pre-submission discussions with the FDA. These typically involve submission of actual study protocols, including the entire sequencing pipeline from sample preparation to data analysis; the latter will be prepared in collaboration with the Central Genotyping and Genome Sequencing Facility(-ies)."

The RFAs were specifically for the Phase III portion of eMERGE – an NIH-organized and -funded effort launched in 2007 to support a consortium of researchers using data from biorepositories, genotyping, and sequencing tests to study disease-linked genomic variants and assess whether incorporation of some of these markers into EMRs improved patients' outcomes. So far, researchers in the network have been focused on genotyping patients and incorporating certain variants into their EMRs with IRB approval. Some sites are performing next-generation sequencing in CLIA-certified labs.

The third phase of the project, slated to begin in mid-2015, will expand and validate eMERGE's library of phenotypic algorithms, and discover links between patients' phenotypes and their genomic data garnered from NGS tests. There will be more clinical grade sequencing performed in this part of the project. Ultimately, the aim of this phase of the project is to incorporate certain types of genomic data from advanced sequencing tests into patient's EMRs that researchers determine may improve their care.

According to Laura Rodriguez, director of NHGRI's division of policy, communications and education, this is the first time that the institute has included this language in RFAs, but she indicated that more RFAs may include similar verbiage in the future. In a statement, the FDA informed GenomeWeb that the agency did not develop or approve the language the NIH included in the RFAs. However, experts knowledgeable of the situation say that the agency got interested in extending its oversight over eMERGE study protocols once the NHGRI and NICHD wanted to explore the use of genomic sequencing in the context of newborn screening.

Last year, these two NIH institutes committed $25 million to four research groups investigating how genome and exome sequencing can improve the health of newborns over a five-year period. The four funded efforts, known as the "Newborn Sequencing In Genomic medicine and public HealTh" (NSIGHT) program, are also assessing the ethical challenges posed by these newer technologies.

I guess the value of gold has dropped a lot because Sanger is quite limited in what it can do.

The newborn screening grant recipients "were going to do CLIA-level genetics, but as a research trial," Howard McLeod, a member of the eMERGE external scientific panel, told GenomeWeb. The FDA got involved and wanted the investigators to discuss their study protocols and sequencing methods before starting the trial, said McLeod, who is the medical director of Moffitt Cancer Center's DeBartolo Family Personalized Medicine Institute.

"There was a lot of to and fro, and holding back research," McLeod said. "It was an unusual situation in that the FDA wanted to get involved but the field isn't mature enough to define exactly what they wanted. I didn't think it was very helpful."

Boston Children's Hospital is among of the pediatric sites included in eMERGE and is also involved in the BabySeq Project – one of the genomic sequencing-focused newborn testing studies in NSIGHT that has been impacted by FDA oversight. With the first year of funding nearly gone, the BabySeq Project hasn't started yet, and the researchers involved in the effort are still ironing out the design of the study with the FDA and an IRB. As it stands currently, the study is planning to compare the impact of traditional biochemical screening against situations when NGS-based testing is provided in addition to conventional screening in healthy and neonatal intensive care unit babies.

The FDA is particularly concerned about the effect that information on genetic risk factors will have on families with healthy babies who participate in these newborn studies, researchers say. The agency has asked eMERGE network members to confirm NGS-based sequencing results that they want to report to patients with Sanger sequencing, which it currently considers the gold standard.

"I guess the value of gold has dropped a lot because Sanger is quite limited in what it can do," McLeod said. "One essentially has to develop a new assay for each variant one finds and wants to act on." As such, confirmation by Sanger sequencing of NGS results would increase costs for these labs and also delay reporting test results to patients. Some eMERGE network members are already providing Sanger confirmation, but others are not, and so, the RFA language would impact those labs that had planned to report results directly from NGS tests.

Alan Beggs, director of The Manton Center for Orphan Disease Research at Children's Hospital Boston and one of the lead investigators on the BabySeq Project, told GenomeWeb that the investigators are currently preparing a response for the FDA. "We've been trying to juggle discussions with the IRB and FDA at the same time," Beggs said. "They have to essentially agree on the design of the study."

Cynthia Powell, associate professor of pediatrics and genetics at the University of North Carolina, Chapel Hill, is also leading one of the NSIGHT newborn genomic screening projects and has had interactions with the agency about the study protocol. She believes the agency is particularly concerned about the BabySeq Project and her study at UNC, because both trials have arms where healthy infants will be sequenced. "We've been deemed a high-risk study," Powell said. Although her group was already planning to confirm NGS results with Sanger sequencing, that didn't satisfy the FDA, and Powell says her group will have to submit an IDE.

In discussions with the FDA, Powell was confused as to what device the agency was considering high-risk. "It's the whole thing – from initially recruiting parents, the decision aid tools, the actual sequencing, the pipeline, the variant calling, to the decision making on the part of the parents. It's everything," Powell said, adding that she and her academic colleagues conducting advanced sequencing projects are "guinea pigs for the FDA."

The agency's attempt to ensure the safety of federally-funded research protocols isn't necessarily a bad thing, in McLeod's view. "There's a lot of aspects of medical care that [FDA's device division] hasn't had experience with, so getting the FDA involved in a learning mode could be very useful," he noted. "But if FDA is getting involved to just impose regulation that doesn't really have any clear value in the context of a research trial, I'm not sure it's going to be adding much. In fact, it may slow the generation of the very data needed by the FDA to make rational decisions."

The regulations

The language in the eMERGE RFA reflects FDA's position on research-use only (RUO) and investigational use only (IUO)-labeled products and laboratory-developed tests (LDTs) – all of which the agency has been concerned is being developed and marketed in a manner that circumvents its oversight.

RUO and IUO products are tests, instruments, software, and reagents in the development phase. RUOs may be used to advance knowledge about a disease and IUOs are used in the development of a marketed in vitro diagnostic product. Products in this category are exempt from regulatory controls and don't have to garner premarket approval or clearance from the FDA.

In its final guidance on RUO/IUO products last year, the FDA noted that "mere placement of an RUO or IUO label on an IVD product does not render the device exempt from otherwise applicable clearance, approval, or other requirements. FDA may determine that the device is intended for use in clinical diagnosis based on other evidence, including how the device is marketed." The agency went on to say that if it finds evidence that a product is mislabeled as RUO or IUO, then it will consider that product misbranded and adulterated.

The RFA language is also tied up with FDA's intent to regulate LDTs. According to the FDA, LDTs are tests that are entirely developed and marketed at a single lab, which have historically been exempt from FDA premarket review and only subject to CMS oversight under CLIA. The FDA, concerned that labs marketing tests as LDTs often don't fit this definition, has issued draft guidelines describing a risk-based framework for bringing LDTs under its regulatory oversight.

In an email to GenomeWeb, Elizabeth Mansfield, director of the personalized medicine staff at FDA's Office of In Vitro Diagnostics, explained that studies involving human subjects are "typically considered to be investigations and not research," and such trials are subject to investigational regulations. "As FDA explained in the draft guidance on the LDT oversight framework, FDA intends to continue to enforce investigational device requirements under 21 CFR Part 812 for all clinical investigations of LDTs that are conducted under clinical protocols that require institutional review board approval," she said.

According to Mansfield, the FDA considers the majority of studies that are part of IVD development programs to be "exempted investigations" (defined in 21 CFR 812.2). However, if the IVD is going to be studied in a "non-exempt investigation," for example, "if invasive sampling is performed to obtain the specimen in a way that may pose significant risk to patients, or if test results are returned to patients without confirmation by a medically accepted diagnostic product or procedure," then the investigational device regulations apply.

Furthermore, "if the IVD to be studied in the investigation meets the 21 CFR 812.3 definition of a 'significant risk device,' the investigation can only be conducted under an approved IDE," Mansfield added.

A national IRB?

While IRBs could always ask researchers to garner IDEs for tests used in studies, that hasn't been the standard practice. IRBs have typically depended on CLIA regulations to ensure investigational lab tests are being performed accurately in trials. "If a test for a research study is performed in a CLIA lab and the results acted on for a patient, most IRB's are quite comfortable with that," McLeod said. "So, while there was always a possibility that an IRB could request that some sort of an exemption be required for a test, practically it hasn't been something that is commonplace."

We're not like 23andMe. We're not marketing this to the public.

FDA's desire to regulate study protocols spurred by NIH's announcements on the newborn genomic screening grants caught the research community off guard, according to McLeod. "Everyone knew FDA wanted to get involved in the clinical side, but the idea of them getting into research, and [regulating] the actual data that the FDA needs to make decisions [on tests], just seemed counterintuitive and surprised a lot of people."

Beyond the newborn genomic screening studies and the eMERGE efforts, FDA's actions could have implications for many other NHGRI-funded efforts. Under its Division of Genomic Medicine, the institute is focused on advancing projects that can establish best practices for moving genomic discoveries into the implementation phase.

Ultimately, FDA is concerned that researchers in these projects are using unapproved NGS platforms to make healthcare decisions, said Dan Roden, who is leading Vanderbilt University's participation in eMERGE. The FDA regulates tests based on their intended use and risk to patients, and so, there isn't a single NGS platform with FDA's blessing that researchers can use across investigations.

The FDA last year cleared Illumina's MiSeqDx platform in the context of cystic fibrosis and a universal reagent kit that simplifies the process for researchers to develop their own tests. But researchers using the reagent kit would still need to demonstrate analytical and clinical validity for their tests with the FDA. Then, in September, Thermo Fisher Scientific announced that it has completed listing its Ion PGM Dx NGS system with the FDA as a Class II medical device, since the instrument has the same intended use as the MiSeqDx platform.

"You can envision situations certainly where very successful sequencing solutions might deliver information that's not accurate or delivers information that people act on, but shouldn't, or [provides] information they should have acted on but didn't," said Roden, assistant vice chancellor for personalized medicine at Vanderbilt. "It all sounds great until you consider whether there could be risk as well as benefit to patients."

As a member of the FDA's science board, Roden says he has some sympathy for the agency's mission to ensure the public's health. "They can't just say, 'Oh this sounds really cool, let's just approve it,'" he said. "They're sort of stuck and at the end of the day they're going to want evidence that the [NGS] platforms work as well as Sanger sequencing."

NHGRI's Rodriguez acknowledged that FDA regulations will increasingly be a consideration as study protocols involve returning data to participants that inform their care, even if it is provided through a research investigation. "The inclusion of this language in the eMERGE announcement is representative of the progress in the science," she said. "The intent is to make investigators aware that these FDA procedures might be relevant to their proposals and alert them to think ahead and consider any potential implications within their grant applications."

However, in regulating the use of molecular diagnostics in research studies, UNC's Powell sees FDA becoming a "sort of a national IRB," where "they'll have control over all research studies involving molecular genetics."

Among these academic groups involved in cutting edge genomic research projects there is brewing resentment that the FDA's actions against their study protocols place them on the same plane as direct-to-consumer genomics firms. The FDA last year sent a warning letter to 23andMe asking the company to stop marketing its genetic tests directly to consumers without the agency's approval or clearance. As a result, 23andMe halted reporting health-related test results to customers.

"Most of us are involved in ethics groups here at our universities … and these are research studies," Powell said. "We're not like 23andMe. We're not marketing this to the public. [Study participants] will go through very lengthy informed consent. If people aren't interested they don't have to participate, and we're certainly not charging them for any of this. But the FDA is still extremely interested."

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