By Turna Ray
It's a given that technology moves faster than regulation, but when it comes to the US Food and Drug Administration's framework for laboratory-developed tests, the pace of progress has been particularly slow.
Four months after the FDA announced its intent to regulate LDTs, the agency has yet to put any meat on the bones of its plan to base forthcoming regulations on the intended use and the risk of a given test, and FDA officials have reiterated that they are keeping all ideas on the table.
Yet even as the agency wrestles with the nuances of regulating tests and platforms that are already in use, it faces an even greater challenge as drug developers, test manufacturers, and personalized medicine researchers steadily migrate to assays based on increasingly affordable sequencing technologies.
At the FDA's July public hearing on LDT regulation, when several audience members asked about the agency's plan for managing the regulatory challenges related to sequencing technologies, officials responded without elaboration that they were watching this evolving field.
While the FDA isn't likely to regulate whole-genome-based testing any time soon — officials have stressed that they don't want to stifle innovation — the agency will eventually have to confront the inevitable integration of sequencing-based diagnostics into medical decision-making as it lifts its enforcement discretion over all LDTs.
So far, the agency has not provided any details of its thinking on the issue. "All we can say at this time is we are in the process of working on the framework, but I can't provide any specifics at this time," FDA spokesperson Erica Jefferson told PGx Reporter.
Test developers and laboratories that are currently in discussions with the FDA about their sequencing platforms understand that diagnostics based on sequencing technologies will have to meet the FDA's regulatory standards for analytical and clinical validity — the same as non-sequencing-based LDTs.
When it comes to regulating sequencing-based tests, however, some say it will be particularly difficult for the agency to ensure the clinical validity of the numerous genomic associations that they will reveal about disease risk and drug response.
"When we come to full-genome sequence analysis, then the issues will be only a very little bit about accuracy and reliability of sequence data, but much, much more about how to make meaning of it," said Robert Cook-Deegan, director of Duke University's Center for Genome Ethics, Law & Policy. "The risks are much more about wrong interpretation, incomplete interpretation, and most tellingly the lag between the ability to determine accurate sequence information and the ability to understand its biological and medical significance."
As diagnostic developers more readily utilize sequencing platforms, they expect that the complexity and the amount of data they will have to submit on their products to the agency will increase, which in turn, could slow things down even more at the FDA when it comes to clearing new, innovative tests.
Even without this data, the FDA has admitted it is already overwhelmed by the amount of genomic data submissions it has received from companies seeking advice on the co-development of drug/diagnostic products. In relaying a list of do's and don'ts when simultaneously developing a drug and a companion test, an FDA official recently admitted that the agency might take longer than usual to come back to sponsors about their pre-investigational device exemption applications because regulators are "inundated" and a "little behind," since "companion diagnostics has just exploded" (PGx Reporter 08/22/10).
Thus, when one considers the colossal challenge of interpreting the millions of SNPs, insertions/deletions, and copy number variations from tests using whole-genome or targeted sequencing approaches, another issue becomes obvious: The FDA needs help.
As an example, it took a team of 31 scientists nearly two years to sift through roughly 2.6 million SNPs and 752 copy number changes in order to clinically annotate whole-genome data from one man, bioengineer and Helicos co-founder Stephen Quake (PGx Reporter 05/12/10).
The agency, although reticent about the specifics of its LDT regulatory strategy, seems to understand the breadth of the task before it. In speaking broadly about LDT regulation, the agency has said that it plans to align its regulatory activities with the Centers for Medicare & Medicaid Services and is considering enlisting the help of an independent standards-setting body.
Other ideas in play include the development of a new FDA division with the funding and internal expertise to evaluate so called "advanced personalized diagnostics" (PGx Reporter 06/23/10).
Some have put forth the idea that the agency should delineate some well-established or non-medical genetic tests as over-the-counter, which would require less regulatory oversight. Physician-prescribed tests, in this paradigm, would be those linked to the diagnosis or treatment of disease and would have to meet FDA's criteria for test clearance or pre-market approval.
Finally, in struggling with how to address the clinical validity question of increasingly complex diagnostic technologies, an idea has been making the rounds that would have the FDA approach sequencing-based diagnostic tests similar to the way it deals with X-rays and magnetic resonance imaging tests. In these cases, the FDA oversees the technological features of the instrumentation, but leaves the interpretation of test results to a medical professional trained in the practice.
While the FDA takes its time crafting regulation, the industry appears to be moving toward integrating sequencing technologies into its drug and diagnostics development pipelines.
For example, Genomic Health disclosed recently that its internal research focus has shifted toward next-generation sequencing. In the coming years, the company is planning to migrate all its cancer diagnostics to a next-generation sequencing-based Universal Cancer Assay (PGx Reporter 09/29/10).
Similarly, large pharmaceutical players are also starting to think about how sequencing technologies can be used to reduce late-stage drug failures and develop more efficacious personalized drugs.
As reported by PGx Reporter sister publication In Sequence, at a recent conference, researchers from Merck, GlaxoSmithKline, and Johnson & Johnson discussed how they have been using targeted sequencing for early biomarker discovery and for stratifying patients in drug trials. Still, these firms all said that they have not yet implemented whole-genome sequencing due to its expense (IS 08/10/10).
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Pfizer has similarly said that it is applying next-generation sequencing for target discovery, but that the cost of testing and the size of clinical trials needed for biomarker validation still pose barriers for using this technology more readily in drug development (IS 09/07/10).
As industry moves towards sequencing technologies, those who believe that consumers should be more informed and have greater access to their genomic data are making strides toward making whole-genome sequencing accessible to the general public. This week, Harvard Medical School's Personal Genomes Project announced that it will sequence the genomes of 1,000 participants based on their phenotypes. The PGP, which aims to sequence and publish the genomes of 100,000 informed participants, has so far published the data of 10 people on its site.
Early adopters have projected that whole-genome sequencing will become accessible to the lay public within the decade, as physicians and consumers become more used to handling genomic data and thinking in terms of probabilities of risk (PGx Reporter 05/12/10).
But that timeline may appear far too optimistic when viewed through the FDA's regulatory lens.
Duke's Cook-Deegan attempted to illustrate the regulatory challenge before the FDA by citing the example of genetic sequencing for long-QT syndrome. A genetic test for this syndrome can influence treatment for a life-threatening condition, but there are as many as 30 autosomal dominant forms, as well as other recessive and X-linked mutations for this condition.
"The clinical significance of finding a sequence variant means keeping track of lots of patients for a long time and seeing what happens to them and comparing that to others with the same sequence variant and those who do not share it," Cook-Deegan noted. "That is, interpretation of sequence data will take careful research on lots of people over extended periods."
For some mutations there are well-established genotype-phenotype correlations in the medical literature, but in other cases, researchers have found sequence differences but they can't yet interpret their clinical significance, he explained.
"So the issue about giving people accurate information about their health is very real, and feels like the sort of thing that the FDA probably has an important role in; but it's not about whether the genetic test is accurately detecting the sequences, but rather how to use information properly for the benefit of patients," Cook-Deegan said. "And that's the easy case of clearly medical (as opposed to the mixed medical and social) information."
Carving a Path
Jorge Conde, CEO of whole-genome analysis provider Knome, believes that although the agency is "diligently" working with sponsors to craft regulation for LDTs of all types, the issues related to overseeing sequencing-based diagnostics will take some time to iron out.
"Sequence data and its interpretation is a very, very broad concept," Conde said. "What would matter from a regulatory standpoint is how that broad concept [would] get broken down into specific applications and the specific intended use of those applications."
In the case of pharma and biotech using sequencing to assist in the development of drugs, "that is a very different application and therefore will require a very different approach to some of the other challenges that are being worked through right now, which is how do we collectively get access to [our] own data and do so in a way that is clear and controlled and responsible," Conde said.
For the time being, instead of addressing the technological aspects of sequencing platforms, it appears that the agency is more concerned with how whole-genome sequencing data is marketed to the public. Currently Knome is in discussions with the FDA about its KnomeComplete whole-genome sequencing service, which it was previously marketing directly to consumers. In June, the FDA sent letters to Knome and four other firms marketing DTC genomic analysis services, informing them that their tests might require regulatory approval as medical devices under the Food, Drug, and Cosmetic Act (PGx Reporter 06/16/10).
Among the companies that received the letters, Knome's was the only sequencing-based testing service. As such, the company is in a unique position to pave the regulatory path for other sequencing services and platform providers.
KnomeComplete, which costs more than $68,000, is a service that provides customer's complete genome sequence data; allows consumers to visualize their data through a genome browser called KnomeXplorer; provides reports describing customers' genetic basis for certain traits and their genetic predisposition for diseases; and offers an in-person discussion of the results with geneticists, clinicians, and bioinformaticians.
FDA's letter to Knome expresses concern over the fact that KnomeXplorer "analyzes genetic test results that are generated by an external laboratory in order to generate a patient specific report" that describes the genetic basis of specific disease traits or conditions. Concerned that consumers may use this genomic data to make medical decisions, the FDA informed Knome that the agency does not consider KnomeComplete to be an LDT.
Conde wouldn't discuss specific requirements the agency has asked the company to meet for its sequencing service. However, immediately after Knome received the FDA letter, the company stopped marketing KnomeComplete as a DTC service, and said that physician involvement was necessary. At the time of this article's publication, there was no mention of KnomeComplete on the company's site as an available service.
Conde emphasized to PGx Reporter, however, that the majority of its sequencing services are provided to researchers and a "relatively small part" of Knome's business is marketed to consumers who can afford the hefty price tag. "We’ve tried to be very clear in pointing out that none of the information [gleaned through our service], whether it’s risk assessment or PGx related, is intended to be clinical," Conde said. "So if there is a need for differentiation in terms of our responsibilities, as we receive guidance from the regulatory authorities, that is something that we will have to work into the system."
In Conde's view, clinical validation requirements for tests that will impact the diagnosis of disease should meet a much higher regulatory threshold than genomic tests that are not meant for medical decision-making. The latter category is where KnomeComplete falls, according to Conde.
No company wants to be blindsided by FDA regulation. After the flurry of regulatory activity this summer over the DTC marketing of genomic tests, diagnostic companies and platform providers seem to be planning ahead in terms of regulation.
For instance, Illumina has recently said that it is thinking about filing for 510(k) clearance for its HiSeq 2000 sequencing platform. As reported by PGx Reporter sister publication In Sequence, the company has seen a strong demand for HiSeq since its launch earlier this year, and as such the company is mulling whether to file for FDA clearance (IS 09/21/10). Life Technologies has also said that it plans to obtain 510(k) clearance for its SOLiD 4 hq sequencer, an update to its current platform that is scheduled for launch later this year.
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These firms have not provided additional details about their plans for obtaining FDA clearance, or which tests they intend to eventually submit for approval on their platforms.
Another company that is giving some thought the regulatory requirements it will have to meet for sequencing-based diagnostics is Genomic Health.
Although the commercial availability of its Universal Cancer Assay is years away, Genomic Health Executive Chairman Randy Scott envisions that the analytical validation for such a platform will need to be proven "once and for all" even though it is operating multiple tests. When it comes to clinical validation, Genomic Health will need to show for each test that the genomic data correlates with a disease-specific outcome and response to different drugs.
"Getting regulatory approval ... will require work and really good clinical validation programs," Scott said. "The key issue is really going to be the type of evidentiary standards that are required by the FDA for approval of a process."
Since the development of the Universal Cancer Assay is in its infancy, the company is currently investigating all the available sequencing technologies. "The field is moving very rapidly, so in the future I suspect there will be multiple DNA sequencing platforms that will be validated and FDA-approved for this kind of work," Scott said.
Genomic Health's RT-PCR-based Oncotype Dx tests for breast and colon cancer recurrence are currently marketed as LDTs and not regulated by the FDA. However, the company has said it supports risk-based FDA oversight of LDTs and has been involved in discussions with the agency regarding its Oncotype DX platform.
Myriad Genetics, another company that has benefited from the FDA's policy of "enforcement discretion" and has been marketing its BRACAnalysis test as an LDT, recently told investors that it has been considering the type of regulations it will have to meet under the FDA's new requirements, whatever they may be.
BRACAnalysis is a Sanger sequencing-based test offered through Myriad's CLIA-certified lab in Salt Lake City, Utah. Although BRACAnalysis is used by doctors to make serious medical decision about women's likelihood of getting breast and ovarian cancer, Myriad has so far avoided the gavel of FDA regulation because there is a vast body of clinical evidence validating the link between BRCA 1 and BRCA 2 mutations and the risk of hereditary breast and ovarian cancer.
And while Myriad aggressively markets BRACAnalysis through DTC advertising, the test is available to women only after a doctor has evaluated them medically and learned their family history. It's a fine point that has likely kept Myriad from having to meet FDA regulation for BRACAnalysis over the years.
Now, even with the specter of regulation hanging over its head, Myriad President Mark Capone told investors recently that the company's tests will not be materially impacted by changes in LDT regulation (PGx Reporter 09/22/10). "Myriad's view is that many of our tests will probably be grandfathered by the time this regulation is completed," Capone said, adding, "We think we're in a good position to flourish in a regulated LDT environment."
Playing With Ideas
Since the FDA's public meeting on LDT regulation in July, agency officials have said that they are considering all ideas in crafting LDT regulation — from downgrading in risk classification certain regulated tests as a way to manage its limited resources, to phasing in regulation of LDTs that aren't currently regulated, among other ideas.
One idea that makes practical sense, particularly when considered in the context of regulating sequencing technologies, is the involvement of an independent standard-setting body or third-party inspectors to help the agency with its increasing regulatory burden.
Draft legislation under development by Senator Orrin Hatch (R-UT) includes provisions for the establishment of new FDA division responsible for overseeing "advanced personalized diagnostics," a category in which sequencing-based diagnostics for medical decision-making would no doubt fall.
The idea of a separate FDA division has support among industry players. Mara Aspinall, CEO of personalized cancer diagnostics firm On-Q-ity and former president of Genzyme Genetics, has long been a proponent of creating a separate diagnostics division at the FDA. Aspinall advised Hatch's legislative team in crafting the draft bill.
Genomic Health has been involved with the Coalition for 21st Century Medicine to promote a "smart approach" to regulation of laboratory-developed tests, including sequencing-based tests, at the FDA. The development of a new division at FDA is among several regulatory approaches the company supports, "especially for information products that are going to come out of genomics," according Genomic Health's Scott.
In terms of an independent standards-setting body to help the FDA regulate the influx of LDTs that will fall under its oversight, United States Diagnostics Standards was mentioned at the LDT meeting as a possible option. USDS was founded by Jeffrey Cossman, who previously served as chief scientific officer of the C-Path Institute.
Cossman told PGx Reporter that there is currently "no clear answer" as to how the FDA might regulate genomic tests based on sequencing technologies. But, he added, the agency can't remain silent on this topic for too long.
"As new versions of sequencing technologies are coming out and the cost is getting in the range where clinical labs can use them more, the applications are going to be broad and there is going to be a boom in this [field]," Cossman said. "It’s going to be difficult to be able to compare one [sequencing platform] to the other, and it’s going to require standardization of that process, having a gold standard of some kind, where you can determine what a predicate device is and how to compare a new device to it."
Cossman believes that USDS is well-positioned to assist companies in their discussions with regulators regarding sequencing-based diagnostic tests. As a neutral third party, USDS could provide the FDA with an independent panel of experts who in turn could inform the agency about the performance, reliability, and clinical application of new sequencing technologies in the care of patients.
"Through this process, the FDA has access to a sound medical and scientific basis to judge the relative risk of the molecular diagnostic test and whether it stands alone or is used together with other information in determining management decisions," Cossman explained. He noted that USDS is in discussion with multiple diagnostics firms seeking regulatory input on their tests, but could not provide details as these talks were confidential.
Another idea that has legs in certain personalized medicine circles is modeling regulations for sequencing-based tests after the agency's oversight of technologies like X-rays and MRIs. In this model, the agency wouldn't be responsible for overseeing the interpretation of genomic data in medical care.
"The X-ray doesn’t itself give you the diagnosis; it’s done by whoever is interpreting the result," Cossman explained. "For sequencing technologies, they can be thought in an analogous way as a scan of the genome. If used by someone skilled in the art of interpreting that, like a molecular biologist or a geneticist, that scan can be used to come to some medical decision.
"So, maybe they have a pathway already in place [that] they’re using for other kinds of devices that are analogous," Cossman posited.
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Genomic Health's Scott agreed that the regulatory paradigm for technologies like X-rays and MRIs may serve as a model for creating an oversight framework for genomic tests. With MRIs you have "a technology that is capable of imaging and providing data, but you still need a physician to be able to interpret that in the context of the rest of the medical information," Scott said. "But you want the physician to be able to get as much information about the underlying nature and cause of the disease as possible."
Ultimately, it should ultimately be up to doctors to decide how to treat their patients based on genomic information, Scott believes. "We should get this information to the hands of physicians rapidly and in a way that doesn’t stifle innovation," he said.
Meantime, for supporters of DTC genomics, FDA regulation of genomic tests is viewed as a federal restriction on people's right to access their own DNA.
Google-backed DTC firm 23andMe is one of the staunchest proponents of giving consumers unfettered access to their genomic data. At a congressional hearing on DTC genomics, 23andMe was the only firm to not back down from the DTC model when asked by legislators whether the company would stop marketing its services directly to consumers (PGx Reporter 07/28/10). 23andMe has a partnership with Illumina, through which the company can provide drug response and disease predisposition data for customers who have gotten their whole genomes sequenced.
Duke's Cook-Deegan believes that since a significant portion of the information coming out of sequencing-based tests won't be medical, FDA regulation of such technologies could clash with those who believe that the government should not restrict access to their own genomic data.
"If we force an FDA-style regulatory framework, which is inherently heavily focused on medical thinking, sequence data will have to be filtered through health professionals who are not particularly well trained to interpret it, and more importantly in an economic sense their labor for helping interpret tests is likely to cost more than the sequencing itself," he said.
One scenario that stakeholders have suggested is a compromise that would allow consumers direct access to some kinds of genomic data, in the form of over-the-counter genomic tests that have minimal regulatory oversight, while other genomic data would only be available with the guidance of their doctor.
Arguing against the notion that physician involvement in mediating consumers' access to genomic tests is "professional medical hegemony," Stuart Hogarth of King's College London advocated just such a paradigm for regulation genetic test in an article published in Public Health Genomics in June.
"Regulatory policy governing pharmaceuticals has not moved into a post-paternalist era. There continues to be a mixed economy of provision, with some drugs available DTC in pharmacies but many others only available via a doctor’s prescription," Hogarth observed.
"There seems to be no public desire for this mixed model to change. Fittingly, the most convincing refutation of the post-paternalist argument comes from the public itself," he wrote, adding that when it comes to access to genomic tests, the majority of people will likely favor a similar model where some data is available DTC, some with a doctor's prescription.
Mary-Claire King, a genetics pioneer who discovered the link between BRCA1 mutations and the hereditary risk for breast and ovarian cancers and who runs a sequencing laboratory at the University of Washington, believes that the FDA is rightly getting involved in regulating genomic tests.
According to King, the division between DTC and physician-guided tests is something that the FDA needs to delineate "at a minimum."
"As each new technology for detecting genetic variants comes along, it needs to be vetted again from scratch and sequencing technology is like every other technology in that way; it’s just enormously more powerful" than previous technologies, King said. "With that power comes such a large amount of data that there is real danger of mischief and [the possibility that] what is returned to participants or consumers [is] simply not correct."
Like others in the field, King foresees a regulatory challenge for the FDA in establishing the clinical validity of sequencing-based diagnostics. The concern is not so much that "the base pair has been misidentified, it’s that the base pair doesn’t mean what the consumer is told it means by the advertisements of the companies returning it," she observed.
Ultimately, however, it will fall on the FDA to ensure the safety and efficacy of these immensely powerful and endlessly complex tests, she believes.
"The FDA is wisely querying different groups of experts … but I do think the FDA is the right home" for regulating sequencing technologies, King said. "These things do need to be regulated in the same way the FDA regulates over-the-counter medicines; they need to regulate claims for over-the-counter genetic tests, to make sure that they don’t say more or different than what is true."
As the director of an academic clinical laboratory applying sequencing approaches to conduct medical research, King's attitude toward regulation is significantly more relaxed than that of a commercial clinical lab director or diagnostic developer.
"If the FDA takes a larger role, then what is a CLIA process for me now could be a CLIA and FDA process. [The FDA] would have to tell us what we have to do, once [that regulation] comes in place, but we’d go through it," she said. "Even public-sector labs are accustomed now to passing through regulatory pipelines for various kinds of processes that we undertake. So, it wouldn’t be qualitatively different than what we do, [even though] we do not have an FDA process in place now."
Ultimately, she noted, FDA regulation "doesn’t disturb me."