By Turna Ray
The US Food and Drug Administration's decision last month to explore risk-based strategies to regulate all laboratory-developed tests didn't come as a surprise to most players in the molecular diagnostic industry.
At a public meeting slated for July 19-20, FDA will seek input on issues it should consider when regulating LDTs; potential challenges faced by clinical labs in meeting FDA's increased oversight of these tests; risks and benefits associated with directly marketing genetic risk data to consumers; and education that clinical labs need in order to meet the agency's requirements.
Given FDA's lack of clarity over the past several years regarding its oversight of LDTs — most significantly regarding the subclass of such tests called in vitro diagnostic multivariate index assays — there is significant interest in the meeting, which has already been moved to a larger venue to accommodate the number of people expected to attend.
Ahead of the meeting, Pharmacogenomics Reporter took stock of industry expectations and found that most test developers are looking forward to greater clarity from the agency and are prepared to make adjustments for FDA regulation in whatever form it comes.
Certain diagnostic firms — particularly IVDMIA developers that have already cleared products through FDA — seem at ease with the agency's intent to regulate LDTs, though it is still uncertain what requirements the FDA would impose for IVDMIAs that it hasn't yet cleared, such as Genomic Health's Oncotype DX test.
Another area of uncertainty is direct-to-consumer genomic testing. While FDA's recent letters to several DTC genomics firms suggest that the agency does not consider the majority of these tests to be LDTs, FDA has provided no indication of the types of requirements these companies will have to meet.
Among industry players, confusion with regard to FDA's approach to LDTs has been building since the agency in 2006 announced plans to regulate IVDMIAs (PGx Reporter 08/01/07).
After issuing two draft guidances on IVDMIA regulations that left test developers less than satisfied, the agency came under pressure from large diagnostic players and biotech firms "to level the playing field." Led by a Citizen Petition from Genentech, many diagnostic developers urged FDA to take a risk-based approach to ensure that it extends its oversight over all predictive LDTs (PGx Reporter 12/17/08).
The FDA has always maintained that it holds regulatory authority over all LDTs, but has chosen not to exercise this authority since the implementation of the Medical Device Amendments of 1976. As a result of FDA's practice of enforcement discretion over the majority of LDTs, these assays have been able to come to market without having to go through the agency, as long as the laboratories where tests were analyzed were accredited under the Centers for Medicare and Medicaid Services' Clinical Laboratory Improvement Amendment. Meanwhile, the FDA has focused its regulatory muscle on diagnostic kits, analyte-specific reagents used in LDTs, and IVDMIAs.
Now, after four years of regulating some but not all IVDMIAs currently in the market, the FDA has signaled that it aims to regulate all LDTs in a risk-based manner.
FDA Clearance Gives Security
Although in many ways FDA is starting from scratch in crafting its regulatory approach toward LDTs, many firms that have garnered premarket approval or 510(k) clearance for their tests appear secure with any forthcoming regulations, even though what those regs will be is unknown.
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"Based on previous FDA public statements, we were not surprised by this announcement," Deborah Neff, CEO of Pathwork Diagnostics, told Pharmacogenomics Reporter. "Our strategy has always been to develop our tests at an 'FDA submission level' for our validations. So, as a company that has developed and received two FDA clearances for our products, we are certainly comfortable to have FDA focus on this issue."
In 2008, Pathwork received 510(k) clearance for its Tissue of Origin test, deemed to be an IVDMIA by FDA's draft guidelines (PGx Reporter 08/06/08). According to Neff, having gone through the FDA regulatory process already for several of its tests, the company feels prepared for any additional commitments that it may have to fulfill under new regulations. "In fact, we anticipated this development and this was one of the reasons why we made getting FDA clearance a key business priority," she added.
Agendia has also backed FDA's expressed intent to regulate all LDTs, since that's what the company has been pushing for all along. The company has long been a supporter of Genentech's Citizen Petition, since it has direct experience with the uneven playing field created by FDA's selective regulation of LDTs.
In 2007, the company was the first firm to gain 510(k) clearance for an IVDMIA with its MammaPrint test for breast cancer recurrence. Since then, the company has garnered another clearance for MammaPrint allowing the test to be marketed in women older than 61 years. Asuragen's RNA Retain, a stabilizing solution that allows tumor samples to be shipped for analysis, and Agilent's High Density Microarrray Chip, the platform upon which MammaPrint Operates also have FDA clearance (PGx Reporter 12/23/09).
Although MammaPrint has gone through the FDA regulatory process, its competitor Genomic Health still markets its Oncotype DX test as an LDT through its CLIA-certified laboratory. As such, Agendia welcomed FDA's announcement that it would extend oversight over all LDTs.
"The FDA has fine-tuned its position," Hans Herklots, head of corporate communications at Agendia, told Pharmacogenomics Reporter. In his opinion, the company stands in a better position after receiving FDA's go-ahead for MammaPrint, even though the agency has decided to hold off on finalizing the IVDMIA guidance until it addresses LDT regulations broadly.
"To think that the FDA's IVDMIA guidelines will disappear is too easy," Herklots said. "We think that the risk-based approach is the right approach … because that's putting the patient first. It's no longer just a matter of complexity of the test."
In Herklots' opinion, wherever FDA's regulatory stance on LDTs ends up, it is likely to be something all industry stakeholders can live with, much more so than before. "I think the agency is interested in putting something in place that is workable for industry at large and also the academic laboratories," he said.
"It's a new process, so we'll all start all over again," Herklots added. "But in the meantime the FDA's clearance for MammaPrint stands and whatever it means for other LDT manufacturers I have no idea. It's too early to anticipate that."
Leveling the Playing Field
Genomic Health is often upheld by industry observers as one of the most successful beneficiaries of FDA's inconsistent LDT regulation. The company's continued marketing of Oncotype DX without FDA clearance, but as an LDT provided through its CLIA-certified lab, has often been a sore point for other IVDMIA developers that have taken pains to garner FDA clearance.
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The agency and Genomic Health have been discussing the regulatory status of Oncotype DX since the agency first began mulling its IVDMIA guidance in 2006. At that time, FDA sent a letter inviting the company to talk to the agency about the test, but it has never officially asked Genomic Health to submit Oncotype DX for approval or clearance. Yet, Genomic Health officials in the past have said the 21-gene breast cancer recurrence test would likely fall under the agency's definition of an IVDMIA (PGx Reporter 02/01/06).
However, the clinical and analytical features of Oncotype DX for both breast and colon cancer recurrence have been validated in numerous studies published in peer-reviewed journals. Even if the tests don't have FDA's stamp of approval, the rigor of Oncotype DX's validation has appeased insurers, the majority of which reimburse for the breast cancer test. The company is in the process of establishing relationships with payors for its recently launched colon cancer test.
It is worth noting that Genomic Health's success in garnering broad reimbursement for its tests comes during a time when the payor community has been openly resistant to paying for the majority of personalized medicine tests and has stringent criteria for proving the clinical validity and clinical utility of such tests.
A Genomic Health spokesperson told Pharmacogenomics Reporter this week that the company "continues to prepare for anticipated regulatory changes and any new requirements that may apply to our tests." The company issued a statement when FDA first announced its intent to regulate all LDTs expressing support of the agency's actions.
The spokesperson added that the company plans to attend FDA's meeting in two weeks. "Beyond the meeting, we look forward to providing information that contributes to the development of a regulatory framework that meets the needs of patients and supports innovation," the spokesperson added.
In the Federal Register announcement for the public meeting on LDTs, the FDA states that it will consider "approaches of risk stratification for LDTs;" the circumstances under which a doctor might choose testing a patient via an LDT over an FDA-cleared test; and whether clinical and analytical validation requirements should differ between FDA regulated and non-regulated tests. Additionally, among numerous other topics, the agency will hear from attendees on how increased oversight might impact test development for rare conditions, reimbursement, and costs to consumers.
Although the agency has revealed little with regard to specific regulatory strategies it is considering, FDA officials support the idea of a diagnostics database that would register all tests and allow the agency to review evidence for them and track marketing claims made by companies.
A voluntary registry is being developed at the National Institutes of Health, but a mandatory registry for a new subset of tests, called "Advanced Personalized Diagnostics," housed at the FDA has also been proposed in a draft bill circulating Capitol Hill (PGx Reporter 06/23/10).
Genomic Health said that it supports the "registry concept" as a risk-based regulatory strategy for all diagnostics.
DTC Genomics' Risk/Benefits
While the regulation of DTC genomic testing firms may not be directly addressed at FDA's meeting, the agency plans to seek input on the risks, benefits, and costs of DTC testing; concerns that DTC testing could cause consumer fraud; and the risks and benefits of patients taking medical action based on preliminary diagnostic test claims.
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Concerns surrounding DTC genetic testing were escalated last month when Pathway Genomics announced plans to market the saliva-collection kits for its genetic testing service at Walgreens and CVS stores. The action spurred FDA and Congress to issue letters to several players in the DTC genomics industry (PGx Reporter 06/16/10).
The players in the DTC genomics industry have extended their willingness to work with government regulators and many of these firms have long advocated for overarching federal guidelines as opposed to a web of varying state regulations.
However, FDA's recent letters to DTC firms suggest that the agency doesn't consider most of these gene scans to be LDTs. As such, DTC genomics firms' services will likely be regulated as medical devices requiring premarket approval or 510(k) clearance. If this is the case, most of these DTC firms will be entering a regulatory environment they are not used to playing in.
In particular, DTC firms haven't developed their products in line with the design controls required by the FDA for medical devices, pointed out one industry observer. "Many of these products were not created under what's called the design controls, one of the elements of the quality systems," which FDA-regulated medical devices have to include, Jim Prutow, a director at the management consulting firm PRTM, told Pharmacogenomics Reporter. DTC firms facing FDA regulation "are going to have to go back and recreate the development process and [develop] a design history file" for their testing services, he said.
Right before FDA sent its letters out to DTC firms, 23andMe informed customers that its contracted lab, the Laboratory Corporation of America, incorrectly processed samples, resulting in as many as 96 customers receiving reports that were not their own. The batch of mismatched records loaded on June 1 was due to "human error" and the "incorrect placement of a single 96-well plate used in processing samples," 23andMe explained (PGx Reporter 06/09/10).
After the mishap, 23andMe said it adjusted the mounting process for these 96-well plates in a way that "physically prevents any incorrect manual placement of the plates used [in] processing" samples. Additionally, the company said it is considering implementing various safeguards to ensure this type of error does not happen again, including removing manual steps at the lab, completely automating the sample analyses, and implementing further data checks before uploading it to customer accounts.
LabCorp's mixup of 23andMe customers' samples might signal that the very quality systems that FDA would require for a medical device are not yet in place at these firms.
"A quality system has rigors in place" to ensure the traceability of steps in the workflow and to maintain a system of checks and balances throughout the process, Prutow said. "I can't say for sure that a quality system would definitely have prevented this mix-up, but at least all the work that we do with medical device and diagnostics companies would indicate that these are the types of things that your quality system is meant to prevent."
Prutow, who has consulted with DTC genomics firms, added that the research culture prevalent at most DTC firms suggests that they will need time to get used to operating by FDA's guidebook. "It's difficult when you have a research culture that is prevalent in these DTC companies," Prutow said. "Moving into an FDA-regulated market, you're going to have to follow a rulebook and it can be difficult to change that culture."
23andMe declined to comment for this article, but the company has certainly recognized that the nascent DTC genomics industry is inexperienced when it comes to navigating regulatory waters and has requested help from those in the know.
In a June 24 letter to FDA Commissioner Margaret Hamburg and NIH Director Francis Collins — two leaders who have promised to join their agencies in advancing personalized medicine — 23andMe asked for guidance on aligning industry standards in order to reduce divergence in reporting genetic risk scores.
Specifically, 23andMe asked NIH and FDA to establish an expert group to issue acceptable analytical validity of tests; standards for positive and negative predictive values of tests; and best practices for transparency in reporting predictive values so they can be compared across companies.
In 2009, 23andMe, Decode, and Navigenics, voluntarily published a consensus document outlining technical standards that they planned to uphold in their tests, such as the accuracy of the DNA chips they use, their methodology for characterizing individual risk, and criteria for determining which SNPs to include in their analysis. However, at the time, experts held that more work needed to be done in this regard, particularly with regard to clinical validation.