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Five BCW Index Shops Join Alliance to Curb FDA Plan to Regulate Certain Molecular Dxs

This story originally appeared in Biocommerce Week, a newsletter that has been discontinued.
More than one-fifth of the companies listed on the BioCommerce Week Index have joined an international coalition that aims to curb plans by the US Food and Drug Administration to regulate certain homebrew diagnostics ordinarily monitored by Clinical Laboratory Improvement Amendments.
Bio-Rad, Thermo Fisher Scientific, Luminex, Millipore, and Sequenom are part of the Coalition for 21st Century Medicine, a 26-member alliance that believes the FDA’s goal of regulating so-called in vitro diagnostic multivariate index assays may hobble diagnostic research by making the process too costly and arduous.
The group said its “mission is to improve the quality of healthcare by encouraging the research, development and commercialization of innovative new diagnostic technologies … [and] ensuring that high quality, innovative diagnostic tests are available to patients and physicians in a transparent and timely fashion.”
The implication is that the FDA’s desire to regulate IVDMIAs could stifle these goals. The FDA’s stance, outlined in a draft guidance issued last fall, could also affect how — and at what cost — certain molecular diagnostics reach the market.
The FDA’s involvement in this area occurs at a time when a number of companies in the BCW Index have indicated that they plan to enter the molecular diagnostics market, which they see as a significant revenue engine [see BioCommerce Week 1/17/2007].
Numbers Game
According to the FDA, IVDMIAs use mathematical formulas to interpret gene and protein data to guide medical decision-making. The agency views these products as “test systems” that use clinical data to empirically identify variables in an algorithm; employ the algorithm to integrate these variables to calculate a patient-specific score, which cannot be independently confirmed without access to the proprietary information; and report the test result, which cannot be interpreted by the well-trained health care practitioner without information from the test developer regarding its clinical performance and effectiveness.
According to the agency, such tests, ordinarily overseen by CLIA regulations, must instead be cleared by the agency due to their complexity [see 9/13/2006 issue of BioCommerce Week sister publication PGx Reporter].
The agency has already approved one such diagnostic, a test called MammaPrint, made by Dutch diagnostic company Agendia, which helps physicians determine the risk of breast cancer recurrence. Agendia has said it approves of the FDA’s IVDMIA guidance.
Another company, Albuquerque, NM-based Exagen, also supports the draft guidance and said it plans to file its first test, for breast cancer recurrence, with the FDA within the next two months.
Over the past year the FDA has told some test developers, including Genomic Health, Correlogic, LabCorp, Agendia, and InterGenetics, that CLIA certification may not be enough to bring certain of their products to market. The agency said these firms may need to file for FDA clearance — which could extend the time and cost it takes to bring a test to market.
It wasn’t immediately clear which BCW Index companies have potential IVDMIAs in their pipelines, but the FDA’s definition could potentially paint many tests with this brush.
At least two BCW Index companies have products or other assets that could fit this bill: Waters’ MarkerLynx db application manager for MassLynx 4.1 software, which is designed for multivariate statistical analysis and database searching in metabolomic biomarker research, and a small suite of tests that Qiagen plans to sell.
Qiagen has spent the past two years building its portfolio of molecular diagnostics assays through internal efforts and acquisitions, and last fall acquired multiplex-assay maker Genaco for up to $40 million (see BioCommerce Week 11/1/2006).
A Qiagen spokesperson this week told BioCommerce Week that the companyplans to submit two of Genaco's multiplex assays — one for avian flu and one for bacterial infections — for FDA (510k) clearance as IVDMIAs this year. Qiagen next year plans to submit three additional IVDMIAs — two for respiratory infections and one for nosocomial infections — in the same manner, the spokesperson added.
A spokesperson for Waters said the MarkerLynx product, which debuted in 2005, is sold exclusively to pharma companies, which use it in pre-clinical research [BioCommerce Week 6/9/2005]. It therefore would be exempt from the regulatory framework outlined in the IVDMIA guidance.
‘Consider the Alternatives’
The coalition made its debut on the same day the FDA held a public forum on the draft guidance, entitled “Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays.”
The coalition, which participated in the meeting, said it is concerned that if the IVDMIA guidance is implemented as drafted, vital medical tests may become unavailable, innovation and improvements could be impeded, the cost of research and development could rise, and insurance coverage for laboratory tests could erode or disappear.
Presenting on behalf of the coalition, Tom Tsakeris, president of Devices and Diagnostics Consulting Group and former director of the FDA’s Division of Clinical Laboratory Devices, said that “laboratory-developed tests, including tests and services that would be considered IVDMIAs under the draft guidance, are an essential part of public health and are the future of personalized medicine. To preserve this future, FDA should go through formal rulemaking procedures and carefully consider the alternatives.
“We believe a formal FDA notice and comment rulemaking process is the best way to ensure complete, on-the-record input from all affected parties,” he added. “We urge FDA to pursue a process in which doctors, patients, and innovators can add their experience and voice to this important proceeding.”
During the forum, most of the 30-some presenters claimed that the draft guidance, as it currently stands, is untenable, even potentially illegal. The document raises “concerns over FDA’s legal authority to regulate clinical laboratories,” is unclear over the definition of in vitro diagnostic multivariate index assays, and does not clearly identify the elements of an IVDMIA that comprise a medical device subject to FDA regulation versus those regulated under CLIA, Paul Radensky, a health law attorney with McDermott, Will, & Emery, said during the meeting.
Legal Authority
Several presenters suggested that the FDA has no legal authority to regulate IVDMIAs, a notion FDA officials tried to dispel.
“There is a lot of confusion about the regulation of diagnostic tests that are developed by, and used in, a single laboratory,” Courtney Harper, associate director of OIVD’s Division of Chemistry and Toxicology Devices, acknowledged at the start of the meeting.
She said the agency believes this confusion “derives in part” from the way it regulates lab-developed tests that use commercially available analyte specific reagents and other commercially available, FDA-regulated components.
In the preamble to its final ASR rule, the FDA said that “clinical laboratories that develop [in-house] tests are acting as manufacturers of medical devices and are subject to FDA jurisdiction under the act.” However, the agency has historically held off regulating lab-developed ASRs and tests developed in single labs.

“IVDMIAs, a growing category of tests, include elements that are not standard primary ingredients of in-house tests that raise safety and effectiveness concerns.”

But in its draft guidance, the agency decided that it, and not CLIA, should regulate IVDMIAs since they “do not fall within the scope of laboratory-developed tests over which FDA has generally exercised enforcement discretion.”
“IVDMIAs, a growing category of tests, include elements that are not standard primary ingredients of in-house tests that raise safety and effectiveness concerns,” Harper said.
However, Richard Samp, chief counsel of the Washington Legal Foundation, countered that the Medical Device Amendments of 1976, under which the FDA claims its authority, “do not have anything at all to say about laboratories or lab testing.” Rather, it grants regulatory authority to CMS under CLIA.
Samp was referring to the 1976 Medical Device Amendments to the Food, Drug & Cosmetic Act, which created three classes of devices defined by the level of regulatory control issued, with Class III devices being the most regulated.
According to the draft guidance, IVDMIAs will likely be Class II devices, requiring premarket notification in the form of a 510(k) submission, or fall in the Class III category, requiring premarket approval. 
Samp argued during the meeting that Congress never intended to grant the FDA the authority to regulate IVDMIAs under the 1976 amendments. “It was not until the 1990s that FDA first began to suggest that it might possess regulatory authority over labs offering [laboratory-derived tests], and it is only in the past year that FDA has sought to exercise its alleged authority,” Samp said.
“In the absence of authority from Congress, FDA’s recent attempts to regulate lab tests are improper and should cease,” he said.
FDA Won’t ‘Simply Go Back’
The agency conceded that it can better clarify the scope and intent of the guidance. Steven Gutman, director of the Office of In Vitro Diagnostic Device Evaluation, maintained that it is not the agency’s intent to “surprise or confuse people” or issue regulations that would delay the entry of innovative products to the market.
Other FDA officials acknowledged that while the guidance needs to be refined, the agency would likely move forward with its plans to regulate IVDMIAs in some form.  
Daniel Schultz, director of FDA’s Center for Device and Radiological Health,
held that “the idea that we can simply go back to the way we were several months ago – that to me is the one notion that would be unacceptable.
“The field is moving very quickly, the technology is moving very quickly, expectations in this room and throughout the country are moving very quickly in terms of us being able to get a handle on this type of technology,” he said. “I think we need to keep moving forward based on today’s discussion.”
At the end of the meeting, Gutman pointed out that the agency has been clear in expressing its discomfort over the lack of federal oversight of IVDMIAs. He noted that the FDA “always expected that the document was not perfect and I guess you have suggested the same.
“As we were interacting with people in the early life of the document, I thought that people were either over-reading or misreading the document,” Gutman said in his closing comments. “So, I was blaming you, not us, but I will take part of the blame perhaps for not having crafted language that clearly. …
“We didn’t think that this was going to be easy,” he added. “And you reinforced that.” 
Gutman urged presenters to offer constructive comments on the draft guidance by March 5. The deadline for the public to comment on the document was extended from a Jan. 5 deadline after the agency sensed growing interest in the issue.
Turna Ray contributed to this report.
A version of this article appeared in the Feb. 14 issue of Pharmacogenomics Reporter, a BioCommerce Week sister publication.

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