Back from Break: FDA Issues Letter to Pathway Genomics for Cancer Screening LDT; Proposed Legislative Alternatives to FDA Framework Continue to Emerge

September 29, 2015

By Jamie K. Wolszon & Jeffrey N. Gibbs

As kids around the country return to school, FDA also appears to be returning from a break—in this case a break from public enforcement-type activities related to laboratory-developed tests (LDTs)—with the issuance of a letter to Pathway Genomics.  FDA has a litany of concerns, including that the test appears to be marketed without requisite FDA approval, clearance, listing or adequate clinical validation and the test may hurt the public health.  Meanwhile, Congress is back in action—or what passes for action these days—and there is yet another proposed legislative alternative to the FDA Framework—this time from laboratory accrediting body the College of American Pathologists (CAP).  And while we are on the topic of LDTs, we also think it is worth noting that a significant number of comments submitted to the Framework draft guidance docket still have yet to be made available, and some critics have voiced suspicions that comments favorable to the proposal are more likely to be posted in a timely fashion, and unfavorable comments to remain unpublished.

FDA Letter to Pathway Genomics

As we have previously reported (here, here, and here), in October 2014, FDA issued its controversial two draft guidances that outlined its proposal to actively regulate LDTs.  Since that time, we are unaware of any public action by FDA against an LDT—until now.

On September 21, 2015, FDA sent a letter to Pathway Genomics stating that the CancerIntercept Detect, a non-invasive blood test intended for use as a screening tool for the early detection of up to 10 different cancer types in high-risk populations, appears to be an unapproved device that does not have a PMA, 510(k) or requisite listing.  Although it is not a Warning Letter, FDA posted the letter on its website, indicating that it believes it is important to communicate.  FDA stated that the Company was marketing the test under a “direct-to consumer type model.”  FDA continued: “Under this model, you ship blood collection tubes, a medical device, for use with CancerIntercept Detect.”  The use of the collection system provides the articulated jurisdictional hook for the agency.

The letter also states that the test lacks adequate clinical support for the claims it is making.  “We have also examined published literature and have not found any published evidence that this test or any similar test has been clinically validated as a screening tool for early detection of cancer in high-risk individuals. We have reviewed the information presented on your website in the white paper, entitled ‘Liquid Biopsy for the Detection and Monitoring of Cancer: Analysis of 96 Hotspot Mutations via Plasma Derived Circulating Tumor DNA,’ dated September 2015. It is unclear how the literature that you cited, addressing the presence of circulating tumor DNA (ctDNA) in already-diagnosed patients, is adequate to support the expansive claims of screening for early cancer detection using ctDNA in undiagnosed patients for up to 10 different cancers with the CancerIntercept Detect,” the letter states. 

FDA calls on the Company to discuss with the Agency “your offer of the CancerIntercept Detect and the associated blood specimen collection device, and any validation strategies you have undertaken beyond those reported in the publications cited in your white paper, including your determination of the test’s clinical sensitivity and specificity and the corresponding positive and negative predictive values for its claimed intended use.”  The letter requests a proposed timeline from the Company within 15 days. 

The letter states that the Agency “is committed to working with you as we strive to protect the public health without unnecessarily imposing regulatory burdens on the marketing of products of potential clinical importance.”  We do not recall seeing similar language in similar letters by FDA.  The inclusion of this language suggests that the Agency is sensitive to the current climate as the draft guidances are pending.

Pathway Genomics released a response on September 24, 2015, stating that it would respond to the FDA letter.  The Company did not take a conciliatory tack, contesting the assertion that it was offering a DTC model.   “We assure that there is physician involvement in the ordering, review and follow-up of CancerIntercept testing.  We believe that CancerIntercept Detect is a laboratory-developed test and, as a CLIA and CAP certified clinical laboratory, we are offering it as such.  While Pathway Genomics is involved in educating and marketing the tests to physicians and consumers, we do not believe this is a direct-to-consumer model.”  The Company also took issue with the statement that there was not adequate clinical support: “We believe we have performed appropriate validation of the test as a laboratory-developed test, and we are in the process of performing additional studies.”

This is not the first time that Pathway Genomics has been the subject of FDA scrutiny:  In May 2010, FDA sent a letter to Pathway Genomics objecting to its home-use saliva collection kit to analyze for predisposition for over 70 genetic conditions.

CAP Adds to Legislative Proposals that Would Serve as Substitute for Framework

The FDA letter comes on the heels of CAP unveiling what is now the third publicly proposed legislative alternative to FDA’s Framework.  As we previously reported, the Association of Molecular Pathology (AMP) announced in a press release that it has met with the Senate Health, Education, Labor and Pensions Committee to propose a legislative solution to modernize the Clinical Laboratory Improvement Amendments (CLIA), including premarket review by the Centers for Medicare & Medicaid (CMS) or its designated third parties, as a substitute to the FDA Framework.  We also previously reported that a group of labs and in vitro diagnostic kit companies called the Diagnostic Test Working Group have tried to craft their own legislative solution. 

The CAP proposal would amend the Federal Food, Drug, and Cosmetic Act to subject high-risk LDTs to existing FDA pre-market and post-market requirements.  The proposal also would modify CLIA to subject low and moderate-risk tests to CMS regulation; under the proposal, CMS or a third party would review moderate-risk tests.  Low-risk tests would not undergo premarket review.  In several respects, the CAP legislative proposal is similar to the AMP proposal.  For instance, both similarly define high-risk, moderate-risk and low-risk tests.  Both exempt low-risk tests from premarket review, would give CMS or third-party reviewers sole authority to review moderate-risk tests, and FDA would only get involved for high-risk tests (all high-risk tests under the CAP proposal and a subset of high-risk tests under the AMP proposal).  Both would exempt tests for rare disorders from premarket review.  However, the CAP proposal, unlike the AMP proposal, incorporates certain elements of the FDA Framework (with modifications), such as exceptions from premarket review for tests for unmet needs and “traditional LDTs,” and a separate requirement for notification to the Secretary (presumably through CMS but it is unclear) of tests.

The flurry of legislative proposals is enough to make even the most dedicated LDT-watchers lose track.  In an effort to provide some clarity about the competing proposals, we provide a chart comparing some of the key provisions of the AMP and CAP proposals, as described in publicly available documents.  We do not include the DTWG proposal in this chart as it has been reported that members of the group are working with the House Energy & Commerce Committee on a revised version; we fear that the DTWG proposal will change as soon as this blog is posted.  Of course, if any legislation is enacted, it is likely to look different from what is proposed.

Large Number of Comments to Framework Still have Yet to be Posted

We previously reported that, according to, FDA has received 236 comments on the draft “Framework” guidance; however, it has only posted 170 of those comments.  As of this writing, that number has not changed.  But some critics are suspicious that FDA is more likely to post a comment if the comment is favorable to the proposal than if the comment is negative.  One member of the laboratory community, which submitted comments that criticized the proposal well within the deadline for comments, said that FDA did not initially post their comments.  When they called to inquire, they were informed that it had been flagged for an inappropriate reason, and the comments were subsequently posted.  By contrast, according to the individual, one company submitted comments that were favorable to the proposal after the docket deadline, and those got posted within a few weeks.  Several weeks after that company submitted their comments late, additional comments were posted that had been submitted on time but were against the proposal.  Whatever the objective validity of their concerns, it speaks to a perception that FDA is not acting fairly.