CDRH Holds Webinar on Draft LDT Guidances – Highlights that Guidances Hold More Questions than Answers

By Allyson B. Mullen & Jeff N. Gibbs –

On October 23, 2014, CDRH held a webinar regarding the two Laboratory Developed Tests (LDT) draft Guidance Documents that were released on October 3 (previously blogged on here and here).  The webinar began with a high-level description of the draft guidances.   While the discussion generally restated the fundamentals of the draft guidances, one point of interest was that FDA plans to address all comments that it receives during the comment period.  Addressing all substantive comments would be a requirement had FDA gone through notice and comment rulemaking, but it is not a requirement for the issuance of a guidance document.

Afterwards, Katherine Serrano, Liz Mansfield and Alberto Gutierrez fielded questions.  The breadth of the questions were wide ranging and highlighted that these guidances, if finalized, will have a wide-reaching effect on laboratory diagnostics, patient care and the economy.  Also, the number of questions underscored that there are many open issues – some FDA easily answered, some FDA said it has considered, but had not yet addressed, and others that it sounded as though FDA had not even considered. 

Key questions and answers included:

• There was a question regarding what will constitute labeling for an LDT.  FDA did not have an answer.
• FDA said it may consider issuing a second draft of the guidance documents.  This is unusual, but if there are extensive, significant comments and the need for extensive revisions, it would be appropriate.
•  If a test falls into one of the categories in the LDT Framework Guidance, but is also a companion diagnostic, the companion diagnostic guidance document will control.
• It is not clear what rules will apply if an LDT falls into two categories within the LDT Framework Guidance.
• Laboratories will be required to submit during the timeframes in the Framework Guidance, not obtain clearance.  LDTs will only be required to come off of the market if FDA disapproves the LDT submission.  

This comment raises an interesting but important nuance regarding how FDA currently interacts with 510(k) applicants.  Under the current 510(k) process, applicants generally receive only one request for Additional Information, due to time limitations set by the user fee goals.  If additional information is still required as the 90-day review clock is nearing its end, FDA will give the applicant the option to withdraw its 510(k), gather the additional information and resubmit.  Most companies choose withdrawal over a not substantially equivalent letter.  If, however, laboratories will be required to withdraw their tests from the market if they withdraw their application, will laboratories wait for an NSE letter and then appeal?  How will FDA accommodate labs that can supply additional data relatively rapidly but not before the clock runs out?  Given that most laboratories have little to no experience working with FDA, it is very likely that many LDT 510(k)s will not be fully resolved during their first review cycle.

• For more established LDTs, clinical practice guidelines may be used to help establish clinical utility in a premarket submission.  Alberto Gutierrez stated that in the Agency’s review of IVD submission, it only considers clinical validity, not clinical utility.
• Analyte Specific Reagents (ASRs) and Research Use Only (RUO) materials can be used as components of an LDT.  If an RUO component is used, however, the LDT premarket submission will be required to establish quality control over the RUO.
•  Advisory committee panels will be used to establish the priority and timelines for LDT premarket submissions.
• Public Health laboratories and neonatal screening tests are within the scope of the draft guidances.  Laboratory Information Systems (LIS) are outside the scope of the draft guidances.
• FDA encourages laboratories to do a pre-submission to obtain FDA feedback regarding existing clinical data for their tests or for planned studies to gather data for a premarket submission (see our prior post on the pre-sub program here).
• FDA agrees that guidance regarding applicability of the Quality System Regulation (QSR) to a laboratory setting is necessary.  It is not clear when this guidance will be available for comment.  (The manner in which QSRs will be applied is a significant factor for labs; without this insight, it is difficult to assess the nature or extent of the increased operational regulatory burden labs will bear.)
• FDA does not yet know how to handle genetic profile panels.  If one marker on a genetic panel is currently cleared or approved as a companion diagnostic, then that marker will be deemed a companion diagnostic which does not fall within the Unmet Needs Category and will require approval in the highest risk group.  FDA acknowledged that it does not know what to do about the other markers in these types of panels.
• If a test is for a rare disease under the draft Framework Guidance, it is possible the lab could get an Emergency Use Authorization to run a large number of the tests during an outbreak situation, but it is unclear how this situation would be handled.  
• LDTs for Unmet Needs will have 1 year to submit a premarket application after another company receives 510(k) clearance or PMA approval for the same intended use.
• FDA considered coordinating with NY State and CAP regarding the existing laboratory certification programs, but it did not want to appear to be passing off its own responsibilities.  FDA encouraged laboratories to comment on how these programs could be useful in the FDA review process.  

Finally, when specifically asked about the “bad” LDTs that it is aware of, CDRH named OvaSure, an ovarian cancer test that has been off the market for nearly 6 years, a false whooping cough outbreak at Dartmouth where people were given antibiotics unnecessarily due, in part, to an LDT, and a New York Times article regarding Vitamin D testing.  FDA went on to say that it is aware of other “bad” LDTs, but because of the type of work the Agency does, the information sometimes cannot be made public.  In response to a question, FDA stated that it has investigated the veracity of the information that it has received regarding “bad” LDTs, particularly whether there is a conflict of interest.  Given the drastic impact that these draft guidances are poised to have on laboratory testing and healthcare, and that FDA is basing the need for regulating LDTs in part on safety issues, it would seem to us that FDA should provide a stronger record for its position.  If this were notice-and-comment rulemaking, the example cited probably would be insufficient to survive judicial scrutiny.