Monday, September 22, 2014

CDC Atlanta Forum on FDA LDT Regulation Announced: For November 4-5, 2014.

The CDC has announced a three-agency forum on FDA LDT regulation, to be held in Atlanta November 4-5.  (FDA LDT regulation is only part of the agenda.)

The CDC writes (federal website here, my cloud archive here):


  • The agenda will include agency updates from CDC, CMS, and FDA. 
  • Presentations and discussions will include the FDA Draft Guidance on Laboratory Developed Tests.

The CDC's published post-meeting notes are clipped further below.

Pre meeting agenda....This meeting's topics will also include:

* CLIA-waived testing, including the process and criteria for waiver approval; 

* a report from the workgroup charged with providing input to CLIAC regarding the acceptability and application of virtual cross-matching in lieu of serologic cross-matching for transplantation; 
* and issues related to laboratory biosafety in the United States.

The agency adds, "Space is limited...the room seats 100 people."

Earlier blogs and links available on this blog, here and here.  My first article was an overview of the FDA LDT proposal.  The second article covered mid September 2014 hearings by the House Ways & Means committee on the FDA LDT proposal.

The FDA's draft guidance was officially released for 120 days of public comment on October 3, 2014 (here).

After the meeting, the CDC CLIAC posted meeting minutes, here.  The FDA LDT portion begins on page 17.   I have also cut/pasted (not formatted) the FDA LDT meeting notes below.

FDA Draft Guidance on Laboratory Developed Tests 
CDC CLIAC, Addendum 10 
Alberto Gutierrez, PhD 
Director Office of In-Vitro Diagnostic Device Evaluation and Safety (OIVD) 
Center for Devices and Radiological Health (CDRH) 
Food and Drug Administration 

Dr. Gutierrez provided an update on the proposed regulatory framework for laboratory developed tests (LDTs). He explained the evolution of LDT technology created a public health need for greater oversight of these tests. He described the benefits of FDA oversight of LDTs, which includes independent premarket reviews, clinical validation, post market surveillance and controls, and oversight of investigational stage devices. Dr. Gutierrez next discussed the FDA’s LDT draft guidance ( Diagnostics/UCM407409.pdf) which includes the collection of information on all LDTs through a new notification process, use of advisory panels to obtain input on risk and priority for regulation, a phased-in regulatory framework over approximately nine years beginning with the highest-risk LDTs, and continued enforcement discretion for specific categories determined by the FDA to be in the best interest of public health. He provided a timeline emphasizing that premarket review of new highest-risk LDTs will occur immediately after the final LDT guidance is published. The FDA will publish a priority list for the timeframe for premarket submissions for the remaining high-risk LDTs in year two and a priority list for moderate-risk LDTs in year four. The next steps include the publication of the draft guidance, a Federal Register Notice announcing the 90-day public comment period, and a public meeting in early January 2015 to collect additional input during the comment period.

Committee Discussion 
• A member asked if the majority of LDTs are either molecular diagnostic tests or biochemical assays. Dr. Gutierrez responded that the majority of LDTs are molecular diagnostics but there are many other LDTs as well.
• A member requested clarification on the distinction between low, moderate, and high risk LTDs. Dr. Gutierrez explained that since 1976, the FDA has been performing a similar classification of in vitro diagnostic (IVD) products according to the level of regulatory control necessary to assure safety and effectiveness. To explain the classification scheme being proposed for LDTs, he used cancer biomarkers as an example of the same analyte having different risks depending on usage. Biomarker based
tools used in screening for the early detection of cancer in asymptomatic people
are classified as high risk because false negatives may result in missed diagnoses and
false positives may result in unnecessary therapies. In contrast, use of the same
biomarker-based tools for a patient diagnosed with cancer is classified as moderate
risk because the clinician will use the test in combination with other tests to monitor
the patient, and a false test result is of lower risk to the patient.

• The AdvaMed liaison commented that industry advocates a risk based approach in regulating all diagnostic tests. The proposed LDT guidance should take into account the possible effects on review and clearance times for these devices, given the recent trend by FDA in reducing these timeframes. He stated that industry hopes that the increased load caused by the addition of LDT regulation does not adversely affect the current clearance times.
• One member asked if the FDA would use discretion and not regulate LDTs that are not marketed but used internally within an academic center or CLIA-certified laboratory. Dr. Gutierrez explained that traditionally, LDTs are defined as those tests that are developed and performed in laboratories associated with hospitals or clinical systems where there is a clinician-patient-pathologist relationship. He indicated he hoped FDA would be able to move to enforcement discretion with these tests.
• Another member asked about the process and timeline for premarket reviews and approvals. Dr. Gutierrez explained that premarket review for Class III (high-risk) devices must show the device is safe and effective. There is a twelve-month review time, which can be longer depending on whether the submitter provides all the required data and if the quality systems are in place. Dr. Gutierrez stated that low-risk LDTs would be exempt from premarket review.
• The same member inquired about the LDT notification process. Dr. Gutierrez commented that there will be an online process for notification. The FDA is collaborating with the National Institutes of Health (NIH) to link the NIH genetic registry site to the FDA notification process. When a test is registered with NIH, the user will be able to transfer the data to the FDA, input missing data, and submit the test notification.
• The member asked if traditional LDTs will require notification. Dr. Gutierrez responded that the draft guidance does require notification. However, the topic is open for public comment on whether to allow laboratories to only notify the FDA of their LDTs that will be regulated or require notification of all LDTs to assist FDA in determining the current catalog of available LDTs.
• Regarding notifying the FDA about LDTs for biosecurity agents, Dr. Zehnbauer asked how detailed the provided information would need to be and how the FDA would determine what information to share with the public. Dr. Gutierrez responded that it has not been determined if the database will be publically available. Based on public safety and security, not all information may be available to the public.
• Another member expressed concern that the LDT review timeline might result in a delay of patient access to lifesaving methodologies. Dr. Gutierrez responded there is
always a risk-benefit issue in determining whether a test is safe and effective versus the immediate benefits it presents to the patient population. In terms of the immediate public health effect, LDTs available on the market when the guidance is published will be allowed to remain on the market until the review to determine clinical validity is complete.
• One member provided a scenario of a laboratory selling their LDT for detection of multiple pathogens on asymptomatic patients’ vaginal swabs and asked how the FDA would regulate this. Dr. Gutierrez responded the LDT would need to be entered into the FDA notification system and regulation would be determined based on risk. He commented that regulation will be able to limit laboratory manufacturers from making claims that are risky and not credible.
• A member asked how the CMS reimbursement program plans to assess the clinical utility of LDTs. Dr. Gutierrez responded that the FDA does not address the payers’ part since they assess clinical validity rather than utility. The payers will need to determine the evidence needed for reimbursement. The same member further inquired about communication between CMS and FDA on regulation and payment since they both impact the laboratory. Dr. Gutierrez responded that recently the FDA and Medicare worked together to pilot a parallel review program.
• A member urged exemption from notification for traditional LDTs that are used within the developing institution and not marketed, stating a precedent exists with the current notification exemption of software that is developed for use within the institution. The member added it is often difficult to determine the point during test development when notification should occur since many tests are never fully developed and by adding a notification requirement, academic creativity and innovation may be hindered. Dr. Gutierrez responded that there is a point during test development when the laboratory decides to offer the test and CLIA requires establishing performance specifications prior to its use with patient specimens. At this point, the laboratory has passed the test development stage.
• Another member asked if the manufacturing component that is required as part of the premarket approval process will be required for high-risk LDTs. Dr. Gutierrez responded that it is currently required in the proposal but open for comments.
• A member asked where research use only (RUO) instrumentation fits into the LDT guidance. Dr. Gutierrez responded that RUO becomes irrelevant if an instrument is sold as a medical device; the manufacturer has the responsibility to ensure all FDA requirements are met such as good manufacturing practices, agency reporting, and regulatory control. For instruments used for LDTs, the laboratory has the responsibility to determine if the instrument is safe to be used for clinical diagnostics under the quality system regulations, and many laboratories do not have the controls required for quality systems in place.
• Another member asked where manufacturer’s assays, sold as kits, fit into the LDT guidance. Dr. Gutierrez commented that LDTs span many different assays and many resemble commercial products where the only difference may be that the LDT is not distributed to other laboratories.

• In summary, the Chair noted the FDA may need to refine the definition and clarify the types of tests considered LDTs and include additional clarification on traditional LDTs. The process for risk categorization may need additional explanation to help  laboratories determine if their LDT requires notification.

The AdvaMed liaison presented a statement of industry support of a risk-based approach, but wanted to ensure that premarket review timelines would not be affected by the new LDT guidance.

The Chair noted discussion around LDTs with biosecurity implications and the need to not publicize data that may affect the security and health of the public. He also noted comments regarding how the LDT review process could be aligned with reimbursement.