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On September 30th, 2014 the U.S. Food and Drug Administration published the draft guidance entitled “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)” (“Guidance“). The publication of the draft Guidance is the next step in FDA’s implementation of its risk based approach to oversight of LDTs. In addition to noting FDA’s intention for bringing under its review many devices or tests that previously were exempt under the FDA’s enforcement discretion, the FDA’s draft Guidance also imposes new requirements, such as registration and notice, for all LDTs.

This post summarizes the proposed new categories of LDTs, the new notice requirements, and FDA’s implementation timeline as set forth in the draft Guidance.

Device Categories

Medical devices are classified as Class I, II or III, based upon controls necessary to provide a reasonable assurance of the safety and effectiveness of the device. Guidance at page 11. The intended use of the device, technological characteristics, and patient risk should the device fail, are additional considerations for device classification. Guidance at page 11.

The Guidance indicates that FDA will rely on the existing medical device classification system to evaluate the risk of the LDT and rely on input from industry experts to classify devices not previously classified by FDA. Guidance at page 12. FDA will issue an additional draft guidance within 18 months of the finalization of the Guidance (final guidance) to inform the public of what it considers generally to be Class I, II or III. The final guidance should issue within 24 months of finalization of the Guidance. Guidance at page 26.

FDA defines the term laboratory developed test as an in vitro diagnostic that is intended for clinical use that is designed, manufactured, and used within a single laboratory. The Guidance provides the following as an example of an LDT:

“A laboratory uses peer reviewed articles to guide development of a new diagnostic device. The laboratory uses general purpose reagents and analyte specific reagents combined with general laboratory instructions and develops a testing protocol, that together constitute a test system that is then verified and validated within the laboratory. Once validated this device is used by the laboratory to provide clinical diagnostic results.”

Guidance at page 5.

Thus, FDA does not consider tests or devices that are designed or manufactured completely or partly outside the laboratory that offers and uses them as LDTs. The Guidance also recognizes that tests may be offered as LDTs even though they do not meet FDA’s definition of LDT. However, the Guidance indicates that FDA intends to apply a risk based approach to any in vitro diagnostic that is offered as an LDT by a CLIA-certified laboratory in the interest of ensuing continuity in the testing market and patient access to the tests.

Continued Enforcement Discretion and Minimal Requirements For Certain Devices

Certain LDTs, such as those used solely for forensic purposes and those used in connection with tissue transplantation when used in a CLIA-certified laboratory, will be exempt from FDA oversight for all applicable regulatory requirements (exempt devices).

The Guidance states that FDA intends to exercise enforcement discretion for applicable premarket review requirements and quality system requirements for the following devices:

  • Low-risk LDTs (Class I devices);
  • LDTs for rare diseases;
  • LDTs that fall within the traditional definition of LDT, as described above; and
  • LDTs for unmet needs, when no FDA-approved or cleared equivalent device is available for the unmet need.

Notice and Basic Information

With the exception of the exempt devices, all manufacturers of LDTs are required to provide notice and basic information to the FDA regarding their tests, such as notice of manufacturing and provide basic information regarding such devices. Notification to FDA is expected to occur once for each LDT, unless significant changes are made to the test. For LDTs currently on the market or those to be launched within 6 months of the publication of the final guidance, the manufacturer of the LDT should provide notice to the FDA within 6 months of publication of the final guidance. If a new LDT is to be launched after 6 months from publication of the final guidance, notification must be provided to the FDA prior to offering the LDT for clinical use. The Guidance notes that when the manufacturer makes a significant change to the LDT, it is considered to be a new device and therefore new notification is required prior to offering the LDT for clinical use. Guidance at page 17.

If notification and listing is not provided to the FDA for a LDT within the appropriate timeframe, it is assumed that the laboratory will have opted not to be within the scope of the FDAs enforcement discretion policy with respect to the registration and listing requirements.

In addition to the notification requirements noted above, the Guidance indicates that the FDA intends to enforce the manufacturer reporting requirements of the Medical Device Reporting (MDR) regulation (21 CFR Part 803, Subpart E) that is, to submit reports to FDA of adverse events i.e., if the use of the device contributed to the death or serious injury of a patient. Adverse event reporting for LDTs should begin 6 months following publication of the final guidance.

Guidance at page 19.

Premarket Review Requirements

The Guidance states that with the exception of the exempt devices, FDA intends to phase in the enforcement of applicable premarket requirements over time based on the risk associated with the device. Guidance at page 20.

For laboratories that manufacture traditional LDTs, FDA intends to continue to exercise enforcement discretion with respect to premarket review requirements.

High and Moderate Risk LDT

The Guidance states that for high risk and moderate risk LDTs, FDA intends to enforce applicable regulatory requirements, including registration and listing (with the option to instead provide notification, discussed above), adverse event reporting, premarket review and quality system requirements as noted below.

High-risk LDTs (Class III devices) are to be reviewed as follows. Registration and listing (with the option to provide notification) of the LDT and adverse event reporting are to begin 6 months after publication of the final guidance. Premarket review requirements are to begin 12 months after publication of the final guidance and phased-in over 4 years for the remaining high-risk devices. Devices can remain on the market during review and FDA’s consideration of applications to ensure patient access to the devices.

FDA’s focus on high-risk devices begins with the following:

  1. LDTs with the same intended use as an FDA-approved companion diagnostic;
  2. LDTs with the same intended use as an FDA-approved Class III medical device; and
  3. Certain LDTs for determining the safety or efficacy of blood or blood products.

FDA’s focus on moderate-risk LDTs (Class II devices) is as follows. Registration and listing (with the option to provide notification) of the LDT and adverse event reporting is to begin 6 months after publication of the final guidance. Premarket review requirements begin after the high-risk (Class III) LDTs are completed 5 years after publication of the final guidance, and phase-in over 4 years.

Guidance at page 13.

LDT Devices of Higher Concern to FDA

The Guidance states that FDA will initially focus its enforcement by first generally enforcing the premarket review requirements beginning 12 months after publication of the final guidance for the following LDTs:

  1. LDTs with the same intended use as a cleared or approved product companion diagnostic;
  2. LDTs with the same intended use as an FDA-approved Class III medical device; and
  3. Certain LDTs for determining the safety or efficacy of blood or blood products.

Guidance at page 24.

The Guidance notes that for 12 months following publication of the final guidance, FDA intends to exercise enforcement discretion with respect to premarket review requirements for currently marketed LDTs in the above three categories. FDA will begin enforcing premarket review requirements for these categories at the end of the 12-month period. If a premarket submission is timely made, the FDA will exercise enforcement discretion when the submission is under review. The Guidance also states that FDA intends to begin enforcing premarket review requirements immediately upon publication of the final guidance for all new LDTs in the above three categories.

Notice and Comments

Devices and tests that are utilized in the practice of personalized medicine are likely considered of higher risk and of higher concern to FDA. Thus, the Guidance should be carefully reviewed for its impact on current and future device development and services.

The public is invited to submits comments and suggestions regarding the Guidance by February 2nd, 2015. Written comments can be submitted to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville Maryland 20852. Electronic comments can be submitted to http://www.regulations.gov.

A webinar will be held on October 23, 2014 at 2:00 p.m. EST during which FDA will address clarification questions on the proposed framework. To participate, one must both dial into the conference call for audio and connect to the MyMeetings website to view the slide presentation:

The notice indicates that registration for the webinar is required but participants are encouraged to connect and dial in no later than 1:45 p.m. The webinar is intended to provide clarification on the proposed framework only; comments on the framework should be submitted to the docket (instructions for submitting comments are provided in the notice that is published in theFederal Register) and/or presented during a January 2015 public meeting. Additional information can be found on the FDA’s website.