Advances in medical technology have increased the use of diagnostic tests to guide therapeutic decisions for many diseases and conditions, especially in the context of personalized medicine. Citing the need to ensure that certain tests used by health care professionals that diagnose and treat patients are accurate, consistent and reliable, the U.S. Food and Drug Administration (FDA) signaled that the Agency is lifting its enforcement discretion over certain laboratory developed tests (LDTs) that aid physicians in selecting appropriate therapies for patients. “LDTpacket Guidance” (Guidance) provides anticipated details of a draft guidance to be issued no earlier than 60 days from the July 31, 2014 publication of the Guidance, and fulfills the agency’s requirement to notify Congress of its intent to publish the draft guidance consistent with the Food and Drug Administration Safety and Innovation Act of 2012.

The Guidance proposes a risk-based, phased-in framework for oversight of LDTs that is in accordance with FDAs current regulation of in vitro diagnostic devices (IVDs).

The Need for Increased Regulatory Oversight of LDTs

In support of increased regulatory oversight, the FDA makes note of the evolution of LDT technology, marketing and business models. Historically, LDTs were manufactured in small volumes by local laboratories. These tests were used and interpreted directly by physicians and pathologists working within a single institution. In addition, traditional LDTs were manufactured using components that were legally marketed for clinical use. More recently, LDTs are manufactured with components and instruments that are not legally marketed for clinical use and rely heavily on high-tech instrumentation and software to generate results and clinical interpretations.

The FDA also noted that business models have changed. For example, overnight shipping and electronic delivery of information makes it possible, and not uncommon, for a single laboratory to provide device results nationally and internationally. Moreover, many new LDTs manufacturers are large corporations that nationally market a limited number of complex, high-risk devices.

Noting the changes in the complexity and use of LDTs, the FDA believes that the policy of general enforcement discretion towards LDTs is no longer appropriate, and that historical oversight by the Centers for Medicare & Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments (CLIA) regulations are deficient in several aspects. They are noted to fail to:

  • Adequately assure the safety and effectiveness of LDTs;
  • Require adverse event reporting, making it difficult for regulators to detect devices that are inaccurate, ineffective or unsafe;
  • Require the removal of unsafe devices from the market;
  • Assess the quality manufacturing of devices; and
  • Require informed consent for patients who participate in LDT clinical studies or establish procedures for the conduct of such studies.

Most importantly, the Agency notes serious concerns regarding the lack of independent review of clinical validity of LDTs. Clinical validity is defined as the ability of a diagnostic device to measure or detect the clinical condition for which the device is intended. LDTs, it is noted, have not been properly clinical validated for risk of missed or incorrect diagnosis, failure to administer appropriate treatment or administration of potentially harmful treatments with no benefit. Guidance at page 8.

Risk-Based Approach and Timelines

The Guidance indicates that the FDA will rely upon the existing medical device classification system to evaluate the risk category of LDTs and will use expert advisory panels to help classify devices not previously classified by the FDA. The Guidance indicates that the FDA will continue to exercise enforcement discretion over two specified tests – tests used solely for forensic or law enforcement purposes and those used for transplantation, when used in CLIA-certified, high complexity histocompatibility laboratories.

For those defined as low-risk LDTs (e.g., Class I devices), the FDA indicated that it will continue to exercise its discretion with respect to applicable premarket review requirements and quality system requirements, but will enforce other applicable regulatory requirements and adverse event reporting.

For the remaining LDTs, such as high and moderate risk LDTs, the FDA indicated an intention to enforce applicable regulatory requirements including registration and listing, adverse event reporting and premarket reporting. Enforcement will commence six months after the finalization of the draft guidance. Premarket review requirements are to begin 12 months after finalization for the highest risk devices and will be phased-in over 4 years for the remaining high-risk devices. However, high-risk devices may remain on the market during review and FDAs considerations of applications.

High-Risk Companion Diagnostics

Diagnostic tests that match therapies with patients are key to personalized medicine. Due to the clinical importance and relevance of these tests, the Guidance signals with certainty FDAs intention to regulate these tests consistent with IVDs. Undoubtedly, the FDAs impending oversight of these tests will be controversial due to the increased cost of compliance for these previously unregulated tests. However, many in the forefront of personalized medicine would disagree. Dr. Francis Collins, speaking on behalf of the NIH, noted that the “NIH supports our sister agency’s proposal and thinks that this thoughtful framework which focuses greatest attention on tests with the most significant clinical impact will protect public health, without putting a damper on biomedical innovation or placing an undue burden on the industry.” (Collins Statement, July 31, 2014.)