FDA Releases Official Draft Guidance for LDTs; 120 Day Comment Period

On September 30, 2014, the FDA officially released its two major guidance documents on LDT regulation: The first guidance covers a framework for FDA review, for risk classification and for proposed LDT safe harbors such as unmet needs.   The second guidance covers "reporting" for LDTs as medical devices, i.e. adverse event reporting.

The guidances were released to Congress on July 30, 2014, under a legislative requirement that Congress be given 60 days notice before the "official" release and comment period.  Which starts now.

The documents are dated October 3, 2014, so the 120 day comment period will extend until about January 1, 2015.

FDA Draft Guidance for the LDT Regulatory Framework, here.
FDA Draft Guidacne for LDT Adverse Event Reporting, here.

Federal Register notice of the release and comment period - for Framework, here; for Reporting, here.

The FDA commented it made no changes to July documents, except in the definition of combination diagnostic and in the exact grammar for "traditional LDTs" composed of components legally marketed for clinical LDT use (e.g. ASRs).  They clarify that they are proposing special allowances when LDTs are made from components marketed legally ^for clinical test use.  RUOs are marketed legally, but not marketed legally ^for clinical test use.

IOM Publishes Ebook: Characterizing the Uncertainty of Risks and Benefits.

A fundamental problem shared by both regulatory agencies like the FDA and payers like CMS is assessing the level of net benefit for a new product or service.  

Much has been written over the last twenty years about quantitative (e.g. turnkey) assessment of risk and benefit, but it is very difficult to do so.  In clinical trials, the benefit is usually a fixed statistical endpoint - survival was increased by 4 months plus or minus one month, or strokes per year were reduced by 20% plus or minus 3 percent.  On the other hand, "risks" or adverse events are ungainly, random, unpredictable events of all kinds differing widely in impact and frequency.   It would be easy if we could say, the benefit is "ten plus minus two" and the risk is "negative five, plus minus one" so that the net benefit is favorable, in this case, about plus five with a modest standard deviation and certainly greater than zero.  Comparing risks and benefits is never easy largely because "benefits" are well trained animals in a tight box, and "risks" are an ungainly wild menagerie.

Although the terminology may vary, the same issues face payers and regulators, with the payers typically adding more concerns about comparative effectiveness, overutilization, and external validity (will it work outside the trial).  In a word, payers see or infer much bigger "error bars" that the original trialist and statistician.

Given the difficulty in adding and subtracting risk and benefits against each other, a core problem is uncertainty.  This year, the FDA and Institute of Medicine held two full day public workshops specifically tied to "uncertainty" in risk-benefit decisions.  (See my April 2014 blog, here.)   IOM has now released a 123 page ebook for free download, here.

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):

MATTERS FOR DISCUSSION: 

• 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.

House Energy & Commerce Holds Hearings on FDA LDT Proposal [September 9, 2014]

On September 9, 2014, the House Energy & Commerce committee held a hearing through which a range of stakeholders could discuss the FDA's recent proposal to regulate laboratory developed tests.   The six speakers included Jeffrey Shuren, MD JD, the head of the Center for Devices at the FDA, followed by a series of public stakeholders:  Christopher Newton-Cheh of MGH, representing the American Heart Association; Andrew Fish, representing AdvaMed Diagnostics; Alan Mertz, representing the Americal Clinical Laboratory Association (ACLA), Charles Sawyers MD, recent president of the American Association of Cancer Research, and Kathleen Wilsey PhD, co-founder of the Coalition for 21st Century Medicine.

This newly arising topic has been integrated into a months-long series of hearings by the "21st Century Cures Initiative" in the House:  here.