FDA’s workshop yields thoughtful observations on the state of clinical lab testing

On January 8–9, 2015, experts from all corners of the clinical laboratory community gathered to provide input on FDA’s proposed regulatory structure for laboratory-developed tests. Following is a short selection of comments from the first day of the workshop, offering just a hint of the depth of participants’ observations. The full transcript for both days is available from FDA via www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm423537.htm.

The practice of medicine. One factor deciding whether an LDT is a high-risk test or not is whether it provides guidance on selection of treatment or may be interpreted in doing so. . . . Simply reporting test results is not the practice of medicine. But providing accompanying guidance on treatment selection, especially when the basis for the guidance is neither sufficiently rigorous nor transparent, may cross the boundary of the practice of medicine.—Edward Kim, MD, Levine Cancer Institute, American Society of Clinical Oncology.

Unlike manufacturers. Laboratories develop LDTs as part and parcel of the practice of medicine. They operate in a fundamentally different manner than manufacturers, which manufacture products that are distributed in interstate commerce. FDA’s effort to expand its jurisdiction and treat labs as manufacturers will interfere with the practice of medicine, disrupting the ability of doctors to obtain tests they need to provide the best care to their patients.—Alan Mertz, American Clinical Laboratory Association.

Investment in testing. In 2014 the biotechnology sector has seen approximately $5 billion dollars of investments, which is the second-largest sector receiving venture capital last year. Unfortunately this trend has not trended for LDT-type companies. In fact, investment in that space has pretty much dried up. . . . The primary reason for this decline is the universal perception that [there is] regulatory uncertainty for LDTs, and the lack of adequate payer reimbursement. This uncertainty continues to hold back investment in breakthrough personalized medicine innovation that could significantly advance how we develop drugs and treat patients with critically important diseases such as Alzheimer’s, diabetes, and cancer.—Kelly Slone, National Venture Capital Association.

Infectious diseases. We are concerned that provisions in the draft guidance could seriously curtail LDTs for infectious diseases. . . . We ask FDA to consider continuation of broad enforcement discretion over LDTs for infectious diseases as carried out in university, hospital, and public health laboratories. The concerns expressed by FDA concerning LDTs developed by commercial entities and marketed nationwide rarely apply to infectious disease LDTs. Careful consideration must be given to cost and unintended consequences of regulatory extensions that could adversely affect the public and private health of our citizens.—Gregory Storch, MD, Washington University, St. Louis Children’s Hospital, American Society for Microbiology, Pan-American Society for Clinical Virology.

Compliance impact. Implementation of the proposed framework will necessitate personnel well versed in the FDA approval process. This may require the hiring of new staff or training of existing staff for those laboratories, many of them small operations. The compliance impact over and above existing standards may prove too great to continue offering a test or may serve as a deterrent to developing new assays. . . . Therefore, ASCP opposes any policy change that would bar laboratories in toto from marketing LDTs during the approval phase unless FDA can determine during initial review that particular LDT poses significant potential for harm.—William Finn, MD, University of Michigan, IHA Pathology and Laboratory Management, Ward Medical Laboratory, American Society for Clinical Pathology.

Supplemental guidance. The regulatory uncertainty for LDTs over the past several years has discouraged investment, thus hampering innovation, which in turn has deterred advancements to clinical care, to the detriment of patient care and safety in the United States. . . . We thus encourage FDA to issue a supplemental guidance addressing the critical questions raised at this public meeting and in comment letters; and to provide the opportunity to comment on any supplemental guidance before finalizing the framework. Clarity and transparency will aid in addressing the regulatory risks and unpredictability facing companies and their investors.—Melinda Griffith, JD, CardioDx, Coalition for 21st Century Medicine.

Assessing validity. Clinical validity is information that is accumulated over time; requires adoption into medical practice by trained, thinking professionals; and comes in many forms and requires flexibility and nimbleness. It is through my [own] and my treating clinician counterpart’s medical knowledge as professionals that we can jointly assess the clinical validity of any individual analyte and evaluate whether there is potential benefit for our patient. This is the practice of medicine.—Dara Aisner, MD, PhD, University of Colorado.

Detailed guidance. It is imperative that the agency provide detailed substantive guidance on many unresolved issues before its proposed framework is finalized and before commencing a timeline for compliance by affected laboratories. These issues include clearly identifying the device within the LDT; harmonizing CLIA quality system regulations with the agency’s [framework]; clarifying guidance on labeling requirements useful for patients and clinicians; accommodating intraprovider medical communications in the context of an FDA framework that typically imposes substantial limitations upon medical product manufacturer communications; and finally, clarifying that any new requirements apply uniformly and consistently to all clinical laboratories, disregarding ownership, academic, or other business alliances.—Scott Schell, MD, MBA, PhD, KEW Group.

Evidentiary standards. The fact is, in evaluation of diagnostics, randomized controlled trials are relatively rare as a methologic approach; [instead they are] typically compared to a reference standard. I think we will find the complexity in some tests being developed [is that] there may be no reference standard. We have situations in which the test itself is beginning to define the new disease or a spectrum of disease. I believe that we could all benefit if FDA proceeds to provide guidance on clinical utility—not just what it is, but what are the evidentiary standards and methodologies available in various contexts. This will become more complicated as we . . . move from single biomarkers to really complex algorithms that are intended to predict or assess the presence of disease.—Naomi Aronson, PhD, Blue Cross Blue Shield Association.

Test modifications. FDA should revise the part of the proposal which deals with modification of FDA cleared or approved tests. . . . The agency has been struggling with that question for manufacturers for years. Setting this up for the labs is going to create another whole regulatory burden and a quagmire that I think is best avoided.—Jeffrey Gibbs, JD, Hyman, Phelps, and McNamara PC.

Rare diseases. We believe the proposed application of the regulatory framework to testing services for rare diseases, unmet needs, or emergency use is unworkable, dangerous to individual patients, and undermines public health. Laboratory developed testing services are often the only option for those with suspected rare diseases since the commercial market for such tests is nearly nonexistent. . . . These tests constitute a small volume of tests for most laboratories and subjecting them to FDA oversight requirements would result in laboratories dropping the test completely, leaving patients and physicians without an option for screening and diagnosis. As currently written, the exemption for rare diseases is for rarely performed tests, not rare diseases.—Katherine Johansen-Taber, PhD, American Medical Association.