Joseph L. Hackett
Center for Devices and Radiological Health (HFZ-440)
Food and Drug Administration
2098 Gaither Road
Rockville, Maryland 20850

Dear Mr. Hackett:

The American Association for Clinical Chemistry (AACC) welcomes the opportunity to comment on the Food and Drug Administration's (FDA's) "Draft Guidance on Labeling for Laboratory Tests." In general, we support the agency's efforts to improve the type and quality of product data available to clinicians. However, AACC recommends that you revise this document, so that the intent, potential benefits and requirements associated with this guidance are more clearly understood by laboratorians and manufacturers alike. Our specific comments follow:

The document identifies two endpoints, "Operational Truth" and "Laboratory Equivalence," for manufacturers to use as benchmarks for comparing new product test results. Operational Truth is characterized by the comparison of test performance to patient status or outcome, whereas Laboratory Equivalence involves a comparison to a predicate or similar device.

AACC recommends that the FDA further define the term Operational Truth. The proposed definition assumes that diagnostic outcome is the only effective use of a test. However, there are many instances when a test is only one indicator assisting in the diagnosis of a patient, rather than singularly determining patient status. For example, a high cholesterol result by itself tells the physician little about the patient's overall health. It is when the result is analyzed in conjunction with other symptoms that it becomes more meaningful.

In addition, the guidance document states that "studies of 'true' diagnostic state test performance would be performed in the intended use population that includes patients with relevant confounding medical conditions to help determine test performance." These studies can become very costly, depending on the type and size of the study.

AACC recommends that the FDA provide manufacturers with more details regarding 'acceptable' study designs and sample size for each endpoint.

Also, we are concerned that the FDA is placing too much emphasis on the concept of "Operational Truth." We believe the current system, whereby the vast majority of devices and reagents are cleared by comparing a new device with a predicate in use, is adequate. We suggest that "Operational Truth" be applied only to new tests and technologies that the Agency has little or no experience.

Proposed Labeling
The document states:

2. "In cases where a candidate device is being compared to a predicate, the predicate and conditions under which it is performed should be defined. Conditions of use include operator experience, clinical laboratory facility or other test setting, controls applied, specimen acceptance criteria, etc...

  • A test that has been characterized to a predicate but has not been compared to "true" diagnostic states should be labeled WITHOUT sensitivity and specificity claims. Relative performance may be described in terms of agreement, copositivity and co-negativity, or using other similar terms."

AACC agrees that laboratories must have the most accurate data available to ensure the validity of patient test results. However, we are concerned that this provision would add significant research costs to the manufacturer without corresponding benefit to the laboratory, clinicians or patients. To limit the use of commonly used and understood clinical performance indicators (e.g., clinical sensitivity, clinical specificity and predictive values) to terms of agreement would unnecessarily stratify test labeling.

For many conditions where clinical symptoms are not correlated with diagnosis or absent, such as sexually transmitted disease or genetic disease, equivalence may be the sole means of demonstrating assay performance. To suddenly minimize the basis for determining assay performance to a simple "percent agreement" fails to provide clinical sensitivity and specificity as a real "operating truth," which is the basis for assay selection and implementation.

Also, for an automated device or system there is little or no benefit to stipulating the operator or location characteristics. These variables are important only when they are expected to affect the quality of the result due to sample integrity, operator training or other qualification. Other conditions, such as appropriate controls and specimens are already required under existing regulation for in vitro diagnostics.

New Test Modality for Old Disease AACC also recommends that the agency recognize the use of patient outcome data as a method of comparison for demonstrating the substantial equivalence of results between a new and existing test. This method has been successfully used in the past (e.g., Troponin and CK-MB) and should be recognized in the document.

Molecular Diagnostic Tests Further, the document does not state how molecular diagnostic tests will be addressed. For such tests, there are no predicate devices for disease manifestation. To restrict the introduction of new technology/devices in order to gather the requisite data on diagnosis (i.e. disease occurrence) could take many years, since the presence of a mutation does not indicate when, or if, a patient will develop the symptoms of the disease.

There are, however, multiple predicate methods against which new molecular methods could be compared and correlated. Thus, we recommend that the FDA permit molecular genetics manufacturers to use this pathway for linking mutation detection with disease and accurate diagnosis.

By way of background, AACC is the principal association of professional laboratory scientists--including MDs, PhDs and medical technologists. AACC's members develop and use chemical concepts, procedures, techniques and instrumentation in health-related investigations and work in hospitals, independent laboratories and the diagnostics industry nationwide. The AACC's objectives are to further the public interest and educational activities and to help maintain high professional standards.

If you have any questions or we may be of any assistance, please call me at (405) 271-3571 or Vince Stine, Director, Government Affairs, at (202) 835-8721.



K. Michael Parker, PhD

Page Access: