Abstract
T
The IVDMIA test, the MammaPrintTM breast cancer test by Agendia, Inc. (www.agendia.com), was recalled due to reporting errors and clinical laboratory management problems. MammaPrint was reviewed and cleared by the FDA in 2007 (FDA, 2007b) and received multiple reviews and clearances by the FDA in the years since its market introduction in the United States. The manufacturer of this test voluntarily complied with the draft guidelines proposed by the FDA in order to receive IVDMIA premarket clearance status. However, since the time of its issuance, the IVDMIA Draft Guidance—which proposes to oversee and regulate complex laboratory-developed tests as medical devices under the Food Drug and Cosmetic Act—has been controversial. At the current time, the final Guidance appears stalled in review at FDA.
A recall notice for MammaPrint was publicly filed in April 2010 (FDA, 2010). This public recall notice highlights the advantage of a mandatory reporting mechanism provided under FDA rules; such a mechanism does not exist for traditional CLIA testing. The authority provided to FDA under the law has significant advantages over the rules that govern laboratories under the CLIA statute. For example, in this case, patients and the public became aware of issues involving the test about which they might not otherwise be notified. Further, as a consequence of the recall, the trade press and industry blogs investigated the issues and reported that the company was aware of testing errors since late last year (Ray, 2010). Providers and patients should be aware of testing errors and the consequences of treatment decisions made based on these results. What does timely disclosure mean and when does the community become informed?
There are additional questions one must ask. How is timely reporting defined? Is timeliness possible if a formal recall procedure begins many months after test result errors are known and reported? How does the regulatory system (either FDA clearance or CLIA approval) assure quality, test performance, and ongoing delivery of high quality testing services to patients if it is not facile and transparent?
Another important factor to consider is the potential difference between the intended use claim on the FDA clear label and the actual use of the test in clinical practice. If these do not align, the risk to patients might be substantially higher than the strict label indication. If the FDA performs a recall risk assessment based on the literal reading of the cleared label, rather than actual review of the clinical circumstances of use, there may be a gap in ascertainment of actual and/or potential harm to patients. If we are to move forward to assure safety, effectiveness, and ongoing quality assurance for all advanced diagnostics in the future, we need excellent oversight of genetic testing. This, in turn, requires multiple stakeholders to examine the advantages, disadvantages, and gaps in regulatory policy.
The Teachable Moment
What is a diagnostic test recall?
Overview
A recall is a formal method of removing or correcting a product that is in violation of laws administered by the FDA. A recall is usually a voluntary action that takes place because manufacturers carry out their responsibility to protect the public health and wellbeing from a product that presents a risk of injury or gross deception, or is otherwise defective (per the Code of Federal Regulations. Title 21, Part 7, Enforcement Policy). Under the Medical Device Correction and Removals Rule, manufacturers are required to make a written report to FDA of any correction or removal of a medical device if the correction or removal was initiated to reduce a risk to health posed by the device.
A recall is an alternative to an FDA-initiated court action for removing a product that has been distributed.
Definitions
Recall
A firm's removal or correction of a marketed product that the FDA considers to be in violation of the laws it administers and against which the agency would initiate legal action.
Recall strategy
A planned course of action to be taken in conducting a specific recall, which addresses the depth of recall, need for public warnings, and extent of effectiveness checks for the recall.
Recalling firm
The firm that initiates a recall or, in the case of an FDA-requested recall, the firm that has primary responsibility for the manufacture and marketing of the product to be recalled.
Removal
The physical removal of a device from its point of use to some other location for repair, modification, adjustment, relabeling, destruction, or inspection.
Risk to health
(1) A reasonable probability that use of, or exposure to, the product will cause serious adverse health consequences or death. (2) That use of, or exposure to, the product may cause temporary or medically reversible adverse health consequences, or an outcome in which the probability of serious adverse health consequences is remote.
Health hazard evaluation
An evaluation of the health hazard presented by a product being recalled is conducted by the FDA and takes into account the following factors:
Whether any injuries have already occurred from the use of the product. Whether any existing conditions could contribute to a clinical situation that could expose humans to a health hazard. Any conclusion shall be supported as completely as possible by scientific documentation and/or statements that the conclusion is the opinion of the individual(s) making the health hazard determination. Assessment of hazard to various segments of the population with particular attention paid to the hazard to those individuals who may be at greatest risk. Assessment of the degree of seriousness of the health hazard to the populations exposed. Assessment of the likelihood of occurrence of the hazard. Assessment of the consequences (immediate or long-range) of occurrence of the hazard.
On the basis of this determination, the FDA will assign the recall a classification (Class I, II, or III) to indicate the relative degree of health hazard of the product being recalled.
In this instance, the FDA has given the MammaPrint recall a Class II designation.
Classification
Recalls are classified into a numerical designation (I, II, or III) to indicate the relative degree of health hazard presented by the product being recalled.
Class I: a situation in which there is a reasonable probability that the use of a product will cause serious adverse health consequences or death. Class II: a situation in which use of a product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote. Class III: a situation in which use of, or exposure to, a product is not likely to cause adverse health consequences.
Recall strategy
The FDA will review the adequacy of a formally proposed recall strategy from the recalling firm and recommend changes as appropriate to the test, test systems, or processes.
Recall letter
A recalling firm is responsible for promptly notifying each of its affected direct accounts about the recall. The format, content, and extent of a recall communication should be commensurate with the hazard of the product being recalled and the strategy developed for that recall.