CHAPTER 1 Kathleen B. Whitaker, Sally A. Hojvat, and Estelle Russek-Cohen Food and Drug Administration, White Oak, MD, USA The Medical Device Amendment (MDA) of 1976 [4] was the result of a long history of fraudulent medical devices beginning as early as the 1700s with Dr. Elisha Perkins’ patent tractors, which consisted of two rods of brass and iron about three inches long purported to eliminate disease from the body. Despite the surge of fraudulent medical devices throughout the years, no substantial regulation was enacted to ensure the safety and effectiveness of devices. The enactment of the Food Drug and Cosmetics (FD&C) Act of 1938 was the first step towards eventual implementation of device regulation. The subject matter in this section as well as the remainder of the chapter will be confined to a discussion of the regulations that affect the classification of microbiological devices, as well as the various FDA processes which enable the commercial interstate sale and distribution of clinical microbiology in vitro diagnostic devices (IVDs) by the Center for Devices and Radiological Health (CDRH). The following definition of an in vitro diagnostic device can be found in the FDA regulation 21CFR (Code of Federal Regulations) 809.3 The MDA of 1976 required that all medical devices be divided into three product classes by virtue of the types of controls necessary to assure the safety and effectiveness of the device. As can be seen from the above descriptions, classification of an IVD is risk based. In addition, device classification is inherently tied to the intended use of a device. For example, when the intended use for a device is as an aid in the assessment of serological status for sexually active adults and expectant mothers the device is classified as Class II as risks may be mitigated with appropriate controls. However, when the intended use for a device is an aid in the assessment of response to therapy in immunocompromised patients, e.g., transplants recipients where there is a substantial increase in risk such as death from cytomegalovirus (CMV) infection, the device classification is Class III. Microbiology device regulations and their classifications can be found in 21 CFR, Microbiology Regulation, Sections 866.1 through 866.3980. The following are examples of Class I and Class II microbiology devices. Many times assay developers will look at a classification and find it exempt from section 510(k) of the act. It is important to note here that 21 CFR 866.9 Limitations of Exemptions from Section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act) contains several important points that are specifically related to microbiology devices. They are: Table 1.1 illustrates the types of submissions sent to the FDA for review for each device class, the metric for the successful completion of that submission, and the final action taken to enable that device to enter interstate commerce. Table 1.1 Types of FDA submissions with associated device classes After having established the regulatory class of a device and prior to introduction into the market of a device intended for human use, each assay developer must submit a 510(k) to the FDA unless the device is exempt from 510(k) requirements of the Federal Food, Drug, and Cosmetic Act (the act) and does not exceed the limitations of exemptions in .9 of the device classification regulation chapters (e.g., 21 CFR 862.9, 21 CFR 864.9 and 21 CFR 866.9). The purpose of the 510(k) submission is to demonstrate to the FDA that the new device is at least as safe and effective, that is, substantially equivalent to, as a legally marketed device or predicate device (21 CFR 807.92(a)(3)). While the basic content of a 510(k) has been established under 21 CFR 807.87, it is important to note that the types of information and data required may likely vary according to the analyte being detected as well as the differences between the new device and the predicate device. The FDA has 90 days for review of the submitted 510(k) in which to make a decision on whether a device is substantially equivalent. Primary in the determination of substantial equivalence is that the new device has the same intended use as the predicate device. In addition, while the new device generally has the same technological characteristics, this is not a requirement. New devices with the same intended use yet different technological characteristics will be expected to supply appropriate clinical or scientific data if deemed necessary by the Secretary of Health and Human Services or a person accredited under Section 523, that demonstrates that the device is as safe and effective as a legally marketed device, and does not raise different questions of safety and effectiveness than the predicate device. Following review of a 510(k) submission which the FDA finds substantially equivalent, each submitter will receive an order, in the form of a letter, from the FDA which finds the device to be substantially equivalent and states that the device can be marketed in the United States. This “clearance order” permits commercial distribution of the device. Alternatively, following the review of a 510(k) submission, the FDA may find the device not to be substantially equivalent (NSE) to the predicate device. In general, an NSE decision is based on one of the following reasons. In the first case, the FDA will issue a letter stating that the device has automatically been classified as Class III and requires a premarket amendment (PMA), or that the device may be eligible for the de novo petition program (see below). In cases where the information submitted is not sufficient to make a determination of substantial equivalence, the FDA will issue a letter identifying the deficiencies, which are usually performance related, and request additional information to resolve these deficiencies. The FDA will interactively work with developers to resolve the deficiencies within the time frame specified by regulation and guidance. If the information or justifications supplied are insufficient, the FDA will issue a NSE letter. If a sponsor does not respond at all to the request for additional information within the time frame specified by regulation and guidance, the FDA will consider the submission withdrawn. In either case above, the sponsor does have the opportunity to make a new 510(k) submission that addresses the outstanding items from the original review. The new 510(k) submission should cite the previous 510(k) number and specify how the outstanding items have been addressed and whether the new submission contains only the original information or additional new information. In response to devices that had been found NSE due to the lack of a predicate device, the Food and Drug Administration Modernization Act of 1997 (FDAMA) added the “de novo” classification option as an alternate pathway to classify such devices. The formation of this pathway enables FDA to make a risk-based classification determination for the device under Section 513(a)(1) of the FD&C Act. Devices which may be eligible for this pathway must be low to moderate risk devices and the assignment of substantial benefits to patients is not as high as that for Class III devices. Such devices should be sufficiently understood to explain all the risks and benefits of the device such that all risks can be appropriately mitigated through the application of general and/or special controls to provide reasonable assurance of safety and effectiveness. Once a device is granted marketing authority under the de novo petition program it is also eligible to serve as a predicate device for new devices that can be regulated via a 510(k) submission, thus enhancing the need for an appropriate risk-benefit profile when considering the safety and effectiveness of the device. The majority of microbiology devices using the de novo classification option will have both analytical and clinical data in support of the petition. Nonclinical testing may include, but is not limited to, testing such as the limit of detection (LoD) of the analyte, precision and/or reproducibility of the assay, interference testing, and cross-reactivity with other microbiological or nonmicrobiological analytes. A variety of clinical testing methods are also used in support of the petition. The clinical testing may involve anything from a randomized clinical trial, comparison of the new device to a putative gold standard using clinical specimens, and comparison of the new device to a patient infected status (PIS). Since the factors that the FDA considers as part of the benefit-risk determination (as well as examples) when reviewing a de novo petition are detailed in the guidance document “Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications” only a brief mention of them will be made here. For microbiological devices the types of benefits may include the impact on clinical management of a patient, for example, the use of viral load assays to predict a patient’s response to therapy; the diagnosis of a specific pathogen which may have an impact on public health such as devices that identify influenza virus or Chlamydia trachomatis; and the ability to identify a specific pathogen to enable correct immediate treatment, such as those devices that identify Clostridium difficile. Other benefit considerations may be the magnitude of the benefit, the probability of the patient experiencing a benefit and the duration of the effect(s) of the benefit. The risks associated with microbiological devices are most often considered in terms of the risk of a false positive or a false negative result. A false positive result for a diagnostic assay may cause a patient to receive unnecessary therapy such as receiving a course of antibiotics for a viral infection, or may have severe consequences if a pregnant woman is misdiagnosed with a positive result for herpes simplex virus or rubella. A false negative result may also have either mild or severe consequences. For example, a false negative may lead to the incorrect treatment for bacterial meningitis, with severe consequences. In addition to the individual effects, the aggregate effects of a misdiagnosis are also considered. Misdiagnosis of an individual with C. difficile infection may cause an infected patient to be housed with uninfected patients thus causing spread of the disease to the other residents of a hospital ward. Similarly, misdiagnosis of a sexually transmitted infection (STI) may also have significant ramifications in the spread of the pathogen in a population. Possible mitigation of potential risks is also extremely important when determining the risk-benefit of a device. Mitigations such as restrictions in the labeling of a diagnostic device and restrictions in the use of a device to a segment of a population are two important safeguards that are often employed.
Role of the US Food and Drug Administration in the Regulation of Clinical Microbiology Devices
1.1 Historical overview of in vitro diagnostics
1.1.1 Device classification via the MDA of 1976
Class
Premarket submission
Success metric
Action
III
PMA
Safety and effectiveness
Approval
II
510(k)
Substantial equivalence
Clearance
I
None (if exempt) 866.9 limitations to exemptions
II (de novo)
De novo request
Safety and effectiveness
Approval
1.2 Current microbiology device review regulatory pathways: practical considerations
1.2.1 Premarket notification 510(k)
1.2.2 De novo petitions
1.2.2.1 Scientific evidence supporting a de novo petition
1.2.2.2 Benefit-risk determinations
1.2.2.3 Benefits of a new device
1.2.2.4 Potential risks associated with a new device
1.2.3 Premarket application
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
