Regulations & Standards

Published: June 6, 2012
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In Vitro Diagnostic Performance Evaluation Studies: Part 2

Part 2 of this two-part series discusses considerations when planning studies where results will be used for both CE marking and U.S. approval and clearance.

By: Maria E. Donawa, MD

IVD medical devices are extremely important products for which performance evaluation studies can provide necessary evidence on safety and performance. Part 1 of this article discussed European requirements related to performance evaluation studies. Part 2 discusses considerations when planning studies where results will be used for both CE marking and U.S. approval and clearance.
European and U.S. terminology differences
The term “performance evaluation studies” is used for European IVD studies, as specified in the European In Vitro Diagnostic Medical Devices Directive (IVDD; 98/79/EC). By contrast, FDA considers investigations with IVD medical devices as clinical studies regulated under the Investigational Device Exemption (IDE) regulation in Title 21 Code of Federal Regulations Part 812 (21 CFR 812), although many IVD studies are exempt from most of the provisions in this regulation.
For example, instead of “device for performance evaluation,” FDA refers to a device used in clinical studies as an “investigational device,” whether or not it is an IVD or other type of medical device. In Section 812.3(g) of the IDE regulation, “Investigational device” is defined as “a device, including a transitional device, that is the object of an investigation.” In Section 812.3(h) of the IDE regulation, “investigation” is defined as “a clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device.” No distinction is made between IVDs and other types of medical devices. This is important because European manufacturers may mistakenly believe that U.S. regulations and requirements related to clinical studies do not apply to IVD studies involving patient samples when they are used to support safety and effectiveness, or safety and performance in the case of studies for CE marking purposes.
Determining IDE study exemptions
It is critical that any company considering the inclusion of a site in the United States for the conduct of an IVD study evaluate the IDE regulation and the extent to which it is applicable to the IVD study. FDA guidance document “In Vitro Diagnostic (IVD) Device Studies – Frequently Asked Questions,” which can be downloaded from, was developed to provide general guidance on IVD study requirements. In particular, it addresses IVD studies that are exempt from most of the requirements under the IDE regulation.
In response to the second question in the guidance document—How do I determine the applicability of the IDE regulaton to my IVD study?—it is suggested that readers begin with the exemptions in 21 CFR 812.2(c) of the IDE regulation. This explains that an IVD study is exempt from most requirements of the IDE regulation if the IVD device:
•    Is properly labeled in accordance with 21 CFR 809.10(c)
•    Is noninvasive (the meaning of noninvasive is given in 21 CFR 812.3(k), which specifies that simple venipuncture is considered noninvasive)
•    Does not require an invasive sampling procedure that presents significant risk
•    Does not by design or intention introduce energy into a subject, and
•    Is not used as a diagnostic procedure without confirmation of the diagnosis by another medically established diagnostic product or procedure.
Readers should refer to FDA guidance for a complete discussion of these criteria.
Other U.S. regulations covering IVD studies
In addition to the IDE regulation, some of the other regulations that may apply to IVD studies include:
•    21 CFR 50, Protection of Human Subjects
•    21 CFR 54, Financial Disclosure by Clinical Investigators
•    21 CFR 56, Institutional Review Boards
•    21 CFR 809, In Vitro Diagnostic Products for Human Use
•    21 CFR 11, Electronic Records; Electronic Signatures
It should be noted that the regulations for the Protection of Human Subjects and Institutional Review Boards apply to all clinical investigations regulated by FDA under section 520(g) of the Food, Drug and Cosmetic Act. Therefore, all studies of investigational IVDs that will support applications to FDA are subject to 21 CFR 50 and 21 CFR 56, even if they are not subject to most of the requirements of 21 CFR 812.
With regard to informed consent, the guidance document titled, “Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that Are Not Individually Identifiable,” explains that FDA will exercise enforcement discretion with regard to informed consent requirements where IVD studies meet certain criteria, including the exemption criteria in 21 CFR 812.2(c), use of leftover specimens not individually identifiable and other criteria. Readers should refer to the guidance document for a complete explanation of this policy. It is available at
The requirements for financial disclosure in 21 CFR Part 54 apply to those submitting a marketing application for a human drug, biological product or device and who submit “covered clinical studies.” Readers should refer to the definition of “covered clinical study” in 21 CFR 54.2(e). The applicant must submit certification using Form FDA 3454, or disclosure statements using Form FDA 3455, where the applicant either contracted with one or more clinical investigators to conduct the studies or submitted studies conducted by others not under contract to the applicant.
In addition to the aforementioned regulations, it is useful to keep in mind that applicants of U.S. regulatory submissions must comply with the requirements for the registration of clinical studies in That is, a provision of the U.S. Public Health Service (PHS) Act, which went into effect on 26 December 2007, requires that a certification accompany certain human drug, biological product, and device applications and submissions to US FDA indicating that the requirements of the new provision have been met. The purpose of the certification is to provide a means for ensuring that the public has access to information about certain clinical trials. Form FDA-3674, “Certification of Compliance with Data Bank,” is the form that is used to document compliance with the clinical study registration requirements. It is important to refer to the FDA guidance document on the subject, available from It clarifies, for example, that under current FDA policies, a certification is not required for 510(k) submissions that do not refer to, relate to, or include information on or from a clinical study.
FDA guidance documents
Any manufacturer planning to use European performance evaluation study data in support of U.S. applications or submissions should identify any applicable FDA guidance documents that may have an effect on the study design. These guidance documents may be general or device-specific, and are listed on the FDA Web site,
For example, guidance document “510(k) Submissions for Coagulation Instruments,” issued on June 19, 2003, covers coagulation instruments (21 CFR 864.5400) and multipurpose systems for in vitro coagulation studies (21 CFR 864.5425). The guidance document recommends that the study device be evaluated in at least two external sites in addition to that of the manufacturer. Furthermore, performance should be assessed in the testing environment where the device ultimately will be used by individuals who will use the test in clinical practice, such as trained technologists.
An example of a more general guidance document on IVD devices, where the final result is qualitative, even if the underlying measurement is quantitative, is “Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests,” issued on March 13, 2007. This is an important guidance document, available at that provides advice on statistically appropriate practices for reporting results from studies evaluating qualitative diagnostic tests and practices considered inappropriate by FDA.
FDA–recognized standards
Before initiating IVD studies where the data will be used to support U.S. applications or submissions, manufacturers should determine whether FDA–recognized standards apply to the device being studied. This is also critically important because failure to comply with these standards can delay FDA approval or clearance. At the time of writing, 102 standards are listed for the in vitro diagnostics product area. A list of the standards can be obtained at by selecting the In Vitro Diagnostics product area. Once a relevant standard is identified, it is important to review the standard’s supplemental information, which can be accessed by clicking on the title of the standard. Supplemental information indicates the relevant CDRH offices and divisions associated with the standard, the devices covered by it, the affected application or submission processes, the extent of recognition of the standard, and other useful information.
Pre-IDE process
The pre-IDE process is an informal presubmission process, which may involve the transmission of analytical or clinical protocols to FDA for review and comment before proceeding with studies or questions on the regulatory pathway. In some cases, the process may involve telephone calls with the agency or even face-to-face meetings. The term pre-IDE has been used for this process so that FDA can assign it an official tracking number, just as numbers are assigned to 510(k)s and PMAs. The process does not mean that manufacturers are required to subsequently submit an IDE application. Information on the circumstances under which it is appropriate to request a protocol review or a pre-IDE meeting is provided on the FDA Web site at
BIMO program
In addition to regulatory differences between the United States and Europe regarding the regulation of IVD studies using patient samples, another important difference is that FDA conducts bioresearch monitoring (BIMO) inspections, which may include an evaluation of clinical investigators, sponsors, contract research organizations, and monitors involved in IVD clinical studies. Information on FDA’s BIMO program is provided at In addition to the general information on the BIMO program, FDA has developed a guidance document on BIMO inspections of IVDs, which can be downloaded from
European/U.S. IVD study strategy
This article covers important considerations and checks that should be made by manufacturers intending to use European IVD performance evaluation study data to support U.S. IVD applications or submissions. Depending on the particular IVD device, other important issues may need to be identified and addressed. The purpose of this article is to draw attention to the need to do this before costly and time-consuming performance evaluation studies are begun, so that needless duplication can be avoided. 

Maria E. Donawa, MD, is a physician, pathologist, and pharmacist with more than 30 years’ regulatory experience. She worked with FDA before becoming president of what is now Donawa Lifescience Consulting (Rome, Italy;, a full-service European CRO and international consultancy company that provides regulatory, quality, and European Authorised Representative services to life-science companies. Donawa can be reached at

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