Regulations & Standards

Published: November 7, 2012
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Proposed Guidance on IVD Clinical Evidence and Performance Evaluation

Manufacturers of IVD devices should be aware of three proposed Global Harmonization Task Force guidance documents on clinical evidence for IVD devices.

By: Maria E. Donawa

Manufacturers of IVDs should be aware of three proposed Global Harmonization Task Force guidance documents on clinical evidence for IVD devices.Manufacturers of IVD devices should be aware of three proposed Global Harmonization Task Force guidance documents on clinical evidence for IVD devices. The documents cover definitions and terminology, determining scientific validity, performance evaluation, and clinical performance studies.
The Global Harmonization Task Force (GHTF), created in 1992 in an effort to promote the international harmonization of medical device regulation, is a voluntary group of representatives from national medical device regulatory authorities and the regulated industry. GHTF develops guidance documents that provide a model for the regulation of medical devices that can then be adopted by regulatory authorities. The model, which is based on a set of Essential Principles of Safety and Performance, is closely aligned with the European medical device regulatory framework.
The GHTF soon will be replaced by the International Medical Device Regulators Forum (IMDRF), created in February 2011 to discuss future directions in medical device regulatory harmonization. In contrast to the GHTF, membership is limited to representatives from medical device regulatory authorities; however, IMDRF may permit nonregulator stakeholders to join working groups. Fortunately, IMDRF has indicated that it will develop a formal strategy for the management and maintenance of GHTF documents. The adoption of the documents discussed in this article, expected to occur in late October 2012, and their subsequent publication, will be managed by GHTF; however, future revisions will be managed by IMDRF.

Guidance on Key Definitions and Concepts

The proposed document, Clinical Evidence for IVD Medical Devices–Key Definitions and Concepts, dated September 16, 2011, can be obtained from the GHTF website. As with all three proposed documents discussed here, the contents could change as a result of comments received or further deliberations during development of the final document.
The proposed document provides definitions and explanations for the following terms:

  • clinical evidence of an IVD medical device;
  • scientific validity of an analyte (measurand);
  • performance of an IVD medical device, including analytical performance and clinical performance;
  • performance evaluation of an IVD medical device;
  • clinical utility of the IVD medical device;
  • intended use/purpose.

In addition, it attempts to illustrate, with a figure consisting of two overlapping circles, that scientific validity and clinical performance are common elements of clinical evidence and clinical utility.
For example, “clinical evidence of an IVD medical device” is defined as “all the information that supports the scientific validity and performance for its use as intended by the manufacturer.” The term “performance evaluation of an IVD medical device” is defined as the “assessment and analysis of data to establish or verify the performance of an IVD medical device.” The proposed document also explains that performance evaluation data “are typically generated from verification and validation studies (including, where appropriate, clinical performance studies using human specimens) or obtained from a literature review that confirms the performance characteristics of the product.” These definitions are consistent with the requirements specified in the In Vitro Diagnostic Medical Devices Directive (IVDD; 98/79/EC). That is, the conformity assessment procedures of the IVDD, which specifies that performance evaluation “data should originate from studies in a clinical or other appropriate environment or result from relevant biographical references.” The new proposal for a European IVD regulation is even more closely aligned with the GHTF approach. In addition, GHTF concepts are consistent with the process of evaluating clinical data for establishing or supporting safety and effectiveness of an IVD medical device for U.S. clearance or approval; however, it will be necessary to comply first and foremost with all applicable U.S. laws and regulations and, where appropriate, follow relevant FDA guidance documents. It is also useful to note that FDA has stated that the principles outlined in an agency guidance document on the use of published literature for supporting Premarket Approval (PMA) supplements may be applicable to 510(k), PMA, and Humanitarian Device Exemption submissions.1

Scientific Validity and Performance Evaluation

The proposed document, Clinical Evidence for IVD Medical Devices - Scientific Validity Determination and Performance Evaluation, dated September 16, 2011, can be obtained from the GHTF website. The purpose of the document is to provide guidance on how to collect and document clinical evidence for an IVD medical device as part of the conformity assessment procedure before placing the device on the market, as well as to support its ongoing marketing. It is also intended to provide guidance to regulators and others when assessing clinical evidence provided by manufacturers.
The principal areas covered in this document are: definitions, general principles of clinical evidence, scientific validity determination, performance evaluation (including analytical performance and clinical performance), and clinical evidence report. Appendix A provides a possible format for a literature search report. Appendix B includes a flow chart illustrating possible methodology for documenting, screening, and selecting literature within a literature search report. The definitions provided in the document, such as “diagnostic sensitivity,” “diagnostic specificity,” “examination,” and others are consistent with the European harmonized standard, EN ISO 18113-1:2011, In vitro diagnostic medical devices - Information supplied by the manufacturer (labelling) - Part 1: Terms, definitions and general requirements (ISO 18113-1:2009).
Section 5.0, General Principles of Clinical Evidence, provides useful concepts regarding clinical evidence and
its importance as well as information on methods for generating and documenting clinical evidence for an IVD medical device.
Section 6.0, Scientific Validity Determination, discusses when it is necessary to determine scientific validity, the potential sources upon which to base scientific validity, and important principles in the appraisal and analysis of scientific validity information.

Performance Evaluation

Section 7.0, Performance Evaluation, of the proposed document on scientific validity determination and performance evaluation, places IVD medical devices into three categories: established and standardized tests, established and nonstandardized tests, and novel tests, referring to these categories when providing guidance on the type of analytical performance data, and, where appropriate, clinical performance data that should be generated. Section 7.1, Analytical Performance, explains that analytical performance, namely technical test performance, generally using human specimens, is always expected for IVD medical devices. The document states that analytical performance data may include data to demonstrate accuracy (in terms of trueness and precision), analytical sensitivity, analytical specificity, linearity, limit of detection and limit of quantitation, cut-off, measuring range, carry-over, determination of appropriate specimen collection and handling, and endogenous interference on assay results.
The guidance provided in Section 7.2, Clinical Performance, is analogous to guidance on clinical evaluation as part of the European CE marking process and GHTF guidance applicable to medical devices other than IVD medical devices.2, 3 The potential sources of clinical performance data can be derived from clinical performance studies, literature, and experience gained by routine diagnostic testing. Each of these data sources is discussed in this section; however, a separate guidance document has been developed for clinical performance studies and is discussed next. Once clinical performance data have been identified, the data must be appraised to determine the relevance and quality to address questions about the IVD medical device and the data’s contribution to demonstrating the device’s clinical performance. A clinical performance analysis collectively evaluates all appraised information in terms of weight and significance.

Clinical Performance Studies

The proposed document, Clinical Performance Studies for In Vitro Diagnostic Medical Devices, dated January 26, 2012, can be obtained from the GHTF website. It begins by stating that the purpose of a clinical performance study is to validate aspects of IVD medical device performance that cannot be determined by analytical testing, literature, or previous experience gained by routine diagnostic testing. A discussion of all sections of the document is beyond the scope of this article; however, three are discussed below.
Section 6, Clinical Performance Study Design Type, discusses the types of clinical performance study designs as observational or interventional. An observational study refers to a study in which test results are not used for patient management and do not impact treatment decisions. Interventional studies are those in which test results may influence patient management decisions and may be used to guide treatment. Readers should refer to the proposed document for a full description of these types of designs. The proposed document also lists several practical examples of each type.
Section 7, Clinical Performance Study Design Considerations, discusses the effect that the test purpose, such as diagnosis, screening, or monitoring, will have on the study design, such as sample size. This section also discusses the use of different types of samples in clinical performance studies, including purposefully collected, leftover, and archived specimens. Other parts of this section provide guidance regarding site location, statistical design, potential risks, and ethical considerations, including informed consent and ethics committee involvement.
Section 8, Clinical Performance Study Protocol, provides a useful list of important information that should be provided regarding study design such as: purpose, objectives, study population, description of test method(s) and interpretation of results, site training and monitoring, specimen type, specimen collection, preparation, handling and storage, inclusion and exclusion criteria, limitations, warnings and precautions, data collection/management, data analysis, required materials, and number of study sites.

Word of Caution

The content of the GHTF IVD medical device proposed documents discussed in this article could change before publication as final documents. Nonetheless, even as proposed documents, they provide useful interpretations concerning important principles and concepts on IVD performance evaluation data. Manufacturers using these proposed documents, and eventually their final versions, in their efforts to meet specific country and regional regulatory requirements will need, however, always to base their actions on the laws and regulations in those regions or countries, as well as on relevant standards and guidance documents, and the results of any consultations with official bodies and regulatory authorities.

References

1. Center for Devices and Radiological Health, FDA, Guidance for Industry - Supplements to Approved Applications for Class III Medical Devices: Use of Published Literature, Use of Previously Submitted Materials, and Priority Review (20 May 1998), www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments...
2. Global Harmonisation Task Force, Clinical Evaluation (May 2007), www.ghtf.org/sg5/sg5-final.html
3. Clinical Evaluation: A Guide for Manufacturers and Notified Bodies (MEDDEV 2.7.1 Rev.3, December 2009); http://ec.europa.eu/enterprise/sectors/medical-devices/files/meddev/2_7_...

Maria E. Donawa is a physician, pathologist, and pharmacist with more than 30 years’ regulatory experience. She can be reached at medonawa@donawa.com.
 


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