Medical Device Link.

Originally Published IVD Technology March 2004

REGULATIONS & STANDARDS

Debra M. Foster is director of clinical studies and Anastasia N. Derzko is biostatistician at Spectral Diagnostics Inc. (Toronto). They can be reached at here and here, respectively.

Conducting clinical research in the IVD industry is challenging. It encompasses a broad range of activities, from consumer preference studies to fully regulated pivotal studies. One of the most challenging aspects of clinical research is developing a sound body of clinical evidence that establishes an IVD’s effectiveness and safety. In addition, the processes involved in producing these clinical results must be rigorous and thorough. 

Good clinical practice (GCP) is an internationally recognized ethical and scientific quality standard for designing, conducting, recording, and reporting clinical trials that involve human subjects. GCP enhances study validity by ensuring the quality of clinical trials. Complying with GCP also ensures that the rights, safety, and well-being of trial subjects are protected, and that the clinical trial data are credible.¹ 

In most cases, how well a clinical trial is conducted can determine whether an IVD’s application for market approval is successful or becomes an extended, expensive, and frustrating experience. Therefore, IVD manufacturers should not only comply with the relevant legal requirements in the Code of Federal Regulations (CFR), but also employ international GCP guidelines when planning and conducting all clinical studies. This article will explore both FDA’s and the International Conference on Harmonization’s (ICH) GCP requirements that apply to IVD clinical studies. 

GCP Regulations and Standards

In the United States, FDA regulations related to GCP have been established in the CFR. The agency regulates all clinical investigations involving human participants, including human tissue samples, in biomedical research according to the laws in the CFR. This includes studies that support marketing applications for IVDs. Complying with these regulations is mandatory to ensure the protection of the rights and safety of subjects involved in clinical investigations. These regulations cover such areas as informed consent, institutional review boards (IRB), electronic records, and investigational device exemptions (see Table I).

At the same time, as global harmonization of regulatory standards emerged during the 1990s, ICH released a document entitled, “Good Clinical Practice Consolidated Guideline.”² This document has been adopted as the international guideline that clearly defines the roles and responsibilities of the investigators and sponsors in clinical studies. This guideline also explains how clinical trial protocols should be prepared according to international standards, and the investigators’ and the sponsors’ responsibilities regarding essential documents.¹

Table I. FDA regulations related to good clinical practice as established in the Code of Federal Regulations (click to enlarge).

While the CFR dictates the legal requirements relating to GCP, explicit guidance on how to perform clinical trials is not included in the CFR. On the other hand, ICH’s GCP guidelines provide such a quality standard for conducting clinical studies. IVD manufacturers should therefore follow not only the GCP requirements in the CFR, but also the ICH guidelines, to ensure that clinical studies are founded on good science. Following these regulations also ensures manufacturers that their clinical trial activities and data adhere to documentation rules such that the appropriate and historical study-related information of an IVD’s performance is maintained. In addition, employing ICH’s GCP guidelines assures a successful inspection in the event that clinical trial data are inspected and audited by third parties.

By launching the Office of Good Clinical Practice, FDA has shown clear support for the use of GCP as part of the quality assurance process for clinical studies.³ The agency’s Good Clinical Practice Program promotes greater contact between FDA and the IVD industry, and provides guidance and direction regarding the quality assurance of clinical trials.⁴

With FDA demanding increased rigor in clinical studies supporting IVD pre-market applications, and the global pressures for harmonizing study design and performance, the success of IVD clinical studies depends on more than merely complying with the regulations. Such success also depends on following international standards for good clinical practice as established in the ICH GCP guidelines. However, while compliance with the ICH guidelines carries numerous advantages, study sponsors should be aware of the potential burdens associated with compliance (see Table II).⁵

Implementing GCP

Table II. The advantages and disadvantages of implementing good clinical practice.21 (click to enlarge).

One of the primary GCP requirements for IVD studies is the drafting of a clinical trial protocol. A clinical trial protocol is a complete written description of and scientific rationale for a research study involving human subjects. The protocol must address the following three elements: study objectives and methods, study design and statistical requirements, and ethical principles. 

Study Objectives and Methods. The first step when developing a clinical trial protocol is to establish clear study objectives that may form the basis of a study’s regulatory claims. Once the study objectives are established, the next step is to determine the study methods: what information, both clinical and device related, will be collected and how this information will be recorded. For example, if the study is to analyze the sensitivity and specificity of a proposed diagnostic test, then the protocol must include comparisons to a gold standard, whether it is another diagnostic test, if available, or an established clinical diagnosis. 

Analyzing an IVD’s performance can be difficult due to the common lack of a gold standard. As a result, an IVD must often be compared to an imperfect standard, which may lead to discrepant results, a situation in which the new test and the standard disagree. These discrepant results may be due to errors in the new test or deficiencies in the standard. Resolving such discrepant results is often done by retesting those samples where the two tests disagreed, against another standard, to assess which one is right. This may significantly alter the analysis of an IVD’s performance. Analytical methods for resolving such discrepant results with measurable and attainable endpoints form an important part of a sound study. Guidance on this topic for IVDs can be found in an FDA statistical document.⁶

Study Design and Statistical Requirements. Having established the study methods, selecting appropriate study sites, as well as qualified individuals to perform the necessary diagnostic procedures and carry out the clinical protocol, is the next step. The process of determining study design also includes deciding appropriate patient populations, sample sizes, and statistical analysis methods that address the objectives of the study.
Regarding statistical requirements, although ICH released statistical principles for clinical trials as part of its GCP guidelines, they are clearly directed toward trials for assessing therapeutic efficacy. However, the key objective of these statistical principles is to provide “guidance to deal with minimizing bias and maximizing precision,” which is also of integral importance in IVD clinical studies.⁷ 

Meanwhile, in March 2003, FDA issued a draft guidance specifically for statistical reporting of results from studies evaluating diagnostic tests.6 This guidance describes statistical methodologies for analyzing diagnostic tests, as well as alternative procedures for those diagnostic devices that may not fit the classical paradigm. Such methods as the reporting of sensitivity and specificity (i.e., classical paradigm) versus the reporting of agreement using an imperfect standard (i.e., no gold standard) are discussed. The guidance also outlines FDA’s requirements with respect to data presentation for diagnostic tests. For example, in cases where a qualitative result is obtained from an underlying quantitative test result, data ranges, histograms of results by disease state, and receiver operator characteristics plots should be included. 

Table II. The advantages and disadvantages of implementing good clinical practice.21 (click to enlarge).

The FDA statistical guidance identifies the methods used by agency statistical reviewers to scrutinize the data presented in support of market applications for diagnostic devices. Its recommendations exceed those in the ICH GCP guidelines and represent the elements required to enhance the likelihood of approval for a diagnostic test. Although this document is a draft guidance and therefore non-binding, it represents FDA’s current position and direction on this topic and as such is meant to guide IVD manufacturers in their clinical trials and regulatory submissions.

Ethical Principles. In any clinical trial, ensuring the safety of human subjects is of paramount importance, and is the primary goal of the ICH GCP guidelines. Assuring patient safety requires not only that a clinical trial protocol be founded in good science, but also that the anticipated benefits of the study justify the potential risks.¹

In order to protect human subjects, study sponsors create consent forms that must contain the legally required elements as established in the CFR. The ICH GCP guidelines also contribute an expanded list of additional informed consent requirements (see Table III). Consent forms are subject to approval by internal review boards or ethics committees. For multisite studies, a somewhat different informed consent form may be required at each site.^8,9

While the majority of IVD studies are considered minimal-risk, a determination of minimal risk must be made by each individual IRB. It is not uncommon to have multiple determinations of this status depending on the requirements of the reviewing IRB.^8,9 Typically, minimal-risk studies qualify for expedited review depending on the procedures set by the reviewing IRB. This potential advantage can minimize the turnaround time for reviews. 

In addition, it is extremely rare for a draft consent form submitted by a sponsor to be accepted upon initial review by the IRB. Even a minimal-risk study must contain the required elements of a consent form. Therefore, for a complicated study protocol, an informed consent document may be many pages long. This poses a challenge, as the timing of informed consent may be critical. A study representative must be aware of and available to administer the informed consent document at the time when the decisions for diagnostic tests are made. 

Maintaining Documentation

FDA assesses compliance with the regulations governing clinical investigations by reviewing a variety of documents. For these purposes, accurate and complete study documentation is important. IVD clinical investigators should maintain meticulous records pertaining to the test devices—such as the date they were received, the lot numbers, and records of the use of test devices for study subjects. It is important to prove test device accountability via record sheets that show that all devices distributed were used according to the study protocol. 

Accurate recordkeeping and product accountability is important in any research undertaking, irrespective of the type of research that is conducted. Although IVD clinical trials possess some unique records that must be reported, such as signed training certificates for device users and signature logs for laboratory personnel using the test device, in general the documentation requirements for IVD studies dictate that standard good clinical practices should be followed. 

Conclusion 

Clinical evaluation is an integral component of the design verification and validation process for IVDs.¹⁰ Clinical trials of IVDs must be conducted to a standard of scientific rigor equivalent to that applied to any other innovation in medicine. Accordingly, there continues to be pressure on IVD manufacturers to increase the breadth and scope of clinical investigations in order to provide valid scientific evidence for the safety and effectiveness of new IVDs. However, the growing trend toward global harmonization of medical device regulations and integration of the ICH GCP guidelines will decrease the confusion and difficulties of bringing new products to the various global markets. Reliance on solid clinical trials conducted in accordance with GCP guidelines will continue to prove invaluable in bringing new and needed diagnostics to market. 

References

1. Guidance for Industry E6 Good Clinical Practice: Consolidated Guideline (Geneva: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), 1996) [accessed 14 January 2004] available from Internet: www.fda.gov/cder/guidance/959fnl.pdf.  

2. International Conference on Harmonization 20/08/03 [accessed 14 January 2004] available from Internet: www.ich.org/IxtServer.jser?@_ID=250&@_TEMPLATE=272.  

3. Guidances and Information Sheets on Good clinical Practice in FDA-Regulated Clinical Trials [accessed 14 January 2004] available from Internet: www.fda.gov/oc/gcp. 

4. DA Lepay, “Good Clinical Practice (GCP), Quality Assurance, and FDA” (paper presented on-line, November/December 2001) [accessed 27 January 2004] available from Internet: www.fda.gov/oc/gcp/slideshows/lepay2001/SQAWeb.ppt.  

5. C Nutley, “Values & Benefits: The Values and Benefits of ICH for Industry” Therapeutic Products Directorate Web site (Geneva: International Federation of Pharmaceutical Manufacturers, 2000) [accessed 14 January 2004] available from Internet: www.ich.org/IxtServer.jser?@_ID=465&@_TEMPLATE=272. 

6. Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests; Draft Guidance for Industry and FDA Reviewers [accessed 14 January 2004] available from Internet: www.fda.gov/cdrh/osb/guidance/1428.html.  

7. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Statistical Principles for Clinical Trials E9 [accessed 14 January 2004] available from Internet: www.ich.org/UrlGrpServer.jser?@_ID=475&@_TEMPLATE=272#E9.  

8. JM Hirshon et al., “Variability in Institutional Review Board Assessment of Minimal-Risk Research,” Academy of Emergency Medicine 9, no. 12 (2002):1417–1420.

9. H Silverman, SC Hull, and J Sugarman, “Variability Among Institutional Review Boards’ Decisions within the Context of a Multicenter Trial” Critical Care Medicine 29, no. 2 (2001): 235–241. 

10. “Therapeutic Products Directorate Guidelines, ICH Harmonized Tripartite Guideline: Good Clinical Practice: Consolidated Guideline, Minister of Public Works and Government Services Canada 1997,” Therapeutic Products Directorate Web site [accessed 14 January 2004] available from Internet: www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/goodclin_e.html.   

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