Medical Device Link.

Originally Published IVD Technology September 2004

REGULATIONS & STANDARDS

Donald M. Powers, PhD, is president and principal consultant of Powers Consulting Services (Rochester, NY), an independent IVD regulatory and quality consulting firm, and a member of the IVD Technology editorial advisory board. He can be reached at powers@frontiernet.net.

Last June, the members of TC212, the International Organization for Standardization (ISO; Geneva) technical committee that develops standards for clinical laboratory testing and IVD test systems, gathered in Utrecht, The Netherlands, for its annual meeting. At the meeting, the committee worked on advancing six more international standards through the ISO standardization process. These standards will be added to the IVD standards that have already been approved since TC212’s inception in 1995. 

The first installment of this article (IVD Technology, July/August 2004) described navigating through the ISO process, as well as why IVD manufacturers should be involved in developing any new standards. This installment will summarize the status of these new standards that have potential regulatory significance to manufacturers.

A standard in and of itself has no regulatory significance. However, while in theory the choice to follow a standard is voluntary, certain standards are less optional than others in practice. For example, in the United States, the pressure to follow a particular standard comes from the perception that FDA reviewers and investigators tend to look more favorably upon those submissions that conform to standards recognized by the agency. 

In Europe, IVD manufacturers are granted a presumption of compliance with the essential requirements of the EU directives if they declare conformance to European harmonized standards. Many of the TC212 standards are now recognized by FDA and are accepted as harmonized standards by the European Commission. Such incentives are difficult to ignore, and manufacturers have found it advantageous to follow the ISO standards.

TC212’s working group 3 has several active projects that should be of interest to IVD manufacturers. Since the projects are at different stages of development, the following discussion will illustrate the steps in the ISO standardization process, which was discussed in part 1. 

Risk-Management Guidelines

TC212 has developed guidelines for the application of risk-management principles to IVDs. These guidelines will be included in ISO 14971, the international standard for applying risk management to medical devices, as Annex H. 

Since ISO 14971 was already undergoing revision, working group 3 had to act quickly. A small project team, consisting of a few IVD manufacturers, regulators, and laboratory-based physicians, proposed draft guidelines last June. 

The members of TC210 and TC212 jointly approved the IVD annex with the second committee draft (CD) of ISO 14971:200x. The comments received with votes are now being addressed in preparation for the draft international standard (DIS). This joint effort between TC210 and TC212 provides those IVD manufacturers not participating in TC210 with an opportunity to comment on the parent risk-management standard in addition to the IVD annex.

So far, few U.S. IVD manufacturers have shown an interest in having a say in the risk-management guidelines that they eventually will have to follow. Only a few IVD companies participated in drafting the guidelines, and few industry comments were received when the early working drafts were circulated. Such apathy is surprising, considering the current regulatory focus on risk management. 

The voting record at the CD stage was even worse, Only two U.S. IVD manufacturers voted on the proposed guidelines, and only one submitted comments. Meanwhile, FDA, the College of American Pathologists (Northfield, IL), and the American Association for Clinical Chemistry (Washington, DC) all submitted comments, as did several individual hospital members of the technical advisory group (TAG).

If IVD companies were waiting to see how the risk-management standard turned out at the DIS stage before taking a position, they may have missed the opportunity to do so. The technical content of an ISO standard is finalized at the CD stage. According to the ISO directives, substantive technical changes are not allowed at the DIS stage (as explained in part 1). However, ISO/TC210 and IEC/SC62A are still debating how to address the risk of “use errors” and “reasonably foreseeable misuse” and are considering a third CD vote before moving the revised ISO 14971 to the DIS stage. This would give U.S. IVD manufacturers one last chance to recommend changes. 

Harmonizing Global Labeling Requirements

Uniform labeling requirements around the world has been a seemingly impossible dream of IVD manufacturers. However, since the European countries managed to reach a consensus on a series of labeling standards, expanding them to the rest of the world no longer seems impossible. 

Toward this end, working group 3 drafted a technical report (ISO/PDRT 18112) that compiles and analyzes the IVD labeling requirements of the major Global Harmonization Task Force (GHTF) partners, Australia, Canada, Japan, the European Union (EU), and the United States, at this moment in time. Although intended to assist the GHTF and standardization efforts, this report also gives global IVD manufacturers a comprehensive, although not authoritative, summary to evaluate their worldwide labeling.

The centerpiece of the report is a large table of labeling requirements as well as recommendations from the relevant GHTF guidance documents. The labeling standards developed by the Committee for European Normalization (CEN) were used as the basis for comparison, since the ISO standards are being developed from the European standards. This should increase the likelihood that the ISO labeling standards will be accepted by the European Commission as official European harmonized standards.

The report highlights the similarities and differences in labeling requirements that IVD manufacturers encounter. It illustrates the dilemmas that manufacturers confront when trying to accommodate all the various requirements in a single label or labeling document. While the report demonstrates that most of the labeling requirements are compatible, it also shows how apparently minor differences can have significant ramifications.

For example, in the United States, small reagent containers are exempted by the Food, Drug, and Cosmetic Act from having to include all of the information normally required on the immediate container label, provided that none of the label space is used for words or symbols not required by U.S. law. The EU also has a small-vial exemption, but requires some information not applicable in the United States. Consequently, if the EU requirements are satisfied (e.g., by including the name of the EU authorized representative), then an IVD manufacturer is denied the small-vial exemption in the United States. Unfortunately, this requirement has been established by U.S. law, which is more difficult to update than a regulation.

In preparing the technical report, working group 3 had to contend with a moving target, since regulatory requirements are continuously evolving. IVD labeling requirements are presently undergoing major changes in Japan and Australia. Nevertheless, the report will allow participating countries to compare the proposed ISO labeling standards against current global requirements.

TC212 unanimously approved the technical report on July 1, 2004. After working group 3 makes updates and corrections to the report, it will be submitted to the TC212 membership for a final vote.

ISO Labeling Standards

The first in the series of international standards on labeling IVD products (ISO/CD 18113-1), which covers reagents for professional use, was unanimously approved at the CD stage with few comments. This is a good sign that international consensus may be possible. In fact, most of the work done in Utrecht on labeling standards dealt with resolving terminology differences, rather than debating the content.

Working group 3 decided to consolidate the general labeling requirements and definitions into a separate document. This will avoid repeating the same general information in all the standards, in accordance with ISO policy. The labeling standards will comprise a five-part series: general requirements and definitions; labeling of reagents for professional use; labeling of reagents for self-testing; instructions for use for instruments for professional use; and instructions for use for instruments for self-testing.

ISO’s ambitious project is intended to support the harmonization of worldwide labeling requirements. Once harmonized, IVD manufacturers can satisfy the requirements of different countries with the same instruction manuals and package inserts. The ISO standards also address state-of-the-art methods of delivery and essential information content. In addition, working group 3 is aligning the labeling standards with the GHTF recommendations to cover the requirements in other countries worldwide. It is expected that the ISO labeling standards will eventually replace the four European standards for the purpose of supporting the essential requirements of the IVD Directive.

Oral Anticoagulation Therapy Monitoring Systems

The standard for oral anticoagulation monitoring systems (ISO 17593) was expected to be controversial, given the lack of consensus on performance criteria and whether patients should be allowed to perform self-monitoring. That prophecy came true. However, a team led by a clinical professor of hematology from Munich rose to the challenge and forged a consensus on criteria that were largely based on unpublished data from studies sponsored by IVD manufacturers. 

To support the chosen criteria, the manufacturers participating in the project agreed to create an annex that provides the rationale for the criteria and includes the scientific and clinical data. Representatives from FDA, the New York Health Department, the Cleveland Clinic, and several leading manufacturers made up the U.S. delegation.

The CD of ISO 17593 was approved in March by a vote of 14 to 2. Dissenting votes at the CD stage are often used to add emphasis to a country’s concerns. In the case of this standard, the comments accompanying the dissenting votes indicated that they disagreed with requiring IVD manufacturers to provide a validated quality assurance (QA) scheme, which was intended to be a good thing. The voters felt QA responsibility should belong to the medical community, independent of the manufacturers. ISO 17593 does not preclude this requirement at the national level. However, since this ISO standard is written only for manufacturers, the responsibilities of third parties are outside its scope. Any standard intended for manufacturers cannot dictate such requirements for the medical community. This is clearly a misunderstanding about the intended audience for the standard, which will be clarified in the next iteration of the standard.

Since being approved by TC212 at the CD stage, ISO 17593 is currently being advanced to the next level, the DIS stage. Decisions regarding the comments were reached at the working group 3 meeting in June, and the revisions have been made. Now the DIS is waiting for the IVD manufacturers to complete the informative annex. If they finish the annex soon, ISO/DIS 17593 could be released for comment and voted on before year-end.

Validating User Quality Control Procedures by the Manufacturer

Manufacturers of professional-use IVD products generally leave quality control (QC) decisions to the laboratories, and most laboratory directors seem to want it that way. However, in some cases, manufacturers may need to provide a specific QC procedure. ISO 15198 outlines a generic process that manufacturers could follow to validate a QC procedure if they choose to recommend one.

The standard was initiated when the 1988 Clinical Laboratory Improvement Amendments included a provision that allowed laboratories to implement reduced QC testing if FDA reviewed and cleared a manufacturer’s validated QC procedure. Validating QC was a new concept at the time. Essentially, it means that a manufacturer has to provide objective evidence that proves that its QC recommendations are effective in detecting erroneous results, or conditions that produce them. With no consensus on how to validate QC (FDA’s initial attempt at guidance met with substantial industry resistance), U.S. manufacturers proposed that TC212 should get all the interested parties involved and develop a consensus standard. Although the initial impetus for the standard has since gone away, the project continued because the working-group members, including half of the participating IVD manufacturers, felt the objective was ultimately worthwhile.

QC for IVDs can be based on statistical control procedures, computerized system checks, or alternative approaches to detecting erroneous results. Unfortunately, it is not possible to develop a single approach that could apply to all devices. Due to the diversity of IVDs and control procedures, ISO 15198 does not contain specific guidance for validating QC recommendations.

After several iterations, a final draft international standard was unanimously approved by the ISO community and should be published by year-end.

QC validation strategies are new to many IVD manufacturers, even though existing standards require them to validate and verify any QC systems they implement as a risk control. Proving a QC scheme can detect fault conditions that would lead to erroneous results requires a different approach than one would use to validate a design or process. A strategy comparable to International Conference on Harmonization guidelines for validating analytical methods, in which validation is based on showing that the performance is suitable for identifying nonconforming product, would make more sense here.

Some industry members of the U.S. TAG entertained proposing an informative annex with guidelines and specific examples. Such an annex would make ISO 15198 more useful to IVD manufacturers, and would promote consistent interpretation by regulatory bodies that recognize this standard. So far, no action has been taken. If manufacturers agree to provide some relevant examples, an annex could be added in the future by amendment. Otherwise, it is doubtful that this generic standard will be helpful to IVD manufacturers.

Other Related Matters

The role of international standards in the United States and their relationship to the European IVD standards continue to be sources of confusion. Clarifying such issues may be helpful.
The implementation of the IVD Directive was supported by a series of harmonized IVD standards developed by CEN. They are often called mandated standards, not because using them is mandatory, but because the European Commission gave CEN a mandate to develop them. The standards are still voluntary.

Some U.S. manufacturers still regard ISO as a European organization that has little relevance in the United States. Such thinking is dated, considering that the secretariats of TC210 and TC212 are in the United States (the Association for the Advancement of Medical Instrumentation for TC210, and NCCLS for TC212), two of the four TC212 working-group conveners are Americans, and U.S. IVD manufacturers have been heavily involved in many of the ISO projects. Their goal is to create international standards and avoid regional standards whenever possible.

As for the relationship between CEN and ISO, they have a formal agreement that is intended to avoid duplicating efforts. Many of the TC212 projects were undertaken as joint projects, with either CEN or ISO taking the project lead, and parallel voting by each organization. In the end, the standards bear both EN and ISO designations when used in Europe.

With the initial TC212 program nearing its completion, the list of CEN standards should be evaluated and considered as candidates to be converted to international standards. The labeling standards discussed above are a good example of European standards that are being expanded to worldwide application. 

Copyright ©2004 IVDT echnology