Medical Device Link.

REGULATIONS AND STANDARDS

Donald M. Powers, PhD, is president and principal consultant of Powers Consulting Group (Pittsford, NY) and is a member of IVD Technology’s editorial advisory board. He can be reached at powers@ frontiernet.net.

This year, the Global Harmonization Task Force (GHTF) is celebrating its 15th anniversary.

During its brief existence, GHTF has been working behind the scenes to examine existing regulatory systems and promote the convergence of international regulatory requirements and practices. This article will discuss the accomplishments of GHTF’s five study groups and describe how the IVD subgroup is addressing the unique aspects of IVD products.

Understanding and complying with international IVD regulations became easier during the past decade, at least for premarket submissions, with the harmonization of regulatory systems throughout Europe. The European competent authorities have now shifted their interests to postmarket surveillance. However, new and updated regulations from Asian countries are starting to emerge at a rapid pace. Although the new entrants tend to build on existing regulatory models, the individual countries often adopt what they perceive as the best individual regulatory practices and end up creating new, and therefore unharmonized, regulatory approaches.

Since 1992, GHTF, a global consortium of the major medical device regulatory authorities and industry trade associations, has been working to avoid such further proliferation of diverse regulatory requirements.^1,2 While most quality and regulatory professionals in the IVD industry know about GHTF, few can explain how it operates or what it has accomplished during the past 15 years. Even though GHTF may have had a relatively low profile in the IVD industry, that is about to change as medical device regulators turn their attention to harmonizing IVD regulations.

GHTF has been attempting to identify the best regulatory practices related to ensuring the safety, effectiveness, and quality of medical devices, and to develop guidance documents that regulatory bodies can use to develop harmonized national legislation. The expected outcome of such harmonization is a reduced impact of regulations on technological innovation and international trade. To this end, GHTF has developed a global regulatory model that can serve as the basis for harmonizing regulatory practices among members. As countries update their regulations and develop new regulations, GHTF hopes they will adopt this new model.

Of course, reaching consensus on a proposed regulatory model is not the same thing as actual harmonization of regulations. In any harmonization process, since countries may have to give up practices they like and adopt others they do not like, convergence on a common regulatory model takes time. For example, the United States has been slow to move toward harmoniza- tion in some areas because so many FDA requirements are dictated by laws and regulations that are not easy to change. In addition, medical device manufacturers are afraid that revisiting existing regulations could result in even more burdensome requirements. Nevertheless, everyone agrees that harmonization of global regulations is still a worthy goal.

GHTF’s current chair, Larry Kessler of FDA, agrees it is time for action on the GHTF initiatives. At a recent conference on medical device standards and regulations held by FDA and the Association for the Advancement of Medical Instrumentation (AAMI), he cited greater use of GHTF guidance documents, single audits on behalf of multiple jurisdictions, and the exchange of vigilance reports among national competent authorities as top priorities during his term.³

GHTF Study Groups

GHTF established five study groups (SG) to focus on different areas of regulation. Each SG includes members from each region of the world, balanced between regulatory and industry advocates. GHTF activities are managed by a steering committee, with leadership rotating among the five founding members (Australia, Japan, Canada, United States, and Europe).

Study group 1 is responsible for developing a global framework to harmonize regulatory systems, including identifying the regulatory principles suitable for harmonization and those that present obstacles to converging on uniform regulations. GHTF assigned SG1 the specific tasks of developing a standardized format that could be used for premarket submissions worldwide and proposing essential labeling requirements.

Table I. (click to enlarge) The regulatory questions answered by SG1’s guidance documents.

SG1 outlined the logic behind its work program in the series of questions and answers shown in Table I, with the answers being a series of guidance documents.⁴ All of these documents are available on GHTF’s Web site (www.ghtf.org).

The scope of study group 2 includes all aspects of vigilance (e.g., adverse-event reporting) and postmarket surveillance. SG2 is attempting to harmonize data collection and reporting systems so that governments can share information about adverse events more efficiently.

Study group 3 covers quality management system requirements. Its work has been closely aligned with ISO TC210, the ISO technical committee responsible for developing quality management standards for medical devices. This active collaboration resulted in an updated edition of ISO 13485 that continues to serve regulatory purposes, even as ISO 9001 has moved in a different direction.

The challenge of examining the auditing practices of member countries and harmonizing regulatory auditing was assigned to study group 4. Eventually, countries may develop enough confidence in the auditing process to accept each others’ inspections with full reciprocity, which would benefit the IVD industry greatly. While the main series of documents produced by SG4, “Guidelines for Regulatory Auditing of Quality Systems,” are of major importance to regulators, individual IVD manufacturers will probably find them of limited interest.

Study group 5, the most recent addition to the GHTF organizational structure, was formed to define the clinical evidence required to demonstrate a medical device’s safety and performance. SG5 is concentrating on harmonized definitions for commonly used terms (e.g., clinical investigation, clinical data, clinical evaluation, clinical evidence), harmonized guidance on the content and format of clinical investigation reports, and the conduct and documentation of clinical evaluations. The group is working closely with other GHTF study groups to adopt consistent terminology and support broader GHTF initiatives, such as the “Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices (STED).”⁵

In addition, the GHTF steering committee is engaged in a high-level dialogue with the International Electrochemical Commission (IEC), the International Organization for Standardization (ISO), and the World Health Organization (WHO) to explore opportunities for cooperation. For example, GHTF has signed formal memoranda of understanding with ISO TC210 and ISO TC194. The latter ISO technical committee develops standards for the biological evaluation of medical devices. GHTF does not yet have such a relationship with ISO TC212, the technical committee responsible for developing standards for IVDs. The more cooperation among such organizations, the less redundancy in work programs, fewer overlapping or conflicting requirements, and more efficient use of increasingly scarce volunteer resources.

GHTF Guidance Documents

GHTF reaches consensus by a transparent process that includes proposed draft documents, open comment periods, and final voting. Final GHTF guidance docu-ments are available on GHTF’s Web site. Proposed documents are also posted on the Web site for public comment. The following is a brief review of the GHTF documents of greatest interest to IVD manufacturers.

Study Group 1. The main documents produced by SG1 are listed in Table I. Most of them have been around for several years, and are still evolving to promote the convergence of regulatory systems.

Initially published in 1999, the “Role of Standards in the Assessment of Medical Devices” (SG1/N012:2006) was recently updated to include IVD standards and a strategy for recognizing updates to standards. Although updates to regulations are infrequent, standards are reviewed and revised frequently. This created a dilemma for regulators and IVD manufacturers when standards are officially recognized by a national authority. The updated GHTF guidance added provisions for a 3–5-year transition period, during which time both versions of a standard can be used.

SG1 has also been instrumental in driving a global consensus on the regulatory definition of what constitutes a medical device, which includes IVDs. Now the group is tackling another challenge: defining what a manufacturer is. FDA has multiple definitions for manufacturer, depending on which regulation is being applied.

In addition, SG1 has been working on the summary technical documentation (STED) project to create a comprehensive template for premarket submissions so manufacturers can show how their devices meet the essential principles. A common STED accepted by all the major regulatory jurisdictions would simplify the preparation of premarket submissions. In December 2003, an initial proposed guidance was completed. Its early use by the European Union (EU) and an FDA pilot program by four divisions in the Office of Device Evaluation (ODE) allowed SG1 to gain valuable experience with the STED format.⁶

The first draft was revised to add more descriptive information and additional recommendations on the use and content of a STED (SG1(PD)N011). Since the public comment period on this second version recently closed in May, a final version for medical devices is expected soon. However, SG1 felt the present STED format does not work well for IVD submissions. In November 2006, the GHTF steering committee approved the development of an IVD-specific STED.

Study Group 2. SG2 has been prolific in publishing documents. One series of guidance documents addressed reportable adverse events, including a proposal for evaluating the reportability of use errors. The individual documents of this series were rolled up into “Global Guidance for Adverse Event Reporting for Medical Devices” (SG2-N54R8:2006). It contains a lot of thought-provoking points to consider and examples that should help manufacturers develop effective MDR decision-making processes.

However, this example reinforces the caveat that GHTF guidances are primarily intended for government regulators, not for individual IVD manufacturers. Relying on a GHTF guidance that is not explicitly harmonized with current FDA regulations could result in a noncompliant situation. The proposal for evaluating use errors also illustrates the difficulty that regulators are having in finding common ground in some regulatory areas. One problem is that this GHTF guidance adopted the concept of abnormal use, which is defined as “an act or omission of an act by the operator or user of a medical device as a result of conduct that is beyond any reasonable means of risk control by the manufacturer,” from IEC 60601-1-6:2004. Although it appears to be a reasonable exemption, the proposed examples of abnormal use include cases that might be considered preventable use errors. FDA has not bought into the distinction between use error and abnormal use, and neither has the concept been included in the new edition of ISO 14971. In both cases, the fear is that it might be used as an excuse not to address preventable use errors.

Another SG2 document addresses the “Content of Field Safety Notices” (SG2-N57R8:2006). Personnel involved in carrying out recalls and field corrections should study this guidance, but again with the caveat that national regulations always take precedence.

Global IVD manufacturers that have to evaluate complaints for reportability in multiple countries may find the report on “Comparison of the Device Adverse Reporting Systems in the United States, Europe, Canada, Australia, and Japan” (SG2-N6R3:2002) interesting. While the other SG2 documents are important for global regulatory harmonization, they deal with subjects such as standardizing data elements, electronic reporting, and communications across governments, which are of limited practical application to IVD manufacturers.

Study Group 3. SG3’s most recent work has focused on developing the guidance, “Implementation of Risk Management Principles and Activities within a Quality Management System” (SG3/N15R8:2005). Although it does not require the adoption of any particular risk management standard, IVD manufacturers that have adopted ISO 14971, “Risk Management for Medical Devices,” will find it helpful. The emphasis on postmarket risk management will enlighten companies that have considered risk management to be a design control responsibility and have neglected to integrate risk management in their CAPA systems.

SG3 also updated and reissued its earlier document on the elements of process validation, “Process Validation Guidance” (SG3/N99-10/Edition 2:2004). This guidance included a flowchart to help decide whether a process required validation and whether to validate based on risk. The new version is more compatible with U.S. regulations that require validation of all processes regardless of the risk unless they can be 100% verified. Unfortunately, the guidance relied heavily on an early FDA validation guidance published in 1987 and did not incorporate evolving validation concepts, such as greater emphasis on process characterization and risk assessments as prerequisites to validation.

The IVD Subgroup

It was only a matter of time before GHTF recognized that some of the guidances developed for medical devices could not be easily applied to IVDs. Industry insiders have long appreciated the unique nature of IVDs, with analytical performance claims that determine their diagnostic performance, stability testing procedures that only indirectly measure the deterioration of key ingredients, and complicated risk analyses that involve laboratory and physician intermediaries. Regulators have similarly struggled with classifying IVDs, which share characteristics with both pharmaceuticals and electromechanical medical devices.

Consequently, an IVD subgroup was created within SG1 to identify the differences between IVDs and other medical devices, so they could be addressed by adding to existing guidances or creating separate documents. For example, IVD requirements were added to the medical device labeling guidance, which now has expanded its title with the words “including IVDs.” GHTF developed two documents specifically for IVDs, which will exist next to their counterparts for medical devices: “Principles of In Vitro Diagnostic (IVD) Medical Devices Classification” (SG1(PD)N045R12) and “Principles of Conformity Assessment for In Vitro Diagnostic (IVD) Medical Devices” (SG1(PD)N046R3). Both documents are out for public comment until September 14, 2007.

The IVD subgroup is currently chaired by Canada, while the secretariat is held by the European Diagnostic Manufacturers Association (EDMA). It consists of regulators and industry representatives from the five founding members, and invited observers from the Asian Harmonization Working Party (AHWP). Some of the IVD subgroup members also participate in ISO TC212, which facilitates informal communication between the two groups.

A current priority of the IVD subgroup is developing a separate STED for IVDs. A new work item proposal was adopted in November 2006, and considerable progress was made on advancing a draft at a recent meeting in Irvine, CA. IVD companies can expect to see a well-designed premarket application template that will incorporate as many of the common elements from the major countries as possible. The draft STED document for IVDs will propose an internationally harmonized format and content for premarket submissions, such as PMA applications and 510(k) submissions in the United States, based on conformity to the GHTF essential principles.

The IVD subgroup will also be working with SG5 to provide IVD input to the guidance documents it is developing on clinical investigation reports and clinical evaluations. While it is well established that most IVDs have not required prospective patient studies, the concept of performance evaluations using banked clinical samples to demonstrate analytical performance may not be familiar to medical device manufacturers on SG5. The IVD subgroup will ensure that the needs of the IVD community are met.

Conclusion

At a joint meeting with AHWP, Ginette Michaud of FDA, the current chair of SG1, emphasized that “harmonization is hard work,” referring to the upfront effort required to develop a common vision and overcome the obstacles posed by existing statutes and regulations. Michaud added that, “Stepwise progress is unavoidable. Successful harmonization requires inclusiveness so that diverse viewpoints are considered (regulators and industry), and commitment to long-term goals.” GHTF’s hard work is starting to pay off, with common definitions of key regulatory concepts, harmonized premarket submissions, and compatible postmarket vigilance systems on the horizon. The IVD subgroup has a promising future in bringing national regulators together with global IVD manufacturers to improve the regulatory climate for the ultimate benefit of patients worldwide.

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