GCP Convergence Improves Transportability of Medical Device Clinical Data

The safety, performance and effectiveness of medical devices are often evaluated by well-controlled clinical investigations before marketing authorization. The integrity of these clinical studies is ensured by compliance with voluntary standards or government regulations known as Good Clinical Practices (GCPs). Four GCPs are most applicable to US and Japanese marketing approvals: US Food and Drug Administration (FDA) regulations and guidance, Japanese GCP ordinances and notifications, ISO14155:2011 Clinical Investigation of Medical Devices for Human Subjects-Good Clinical Practice¹ and ICH E6 (R1) Guideline for Good Clinical Practice.²

Consistency among GCPs is very important to allow data from a clinical investigation conducted in one country to be used for regulatory marketing approval in another country (this is called data transportability). Consistency also may reduce the need for duplicative GCP audits of sponsors, IRBs and investigational sites by different authorities. However, the various GCPs are not identical, which in some cases may impede acceptance of foreign clinical investigation data. Both standards and regulations are evolving and recent revisions further affect consistency among GCPs and the transportability of clinical data obtained under them.

This article discusses the impact of recent revisions to these GCPs on transportability of medical device clinical data obtained from a GCP-compliant study. It also updates a previous study of similarities and differences among GCPs.³ The previous study concluded there were no substantive differences among GCPs with respect to fundamental criteria for ethical human studies, especially as they apply to the US and Japan. The effects of the recent revisions on this conclusion are included in this article.

Previous GCP Comparison Study

The previous study was a joint effort by clinical and regulatory experts in the US and Japan as part of the work of Harmonization-by-Doing (HBD), a cooperative effort to move Japan and the US toward international regulatory harmonization.⁴ HBD Working Group 4 performed a line-by-line evaluation and comparison of the four GCPs mentioned above.

Although that study identified numerous differences in wording, organization, specificity and depth of topic coverage, in general, the GCPs were found to be quite similar. The differences were assessed with respect to four fundamental criteria: 1) rights, safety and welfare of trial subjects, 2) scientific integrity of trial methods, 3) accuracy of the data and 4) reliability as a basis for regulatory decision making. Differences were categorized as substantive, non-substantive or administrative.

Importantly, the study found no substantive differences among the GCPs studied with respect to the four fundamental criteria. This means compliance with any one of the GCPs provided similar protections and requirements. There were no contradictory requirements among the four GCPs. Therefore, compliance with more than one GCP (or all GCPs) in the same investigation is possible.

Several non-substantive and administrative differences among GCPs were identified. This means that some documentation above and beyond what is required by one GCP may need to be collected to improve data transportability. The study report discussed how these differences could be addressed with additional documentation, such that the data could be relied upon by regulatory authorities outside the country or region where the study was conducted. The additional documentation was identified in the previous paper and is updated in tables contained in this article. The sponsor of a trial should also consult with the regulatory authorities before the study to confirm sufficiency of additional documentation.⁵

Since the original comparison study was completed, the GCPs have been revised. The Japanese ordinances and notifications (Japanese GCP or JGCP) have been revised, additional US guidance documents have been issued in draft or final form and ISO14155 underwent a major revision. The following briefly highlights these revisions and discusses their effect on the earlier GCP comparison study results and, consequently, their impact on transportability of clinical data.

Japanese GCP Revisions

[media:1485:embed:align left}] The Japanese GCP ordinance originally issued on 23 March 2005⁶ was revised on 31 March 2009. Also, the Japanese GCP notification originally issued on 20 July 2005 was revised on 24 December 2009, and again on 24 January 2012 with additional notifications. An additional revision was issued in draft form in May 2012. These revisions are summarized in Table 1. The revisions reduce several earlier differences from the US GCPs, as well as other international GCPs.

US GCP Revisions

[media:1486:embed:align left}] In the US, new requirements have been added to US regulations and additional guidance documents have been issued.^7,8,9 These additions were evaluated to determine whether they affected the differences between JGCP and US GCP identified in the earlier paper (see Table 2).

ISO14155 Revisions

[media:1487:embed:align left}] ISO14155, the international standard for medical device clinical trials, was extensively revised and reissued on 1 February 2011. The standard is now more consistent with ICH guidance. Whereas ICH E6 applies to clinical trials of medicines, ISO14155 is specific to medical devices. Revisions to ISO14155 can be generally categorized as shown in Table 3.

Impact of GCP Revisions on GCP Comparison Results

Since these revisions touched on some of the differences identified in the original GCP comparison study, the working group of US and Japanese GCP experts reconvened to assess their potential significance. They considered whether each revision created a new difference among the GCPs, reduced existing differences, increased existing differences or altered the categorization (substantive, non-substantive or administrative) of differences. Each revision was associated with the appropriate section of the previous analysis and the results are summarized in Tables 4 and 5. The revised assessment may assist sponsors planning to conduct a clinical investigation in Japan or the US, or a multinational clinical investigation involving the US and Japan, thereby improving transportability of data for marketing approval in both countries and beyond.

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The GCP experts observed numerous differences in wording, organization and depth of topic among the revised GCPs. However, they determined there still are no substantive differences with respect to the four fundamental criteria in the original study (rights, safety and welfare of trial subjects; scientific integrity of trial methods; accuracy of the data; and reliability as a basis for regulatory decision making). There are no contradictory requirements among GCPs, so compliance with more than one GCP (or all GCPs) is still possible. Compliance with any one of the GCPs provides similar protections with respect to the four fundamental criteria.

The revisions did, however, affect differences considered non-substantive in the previous study. For example, JGCP as revised on 24 December 2009 reduced one of the barriers in the labeling of study devices by allowing an English label to remain on the study device at Japanese sites in a multinational clinical investigation, along with the required Japanese label. Table 4 shows the revised non-substantive differences.

The revisions also affected differences considered administrative in the previous study. For example, the 24 December 2009 revision to JGCP eliminated the requirement that investigational devices be delivered to medical institutions without use of a medical device dealer or third party; devices now may be shipped via courier (e.g., FedEx) rather than hand-delivered to institutions. This revision eliminated a difference identified in the original GCP comparison study. Table 5 shows the revised administrative differences.

Facilitating Data Transportability in Japan, US

These observations suggest it is possible to conduct a GCP-compliant clinical investigation in either Japan or the US, or a multi-center study involving both countries, with the expectation there will be no substantive differences in acceptability with respect to the four fundamental criteria. To achieve full transportability, however, it may still be necessary to address the non-substantive and administrative differences by providing documentation necessary to bridge small gaps. By using the tables of non-substantive and administrative differences and consulting with regulatory authorities, sponsors usually can identify the specific additional documentation.

For example, Table 4 identifies the financial disclosure information required in the US. Its purpose is to show that investigators do not have a financial conflict of interest that may cause them to bias the clinical investigation results. For investigational sites outside the US, gathering additional information demonstrating a lack of conflict of interest and lack of investigator bias in the clinical investigation results could address the needs of the US and other regulatory authorities. Hence, using Tables 4 and 5 in this way to identify and address the need for additional information may be helpful.

Adherence to ISO14155 provides an additional basis for transportability of clinical data. Of note, a working group involving participants with extensive GCP experience from several countries, including the US and Japan, drafted the revision of ISO14155; it represents a current consensus standard for medical device clinical studies, inside and outside the US and Japan. Some form of recognition of this standard by regulators in several countries is expected.

Documentation of compliance to GCP is important. Monitors and auditors typically verify source data and assess compliance with GCP, as directed by the sponsor. The sponsor should inform monitors and auditors (as well as investigators and Ethics Committees) of the additional documentation that may need to be collected throughout the clinical investigation to address non-substantive and administrative differences. If the data will be used for approvals in several countries, informed consent documents should obtain the subjects' permission to disclose their data to regulatory authorities in these other countries. In addition, sponsors should ensure compliance with national laws on protection of confidential personal information.

Of course, compliance with GCPs alone does not ensure transportability. The clinical investigation design including the choice of patient population, sample size, endpoints, follow-up periods and statistical analysis plans must address the requirements of various regulatory authorities. Likewise, the clinical practice patterns of physicians and ethnic makeup of the patient population may differ among countries and may affect patient outcomes; therefore, enrollment from various regions may be required in the study design. Early consultation with the relevant regulatory authorities may facilitate development of a clinical investigation design that is mutually acceptable to those authorities.

Conclusion

Given a clinical investigation design that is appropriate and acceptable to various regulatory authorities, this study shows that non-substantive and administrative differences among GCPs can be addressed with supplemental information and should not be a barrier to transportability and acceptance of clinical investigation data from elsewhere.

References

1. ISO14155. Clinical investigation of medical devices for human subjects-Good clinical practice.
2. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), E6 Good Clinical Practice: Consolidated Guideline; 1996. (Note: While the ICH E6 guideline is specifically applicable to drug and biological products, it has been applied as a GCP reference standard for some device studies, and was therefore included in this analysis.)
3. Harmonization-by-Doing Working Group 4. "Comparing GCP Requirements for Medical Device Clinical Trials in the US and Japan." Regulatory Focus. 2010: April;40-44.
4. US Food and Drug Administration. "Japan - US Harmonization-by-Doing HBD Pilot Program Initiative." www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/InternationalInformation/ucm053067.htm. Accessed 6 November 2012.
5. The term "regulatory authority" is intended to encompass both national regulatory authorities and independent conformity assessment bodies/agencies (e.g., PMDA) that perform marketing authorization reviews on behalf of those authorities.
6. Japan Ministry of Health, Labour and Welfare. "Ordinance of the Ministry of Health, Labour and Welfare No. 36." 23 March 2005.
7. US Food and Drug Administration. Clinical Trials Guidance Documents. www.fda.gov/RegulatoryInformation/Guidances/ucm122046.htm. Accessed 6 November 2012.
8. US Food and Drug Administration. Regulations/FDA Regulations Relating to Good Clinical Practice and Clinical Trials. www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm155713.htm. Accessed 6 November 2012.
9. US Food and Drug Administration. Selected FDA GCP/Clinical Trial Guidance Documents. www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/ucm219433.htm. Accessed 6 November 2012.