Harmonization with the OECD principles of GLP – friend or foe?

Abstract

There is an enormous push internationally and by multi-national companies for global harmonization of Good Laboratory Practice (GLP) principles/regulations. Although many believe harmonization would ease the regulatory burden for global companies, insufficient thought has been given to the vast differences in compliance programs, subsequent reporting/submission requirements, and data quality within the member countries. On the surface, it may not appear that there are significant differences between various GLP regulations and guidance documents. However, there are huge differences in the implementation of such by the various monitoring authorities, and vast differences in the focus and maturity of monitoring programs within the member countries. Although some individual countries have developed high quality standards, many are in their infancy regarding the application and implementation of GLP. Coupled with the emphasis on certification of laboratories, with much less (if any) evaluation of actual studies and associated data integrity, the gap between the various GLP programs becomes increasingly wide. During the development of the Organisation for Economic Co-operation and Development (OECD) GLPs and associated guidance documents, many concessions were made by all parties in an effort to achieve consensus. The resulting documents, therefore, have substantial vague areas that are interpreted differently by the various monitoring authorities. These differences became very apparent at the OECD Harmonization workshop held April 10–11, 2008 in Italy. While some member countries refuse to allow a Sponsor to sign any portion of a report, others including the United States Environmental Protection Agency (EPA) requires the Sponsor signature on the compliance statement. OECD GLPs do not require final reports to contain a description of circumstances affecting data quality, nor are contributing scientist reports required to be appended to the final report. Although a Master Schedule is required to be maintained, there is no consensus of what should be included in the Master Schedule, allowing for various interpretations. Even though data must be archived under OECD GLPs, the time frame provided is ‘after completion of the study’ (with no deadlines given) which could easily result in data being lost after reports are submitted. The FDA and EPA GLPs require archival ‘during or at the close of a study’ (when the final report is signed) assuring all data are secure when the report is signed. However, the most substantial and disturbing issue among the member countries is the requirement for certification of laboratories by most member countries versus emphasis on data quality and integrity in the US, with some of the older member countries focusing on both. Although certification may be optimal for routine testing of chemicals using standardized test methods, the nature of regulatory research in complex safety studies (especially in pivotal pharmaceutical studies) is often unique and specific to the compound being tested. Most discoveries of flaws and issues in regulatory research are the result of intense data audits by either the Sponsor or regulatory agencies, activities that are less common under a certification system. Perhaps the most visible differences within the various programs are in regard to the implementation of OECD Guidance 13 for multi-site studies. Although such studies have been conducted in the US since the onset of GLPs in 1978, this guidance did provide some clarity in the organization and reporting of more complex studies. Such clarity involves the designation of Principal Investigators, reporting of Quality Assurance (QA) inspections, reporting of SOP and protocol deviations to the Study Director, etc. However, many laboratories (and member countries) are being too literal and restrictive in their adoption of this guidance, with some member countries going so far as to adopt the guidance as regulation. This has led some companies, in accordance with their monitoring authority, to break a typical multi-site study into numerous ‘mono-site’ studies, with each phase having its own Study Director. Evidently, in many OECD member countries, companies can chose which model they want to follow – either one multi-site study or numerous mono-site studies. This practice is in violation of one of the core principles of the original FDA GLPs; that is, one study – one Study Director. Providing a ‘certificate’ of GLP compliance to a laboratory does not address the issue of overall study integrity, especially when studies are conducted at various test sites. Additionally, the current practice in numerous member countries of issuing a certificate, which is valid for two years, is completely counter to a strong monitoring program. Could you imagine any regulatory safety program (i.e. food establishments, food processing, drug manufacturing, etc), issuing a certificate with a ‘see you in two years attitude’, that would be remotely effective? What happens when these ‘GLP certified’ facilities decide not to recertify after two years? What happens when a certified laboratory goes out of business? Are all data integrity determinations based on the prior certification? If certificates are going to be used in GLP laboratories, they should simply state that at the time of the monitoring visit, this facility was found to be in compliance with GLP. The gap between member countries that support a strong GLP monitoring program (the intent of the original OECD GLPs) and those defaulting to a simple ISO-based certification program is growing wider by the year. Although, the GLP monitoring system in the US could be enhanced with some type of ‘pre-qualification’ program, it is far superior in evaluating the integrity of studies and data that support critical safety decisions than an ISO-based certification program. Ultimately, if harmonization is to occur, all member countries should adopt a ‘pre-qualification’ program coupled with intense data quality focused monitoring systems. Such a program should also include an easy way to disqualify facilities (and all studies conducted at those facilities) when significant data quality issues are discovered during monitoring visits. To have a truly effective GLP monitoring system in place, evaluations of the state of compliance (and therefore data integrity) must be based primarily on studies, not facilities.