Multi-site study

If the test facility claims to be GLP-compliant but is located in a country where there is no authorised body responsible for GLP monitoring, i.e., a national GLP compliance program, the Study Director needs to be assured that the facility (including the archive, if used) does operate in compliance with GLP principles. This can be achieved by conducting a pre-study QA test site inspection or by a review of documentary evidence, e.g., notice of adverse findings and subsequent responses, or Establishment Inspection reports. The Study Director should ideally discuss the above with QA personnel and send copies of any documentary evidence used to the Quality Assurance Unit (QAU) for inclusion in the QA multi-site study file. 

In some instances, phases of a multi-site study may have to be conducted in a noncompliant facility, e.g., if there are no GLP-compliant facilities that can conduct the work. In the UK there are two options for dealing with this. 

Include a disclaimer or deviation in the Study Director GLP compliance statement. The disclaimer route can be used for a phase of a multi-site study but should generally not be used if the work in question is a critical phase, e.g., application. The remainder of the study must be conducted in accordance with the principles of GLP. This route may not be acceptable to overseas regulators and should be avoided if possible. 

The Study Director/Principal Investigator should ideally discuss all multi-site studies with QA personnel prior to study initiation (or prior to the issue of the protocol amendment if work is not detailed in the protocol). When acting as Study Director, a copy of the current GLP certificates should be requested from sub-contracted facilities and should be retained in QA. 

Published only some of the results from multi-site studies... 

There has to be a documented set of procedures for replacing a Study Director should that become necessary. In addition, for multi-site studies there has to be appointed a Principal Investigator for each site. Principal Investigators have to have the appropriate qualifications and experience to manage the delegated part of the study. 

Study director means the individual responsible for the overall conduct of the study. Principle investigator means the individual who acts on behalf of the study director in case of multi site studies. Master schedule means a compilation of information to assist in the assessment of the workload and the tracking of studies at a test facility. 

Hayashi, S., Kii, Y, Tabo, M., Fukuda, H., Itoh, T., Shimosato, T., Amano, H., Saito, M., Morimoto, H., Yamada, K., Kanda, A., Ishitsuka, T., Yamazaki, T., Kiuchi, Y, Taniguchi, S., Mori, T., Shimizu, S., Tsurubuchi, Y, Yasuda, S., Kitani, S., Shimada, C., Kobayashi, K., Komeno, M., Kasai, C., Hombo, T. and Yamamoto, K. (2005) QT PRODACT A multi-site study of in vitro action potential assays on 21 compounds in isolated guinea-pig papillary muscles. Journal of Pharmacological Sciences, 99, 423-437. 

Ensure, in the event of a multi-site study, that, if needed, a Principal Investigator is designated, who is appropriately trained, qualified and experienced to supervise the delegated phase(s) of the study. Replacement of a Principal Investigator should be done according to established procedures, and should be documented. 

Ensure for a multi-site study that clear lines of communication exist between the Study Director, Principal Investigator(s), the Quality Assurance Programme(s) and study personnel. 

OECD. No. 13 The Application of the OECD Principles of GLP to the Organisation and Management of Multi-site Studies, http //www.olis.oecd.org/olis/2002doc. nsf/LinkTo/env-jm-mono (2002) 9... 

The Application of the OECD Principles of GLP to the Organisation and Management of Multi-Site Studies (2002). 

Ledford M, Friedman KD, Hessner MJ, Moehlenkamp C, Williams TM, Larson RS. A multi-site study for detection of the factor V (Leiden) mutation from genomic DNA using a homogeneous invader microtiter plate fluorescence resonance energy transfer (FRET) assay. J Molec Diag 2000 2 97-104. 

Analysis of cohorts in a multi-site study coordinated by the EMCDDA shows substantial differences in mortality and causes of death between locations. In cities with high HIV infection among drug users, the impact of AIDS from the mid-1980s has raised mortality rates. In Barcelona (Figure 14), mortality reached over 50 per 1 000 users per year from 1 992 to 1 996 before falling markedly, reflecting a drop in AIDS deaths (probably because of new antiretroviral treatments) and, to a lesser extent, in overdose deaths. 

It has to be observed at this point, that, in a very unobtrusive way, with this definition of the Principal Investigator a term has been smuggled into the GLP Principles which could give rise to difficulties in the interpretation of other requirements. This term, the phase of a study, has not been defined in the Principles, and thus had become very much open to the need for interpretation. Although the term has subsequently been defined in the OECD Consensus Document on Multi-Site Studies (OECD No. 13, 2002), it will be specifically dealt with in section 2.10 (see page 97). 

In the wake of this introduction of the possibility of conducting studies at more than one location, another new concept had furthermore to be introduced, namely the one of the multi-site study . Thus, the definition of the test facility now does not only cover the single place where the Study Director is located, but for these multi-site studies, those which are conducted at more than one site the term test facility comprises the site at which the... 

A study can be divided into separate phases which may be conducted at different locations. With the introduction of the terms test facility , test site and multi-site study , the GLP Principles make it clear that there should only be one, indivisible study, even if the study can be conducted in separate phases at different locations. 

The term phase(s) of a study is used at various places in the OECD Principles however, this term was not defined in the Principles and its use has given rise to questions about its meaning, its applicability, and indeed its value in the context of GLP. Even though a definition for this phrase is lacking in the Principles themselves, the term has to be dealt with in this section on definitions, since a clarification of its meaning should be of some importance for the discussion of various other issues in the application of GLP, and since there is now a definition in the OECD Consensus Document on Multi-Site Studies (OECD No. 13, 2002). 

There are many more questions involved in these instances of splitting studies into various, practically independent parts. The question of, e.g., the various problems of Quality Assurance involvement with regard to the Quality Assurance statement in such fragmented studies will be investigated in more detail in section 4.5 (see page 163). The existence of such a great number of more or less unresolved issues within the conduct of multi-site studies finally led to their broad discussion and resolution in an OECD Consensus Document (OECD, 2002). A further problem, which cannot be resolved in the context of GLP, is the question of confidentiality and of various shades of competitor relationships. These issues have to be dealt with in the context of the contractual provisions and need not be considered further in the context of this book. 

The problematic area of study fragmentation which has already been discussed at various places in this book has its reverberations also in the question of the Quality Assurance statement. Especially for multi-site studies, where more than one Quality Assurance unit might have been active, or for subcontracted parts of studies conducted at test sites not connected with the Study Director s facility, the question may arise whether there should be multiple Quality Assurance statements appended to the final report, each of them reflecting the involvement of the different Quality Assurance units with the respective, specific parts of the study. 

In a multi-site study, one of the test sites may have in place its own identification system for all studies or study parts conducted there. This may on the one hand even have its advantages, since in the very improbable, but... 

Principal Investigator means an individual who, for a multi-site study, acts on behalf of the Study Director and has defined responsibility for delegated phases of the study. The Study Director s responsibility for the overall conduct of the study cannot be delegated to the Principal Investigator(s) this includes approval of the study plan and its amendments, approval of the final report, and ensuring that all applicable Principles of Good Laboratory Practice are followed. 

In the last few years, another problem concerning the relations between different national monitoring authorities arose with the more extensive use by test facilities and sponsors of the possibilities to conduct multi-site studies. On the one hand, it thus appeared possible that a test site in one country engaged in multi-site studies sponsored by test facilities in another country would not be inspected by, and not be included in the monitoring programme of, the monitoring authority of its country, thus leaving its GLP compliance in doubt. 

Number 13 Consensus Document, The Application of the Principles of GLP to Multi-Site Studies, Paris 2002... 

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