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Strategies for multi-site GLP studies

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DOI: 10.1007/s00769-002-0573-9

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Accred Qual Assur (2003) 8:61–67
DOI 10.1007/s00769-002-0573-9 GENERAL PAPER
© Springer-Verlag 2003

Joris Van Loco Strategies for multi-site GLP studies

Maureen Moerenhout
Hedwig Beernaert

Received: 14 August 2002
Accepted: 26 November 2002
J. Van Loco (✉) · M. Moerenhout
H. Beernaert
Scientific Institute of Public Health,
J. Wytsmanstraat 14, 1050 Brussels,
Belgium
e-mail: joris.vanloco@iph.fgov.be
Abstract A GLP study can be per-
formed at more than one site. This is
called a multi-site study. Although,
the study is performed at different
sites, it is still one study and must
completely comply with the GLP
principles. The fact that different ac-
tivities are conducted at different
sites implies that the planning, the
organization and the communication
are crucial for the success of the
study. This means that all the staff
involved should know their responsi-
bilities and should have the knowl-
edge and skills to realize all the
phases of the study according to the
GLP principles. To achieve a well
managed multi-site study, several
strategies for setting up such a study
can be followed. This paper focuses
on the responsibilities, communica-
tion, and collaboration of the person-
nel, which are involved in a multi-
site study. Several case studies are
highlighted, and we concluded that
the basic communication triangle in
a single-site GLP study between test
facility management, study director,
and the quality assurance unit should
be extended to the communication
among test facility and test site man-
agement, study director, principle in-
vestigator(s), and the quality assur-
ance units at the test sites.
Keywords Good laboratory
practice · Multi-site study ·
Responsibilities · Communication

Introduction separated or organizationally distinct. A study can be

The “Principles of Good Laboratory Practice” (GLP) [1]
have been developed to promote the quality and validity
of test data used for determining the safety of chemical
products. These principles are to be followed by test fa-
cilities carrying out non-clinical health and environmen-
tal safety studies to be submitted to regulatory authori-
ties.
In the past, many GLP studies were performed at one
single test site; only field trials on plant protection prod-
ucts were conducted at geographically different loca-
tions, because it was required by regulatory authorities
[2].
Nowadays, all types of studies are performed at dif-
ferent locations (test sites). When one or more phases of
a study are delegated to more than one site, it is called a
multi-site study. These test sites can be geographically
multi-sited for several reasons: the test facility has not
the technical know-how to carry out a specific part of the
study and has to use the competence of a specialized
contract laboratory. A study can also be contracted out
when it’s a requirement of the sponsor or regulatory au-
thority, for economical reasons or to overcome tempo-
rary difficulties like understaffing, equipment failure,
etc.
Although the study is performed at different test sites,
it is still one study with one study plan and one final re-
port and must comply with the GLP principles [1]. It is
obvious that when more parties are involved in a study
the risk to jeopardize the integrity of the study will in-
crease, especially when the study is not carefully
planned or when there is a lack of communication. To
provide guidance in the multi-site study, the Organiza-
tion for Economic Co-operation and Development
62
(OECD) has published a consensus document for the ap-
plication of the GLP principles to field studies [3] and
recently a consensus document concerning the applica-
tion of the GLP principles to the organization and man-
agement of multi-site studies was published [4]. Many
problems associated with multi-site studies may be pre-
vented when the study is conscientiously planned and
when all the parties involved know their duties and re-
sponsibilities. Communication among the partners is cru-
cial to perform a study that meets the highest quality re-
quirements.
In this paper different strategies for setting up a multi-
site study are discussed and the responsibilities and the
communication lines among the different partners are
emphasized.
Organizational aspects of a single-site GLP study
The sponsor, test facility management (MGT), the study
director (SD), the responsible person(s) for the quality
assurance unit (QAU), the study personnel, and the ar-
chivist are the key persons in a single-site study. Since
there is only one site, test facility and test site are identi-
cal. A principal investigator (PI) cannot be appointed in
a single-site study since the definition of a PI [1] explic-
itly mentions the term “multi-site study”. A PI acts on
behalf of the SD and has defined responsibilities for del-
egated phases of the study.
There are several requirements in the GLP principles
concerning the communication in a single-site GLP
study (Fig. 1). The straight lines describe the hierarchical
relationship between the units. The dotted lines represent
the communication among the different partners of the
study (Fig. 1).
Each GLP study concerned with the evaluation of the
safety characteristics of a chemical substance is per-
formed on demand of a sponsor. It is recommended that
the sponsor verifies the ability of the test facility to con-
duct the study in compliance with the GLP principles. A
procedure for assessing a contract test facility was pro-
posed by several authors [5, 6]. Before the start of the
study, sponsor and test facility MGT will discuss the or-
ganizational and financial modalities of the study. Often
sponsors will require progress reports during the conduct
of the study. The sponsor is also explicitly mentioned in
the GLP principles concerning the test item, the study
plan, the final report, and the archives. This means that,
not only at the beginning of a study, communication
should be established between sponsor and test facility
MGT, but throughout the whole conduct of the study. To
clarify these issues, an advisory document concerning
the role and responsibilities of the sponsor in the applica-
tion of the GLP principles has been published by the
OECD [7]. The collaboration between the sponsor and
the test facility before and during the conduct of a study
Fig. 1 The communication lines in a single-site study. The
straight lines describe the hierarchical relationship between the
parties. The dotted lines describe the essential communication
lines among the different units involved in the study
has been extensively discussed by several authors [8, 9,
10, 11].
Test facility MGT must appoint an SD before the
start of the study and should ensure that there is a QA
program with designated personnel. The SD must com-
municate effectively with the QAU as required before
and during the conduct of the study (i.e., setting up
the critical phases and scheduling the study related in-
spections). Even so, there must be an exhaustive com-
munication about study results and progress between
SD, MGT, study personnel, and scientists. The QAU
must also have a copy of the study plan and any amend-
ments in a timely manner. The QAU should promptly
report any inspection results in writing to test facility
MGT and to the SD. This is an indispensable communi-
cation triangle for the proper conduct of every GLP
study.
After finalization of the final report, the SD will col-
lect study plan, raw data, correspondence, specimen, fi-
nal report, and other records and materials related to the
study and will send them to the archive according to a
standard operating procedure (SOP). The archivist is
designated by test facility management and reports di-
rectly to him/her.
The OECD Series on Principles of Good Laboratory
Practice and Monitoring – numbers 4 and 8 [12, 13] pro-
vide more information related to the responsibilities of
the QAU and SD.
Setting up a multi-site study
A multi-site study is mostly a complex study where parts
of it are subcontracted to specialized test sites. Since the

SD is not located at these test sites, the concept of a prin-
cipal investigator (PI) was introduced. The PI is respon-
sible for the conduct of certain defined phases of the
study, acting on behalf of the SD.
Performing a multi-site study is the responsibility of
the test facility MGT and is decided in consultation with
the sponsor. An adequate planning of such a study is the
key to success. It is essential that all the partners (test fa-
cility- and test site MGT, SD, PI, sponsor, and QAU) are
involved at the earliest stages of the planning and organi-
zation of the study. Several strategies may be followed to
organize such a multi-site study, but the following key
principles should be followed at all times:
– The sponsor, test facility and test site MGT, SD, PI,
and QAUs should outline their cooperation and com-
munication. The relationship among the partners
should be agreed in advance and documented (i.e.,
study plan).
– Test facility MGT has the overall responsibility of the
study and test site MGT has usually the responsibility
of the study related activities performed at their test
site. These responsibilities should be clearly defined.
– The SD is the single point of study control.
– The SD should be informed of the progress of the
study by all test sites. Amendments to the study plan
must be approved by the SD. Deviations of the study
plan should be acknowledged by the PI and commu-
nicated to, and acknowledged by the SD in a timely
manner. The SD should liaise with the PI’s (and with
study personnel directly for test sites without PI).
– QA supervision must be guaranteed during the entire
study. It is recommended that a lead QAU is designat-
ed that has the overall QA responsibility for the entire
study. Observations made by the test facility QAU
(and/or test site QAU) during the study must be re-
ported at least to SD and test facility MGT.
– A multi-site study has one study plan and must result
in one final report.
To put all this theory into practice, we will focus on four
real scenarios of a multi-site study and highlight the re-
sponsibilities, communication and collaboration of the
personnel involved.
Case 1: Splitting the study as an alternative
for a multi-site study
In the past it was common practice that the sponsor de-
cided to split a study into several separate single-site
studies with two or more study plans and reports.
Nowadays it is strongly disapproved by monitoring
and regulatory authorities. The question arises whether
one can derive appropriate conclusions on the safety of a
test item when the results and the conclusions are report-
63
ed fragmentary. Moreover, it can be questioned whether
a study where no test items, but for example only speci-
men are examined may be considered as a study because
the GLP principles mention a study as an experiment or
set of experiments in which a test item is examined un-
der laboratory conditions or in the environment to obtain
data on its properties and/or its safety and can be submit-
ted to the regulatory authority [1].
By consequence, this strategy should not be taken in-
to consideration as an alternative for setting up a multi-
site study.
Case 2: Using external services
Some test facilities delegate certain phases of the study
to external services. These services may involve: interim
study personnel or scientists, an external QAU, etc. It is
the responsibility of test facility MGT that all the GLP
requirements are fulfilled. They must ensure that the ex-
ternal personnel has the appropriate qualifications, that
job descriptions and training records are documented,
that study plan and SOPs are available to them, etc. Fur-
thermore, a document should be available outlining the
responsibilities, the communication lines, and other as-
pects of the cooperation.
Although the described situation seems to be an at-
tractive alternative strategy for a multi-site study, it is
still a single-site study. Important disadvantages of this
strategy are the availability of external personnel, the
knowledge of internal procedures, high expenses, con-
flicts of interests, etc.
Case 3: Subcontracting a part of a multi-site study
to a fully GLP compliant test site
When it is necessary to subcontract part of a study, test
facilities must look for a partner that is fully GLP com-
pliant. These test sites have a GLP-certificate1 and are
referenced in the national GLP monitoring program. Se-
lection and approval of test sites is the responsibility of
the test facility MGT after consulting the sponsor. Test
facility MGT will also designate an SD and a lead QAU.
It may be necessary to perform QA inspections at the test
site in order to judge its qualification to conduct study
phases.
After the selection of the test site(s), the planning and
organization of the multi-site study can start. It is advis-
able to involve all the partners in the planning and the
setup of the multi-site study.
To do so multiple strategies may be followed. A num-
ber of scenarios are described below. For simplicity rea-
1Some national GLP monitoring authorities do not furnish GLP
certificates.
64
Fig. 2 Organizational aspects of a multi-site GLP study when sub-
contracting to a fully GLP compliant test site (case 3.1). The
straight lines describe the hierarchical relationship between the
units. The dotted lines describe the essential communication lines
among the different units involved in the study
sons, only the interactions between test facility- and test
site MGT, SD, PI, QAU, and archivist are discussed and
the number of subcontractors is limited to one. Multi-site
studies may also be performed with two or more subcon-
tractors or a combination of the following strategies.
Case 3.1: Subcontracting to a test site with management,
PI, QAU, and archive
The organizational aspects in the case of subcontracting
a delegated phase of a multi-site study to a test site with
test site MGT, PI, QAU, and archive is represented in
Fig. 2. A typical example is a study where residues of
pesticides on crops are evaluated. The field application is
performed by one test site, while the pesticide residues
are analyzed in a second test site. The analytical facility,
for example, receives the assignment from the sponsor
and seeks for a partner that can perform the field appli-
cation part of the study.
Test facility MGT must clearly describe the commu-
nication lines between the test site MGT, PI, and QAU.
It may be useful to describe the communication lines in
the study plan. As described for a single-site study the
communication triangle among test facility MGT, SD,
and QAU is vital for the success of the multi-site study.
This communication triangle should be extended to test
site MGT, PI, and QAU at the test site. Two basic com-
munication triangles are noticed in Fig. 2: test site MGT-
QAU-PI and test facility MGT-lead QAU-SD. These two
communication triangles are connected via horizontal
communication lines: test site MGT-test facility MGT,
lead QAU-test site QAU and SD-PI.
As we have already mentioned, test facility- and test
site MGT should be in contact with each other from the
earliest stages of study planning and thereafter through-
out the whole study. It is necessary that the responsibili-
ties of test facility- and test site MGT are documented,
for example, in a contract or in the study plan. Test site
MGT has the responsibility for the provision of adequate
site resources and for the selection of an appropriately
skilled PI. It is useful to appoint a substitute for the PI. A
list of the minimal test facility and test site MGT respon-
sibilities can be found in the GLP principles [1]. The ar-
chivists are designated by respectively test facility or test
site MGT.
The SD should involve the PI in the drafting process
of the study plan. There should be a documented agree-
ment that the PI will conduct the delegated phase in ac-
cordance with the study plan and the GLP principles.
Signature of the study plan may serve for this purpose.
The SD should ensure that the study plan, amendments
to the study plan and SOPs are available to the PI,
QAUs, and study personnel. The PI should acknowledge
study plan deviations and communicate them to the SD
in a timely manner. When it is necessary to amend the
study plan, the PI will inform the SD immediately. Study
plan amendments are to be approved by the SD. The SD
should liaise directly with each PI and should be readily
available to the PI. A fully cooperative, open working at-
mosphere between the PI and SD is essential. After final-
ization of the experiments the PI will contribute to the fi-
nal report. In most cases a PI report will be appended to
the final report. The SD will sign and date the final re-
port to indicate the acceptance of responsibility for the
validity of the data and to indicate the extent to which
the study complies with the GLP principles.
The lead QAU is responsible for the verification of
the study plan and the final report. The duties and re-
sponsibilities of each QAU (test site- and lead QAU)
should be documented in detail before the start of the
study. The test site study-based inspections and raw data
verification are delegated to test site QAU. The lead
QAU reports any inspection results to test facility MGT
and the SD, and to test site MGT, test site QAU and the
PI, if applicable.
Test site QAU reports to test facility- and test site
MGT, the SD, the PI, and the lead QAU. To simplify the
communication in this case, test site QAU is not report-
ing directly to test facility MGT and SD, but via the in-
termediate of the lead QAU. Then lead QAU informs
test facility MGT and the SD. On the other hand, test site
QAU is acting as an intermediary for remarks from the
lead QAU to the PI or test site MGT.
Test facility MGT must ensure that lead QAU re-
ceives all the necessary information. Test site MGT and
PI will inform test facility MGT and the SD concerning
actions taken with regard to the QA findings. Test sites
QAU should provide a statement concerning their QA
activities. However, lead QAU is responsible for the QA
statement in the final report.

Fig. 3 A multi-site study without archive and quality assurance
unit at the test site (case 3.2). The straight lines describe the hier-
archical relationship between the units. The dotted lines describe
the essential communication lines among the different units in-
volved in the study
Instructions concerning the retention of data (i.e.,
study plan, final report, any correspondence, raw data,
etc.) samples of test and reference items and specimens
generated at the different sites should be included in the
study plan. Principally, the SD and the PI are responsible
for the transfer of records and materials to the archive. If
the test site had an own archive, the PI should notify the
SD when and where records and materials have been
archived. During the study, the PI should not remove or
destroy any specimen without the prior written permis-
sion of the SD.
Case 3.2: Subcontracting to a test site
with only management and PI
Large contract research organizations (CROs), for exam-
ple, often have multiple GLP-compliant test sites which
are geographically separately located. Often they will opt
to organize there multi-site studies with one test site where
MGT, SD, QAU, and archive are located and a second test
site with only an MGT and a PI since this simplifies the
communication with regard to the QA activities. Central-
ization of study related records and material in one ar-
chive is a second advantage of this option (Fig. 3).
By consequence, the lead QAU should perform all the
study-based inspections and the PI should send the plan-
ning of study related activities directly or via the SD to
lead QAU. Lead QAU needs to report to test facility-
and test site MGT, to SD and PI.
Since no archiving is foreseen at the test site, PI will
transfer all records and materials to the SD. The SD
should ensure that all the records and materials are arc-
hived according to the instructions referenced either in
the study plan or in a specific SOP.
65
Fig. 4 Organizational aspects of a multi-site study when the spon-
sor is located at the test site and when the study director is located
at the test facility (case 3.4). The straight lines describe the hierar-
chical relationship between the units. The dotted lines describe the
essential communication lines among the different units involved
in the study
Case 3.3: Subcontracting to a test site
without principal investigator
A PI who will act on behalf of the SD for the delegated
phases of study may be designated by test site MGT, but
this is not a prerequisite. The SD can decide to take con-
trol over the phases conducted at the test site. In this
case, the SD should interact directly with study person-
nel. In practice, this can only be the case when the test
site is located nearby and when the SD is familiar with
the work and procedures carried out at the test site. On
the other hand, the communication lines may be very di-
rect, almost like in a single-site study, which is an advan-
tage.
Case 3.4: Subcontracting back to the sponsor.
Figure 4 demonstrates that in the case of subcontracting
back to the sponsor, the SD is located at the site of the
CRO or test facility. This situation is often found when a
pharmaceutical company with GLP-compliant laborato-
ries decides to contract a toxicological study to a special-
ized CRO. However, blood samples, test item formula-
tions, etc. have to be send back to the sponsor for analy-
sis. Some sponsors even request that the study related re-
cords and material are archived at their facility.
The sponsor should understand that his/her operations
and staff involved in the study are subject to control by
the SD, including visits or inspections of the lead QAU.
In many cases, monitoring authorities may find devia-
tions in the conduct of the study when the sponsor does
not provide the necessary information to the SD or test
facility MGT (i.e., study plan deviations, QA findings,
etc.).
66

The lead- and test site QAU reports in writing to test
facility- and test site MGT, the SD and the PI. As al-
ready mentioned in case 3.1 the lead- and test site QAU
act as an intermediary between the MGT, the QAU, the
SD, and the PI to simplify the communication between
them.
In this case, the SD and PI will transfer all the records
and materials to the archive of the sponsor at the end of
the study (Fig. 4). The instructions for archiving should
be defined in the study plan.
Case 4: Subcontracting to a non-GLP compliant test site
This is an unusual situation which can be encountered
when part of a study should be performed with a highly
specific technique and only a few laboratories in the
world are capable of doing this. Unfortunately, these lab-
oratories are not GLP-compliant.
If a delegated phase of the study cannot be carried out
at a GLP-compliant test site the study may still be per-
formed in two ways. The first approach is to make the
test site GLP compliant. For this purpose Pomerleau de-
scribed a plan to bring a non-GLP facility into compli-
ance before a study is conducted [14]. One should keep
in mind that this is not an easy task and requires a seri-
ous amount of effort and time.
The second approach consists of a part of the study
which is conducted at a non-compliant site. A specific
statement of the SD in the study plan and within the GLP
compliance statement in the final report should clearly
indicate what was and exclude what was not performed
according to the GLP principles. The sponsor should be
aware that in this case regulatory authorities may reject
the study. Further guidance concerning the use of non-
GLP compliant test facility is provided by the FDA [15].
It is clear that subcontracting to a non-GLP compliant
test site must be avoided at all times.
Conclusions
A multi-site study is a non-clinical health and environ-
mental safety study that is performed at multiple test
sites and must comply with the GLP principles. As these
principles mention, this study must have one study plan,
one study director (and a substitute study director), and
the study must result in a single final report.
The fact that different study activities are being con-
ducted at different sites means that the planning, organi-
zation and communication lines of the study become a
complex matter but are crucial for a successful study.
The communication triangle test facility management
(MGT), study director (SD), and quality assurance unit
(QAU) applied in single-site studies is from utmost im-
portance in multi-site studies.
In this paper we mainly discussed different strategies
to set up a multi-site study and highlighted the different
responsibilities of and the communication lines between
the staff involved. It was pointed out that several of the
proposed strategies have major disadvantages and by
consequence cannot be retained as valid alternatives for
the conduct of multi-site studies, for example, splitting a
GLP study, making use of external personnel and servic-
es, and subcontracting to non-GLP compliant test sites.
When certain phases of the study have to be delegated,
it is recommended to subcontract this part to a fully GLP
compliant test site. For these multi-site studies, the same
communication triangle may be applied as for single-site
studies. However, in most cases of multi-site studies this
triangle should be extended, including communication
lines between test facility and test site MGT, SD, princi-
ple investigator(s), and QAUs of the test sites. All the re-
sponsibilities of the staff involved and the communica-
tion lines between them should be defined in a document
(preferably the study plan) before the start of the study.
Finally, we want to stress that a study will be success-
ful if all the communication lines and the responsibilities
of the personnel are well defined before the start of the
study and if there is an open atmosphere for communica-
tion within and between the test site(s).

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