Vol.3, No.12, 772-781 (2011)
opyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Sponsor-investigator-relationship: challenges, recent
regulatory developments and future legislative trends
Raphael Richard Ciuman
Department of Otorhinolaryngology, Marienhospital Gelsenkirchen, Gelsenkirchen, Germany; ciuman.raphael@cityweb.de
Received 22 September 2011; revised 10 November 2011; accepted 26 November 2011.
Correct definition and management of sponsor-
investigator relationship is of central impor-
tance for planing and executing clinical trials.
During the last decade, there have been nu-
merous modifications of guidelindes, interna-
tional and national legislations and regulations.
This implicated various alterations and shifts of
essential responsibilities and tasks relating to
the investigator, sponsor or sponsor-investiga-
tor what raised financial, clinical and ethical
issues. First experiences with these new regu-
lations and legislations are discussed together
with international differences and their impacts
on clinical trials. Regarding non-commercial
trials and institutional sponsorship, there are
still open organizational and legal questions
after national implementation of the Europeam
Clinical Trials Directive in 2004, although vari-
ous approaches have been suggested in recent
years in Europe. Current trends and controver-
sies are discussed as well. A literature review
was performed summarizing recent experiences
with current legislations and risen controver-
sies of these new legislations showing impact
on future trends.
Keywords: Investigator; Sponsor; Clinical Trial;
Non-Commercial Trial; European Clini ca l Trials
Directive; Conflict of Interest
Sponsor investigator relationship is characterized by
dealing with numerous sensitive tasks like trial man-
agement structure, required sponsor company qualities
and various conflict of interest issues. Correct under-
standing of their distinct responsibilities as well as man-
agement of various possible controversies is essential for
executing clinical trials successfully. Therefore, solicitude
about the regulations concerning the sponsor and the
investigator and their relationship is crucial. The intro-
duction of the European Clinical Trials Directive (CTD)
2001/20/EC [1] and its national implementations, lead-
ing to the 12th amendment of the German Drug Law
(AMG, Arzneimittelgesetz) in August 2004 [2], have
brought along a new legislative terminology and the
necessitiy of a thorough distinction between the various
kinds of sponsorship and investigatorship and associ-
ated trial forms. The CTD does not apply to
non-interventional trials, where trial authorization is not
required in most member states. The European Clinical
Trials Directive and its incorporations into the member
states legislative and regulative framework followed
and were a result of the recommendations for Good
Clinical Practice (GCP) of the International Conference
on Harmonization (ICH) which was founded by the
Food and Drug Administration (FDA), the European
Medicines Agency (EMEA), the Japanese Ministry of
Health, Labour and Welfare (MHLW), the Pharmaceu-
tical Research and Manufacturers of America (PhRMA),
the European Federation of Pharmaceutical Industries
and Associates (EFPIA) and the Japan Pharmaceutical
Manufacturers Association (JPMA) in 1990.
A thorough knowledge and correct understanding of
the relevant legal and regulatory framework is essential
for adequate fulfillment of the various tasks of sponsor-
ship and investigatorship, assurance of high quality
standards, patient safety and successful completion of
clinical trials. The increasing formal, legal and financial
framework in the last decades directly resembled and had
immediate impact on the complexity of the investiga-
tor-sponsor relationship and clinical trials conduct [3].
To ensure a successful outcome, it is indispensable to
achieve harmony of objectives and approaches through
an ideally constructive professional relationship. Be-
fore the start of an investigational new drug clinical
R. R. Ciuman / Health 3 (2011) 772-781
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investigation, the trial protocol is written and signed by
both the sponsor and the investigator. Responsibilities
of the investigator are discussed and a Statement, the
Investigator Form is compiled by the investigator. The
European CTD states that even when the sponsor dele-
gates any or all of his trial-related responsibilities, he
remains ultimately responsible for ensuring that the
conduct of the trial complies with all applicable re-
quirements. The sponsor need not to be located in
Europe, but has to have a legal representative there. In
Switzerland, the sponsor, in the case of a legal entity,
need to be registered or, in a case of a person, has to be
domiciled within the country. Ta ble s 1 and 2 summa-
rize the Responsibilities of Investigatorship and Spon-
Clinical trials imply a number of specific regulatory
requirements beyond those mandated for protection of
human subjects in clinical research. These regulatory
requirements for drug studies address the safety and ef-
ficacy issues unique to the use of pharmaceuticals in the
clinical research setting. Failing to meet the regulations
can have legal and financial implications for the indi-
viduals conducting the trials as well as the organizations
related to the research activities. Of central importance is
the Investigator’s agreement, as sponsors may delegate
investigative any or all duties to other persons and enti-
ties (Table 3).
Conflict of interests (COIs) can be defined as set of
conditions, financial and non-financial, in which profess-
sional judgment concerning a primary interest tends to
be unduly influenced by a secondary interest [4]. It is
obvious that conflicts of interest are common and inevi-
Table 1. Investigator responsibilities.
The Investigators first duty belongs to the patient
Risk/Benefit determination
Trial conductance according to the study protocol/investigational
Supervision of the research staff
Truly given informed consent by the participants
Report and judgment of all adverse events to the sponsor and EC
r together with the sponsor depending on
Retention of study records and documentation
Review of all adverse event reports sent by the sponsor
EC approval (alone o
country regulations)
Report of study data to the sponsor
Table 2. Sponsor responsibilities.
Reporting and evaluating preclinical data
Trial design, trial management, data handling, record keeping
Trial initiation and approvals from the CAs/ECs
Confirmation of review by the ECs
Information on investigational product
Providing information to the investigators of historical and changed
safety data and drug interactions
Data monitoring/in larger trials usage of a Data Monitoring
Committee (DMC), or named Data Safety Monitoring Board
(DSMB) in the USA
Collection of adverse event report forms and judgment of a relation
to study treatment
Together with the investigator jointly responsible for a site-specific
informed consent
Arrangement of patient indemnity
Providing of Investigator’s Brochure (IB)
Information of study end to CA and EC
Quality assurance and Quality Control
Request of EUDRACT No or registration within national databases
Providing the IMP or import of the IMP
Manufacturing, packaging, labelling, coding
Availability of Qualified Person (QP)
Notification of SUSARs to CAs/Ecs
Annual Safety report to CAs/Ecs
Summary of final report to CAs/Ecs
Financing and compensation to subjects and investigators
table in the academic field. The challenge is not to eradi-
cate them, but to recognize them and manage them prop-
erly. The only acceptable way to do this is by full dis-
closure and involvement of all participants, namely the
research subject, the researcher, the institution where the
research is taken place, the sponsor, the ethics committee,
the regulating agencies, the scientific community and
society. Regulatory bodies, scientific journals and insti-
tutions set up various guidelines and thresholds for dis-
closure in the past. However, confusion and concern
about the resolution of conflicting evidence exists. There
is agreement on the necessity of declaring COIs, but
there is no agreement on what constitutes a permissible
degree of COI. At a maximum the investigator has to
abandon either the research interest or proprietary inter-
est to avoid running afoul of regulatory requirements and
incurring serious litigation and public relations risks.
Also, the important matter of complete reporting of data
remains incompletely addressed. The Association of
American Medical Colleges (AAMC) emphasizes the
fact that institutional financial interests, as much as those
of an individual investigator, may threaten a study. It
R. R. Ciuman / Health 3 (2011) 772-781
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Table 3. Challenges of sponsor-investigator-relationship.
General challenges
Variabile responsibility in different countries of trial approval and
notification to the CAs/Ecs
National differences in timelines of applications, adverse event
reporting, data storing
Clear communication and input channels
Risk/Benefit determination
Structural and educational support for trial set-up
Conflict of interest
Challenges to consider in the investigators agreement
Regulatory compliance
Termination rights
Data monitoring and data analysis
Intellectual property and patent rights
Subject injury
Indemnification and liability
Third-party reimbursements
goes well beyond the requirement for full financial dis-
closure of investigators and recommend that individuals
who hold a financial interest in a particular area of re-
search should not be involved in clinical research in that
area [5].
Criteria for data ownership and access, data design,
collection and analysis (including outside analysis) are
common claims a long time to adequately manage the
reasons for publication bias [6], which clearly extends to
non-commercial research [7]. Besides, data ownership
issues start to play a distinctive role inside definitions of
non-commercial sponsors. In the US, the Department of
Health and Human Services recommends that responsi-
bilities involving design of the study and analysis of the
results should be shared between a sponsor and investi-
gators in order to prevent potential influence of financial
relationships on the outcome of the trial [8]. The Inter-
national Committee of Medical Journal Editors (ICMJE)
has set guidelines of sponsored research regarding au-
thors’ access to data, integrity of data, accuracy of data
analysis, authors publishing rights and trial registration
in a data base to qualify for publication [9]. The majority
of quality general medicinal journals require disclosure
of the role of the sponsor and a written assurance that the
investigators accept full responsibility for the conduct of
the study, have had access to all the data and had the
authority to publish it. In addition, these guidelines re-
quire editors to verify (if necessary, by inspecting re-
search contracts and study protocols) that researchers
had full access to all study data and that there were no
restrictions on publication [10].
Concerns about bias, research fraud and the ethics of
clinical trials can be addressed by truly independent and
properly constituted data and safety monitoring boards
(DSMBs). The DSMB is an independent group of clini-
cians and statisticians and meets periodically to review
the unblinded data that the sponsor has received so far.
The DMSB has the power to recommend termination of
the study based on their review, for example if the study
treatment is causing more deaths than the standard treat-
ment, or seems to be causing unexpected and study-re-
lated serious adverse events. Truly independent and
properly constituted data and safety monitoring boards
are of particular importance when academic investiga-
tors or universities have a large financial conflict. The
National Institutes of Health (NIH) requires a Data Sa-
fety Monitoring Board (DSMB) for all Phase III trials
and a safety monitoring plan for Phase I and II trials.
The FDA issued in 2006 guidance for clinical trial spon-
sors for the establishment and operation of clinical trials
monitoring committees [11]. The FDA requires a DSMB
for long-term trials with mortality or major morbidity
outcome measures, when serious adverse events (SAE)
are expected, with novel and/or potentially high-risk
treatments, when very little prior information about the
study treatment is available, when studying an at-risk
population consisting of vulnerable subjects (e.g., eld-
erly or paediatric patients) or with a multicenter or long-
term study. Conversely, an external DSMB is not re-
quired in early phase trials (with the exemption of gene
therapy trials), trials with symptom-only endpoints, and
short-term trials.
In the last decade, numerous studies addressed the
problems of selective data presentation [12-14], data
suppression, named authorship and that industry-spon-
sored trials report less often negative outcomes than in-
dependent studies. Positive and significant results are
more often published than negative and insignificant
results [15-17] and in the past only 25% - 50% of ap-
proval studies were published according to comparisons
with FDA data [18]. Consequently, there have been nu-
merous calls for publicly available study protocols and
results, as industrial financing tends to affect study pro-
cedures, results and publication in multiple ways which
cannot be explained by methodological study quality [19,
20]. In this context, the new trial databases and the ini-
tiatives of publishers of medical journals addressed and
tried to set guidelines to ensure high-standard publica-
tion. In contrast to Europe, in the USA all clinical trials
have to be registered in a database with free public ac-
R. R. Ciuman / Health 3 (2011) 772-781
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cess. In Europe this is not legally enforced but due to an
initiative. In addition, in the USA study publication be-
came mandatory in 2008 [21,22]. The passage of Title
VIII (Section 801) of the FDA Amendment Act (FDAAA)
of 2007, made it federal law to register most intervene-
tional clinical trials at outset and to disclose trial results
(for marketed products) by twelve months after study
completion [23,24]. There exists general agreement by
the industry to make clinical trial results public [25].
Besides PhRMA recently extended its policy to go be-
yond the current FDAAA requirements, calling on its
members to register and disclose results of all studies
involving patients for all products marketed and those
investigational products whose development has been
discontinued [26].
Due to increased regulation and legislation in the last
decades bringing along higher research costs and slower
patient recruitment, many research-based companies
seek to outsource some of their trials to Third World
countries with less stringent regulation like China, India,
Indonesia or Thailand. Nevertheless, the laws and regu-
lations might differ in substantial manner. Sponsors and
investigators must deal with multiple legal jurisdictions,
with different laws regulations and other rules and has to
understand regional differences. Consequently, the spon-
sor often needs to fall back on local resources and con-
tract research organizations (CROs). In India for example,
which is a particularly attractive site for clinical research
due to its genetically diverse population, sponsors do not
have exclusive rights to the clinical data they generate,
as trial reports are in the public domain. Consequently,
manufacturers of generic drugs can use the data to get
regulatory approval for their own versions of drugs.
China has a long regulatory clinical trial approval proc-
ess, which may take up to one year, minimum 195 days
to review an application for a multinational study [27].
Intellectual property rights are only sporadic enforced. In
contrast, Latin American countries like Argentina, Brazil
and Mexico generally comply with ICH guidelines. Vio-
lation of Western standards might be the ground for li-
ability claims in Western and Third World countries in a
jointly manner. The Abdullahi vs. Pfizer Case underlines
the need to ensure that a company conducting clinical
trials in Third World Countries keeps regulatory and ethical
requirements. In this case an US sponsor who conducted a
clinical trial in Nigeria was sued under the Alien Tort Statue
[28], which allows United States courts to hear human
rights cases brought by foreign citizens for conduct com-
mitted outside the United States.
The goals of the CTD 2001/20/EC were primarily en-
forcement of patient protection, enhanced drug quality
standards for clinical trials and enhanced transparency.
These goals were obviously met. In this context, the Eu-
ropean Clinical Trials Directive 2001/20/EC and its sub-
sequent different national implementations set land-
marks in regards of quality assurance and patient safety,
as a GCP-inspection system and trial amendment and
termination provisions were established. On the other
hand the challenges and deficiencies of this framework
are wide-ranging as summarized in Table 4. Challenges
and Deficiences of the European Clinical Trials Direc-
tive 2001/20/EC and its national implementations.
The most challenging of the European CTD is the
concept of the sponsor. Originally, the CTD defined a
sponsor as an individual, company, institution or organi-
sation which takes responsibility for the initiation, man-
agement and/or financing of a clinical trial. In contrast,
the European Commsson stated in its Notice to Appli-
cants in 2009 that a number of parties may agree in writ-
ing to form organisation and to distribute the sponsors
tasks and duties between various sponsors and organisa-
tions [29]. UK legislation with its Medicines for Human
Use (Clinical Trials) Regulations 2004 maintained its
provisions for multiple and shared sponsorship, defined
Ta b l e 4 . Challenges and Deficiences of the European Clinical
Trials Directive 2001/20/EC and its national implementations.
Deficiences and Challenges of the European Clinical Trials Directive
No addressment of multiple, joint or co-sponsorship
No addressment of non-commercial sponsorship and facilities
beyond labelling
No risk assessment classification for graded clinical trial applications
Lack of addressment of facilities for informed consent in disabled
populations or emergency cases
No definition of substantial amendments; No grouping possibility for
No substantive liability rules
EudraCT is not publicly available and does not include
non-commercial trials/no public available database for study
protocols and results
Increased costs due to increased authorization, monitoring and
documentation requirements/increased need for managing
SAE reporting to ECs and distribution to all investigators regardless
of causality provides information overload and information of little
Challenges of national implementations
Definition of IMP and related provisions vary across the MS
Differences in timelines and regulations for clinical trial approval,
adverse event reporting, study record retention
Differences of insurance policies and liability issues across the MS
Lack of EU-wide insurance for multinational trials
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as follows:
single sponsorship—one organization accepts all
sponsor’s responsibilities;
joint sponsorshiptwo or more organizations act
jointly to accept all of the sponsor’s responsibilities;
co-sponsorshiptwo or more organizations take
ultimate responsibility for discrete sponsor respon-
sibilities; e.g. one organisation is responsible for
GCP and conduct the other for pharmacovigilance
and the third for authorisation and EC opinion [30].
The implementation of the European CTD into na-
tional law lead to various regulatory differences in the
EU member states (MS). Significant differences exist in
insurance coverage and liability issues throughout Eu-
rope. Patients are EU-wide covered by the trial insurance,
but differences remained in place regarding the amounts
(total and individual per trial) specified by each MS. Due
to its complicated nature it is obvious that different
countries handle the compensation to the injured re-
search patient differently, including the extent and dura-
tion of coverage and the assignment of responsibility for
paying compensation, the kind of compensable injuries
including death, serious harm pain suffering and eco-
nomic losses, the compensability of harms and of health
problems which are inevitable in a trial. The nature of
the insurance is optional according to US federal regula-
tions and compulsory in Europe [31]. Different interpret-
tations of the European CTD lead to various regulatory
differences in the MS making multinational trials more
difficult. The timelines for Competent Authority (CA) or
Ethics Committee (EC) approval, adverse event report-
ing or retention of study records differ in the MS. In
Spain and France missing response by the CA means
approval. Information of any urgent safety measure to
the CA or EC is required in Germany and Belgium im-
mediately, in England within three days. Most MS re-
quire immediate reporting of Suspected Unexpected Se-
rious Adverse Reactions (SUSARs). In France a declara-
tion SUSARs to the the CA and EC is required every six
months. In France, UK and Sweden it is possible to ap-
peal against negative EC decision. Besides, Germany
and Italy have not established a national ethics review
committee. Both countries continue to have regional
ethics boards. Researchers must apply to each local ju-
risdiction where a proposed trial takes place.
The European CTD does not address procedures in
patients who are unable to give informed consent. Re-
search in populations with difficulties to get informed
consent, e.g. emergency medicine psychiatry, neurology,
has been impacted due to variable and often restrictive
consenting procedures for incapacitated subjects, with
some countries requiring a court-appointed representa-
tive, while others recognise consent from family mem-
bers and occasionally professional representatives [32].
In this context, regulations for strict risk/benefit analysis,
involvement of ECs, relatives and request procedures for
informed consent subsequently are necessary.
So far, there is no simplification or acceleration of
administrative processes contrasting the goal of facilitat-
ing faster access to novel therapies through harmoniza-
tion of administrative regulatory requirements and de-
fining binding timelines for the review and approval
processes. Concern of delays of 4 to 11 months before
trial initiation of cancer studies were expressed [33].
Since the implementation of the ICH-GCP, sponsors
are not only responsible for initiation but also for the
management of clinical trials. It was reported that the
initial response for clinical trials to the implementation
of the ICH-GCP guideline were clinical trial price in-
creases and a decrease in the number of study contracts
[34]. Similar developments were assumed and feared for
the implementations of the European CTD. Because reg-
isters and statistics about clinical trials were not rou-
tinely maintained in the past, every estimation on the
quantitative impact of the CTD 2001/20/EC on the
number of trials remains rudimentary. A perceived re-
duction of commercial and non-commercial trials was
described by numerous authors. The consortium of
European Forum for Good Clinical Practice (EFGCP)
that is comprised by the European Clinical Research
Infrastructure Network (ECRIN), the European Organi-
zation for Research and Treatment of Cancer (EORTC),
Ethics Committee of the Medical University of Vienna
and Hospital Clinic I de Barcelona established the pro-
ject Impact on Clinical research of European Legislation
(ICREL), a one year project to analyze the impact of the
CTD on on the number, size and nature of clinical trials,
on workload, required resources, costs and performance
of European clinical research. An online survey was
launched in May 2008. In 2008 ICREL stated a slight
decrease in commercial trials [35]. Further results were
summarized as follows:
performing clinical trials has become considerably
more difficult and costly;
each year about 21,000 substantial amendments are
notified to the national competent authorities;
each national competent authority gets approxi-
mately 5700 SUSAR reports per year, a 6-fold in-
crease compared to 2003 (multi-reporting, over-
Contrastingly to the ICREL results EORTC, the larg-
est independent cancer research network in Europe,
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anlysed in 2005 its data and concluded that instead of
benefiting patients, the European CTD had hindered
their access to new treatments. The number of new trials
fell from 19 in 2004 to 7 in 2005, and only a third of
patients were enrolled in these trials. Simultaneously,
trial costs increased by 85% and insurance costs from 70
million to 140 million Euros. Trial initiation was about
five months slower than in 2004, mostly the result of the
increased workload of ECs. Besides paperwork and
documentation increased substantially [36].
In Finland, the number of approved applications in
surgery and oncology trials decreased by 42%, from 120
in 2002 to 70 in 2005. Academic drug trials decreased
from 20 to 5 between 2003 and 2005. Nevertheless, the
workload of the ethics committees and competent au-
thorities increased [37].
The national implementation of the European Clinical
Trial Directive has profoundly changed the face of clini-
cal research. Since the regulatory framework is focused
much more on commercial trials and does not address
facilities for the conduct of non-commercial trials be-
yond labeling issues, concerns have been expressed that
non-commercial research projects will be reduced and
the vital medical research conducted at academic institu-
tions curtailed. One of the chief reasons behind the con-
cerns was the increased bureaucracy and related required
paperwork for monitoring and auditing processes. It was
stressed out that it has to be possible to fulfill the bu-
reaucracy of the trials in the daily care setting to avoid
bias introduction. Another concern was that it would be
too onerous for public institutions with limited resources.
One editorial published in The Lancet went so far to ask
if the European CTD would be the death of academic
clinical trials [38]. The first numbers confirmed the wor-
ries about the future of investigator initiated clinical tri-
als. A study published in the British Medical Journal in
August 2008 concluded that for Denmark, there was no
decreasement in non-commercial trials after implemen-
tation of the European CTD, however a decline since
1993 could be shown; may be as a result of the introduc-
tion of the GCP guidelines. However, in Denmark the
underlying circumstances for non-commercial research
are quite outstanding compared with other MS as uni-
versities and university hospitals fund good clinical
practice units that provide free assistance to academic
clinical researchers [39]. In contrast, a report from Aus-
tria based on data of an University hospital mentioned a
decrease of non-commercial trials of 66%. There was no
decline in industry-sponsored trials [40]. Prior to the
directive, academic-sponsored clinical trials in the United
Kingdom required approval only from the EC. Accord-
ing to figures from the Medicines and Healthcare Prod-
ucts Regulatory Agency 1085 clinical trials were carried
out in the UK in 2005 compared with 1252 in 2008 [41].
Consequently, it can be concluded that there is no causal
relationship between reduced numbers of non-commer-
cial clinical trials and the EU CTD. However, there is a
need for adequate resource allocation, environmental
setting and financial circumstances. In this relationship,
not each country can handle this so that a need for clear
regulations for non-commercial trials regarding specific
alleviations for academic research exists. In this relation-
ship, the GCP-Directive 2005 gives member states more
flexibility, to rule investigator-initiated trials as it states
that the conditions under which the non-commercial
research is conducted by public researchers and the
places where this research takes place, make the applica-
tion of certain of the details of good clinical practice
unnecessary or guaranteed by other means [42]. The Di-
rective simplifies requirements for manufacturing, im-
portation and labeling of investigational medical prod-
ucts (IMPs) in non-commercial trials.
The above mentioned controversies, deficiences and
challenges lead to numerous ongoing initiatives and dis-
cussions among academics, industry, patient organiza-
tions and regulatory bodies. Multiple initiatives to ad-
dress the deficiencies and refine the European CTD were
set up. Their results of discussion should be summarized
in the following.
The Roadmap Initiative for clinical Research in Eu-
rope with several stakeholders (EFGCP (the European
Forum for Good Clinical Practice), EORTC, ECRIN,
EBMT (the European Group for Blood and Marrow
Transplantation), CLINT (which facilitates international
stem cell transplantation trials), European Leukemia
Network (ELN), and ICREL) identified five bottlenecks
for clinical research in Europe in March 2010 [43]:
Necessity for a single clinical trial application
across the MS;
Necessity for co-sponsorship regulation;
Risk-based regulatory approaches for IMPs;
Harmonisation of ethical review procedures;
Harmonisation and reduction of overload for
pharmacovigilance reporting.
The Federation of the European Academics of Medi-
cine (FEAM) that was founded 1993 in Brussels with the
objective of promoting cooperation between the national
Academies of Medicine and of extending to the political
and administrative authorities of the European Union the
advisory role that the Academies exercise in their own
countries on matters concerning medicine and public
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health summarized their suggestions for further devel-
opments of the European regulative framework as fol-
lows in August 2010 [44]:
Necessity for streamlining assessment of multina-
tional studies by the competent authorities and na-
tional ethics committees;
Necessity for definition of substantial amendments;
Necessity for definition of special research populations;
Necessity for definition of multiple sponsorship;
Development of a consistent risk-based insurance
system across Europe;
Necessity for a responsible body for SUSARs and
avoiding of adverse event reporting to ECs (only
annual safety report);
Necessities for further strategies for improving the
EU clinical research environment and funding.
The term non-commercial trial emerged from the Eu-
ropean CTD. However, no common definition exists in
the EU to explain what a non-commercial trial is. Re-
garding non-commercial trials and institutional spon-
sorship, there are still open organizational and legal
questions, although various approaches have been sug-
gested in recent years. The European Forum for Good
Clinical Practice (EFGCP) pointed out the necessity to
set-up public sponsors for national as well as interna-
tional studies in May 2005 [45]. Consequently, in the
last years, there were numerous initiatives on national,
regional, institutional and private level for educational,
administrative, funding and legal support to set-up
clinical trials on multiple levels, European, national,
institutional and scientific or investigator-driven, as
summarized in Ta bl e 5 Initiatives for non-commercial
trial support since implementation of the European
Clinical Trial Directive 2001/20/EC. As a consequence
EU-wide infrastructure networks and disease-oriented
scientific networks were set up or existing networks
were reinforced to overcome these obstacles [46,47].
Bergmann et al. suggested an expanded role for expert
organizations like the EORTC. They could provide a
forum for academics and industry to plan within a
regulatory framework and work closely with the regu-
latory authorities and legislative bodies [48]. EORTC
already coordinates multicenter trials. Other authors
called for a network of centers of excellence in clinical
research in Europe, where clinical trials should be re-
ferred to and conducted [49].
Investigator-driven trials often deal with potential di-
agnostic and therapeutic innovations that do not attract
commercial interests, e.g. proof of concept studies, stud-
ies on orphan diseases, comparison of diagnostic or
therapeutic interventions, surgical therapies or novel
indications for registered drugs. Very few public entities
(universities hospitals, funding bodies, charitable or-
Ta ble 5. Initiatives for non-commercial trial support since im-
plementation of the European Clinical Trials Directive 2001/
Initiatives for non-commercial t r i a l support
European Clinical Research Infrastructures Network (ECRIN)
founded in 2004 supports investigators and sponsors with consultan-
cies (such as information on regulatory and ethical requirements,
consulting on centre selection, insurance) and services (such as in-
teraction with competent authorities and ethics committees, study
monitoring ) to overcome the national legislative differences in mul-
tinational trials
Regulatory facilitations on national level were set up
Coordinating centers for clinical research, the Koordinierungszentren
für klinische Studien (KKS) were established at collective centers at
several universities by the BMBF in Germany
Public-limited companies (Sponsor GmbHs) and private hospital
units were set up at hospitals in Germany
Networks and disease-oriented scientific networks were set up or ex-
isting networks were reinforced, e.g. EORTC, ELN
Calls for national or European funding agencies like the NIH
Calls for network of centers of excellence in clinical research in
Europe, where clinical trials should be referred to and conducted
Calls for expanded role for expert organizations like the EORTC
which already coordinate multicenter trials, as they could provide a
forum for academics and industry to plan within a regulatory frame-
work and work closely with the regulatory authorities and legislative
Calls for Academic Research Organizations (AROs) allocated at the
universities which provide almost all services that are required from a
commercial sponsor
Calls for clinical trial networks of universities and hospitals similar to
the USA which receive with from both industry and NIH
ganizations) had the necessary infrastructure to handle
the increased administrative and legal requirements.
Funding was usually insufficient to pay for the increased
administrative costs. In this context, the Guidance docu-
ment on specific modalities for non-commercial trials
mentions in recital 11 of the 2005/28/EC Directive states
that the data from non-commercial trials cannot be used
for registration [50], which is a major obstacle to aca-
demic-sponsored research and to the development of
new indications for marketed medicines, especially in
rare diseases.
Consequently, it exists a need for further definition
and facilitations for non-commercial trials across the
MS. A waiver-system for non-commercial trials and a
waiver for the sponsor to purchase the IMP in
non-commercial trials or harmonizing and providing
uniform models for insurance coverage and liability for
non-commercial trials by the public health system, by
the public hospitals or by the university hospitals might
constitute mile stones in this direction. For example, in
Belgium the sponsor of a non-commercial trial does not
file certain quality data with the government authority
R. R. Ciuman / Health 3 (2011) 772-781
Copyright © 2011 SciRes. Openly accessible at http:// www.scirp.org/journal/HEALTH/
Table 6. Abbreviation list.
AAMC Association of American Medical Colleges
AMG Arzneimittelgesetz, German Drug Law
CA Competent Authority
COI Conflict of Interest
CRO Contract Research Organization
CTA Clinical Trial Agreement
CTD Clinical Trials Directive
DMC Data Monitoring Committee
DSMB Data Safety Monitoring Board
EBMT European Group for Blood and Marrow Transplantation
EC Ethics Committee
EC European Commission
ECRIN European Clinical Research Infrastructures Network
EFGCP European Forum for Good Clinical Practice
ELN European Leukemia Network
EM(E)A European Medicines Agency
EORTC European Organization for Research and Treatment of
FDA Food and Drug Administration, USA
FEAM Federation of the European Academics of Medicine
GCP Good Clinical Practice
ICH International Conference on Harmonization
ICMJE International Committee of Medical Journal Editors
ICREL Impact on Clinical Research of European Legislations
IMP Investigational Medical Product
JPMA Japan Pharmaceutical Manufacturers Association
MHLW Ministry of Health, Labor and Welfare, Japan
MS Member State(s) of the European Union
MS Member State(s) of the European Union
PhRMA Pharmaceutical Research and Manufacturers of America
SAE Serious Adverse Event
SAE Serious Adverse Event
when applying for authorization in respect of a previ-
ously registered drug, does not have to pay any ethics
committee fees and may be excused from certain label-
ling requirements [51]. In Italy 5% of marketing ex-
penses have to be paid to the Italian Medicines Agency
(AIFA) for financing non-commercial trials, e.g. long-
term studies and side-effect studies as the EU CTD fo-
cuses on efficacy testing [52].
A thorough knowledge and correct understanding of
the relevant legal and regulatory framework is essential
for adequate fulfillment of the various tasks of sponsor-
ship and investigatorship, assurance of high quality stan-
dards, patient safety and successful completion of clini-
cal trials. In this context, the European Clinical Trials
Directive 2001/20/EC and its subsequent different na-
tional implementations set landmarks in regards of qual-
ity assurance and patient safety. On the other hand, the
regulatory framework focuses on commercial trials and
does not facilitate the conduct of non-commercial trials.
It brought along enhanced liability issues, insurance condi-
tions, administrative requirements, documentation and
monitoring standards. Hence, it raised various practical and
financial concerns for non-commercial trials. A perceived
reduction of commercial and non-commercial trials was the
result. In the last years, there were numerous initiatives on
national, regional, institutional and private level for educa-
tional, administrative, funding and legal support to set-up
clinical trials. But the regulatory framework still left open
legal questions which need to be answered by the compe-
tent authorities, e.g. guidelines for co-sponsorship are still
The work was part of the Master Thesis of the Study Course for
Pharmaceutical Medicine from the University of Duisburg-Essen and
was made possible thanks to the commitment of the organizers and
teachers of the study course.
[1] European Parliament and Council Directive 2001/20/EC
of 4 April 2001. OJ No L121/34 of 1 May 2001.
[2] German Drug Law (2004) 12 Gesetz zur Änderung des
Arzneimittelgesetzes. Bundesgesetzblatt Teil I Nummer
[3] Wingen, F.I. and Beinhauer, K.G. (2002) Development of
clinical drug trial and the formal, legal and financial
scope. Internist (German), 43, 463-468.
[4] Thompson, D.F. (1993) Understanding financial conflicts
of interest. The New England Journal of Medicine, 329,
573-576. doi:10.1056/NEJM199308193290812
[5] Weber, L.J. (2006) Profits before people? Ethical stan-
dards and the marketing of prescription drugs. Indiana
University Press, Bloomington.
[6] Montori, V.M., Smieja, M. and Guyatt, G.H. (2000) Pub-
lication bias: A brief review for clinicians. Mayo Clinic
Proceedings, 75, 1284-1288.
[7] Hirsch, L. (2004) Randomized clinical trials: What gets
published, and when? Canadian Medical Association
Journal, 170, 481-483.
[8] Department of Health and Human Services (2004) Fi-
nancial relationships and interests in research involving
human subjects: Guidance for human subject protection.
Federal Register Notices, 69, 26393.
[9] De Angelis, C., Drazen, J.M., Frizelle, F.A., Haug, C.,
Hoey, J., Horton, R., Kotzin, S., Laine, C., Marusic, A.,
Overbeke, A.J., Schroeder, T.V., Sox, H.C. and Van Der
R. R. Ciuman / Health 3 (2011) 772-781
Copyright © 2011 SciRes. Openly accessible at http:// www.scirp.org/journal/HEALTH/
Weyden, M.B. (2004) Clinical trial registration: A state-
ment from the International Committee of Medical Jour-
nal editors. The New England Journal of Medicine, 351,
[10] Davidoff, F., DeAngelis, C.D., Drazen, J.M., Nicholis,
M.G., Hoey, J., Hojgaard, L., Horton, R., Kotzin, S.,
Nylenna, M., Overbeke, A., Sox, H.C., Weyden, M. and
Wilkes, M.S. (2001) Sponsorship, authorship and ac-
countability. Canadian Medical Association Journal, 165,
[11] FDA (2006) Guidance for clinical trial sponsors on the
establishment and operation of clinical trial data moni-
toring committees, 71FR 15421.
[12] Ahmer, S., Haider, I.J., Anderson, D. and Arya, P. (2006)
Do pharmaceutical companies selectively report clinical
trial data. Pakistan Journal of Medical Sciences, 22,
[13] House of Commons Health Committee (2005) The in-
fluence of the pharmaceutical industry. Fourth Report of
Session, The Stationary Office Limited, London.
[14] Ferner, R. (2005) The influence of big pharma. BMJ, 330,
855-856. doi:10.1136/bmj.330.7496.855
[15] Turner, E.H., Matthews, A.M., Linardatos, E., Tell, R.A.
and Rosenthal, R. (2008) Selective publication of antide-
pressant trials and its influence on apparent efficacy. The
New England Journal of Medicine, 358, 252-260.
[16] Melander, H., Ahlqvist-Rastad, J., Meijer, G. and Beer-
mann, B. (2003) Evidence based medicine-selective re-
porting from studies sponsored by pharmaceutical indus-
try: Review of studies in new drug applications. BMJ,
326, 1171-1173. doi:10.1136/bmj.326.7400.1171
[17] Lee, K., Bachetti, P. and Sim, I. (2008) Publication of
clinical trials supporting successful new drug applica-
tions: a literature analysis. PLoS Medicine, 5, e191.
[18] Rising, K., Bachetti, P. and Bero, L. (2008) Reporting
bias in drug trials submitted to the Food and Drug Ad-
ministration: Review of publication and presentation.
PLoS Medicine, 5, e217.
[19] Schott, G., Pachl, H., Limbach, U., Gundert-Remy, U.,
Ludwig, W.D. and Lieb, K. (2010) The financing of drug
trials by pharmaceutical companies and its consequences.
Part 1: A qualitative, systematic review of the literature
on possible influences on the findings, protocols, and
quality of drug trials. Deutsches Aerzteblatt International
(German), 107, 279-285.
[20] Schott, G., Pachl, H., Limbach, U., Gundert-Remy, U.,
Ludwig, W.D. and Lieb, K. (2010) The financing of drug
trials by pharmaceutical companies and its consequences.
Part 2: A qualitative, systematic review of the literature
on possible influences on authorship, access to trial data,
and trial registration and publication. Deutsches Aerzte-
blatt International (German), 107, 295-301.
[21] Kaiser, J. (2008) Making clinical data widely available.
Science, 322, 217-218.
[22] PloS Medicine Editors (2008) Next stop, don’t block the
doors: Opening up access to clinical trials results. PloS
Medicine, 5, e160. doi:10.1371/journal.pmed.0050160
[23] US Department of Health and Human Services (2007)
Food and Drug Administration Amendments Act of 2007,
P.L. 110-185.
sActof2007/FullTextofFDAAA Law/default.htm
[24] Hirsch, L. (2008) Trial registration and results disclosure:
Impact of US legislation on sponsors, investigators, and
medical journal editors. Current Medical Research and
Opinion, 24, 1683-1689.
[25] Mayor, S. (2005) Drug companies agree to make clinical
trial results public. BMJ, 330, 109.
[26] PhRMA (2009) Revised clinical trial principles reinforce
PhRMA’s commitment to transparency and strengthen
authorship standards (press release), Washington DC.
[27] Taylor, P. (2009) Emerging clinical trial locations—
China. Market dynamics and regulatory environment.
Business Insights Ltd, London.
[28] Abdullahi vs. Pfizer Inc., 562 F.3d 163, 169 (2nd Cir.
[29] European Commission (2005) Notice to Applicants.
Questions & answers: Clinical trial documents, F2/BL D
2005, Brussels.
[30] Department of Health, UK. (2004) EU Clinical Trials
Directive: Sponsorship responsibilities in publicly funded
trials. Medicines for human use (Clinical Trials) regula-
tions 2004.
[31] Gainotti, S. and Petrini, C. (2010). Insurance policies for
clinical trials in the United States and in some European
countries. Journal of Clinical Research & Bioethics, 1,
1-8. doi:10.4172/2155-9627.1000001
[32] Robinson, K. and Andrews, P.J. (2010) More trials and
tribulations: The effect of the EU directive on clinical tri-
als in intensive care and emergency medicine, five years
after its implementation. Journal of Medical Ethics, 36,
322-325. doi:10.1136/jme.2009.035261
[33] Meunier, F. and Lacombe, D. (2003) European Organisa-
tion for Research and Treatment of Cancer’s point of
view. Lancet, 23, 663.
[34] Ono, S. and Kodama, Y. (2000) Clinical trials and the
new good clinical practice guideline in Japan. An eco-
nomic perspective. Pharmacoeconomics, 18, 125-141.
[35] ICREL (2011) Report of project “Impact on Clinical
Research of European Legislation”.
[36] Therasse, P., Eisenhauer, E.A., Buyse, M. (2006) Update
in methodology and conduct of cancer clinical trials.
European Journal of Cancer, 42, 1322-1330.
R. R. Ciuman / Health 3 (2011) 772-781
Copyright © 2011 SciRes. http://www.scirp.org/journal/HEALTH/Openly accessible at
[37] Hemminki, A. and Kellokumpu-Lehtinen, P.L. (2006)
Harmful impact of EU clinical trials directive. BMJ, 332,
501-502. doi:10.1136/bmj.332.7540.501
[38] Morice, A.H. (2003) The death of academic clinical trials.
Lancet, 361, 1568. doi:10.1016/S0140-6736(03)13211-4
[39] Berendt, L., Hakansson, C., Bach, K.F., Dalhoff, K.,
Andreasen, P.B., Petersen, L.G,. Andersen, E. and Poulsen,
H.E. (2008) Effect of European clinical trials directive on
academic drug trials in Denmark: Retrospective study of
applications to the Danish Medicines Agency, 1993-2006.
BMJ, 336, 33-35. doi:10.1136/bmj.39401.470648.BE
[40] Singer, E. (2007) Future of investigator initiated trials in
EU academia. Basic & Clinical Pharmacology & Toxi-
cology, 101, 11.
[41] Gulland, A. (2009) Number of global clinical trials done
in UK fell by two thirds after EU directive. BMJ, 338,
1052. doi:10.1136/bmj.b1052
[42] The Commission of the European Communities (2005)
Commission Directive 2005/28/EC of 8 April 2005. OJL,
91, 13-19.
[43] European Forum for Good Clinical Practice (EFGCP)
(2010) A road map initiative for clinical research in
Europe. http://www.efgcp.be
[44] Federation of the European Academics of Medicine (FEAM)
(2011) Opportunities and challenges for reforming the EU
clinical trials directive: An academic perspective: State-
[45] European Forum for Good Clinical Practice (EFGCP)
(2011) Conference report: Examining the value and the
impact of the EU clinical trials directive-one year into the
new European GCP reality.
[46] Demotes-Mainard, J. and Ohmann, C. (2005) European
clinical research infrastructures network: Promoting harmo-
nization and quality in European clinical research. Lancet,
365, 107-108. doi:10.1016/S0140-6736(05)17720-4
[47] Demotes-Mainard, J., Chene, G., Libersa, C. and Pignon,
J.P. (2005) Clinical research infrastructures and networks
in France: Report on the French ECRIN workshop.
Therapie, 60, 183-199. doi:10.2515/therapie:2005023
[48] Bergmann, L., Berns, B., Dalgleish, A.G., von Euler, M.
and Hecht, T.T. (2010) Investigator-initiated trials of tar-
geted oncology agents: Why independent research is at
risk? Annals of Oncology, 21, 1573-1578.
[49] Clumeck, N. and Katlama, C. (2004) Call for network of
centers of excellence in clinical research in Europe. Lan-
cet, 363, 901-902.
[50] European Commission (2006) Guidance document on
specific modalities for non-commercial clinical trials re-
ferred to in commission directive 2005/28/EC laying
down the principles and detailed guidelines for good
clinical practice.
[51] Moniteur Belge, Belgium. Loi relative aux Experimenta-
tions sur la Personne Humaine; 7 May 2004.
[52] Italian Medicines Agency (AIFA) (2010) Research and
development working group. Feasibility and challenges
of independent research on drugs: The Italian medicines
agency experience. European Journal of Clinical Inves-
tigation, 40, 69-86.