2010

iMedPub Journals TRANSLATIONAL BIOMEDICINE Vol.1

No. 1:2
doi: 10:3823/401

A Review of Clinical Trials in Spain

Patrick Bohan1*, Ouadah Hadjebi2

1Harrison Clinical Research, Barcelona, Spain, 2Biocompatibles International plc, Farnham, UK. *Correspondence: pbohan@mail.com

Background: The European Directive 2001/20/EC sought to harmonize conditions and regulatory requirements for
the conduct of clinical research in Europe. This article describes the context and recent history of research in Spain,
reviews how clinical trials have been affected and assesses both the challenges and benefits of conducting trials
there. Methods and Findings: Descriptions, findings and opinions are based on field experience and literature review.
Available literature was found to be limited to descriptive data compiled by stakeholders without a general overview
of the entire process of conducting clinical trials in Spain. Conclusions: This review argues that Spain presents several
advantages as the location for clinical research, among them: highly-qualified research professionals; medical exce-
llence; and the embrace of regulatory harmonization processes, which are due to historical factors that have otherwise
limited growth in the pharmaceutical, medical and basic research sectors. Commonly experienced challenges in the
conduct of trials are discussed as well as how these issues can be addressed.

Introduction Findings

The European Directive 2001/20/EC sought to harmonize condi-
tions and regulatory requirements for the conduct of clinical re-
search in Europe. In 2010, the European Commission was engaged
in a consultation process accepting that this objective had not
been achieved and considering the implementation of a new di-
rective or regulation [1]. Nevertheless, it can be argued that the
directive has succeeded in convincing a majority of stakeholders
of the need to harmonize. Current developments in Spain (such
as the Spanish Medicines Agency’s (AEMPS) clinical trials portal
and commitment to the Voluntary Harmonisation Procedure, for
example) are promising and some differences can be beneficial.
The problems that persist are reviewed and found not to be spe-
cific to Spain.
Methods
This review is compiled essentially from field experience with
sponsors, ethics committees and regulatory authorities in Spain.
The available literature tends to focus on specific concerns for each
stakeholder (timelines for sponsors, submission deficiencies for
Institutional Review Boards/Ethics Committee (ECs)) without loo-
king at the entire life cycle of a clinical trial. The focus of this review
is clinical research in pharmaceuticals and essentially in phases I
to III. Phase IV and medical device studies will have some points
in common and be comparable but, because the regulatory en-
vironment is different (for marketed medicines, the regional auto-
nomous governments, for instance, have a bigger role to play), our
conclusions may not be extrapolated to these areas.
Spain, with a population of 46,157,822 and the third largest sur-
face area in Western Europe, features regularly near the top of
many statistical tables [2]. Life expectancy there is one of the
highest in the world: 84 years for women and 78 for men (78
and 70 are the European averages while 70 and 65 are global
averages) [3]. Spaniards are generally happy with their health
system (66.9% thought that the system worked well or well
enough [4]) which was ranked seventh best in the world by the
World Health Organization (WHO) in 2000.
Yet, there is a widely-held belief—even among Spaniards—that
Spain regularly under-achieves [5]. Arguably, however, the am-
bition to realize its full potential is one of the country’s main
competitive advantages. Despite, for example, having one of
the largest pharmaceutical sectors in the European Union (EU)
and a long history of national chemical and pharmaceutical
companies (Uriach was founded in 1850), its companies are
usually either local subsidiaries or relatively small and family-
owned (none with more than 1,000 employees and none
among the world’s top 50 [6, 7]). This has meant that the sector
has been particularly susceptible to mergers and fusions and
thus the resulting down-sizing and rationalizations. This sector
employs approximately 40,000 people (with 10% working in
the area of R&D [8]) but the number of companies is declining:
from 377 in 2000 to 337 in 2005 to 315 in 2006 [9]. Professional
opportunities, therefore, have diminished or disappeared du-
ring a period that the sector has almost doubled investment in
clinical research (€453m in 2008 up from €229m in 2002) the-
reby creating more outsourced opportunities [10]. The relative

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disadvantage, therefore, has had a paradoxically beneficial con-
sequence in the field of contract clinical research because it has
contributed to greater mobility and enterprise of a large pool of
motivated and qualified professionals, many of whom are now
involved in the outsourced sector [11]. It has also solved what
traditionally is seen as an obstacle to better performance: mo-
bility and knowledge transfer. There is little tradition of outward
mobility, not only internationally but also between, for exam-
ple, universities and other research organizations and even bet-
ween departments within the same university [12].
Furthermore, a comparable centripetal force means that some
high-achieving Spanish researchers who have established
themselves elsewhere in the world are being tempted back
home by initiatives such as CARI and INNCORPORA [13]. The
inflexibility associated with the system in the past is opening
out to incorporate possibilities that allow world-renowned re-
searchers such as Dr. Josep Baselga head up both the Barcelona
Vall d’Hebron Oncology Institute (VHIO) and that of Massachu-
setts General Hospital; similarly, Dr. Manuel Hildago combines
responsibilities at Johns Hopkins in Baltimore with that of Hos-
pital de Madrid. These movements have contributed to Spanish
scientific output (as measured by published articles in the life
sciences) increasing by 42.3% between 2000 and 2008 [14].
The traditional lack of mobility associated with research in Spain
has also resulted in the high level of qualification and training
that is typical among outsourced clinical research professionals.
Due to limited prospects and a functionary culture of life-long,
permanent positions, many young life science graduates are
obliged to change careers. Formal training requirements for
Clinical Research Associates (CRAs) in Spain predates even ICH-
GCP with the Royal Decree 561 of 1993. A survey of active CRAs
in Spain has shown that 80% have a Masters degree in monito-
ring (of at least 9 that are currently available) [15]. About 80%
of Spanish CRAs are pharmacists compared to a nursing profile
which is more typical in North America and the UK [16].
As a final example of how an apparent disadvantage has been
turned into competitive advantage, the public health system
continues to produce specialized centers of reference and exce-
llence far above what their limited resources might suggest (per
capita public health expenditure in 2006 was 1,414USD compa-
red to an OECD average of 1,769USD [17]) to some extent becau-
se its wealthier citizens tend to choose private practice for gene-
ral health and primary care but return to the fold of the public
system with more serious ailments: although only about 12% of
the population nationally currently has private health insurance,
in Madrid and Barcelona (70% of Spaniards live in urban areas),
the number of privately insured can be as high as 25%. Overall,
private hospitals account for 29% of all hospital beds (158,306)
and private insurance account for 21% of total health care expen-
diture [18, 19]. The urban concentration of the population also
means that better communication and fewer costs for sponsors.
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2010
TRANSLATIONAL BIOMEDICINE Vol.1
No. 1:2
doi: 10:3823/401
Among others, these factors result in Spain participating in one
of every 10 clinical trials conducted in the European Economic
Area [20]. Before looking more closely the practicalities of con-
ducting clinical research, first let us outline some of the most
typical challenges:
• Lack of clinical research infrastructure
• Delays in set-up
• Complicated submission process
• Delays in site contracts
Perhaps the single biggest challenge to clinical research in
Spain is that it continues to be something additional and optio-
nal for physicians, heavily dependent on their personal interest
and motivation. There is little institutional support or recogni-
tion. This problem is reflected in their hospitals’ organizational
structure with only a small number having dedicated clinical
research administrative departments (and usually only in the
area of onco-hematology: almost 30% of all trials conducted in
Spain are in the area of oncology [20]). A possible contributing
factor to this is the relatively low number of nurses in Spain.
In comparison with western European standards, the relative
number of doctors in Spain is the near the EU average but, in
contrast, Spain displays the fourth lowest number of nurses
(3.7 per 1000 inhabitants compared to an EU average of 7.3 per
1000) [4]. The difficulty that many sites experience incorpora-
ting the demands of clinical research into everyday practice
can result in delays in clearly defining and establishing study
teams and responsibilities, in data entry, as well as additional
costs due to staff-turnover and high workload (training, follow-
up documentation) and difficulty reconciling standard practice
and protocol procedures.
Regarding EC submissions, it has been suggested that the cu-
rrent EC requirement to present the complete protocol in Spa-
nish results in a delay of about 15 days. Despite the precedent
established when 8 ECs required only the protocol synopsis in
Spanish when an avian flu vaccine trial was considered urgent,
no other development on this issue has occurred [21, 22].
EC requirements also vary widely from site to site and autono-
mous region to another (Andalusia and the Basque Country
have regional ECs that duplicate local EC evaluations; Galicia,
Balears and Aragon have regional ECs that evaluate for all hos-
pitals in their areas; others have a mixture). Because of this,
sponsors logically have moved towards the more efficient com-
mittees, creating an imbalance that arguably jeopardizes that
efficiency: results from the Spanish Pharmaceutical Industry
Association Farmaindustria’s BEST project show that just 6 ECs
(from a total of 67 in the BEST database and about 140 accredi-
ted committees nationally) act as lead EC in almost 50% of the
1,062 trials analyzed [10].
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Although regulatory timelines are converging with EU counter-
parts (10 days to validate a submission and the stipulated 60
days to emit an opinion), it is perhaps more revealing to look at
the average time from submission to first inclusion because this
takes into account both the contractual procedure and actual
time a site needs to start recruiting: 256 days again according to
data from the BEST database (it was encouraging to see that 75
trials (of 1,062 in total) managed to do this in under 100 days)
[10]. Improved EC efficiency is certainly contributing to this: in
2006 only 29% of ECs used e-mail communication and it took a
mean 12.4 days for sponsors to receive notification of approval
[23]. Currently, notification is usually given by email within 48
hours of a decision. Some are moving towards using the onli-
ne submission system that the AEMPS has established. Against
this, few ECs have accepted the principle of a single opinion
(that non-lead committees evaluate only local issues) and the
EC Coordinating Center (CC-CEIC) set up as part of the imple-
mentation of the Clinical Trials Directive has had very limited
success in harmonizing their activities.
The contractual process also heavily affects the length of time
needed to initiate a site. A site’s efficiency as experienced via
its EC is also (generally) reflected in how that site conducts
contract negotiation: the BEST data show that 28 sites (of 599
analyzed) participate in more than 50% of the 7,696 trial parti-
cipations (the multiple of number of trials and number of sites).
Ninety-seven (97) sites account for 80% of all trial participations
registered [10]. There is awareness of this problem and it is ge-
nerally being addressed but in different ways and by different
actors with a case in point being that of the region of Valencia
which recently issued a regulation requiring contracts to be sig-
ned within one month of EC approval [24, 25]. Some regions
(Galicia) and a growing number of sites offer their template
contract in English which saves on time, costs and misunders-
tandings. Other solutions to this problem put the onus on the
sponsor instead: in the Basque Country, sponsors are obliged
to make a commitment as part of the EC submission not to re-
quest changes to the regional template contract; in Andalusia,
the contract similarly is not open to negotiation. Although this
may seem excessively rigid, sponsors should bear in mind that
Spanish hospital contracts are generally a reiteration of obliga-
tions anyway undertaken under applicable legislation (Royal
Decree 223/2004) with key sponsor issues such as intellectual
property clearly remaining with the sponsor and other com-
mon sponsor concerns (such as timely entry of study data or
schedule of payments) of little relevance because, in practice,
it is impossible to enforce timely data entry and the site admi-
nistration has little or no knowledge of recruitment rates (this is
usually provided directly by the local CRA). There is a conside-
rable disproportion between EC involvement at approval stage
and their capacity to follow and track the conduct and progress
of those trials [26].
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TRANSLATIONAL BIOMEDICINE Vol.1
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Starting contract negotiation as early as possible (in advance of
EC submission) can reduce time to execution by up to 2 months.
Times continue to be longer than desirable (a mean 125 days for
hospitals from the date of EC submission according to BEST). This
is a critical factor because the CA submission is not complete un-
til the first Conformidad del Centro (CDC: a document stating the
Hospital’s Managing Director’s approval) is sent to the AEMPS.
The CDC can be a confusing document and standard practice va-
ries from granting it once the EC has approved the trial to upon
execution of the contract. Non-Spanish sponsors are also someti-
mes surprised to be asked for power-of-attorney documents for
the person who signs the contract on behalf of the sponsor; this
person may also be required to provide a passport or ID number
which again is perfectly normal in Spain but less so elsewhere.
All the above challenges can be addressed with proper plan-
ned and experienced local support. The research infrastructure
can be addressed to some degree at least at the outset with the
principal investigator by budgeting specifically for outsourced
support for the site. Local CRAs also pay a key role in minimizing
the time between initiation and first patient. The experience of
CRAs also goes some way to compensating for site organiza-
tional deficiencies by providing site management as well as
monitoring. Because several months typically go by between
feasibility and initiation, investigators usually do not start to
plan for recruitment until the day of initiation. Furthermore, the
study team may not have been decided or agreed so it is at this
key moment that local CRAs can step in to establish contact and
fluid communication with key study team members.
Personal contact is still immensely important and Spanish in-
vestigators (for the reasons outlined above) do not respond
well (or at all) to feasibility questions arriving unsolicited by
email. It is important to start the relationship building at this
point. Local experience and knowledge will also result in more
careful site selection: 80% of all trial participations in the BEST
database were in Andalusia, Catalonia, Madrid and Valencia .
These four regions were underrepresented in the subgroup of
trial sites where zero patients were recruited (461 of the 2,596
total trial participations).
It is useful to involve ECs in the selection process and including
personal contact during the pre-trial selection visit to discuss
the submission and contract issues. The EC must first accept to
be lead (reference) EC and it is useful to check that submission
procedures have not changed (some, like La Princesa in Ma-
drid, have already moved to exclusively electronic submission
although not online). To act as lead, the committee must meet
at least twice per month and will have special fees associated.
Seven percent of EC queries have been shown to be related to
the exact wording in the Patient Information Sheet regarding
the 15/1999 Data Protection Act which can easily be anticipa-
ted and corrected before submission [23].
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Counting from contract signature, it takes an average of 69 days Note:

to include the first patient in Spanish site which is about avera- The authors take full responsibility of this article and confirm
ge in the BEST project comparison with the same trials in other that both Harrison Clinical Research and Biocompatibles Inter-
countries, however, when actual recruitment is compared to national plc were not involved in the independent writing of
projected, Spanish sites achieve a 70% score. This points to the this report.
reliability of Spanish investigators; because trial participation is
Table 1: Dossier Elements for Clinical Trials Submission in Spain
generally a reflection of genuine motivation and scientific inter-
est, they tend to be very realistic about recruitment.
Document AEMPS EC†
Receipt of confirmation of EudraCT number X 0
The AEMPS has also stated as a strategic objective its participa-
tion in the Voluntary Harmonised Procedure which will in theory Covering letter X X

greatly simplify and expedite the regulatory process [27]. Since Checklist of submitted documents (Section J) X 0
September 2008, the agency no longer accepts submission in If the applicant is not the sponsor, a letter of authori- X X
paper; instead an online system is used which incorporates and zation enabling the applicant to act on behalf of the
sponsor
improves on the EudraCT system.
Clinical Trial Application (CTA) X X
Protocol and protocol synopsis X X
X X
Conclusions Investigators Brochure
Investigational Medicinal Product Dossier (IMPD) X 0

Given the broad criticism of the Clinical Trials Directive across Request for PEI (Producto en investigación, IMP) num- X 0
ber (if not previously registered in Spain)
Europe [28], it is interesting to contrast that the experience in
Good Manufacturing Practice certificates X 0
Spain has been one of continual improvements in the condi-
Patient Information Sheet/Informed Consent Form and X X
tions for clinical research over the last decade. What is most en-
couraging is that there is a general acceptance of the need to Any other arrangements for recruitment of subjects/ 0 X
Compensation to subjects
continue improving right across the spectrum of stakeholders
Copy/summary of any scientific advice X 0
and a corresponding professionalization in areas that were, until
Receipt of fees payment* X X
relatively recently, almost voluntary in character. Sponsors can
encourage this tendency by expanding their research beyond EC approval/Hospital Managing Director’s approval # X 0

the usual sites and the usual ECs. Sites and ECs can encourage Insurance certificate 0 X
this by measuring and benchmarking their performance against Suitability documents (Investigators, facilities) 0 X
other sites and ECs nationally and internationally. Sites should Collaboration documents (with other departments, 0 X
look to outsource where structural limitations are holding them services, investigators, approval of department head)

back from fully benefiting—scientifically and financially—from
clinical research. Hospital management should likewise look at
clinical research as an investment which improves the overall
capability and performance of their professionals at the same
time as allowing access to new treatments and an additional
source of income. Sponsors, for their part, should look beyond
the narrow approval timeline to improve the feasibility to dos-
sier preparation stage and from approval to enrolment, ensu-
ring the involvement of all parties at all stages.
In summary, Spain presents several advantages as the location
for clinical research, among them, high-qualified research pro-
fessionals, medical excellence, and a movement towards regu-
latory harmonization that has been embraced by the principal
stakeholders.
Acknowledgments
The authors’ thanks go to Maria Gómez, Clinical Operations Ma-
nager, Harrison Clinical Research.
Summary of investigator’s current research workload 0 X
Investigator commitment (protocol signature page) X X
Investigator Payment Schedule 0 X
Case Report Form (CRF) 0 X
* As noted in the article, there is considerable variation in the documentation required from
one EC to another and how they are to be submitted (number of copies, for example) so
only the most typical are listed here. In some cases, originals are also requested.
# Most ECs have fees but not all require payment prior to the signing a contract.
Because these are documents that will only be available after the initial submission is made,
they are critical to overall timelines. The AEMPS authorization, in turn, is not submitted to
the EC but essential for contract signature.
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