ANALYSIS
Europe gets nul points
for harmony in trials
Despite European legislation to harmonise procedures for
ethical approval, Andreas Schnitzbauer and colleagues
found getting approval for their multinational study was still
complex and time consuming
In April 2001 the European parliament
passed a directive to promote good practice in
the conduct of clinical trials.1 Article 7 of the
directive refers to multicentre trials and prescribes an ethics submission procedure that
consists of only one lead ethics commission
in each country performing a detailed evaluation and judgment on the protocol. However,
our experience of getting approval for a trial
after September 2004 suggests wide variation
remains in the ethics processes of European
Union countries.
additional submission and approval from the
local ethics committees.
We had to obtain approval from a total of
38 national and local ethics committees in 10
EU countries. In Austria, Finland (only one
site), Spain, and the Netherlands, each site
submitted to their local ethics committee. In
France and Sweden the protocol was reviewed
by one committee only, a national committee
in France and the committee at the site of the
lead principal investigator in Sweden; the
study was then automatically approved for all
participating national sites. In Belgium, Italy,
Study
Our study was set up to evaluate the poten- Table 1 | Time taken to get ethics committee approval
tial survival and anti-tumour benefits of using (time with committee)
a mammalian target of rapamycin inhibitor
Country
No of committees Median (range)
No of days
(sirolimus) in liver cancer patients who had
Austria
2
35 (26 to 44)
received transplants.2 The study is an invesBelgium
3
119 (119 to 181)
tigator initiated trial in 10 European countries
Finland
1
47
(Austria, Belgium, Finland, France, Germany,
France
1
123
Italy, the Netherlands, Spain, Sweden, and the
Germany
14
43 (29 to 93)
United Kingdom) and three non-EU countries
Italy
7
61 (35 to 107)
(Australia, Canada, and Norway) with a total
Netherlands
2
91 (61 to 120)
of 40 sites in the EU and four sites outside the
Spain
2
75 (72 to 77)
EU. Regensburg University Hospital is the
Sweden
2
30*
trial sponsor and thus is responsible for its
UK:
conduct; this point is a foundation of our trial
National
1
168
Local
3
78 (24 to 98)
and we made this clear to all parties involved.
Total
4
246 (192 to 266)
Although the manufacturer of the study drug
* Approval from second committee was simultaneous.
provides funds for the trial, it is not the study
sponsor and therefore does not conduct or
administer the study, including relations with
ethics committees.
Table 2 | Times from submission to ethical approval
for different submission structures
Procedures for ethical approval
The procedures for ethical approval varied
substantially among EU countries. In general, four different approval procedures were
used: submission and approval for each site,
approval from a lead or national committee
serving as approval for all participating sites in
the country, lead ethics approval from a central site and confirmatory approval at the other
sites, and national ethics approval followed by
1302
Structure
No of
committees
Submission to each site
7
One committee approves
for whole country
Lead committee approves,
other sites send confirmation
Separate national and
local approval
3
24
3+1
Median
(range)
No of days
61
(26 to 120)
77
(30 to 123)
49
(29 to 181)
246
(192 to266)
and Germany, the principal investigator for
the country submitted a proposal to the local
ethics committee, and once it had approved
the study committees at other sites sent confirmatory approval. Notably, for Germany, the
study was originally approved by the Regensburg ethics committee according to the German law existing before the 2001 EU directive.
Although submissions to all other German sites
were made according to the old law, local ethics committees treated the trial as a submission
using the new directive and gave confirmatory
approval. Finally, in the UK the study first had
to be accepted by the national ethics committee and then by the local committee at each
participating site.
Approval of submission
We sent the ethics committees a package of
relevant study documents that included the
main protocol (79 pages), patient information
sheet (six pages), informed consent sheet (two
pages), insurance certificate (10 pages), the
investigator’s brochure of the study drug (267
pages), study synopsis (six pages), letter to
the ethics committee (two pages), a risk-benefit assessment for the project (two pages), a
dose-risk assessment for radiology procedures
(one page), and various locally required documents. The committees confirmed receipt of
the documents through a contract research
BMJ | 30 May 2009 | Volume 338
ANALYSIS
ries did not require a full resubmission to the
committee, being resolved by formal notification of our remedial action.
Eight committees raised more substantial
questions on study documents that required
a complete resubmission. Several committees
asked for additional explanations on statistical
methods and sample size calculations; this section was amended in the protocol. A Belgian
committee made an important comment that
we should incorporate an exclusion criterion
for patients under guardianship or with a
psychological or sociological condition. The
UK committee had extensive queries. These
included a request for a detailed patient information and safety card, a letter to the patient’s
general practitioner with drug safety information, a request for explanation about why
informed consent could be collected either
before or after liver transplantation, a request
to amend the insurance certificate and substantially revise the patient information sheet,
a request to provide multilingual information
sheets for non-English-speaking ethnic groups,
and requests to clarify certain minor aspects
of the protocol text. Although the process was
time consuming, the committee’s comments
were generally helpful, improving our statistical
plan and solidifying patient safety measures.
organisation, which we hired to help with the
submission process.
We compared the time from receipt to
receiving approval for committees in the
various countries (table 1). In countries where
resubmissions were necessary, the total time
calculated included the time from the date of
resubmission until the date of reply from the
ethics committee; additional time needed in
the interim for preparing the response to the
committee or for amending the protocol is
not included in this calculation. Resubmission
was necessary in Belgium, France, Italy, the
Netherlands, Spain, and Germany (two sites);
the national ethics committee in the UK had
substantial queries after the first and second
submissions that we had to answer before final
approval.
The median time from submission to final
approval was 55 days. Nineteen (51%) of the
38 ethics submission procedures took longer
than 60 days: five in Italy, three in Belgium,
three in Germany, two in the Netherlands, two
in Spain, one in France, and three in the UK
(the national and two local committees). Notably, four Italian committees delayed judgment
because they had too many protocols to review
at their regular meetings.
Median ethics submission times differed
substantially according to the procedures used
(table 2). The median was lowest in countries
where every site submitted individually to their
local ethics committee and highest in the UK,
which requires national approval followed
by separate local approval. The UK national
committee requested two resubmissions that
required substantial action on our part (see section below), taking an additional 100 and 56
days, respectively: this interim period between
resubmissions was not included in the time
­calculations.
Cost of approval
Table 3 shows the charges for ethical approval.
The median charge was €400 (£357; $536).
The highest charges were in Italy, where fees
for five of the seven committees were over
€2000 (€6000, €4800, €3120, €2400, and
€2172). Fifteen committees did not charge for
their services (all French, UK, and Austrian
sites; three German sites; two Dutch sites; and
two Italian sites).
Committee queries
Seventeen of 38 (46%) ethics committees had
queries about the patient information sheet,
insurance (even though certificates were
obtained from an international broker in
accordance with the national requirements),
patient safety, and data protection. These que-
Efficient and harmonised process?
Article 7 of the EU directive states: “In the case
of multi-center clinical trials carried out in more
than one Member State simultaneously, a single opinion shall be given for each Member
State concerned by the clinical trial.” Three out
of the four ethics submission procedures that
Table 3 | Fees for ethical approval by country
BMJ | 30 May 2009 | Volume 338 Country
Austria
Belgium
Finland
France
Germany
Italy
Netherlands
Spain
Sweden
UK national
UK local
No of committees
2
3
1
1
14
7
2
2
2
1
3
Median charge (€)
0
1250
400
0
400
2400
0
632
1460
0
0
Minimum (€)
0
300
—
—
0
0
0
632
1000
—
0
Maximum (€)
0
1250
—
—
600
6000
0
632
1920
—
0
1303
ANALYSIS
we observed are consistent with this directive.
Only countries that required individual submissions to local committees do not conform
with the European law. We also identified large
differences in review times and costs.
The time from submission to final approval
was more than three times longer in the UK
than the average time needed in the other nine
countries. The national committee deals with
the ethical integrity of the study, its legal implementation, and safety, while local research
ethics committees evaluate factors such as
investigator, site, and patient suitability.3 The
long approval was due to multiple requests for
further information and slow turnaround. Furthermore, local approval had to be obtained
after national approval rather than in parallel. Compounding this long procedure, the
separate process of contract negotiation was
not allowed to begin at the UK study sites
before we had ethical approval. Although the
approval process led to constructive protocol
modifications, the time taken affected study
recruitment, which is critical in a trial with limited financial and human resources.3‑6 Slower
recruitment automatically leads to increased
start-up costs, with the trickle down effect of
extending total study duration, which also
brings extra costs.
The ethics committee fees for five of the
seven Italian sites were €2000 higher than the
median for all committees (table 3). Considering these costs, it is interesting that five Italian
sites took longer than 60 days to approve the
study (table 1). In contrast, although the costs in
Sweden were higher than the median, approval
took only 30 days. The question arises whether
“for profit” ethics committees might lead to
faster and more consistent decisions. However,
this creates a conflict of interest because commercial committees would generate income
from clients that directly benefit from obtaining
a fast and positive evaluation. Another option
would be to subsidise for profit review boards
through governmental support. The integrity
of the business and service they provide could
then be tightly regulated, thus preventing
potentially unethical and non-transparent processes.7 Pending a consensus on this process, we
suggest that ethics fees should be regulated for
the good of researchers with limited financial
resources.
In conclusion, striking the optimal balance
between turnaround times and identifying
important critical ethical issues is essential to
ensure clinical trials in the EU are safe and cost
effective. An imbalance in this respect was particularly apparent in the UK. Our observations
are based on a single study and may not represent the norm. Nevertheless, our experience
suggests the ethical review process in European
countries remains heterogeneous. Achieving
harmonisation will depend on factors such
as the use of a single language (English) for
protocols and communications, standardising
ethics fees, and centralising the review process,
perhaps to an EU committee. The EU directive gives a reasonable recommendation for
an effective ethical review, but the rules and
regulations should be better standardised and
implemented to improve harmonisation for
multicentre trials, especially those with a sound
scientific basis that are being conducted with
limited funding by the academic community.
Andreas A Schnitzbauer clinical research fellow, Philipp E
Lamby clinical research fellow, Ingrid Mutzbauer clinical study
manager, Carl Zuelke consultant, Hans J Schlitt professor,
Edward K Geissler professor, Regensburg University Medical
Centre, Department of Surgery, Franz-Josef-Strauss-Allee 11,
93053 Regensburg, Germany for the SiLVER05 Study Group
edward.geissler@klinik.uni-regensburg.de
Accepted: 8 January 2009
Competing interests: None declared.
Contributors and sources: AAS wrote the article and analysed
data, PEL collected and analysed data, IM collected data and
coordinated the study, CZ developed the study, HJS was principal
clinician, EKG was principal investigator and wrote the article.
EKG is guarantor.
Provenance and peer review: Not commissioned; externally
peer reviewed.
From the archive: Other recent BMJ articles on ethical review
include “It’s time to change how Europe regulates research”
(Editor’s choice doi:10.1136/bmj.a2986); “Regulation—the real
threat to clinical research” (Analysis plus related correspondence
doi:10.1136/bmj.a1732); and Trish Grove’s blog (http://blogs.bmj.
com/bmj/2008/12/11/trish-groves-on-european-clinical-trials).
1
Directive 2001/20EC of the European Parliament and of
the Council of April 4th 2001 on the approximation of the
laws, regulations and administrative provisions of the
member states relating to the implementation of good
clinical practice in the conduct of clinical trials on medicinal
products for human use. Article 7. http://eur-lex.europa.
eu/smartapi/cgi/sga_doc?smartapi!celexapi!prod!CELEXn
umdoc&numdoc=32001L0020&model=guichett&lg=en.
2 A prospective randomised, open-labelled, trial
comparing sirolimus-containing versus mTOR-inhibitorfree immunosuppression in patients undergoing liver
transplantation for hepatocellular carcinoma. (EudraCT
No: 2005-005362-36). www.clinicaltrials.gov/ct2/
results?term=NCT00355862.
3 Tully J, Ninis N, Booy R, Viner R. The new system of review
by multicentre research ethics committees: prospective
study. BMJ 2000;320:1179-82.
4 Heidenreich K, Möritz A, Löffler H, Oberle-Rolle B. [Clinical
trials in Germany and in the EU in the new legislative
environment. An analysis from the industry’s point of
view.] Bundesgesundheitsblatt Gesundheitsforschung
Gesundheitsschutz 2005;48:415-22.
5 Dreier G, Marx C, Schmoor C, Maier-Lenz H. [The 12th
amendment to the German Drug Law. Chances and
obstacles for investigator-initiated clinical trials.]
Bundesgesundheitsblatt Gesundheitsforschung
Gesundheitsschutz 2005;48:445-52.
6 Maskell NA, Jones EL, Davies RJ, BTS/MRC MIST steering
committee. Variations in experience in obtaining local
ethical approval for participation in a multicentre study.
QJM 2003;96:305-7.
7 Emanuel EJ, Lemmens T, Elliot C. Should society allow
research ethics boards to be run as for-profit enterprises?
PLoS Med 2006;3:941-4.
Cite this as: BMJ 2009;338:b1893
answers to endgames, p 1337. For long answers use advanced search at bmj.com and enter question details
Picture Quiz
What is the target?
1 This patient has erythema multiforme, which is characterised by a maculopapular
rash made of multiple round “bull’s eye” target shaped lesions.
2 Mycoplasma pneumoniae is the infectious agent most likely to be responsible for
both extensive community acquired pneumonia and erythema multiforme.
3 The key to diagnosis is serological testing.
4 Severe community acquired pneumonia that results in acute respiratory failure
with persisting deep hypoxaemia should be managed in an intensive care
unit. Treatment should entail early intravenous administration of an empirical
antibiotic regimen comprising broad spectrum β-lactam and a macrolide.
Statistical question
Likelihood ratios
b, d
1304
case study
Cough and breathlessness not responding
to inhalers
1 The FEV1 to FVC ratio is ≥0.7 (0.84 in this case) and both FEV1 and
FVC are lower than the predicted values; this means that the patient
has a restrictive ventilatory defect.
2 The clinical features and restrictive ventilatory defect suggest a
diffuse parenchymal lung disease. The results in this patient are not
in keeping with asthma, where spirometry would be normal or show
airflow obstruction (FEV1/FVC <0.7).
3 The next two most important investigations include high resolution
computerised tomography of the chest and specific IgG antibodies
to budgie feathers or droppings.
4 The most likely diagnosis is chronic extrinsic allergic alveolitis
(hypersensitivity pneumonitis). To try to avoid irreversible and
progressive lung damage, the patient should be advised to relocate
her budgies and be given a course of steroids.
BMJ | 30 May 2009 | Volume 338