Procedures for ethical review for clinical trials within the EUBMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b1893 (Published 22 May 2009) Cite this as: BMJ 2009;338:b1893
- 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
- for the SiLVER05 Study Group
- 1Regensburg University Medical Centre, Department of Surgery, Franz-Josef-Strauss-Allee 11, 93053 Regensburg Germany
- Correspondence to: E K Geissler
- Accepted 8 January 2009
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.
Our study was set up to evaluate the potential survival and anti-tumour benefits of using a mammalian target of rapamycin inhibitor (sirolimus) in liver cancer patients who had received transplants.2 The study is an investigator initiated trial in 10 European countries (Austria, Belgium, Finland, France, Germany, Italy, the Netherlands, Spain, Sweden, and the United Kingdom) and three non-EU countries (Australia, Canada, and Norway) with a total of 40 sites in the EU and four sites outside the EU. Regensburg University Hospital is the trial sponsor and thus is responsible for its conduct; this point is a foundation of our trial and we made this clear to all parties involved. Although the manufacturer of the study drug 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.
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 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, 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 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.
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 queries 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.
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).
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 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 4 5 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.
Cite this as: BMJ 2009;338:b1893
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).