The TRUFFLE study—a collaborative publicly funded project from concept to reality: how to negotiate an ethical, administrative and funding obstacle course in the European Union

Fundamental questions, however, remain unresolved. For example, pathological fetal growth restriction is one of the more common dilemmas of obstetric care, and many growth-restricted babies are born prematurely. This pathology is an important cause of fetal and neonatal mortality and morbidity in the developed world. The lost opportunities and productivity due to the ensuing child and adult physical and neurodevelopmental impairment are incalculable, as is the cost of adequate life-long medical and social services care. The sheer numbers are stunning: in the European Union (EU) of 25 countries, with a population of more than 450 million and with more than 4.6 million live births per year4, an incidence of 3% means that about 130 000 babies will be born with severe growth restriction every year. We simply do not have reliable data on the incidence of neurological normality in these infants. As skilled fetal medicine practitioners, we are extremely adept at identifying in utero those babies that are growth-restricted by performing complex arterial and venous Doppler investigations, cardiotocography (CTG) and biophysical profiling. However, we have no evidence as to which assessment technique is superior, nor according to which criteria babies are best delivered. In Europe there is equipoise in decision-making between those clinicians who rely on changes in the CTG, most objectively measured as short-term variation, and those who rely on changes in venous Doppler (most commonly assessed by the ductus venosus waveform) to inform timing of delivery. Of those in the latter category, there is a split between those who believe in delivery with ‘early’ ductus venosus changes and those who would rather wait until ‘late’ ductus venosus changes occur. In North America, fetal Doppler is used less frequently in this way, and the standard for timing of delivery is according to biophysical profiling. The question of when to deliver is, however, of such fundamental importance that we cannot leave it to clinical ‘gut instinct’ or national preferences. Thus the case for a study examining the optimum timing of delivery is unarguable. Getting reliable evidence calls for a multicenter randomized controlled trial that will answer these questions once and for all. This has been argued eloquently in the pages of this Journal5, 6. A group of academic clinicians and clinical academics in the fields of fetal medicine and neurodevelopmental pediatrics recognized the need for such a study in 2001. As the TRUFFLE group (Trial of Umbilical and Fetal Flow in Europe) they have set about designing this project, meeting several times per year in their respective institutes throughout Europe. Representing 20 centers in seven EU countries, this group has now spent exactly 3 years on the TRUFFLE project. Not one person in the group has been funded to do what has been done: develop a realistic protocol for a European multicenter study. After peer review, this TRUFFLE protocol appeared on the Lancet website in 20037. Advance publication of the protocol proves that the question addressed and the planned design and analysis have been scrutinized by experts and are considered topical and valid; moreover, it ensures not only transparency and openness, both key ethical demands, but also the possibility for comment. The main concern was, and is, ethics. There can be no doubt over the ethical rationale of a study whose aim is to deliver babies at the best time to reduce long-term neurodevelopmental sequelae. Leaving the uncertainty over timing of delivery unresolved goes against the most basic principles of medical ethics by letting preventable human tragedy persist. However, the results of the TRUFFLE study might (and we hope will) be that one of the three arms of the research gives a significantly better outcome than the other two; the sample size calculation of the study is based on the assumption that there will be 16% more babies with normal neurological outcome in one of the intervention arms compared with the control group at 2 years (66.6% vs. 50% in controls). This is of course the rationale for the study, but one must stress at the outset that as there is no clear evidence in favor of timing delivery according to any prespecified criteria, no informed body of clinical expertise could guess as to what the results would be. Such uncertainty is crucial for justifying a randomized intervention such as happens regularly in, for example, trials of cholesterol lowering drugs, anti-hypertensive agents or other cardiovascular intervention. The stakes are much higher here, however: we are performing an intervention, namely delivery of a baby according to certain criteria (reduced short-term variation on the CTG, early ductus venosus changes or late ductus venosus changes), two out of three of which will possibly be proven ‘inferior’ by our study. To ethically justify this trial, we must be absolutely sure that: (i) clinicians are in equipoise over the management options, (ii) participants are giving truly informed consent, and (iii) the trial will be conducted with the highest clinical and scientific standards possible. We believe that everything has been done to meet these criteria. There are two more obstacles to be overcome: administrative hurdles and funding. The implementation of the EU clinical (drug) trial directive 2001/20/EC in May 2004 changed the European landscape for publicly funded academic research, not only for drug trials, but in general. In England, for example, the policy of the Department of Health is ‘that the operating procedures required by the EU Directive and the “Regulations” [The Medicines for Human Use (Clinical Trial) Regulations 2004] should also apply in general to the review of Research Ethics Committees in the UK of all other research involving human subjects within the NHS’8. This raft of regulation makes it not only considerably more difficult to perform the sort of study that we plan, but also places a legally enforceable onus of responsibility on the investigators. In fact, submitting our study for ethical review in seven countries and 20 trial sites at the present time will lead into fairly uncharted territory. We can only hope that during this review process the formal requirements of commercial drug trials developed by regulators and industry for licensing purposes will not be imposed on the TRUFFLE study, which will compare existing clinical practices for the improvement of healthcare delivery. The results could be counter-productive; in the words of the UK Medical Research Council: ‘ensuring UK (and European) interpretation of the Directive avoids raising unnecessary and costly barriers is vital to the health of Europe’s citizens and indeed, of people across the World’9. Peto and Baigent10 pointed this out, stating that ‘requirements for large amounts of defensive documentation imposed on trials by well intended guidelines on good clinical practice (or good research practice) or excessive audits may, paradoxically, substantially reduce the reliability with which therapeutic questions are answered’. Unnecessary and costly barriers could be the nail in the coffin for our and many other high-impact academic, non-pharmaceutically funded clinical studies, an outcome contrary to public interest. Funding, of course, remains an issue. The Pan-European TRUFFLE project addresses a ‘life-threatening and heavy disabling’11, 12 problem of fetal–maternal medicine. The study's results have the potential to improve the condition of thousands of babies. The importance of pediatric research has been emphasized lately by the EU13. Both the European Medicines Agency and the Federal Drug Administration have mechanisms for accelerated evaluation of products indicated for serious and compelling public health needs. However, no appropriate funding infrastructure is available in the EU for independent clinical research14. A recent report showed this very same weakness in the clinical research infrastructure in the US, where a novel public–private partnership has been proposed, the ‘National Clinical Research Enterprise’15, whose aim is to put in place an efficient system of removing ‘translation block’ which prevents the rapid transfer of therapeutic interventions into routine medical care. This study is in fact only one example in one area of medicine where a very important clinical issue has never been resolved and multiple different investigation and treatment plans abound, depending on clinician, institution or country. Perhaps the European Group on Ethics (EGE)16 should focus on the issue of funding collaborative clinical trials and draw the attention of decision-makers to the importance of community public health issues. To support EU clinical trials aimed at improving public health will produce tangible ‘community added value’ and improve clinical, research and training links between the institutions of member states, surely the very ‘raison d‘être’ of the European Community. There is a unique opportunity to perform this study, with enthusiastic input and support from clinicians around Europe all of whom have collective ownership of the protocol. The TRUFFLE group expects and fully intends to overcome the administrative and funding hurdles that have been raised in this Editorial. To resign and not perform this study would be unethical or even irresponsible, and is therefore not an option; it would neglect the needs of those patients who are the most vulnerable and valuable segment of our societies: unborn babies and their mothers.