Independent academic clinical research is indispensable for optimising standards of care, speeding up treatment access, and ensuring the most efficient use of limited healthcare resources. However, for decades now, initiating investigators have tackled the increasing tension between their desire to undertake innovative research and the level of regulation and bureaucracy deterring them from becoming involved. [1] Much of this burden has resulted from the implementation of the European Clinical Trials Directive 2001/20/EC, which aimed to ensure patient protection and research oversight by unbiased entities. Although established with good intent, the current rules and regulations are stifling academic clinical research and hindering patients’ access to innovative treatment options. [2] The resulting casualties are many, not least clinical research itself. [3] Yet attempts to lower the demands for initiating and conducting academic clinical trials—while ensuring their quality, patient safety, and the integrity of the collected data—have had little success thus far. [4] 

Academic investigators who design and conduct (multicentre) randomised controlled trials (RCTs) encounter multiple regulatory and funding challenges, resulting in substantial costs and delays to the conduct of the trial. [5] As a consequence, such academic trials often have too small a number of patients randomised. This means the trials are underpowered to show statistical significance on clinically important endpoints, or to draw firm conclusions for clinical practice, when those results have not been confirmed in larger study populations. [6] Although no hard claims can be made on a negative primary endpoint, one can often hear the data speak when considering statistically significant, albeit secondary, endpoints. An RCT allows for the most rigorous assessment of an intervention, but if such a trial does not attain its research objective this reflects a lost opportunity that comes at a cost that extends far beyond the invested millions of public and government funding, and the many years of hard work and persistence. Indeed, when considering the unmet medical needs and mounting public health challenges that are the focus of academic clinical research, any treatment modification whose safety, efficacy, and/or cost-effectiveness have been confirmed in an RCT would be considered a major step forward.

The problem that has emerged in academic clinical research is not a failure to adhere to regulations, but an expenditure of vast amounts of research time and money on the collection of irrelevant data and exhaustive documentation. Initiating investigators have to realise that conducting clinical research has become a full-time job with professional requirements and responsibilities, including attracting funding, responding to multiple ethical and regulatory review cycles, establishing clinical trial agreements and contracts, overseeing financial compensation, recruiting patients, focusing on data entry, monitoring and cleaning data (complicated by the anonymous nature of databases), securing protected research time for data analysis and dissemination, and completing large amounts of associated paperwork. [7] The bureaucratic burden and its cost structure have become so enormous that the risks for an initiating investigator are exceeding their chances of successfully guiding a research idea through the clinical trial process. This is particularly true when pharmacotherapy or medical devices are involved, placing the industry almost in a monopoly position when deciding which critical questions need to be answered. The academic initiatives will continue to decrease and clinical research, because of its cost and complexity, will more and more be led by the industry. Unless we learn to foster creativity as single-mindedly as we pursue conformity, future generations of patients may find themselves receiving the same basic medical care as today, with expensive innovative treatments reserved for certain niche indications. 

Moves are now in hand to reform the Clinical Trials Directive 2001/20/EC, with the new Clinical Trials Regulation EU 536/2014 aiming to streamline applications and homogenise and simplify authorisation procedures with strengthened transparency on the data. [8] In our opinion, however, an important opportunity for a comprehensive reorganisation of the regulatory environment is lost as the threat to innovative academic research should be seen on a more fundamental scale, rather than merely the harmonisation of rules on how to conduct clinical trials. It is hoped that all stakeholders will adapt and contribute to recommendations for simplifying and supporting the conduct of investigator-initiated trials, while ensuring their quality, patient safety, and the integrity of the collected data. A lack thereof will render the potential of academic clinical research to achieve important improvements in healthcare unfulfilled. [9]

Kristina Vermeersch, KU Leuven, Laboratory of Respiratory Diseases, Department of Chronic diseases, Metabolism and Ageing.University Hospitals Leuven, Department of Respiratory Diseases, B-3000 Leuven, Belgium.

Thierry Troosters, KU Leuven, Laboratory of Respiratory Diseases, Department of Chronic diseases, Metabolism and Ageing. KU Leuven, Faculty of Kinesiology and Rehabilitation Sciences, Department of Rehabilitation Sciences, B-3000 Leuven, Belgium.

Guy G Brusselle, Ghent University Hospital, Department of Respiratory Medicine, B-9000 Ghent, Belgium

Wim Janssens, KU Leuven, Laboratory of Respiratory Diseases, Department of Chronic diseases, Metabolism and Ageing and University Hospitals Leuven, Department of Respiratory Diseases, B-3000 Leuven, Belgium.

Competing interests:

KV is supported as a doctoral candidate by the Flemish Government Agency for Innovation by Science and Technology (IWT, Belgium).

TT’s institute received speaker and consultancy fees from Boehringer-Ingelheim, AstraZeneca and Chiesi.

GGB has, within the last 5 years, received honoraria for lectures from AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer, Teva, UCB Pharma and Zambon; he is a member of advisory boards for AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron and Teva.

WJ is supported as a senior clinical researcher by the Fund for Scientific Research Flanders (FWO, Belgium); and has received research funding, speaker and consultancy fees from Boehringer-Ingelheim, AstraZeneca, Novartis, Chiesi and GlaxoSmithKline. WJ is co-founder of ArtIQ.

Funding information

This work is funded by the Flemish Government Agency for Innovation by Science and Technology (IWT, grant number: IWT-TBM130233). 

References: 

1 Neaton JD, Babiker A, Bohnhorst M, et al. Regulatory impediments jeopardizing the conduct of clinical trials in Europe funded by the National Institutes of Health. Clin Trials 2010;7:705–18. 

2 Califf RM. Clinical trials bureaucracy: unintended consequences of well-intentioned policy. Clin Trials 2006;3:496–502.

3 European Commission. Impact assessment report on the revision of the “Clinical Trials Directive” 2001/20/EC. 2012. 

4 Federation of the European Academies of Medicine. Opportunities and Challenges for Reforming the EU Clinical Trials Directive: an Academic Perspective Statement. 2010. 

5 Reith C, Landray M, Devereaux P., et al. Randomized Clinical Trials — Removing Unnecessary Obstacles. N Engl J Med 2013;369:1061–5.

6 Vermeersch K, Gabrovska M, Aumann J, et al. Azithromycin during Acute COPD Exacerbations Requiring Hospitalization (BACE): a Multicentre, Randomized, Double-blind, Placebo-controlled Trial. Am J Respir Crit Care Med 2019;In Press.

7 English RA, Lebovitz Y, Giffin RB. Transforming Clinical Research in the United States. 2010. 

8 European Parliament and Council of the European Union. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Off J Eur Union 2014;L:1–76. 

9 Lacombe D, O’Morain C, Casadei B, et al. Moving forward from drug-centred to patient-centred research: A white paper initiated by EORTC and developed together with the BioMed Alliance members. Eur Respir J 2019;53:1–6.