Carrot or stick conducting clinical research in academic environment

Conducting clinical research in an academic environment is significantly dictated by the availability of scarce resources. In contrast, clinical research in a commercial environment may avail of relatively generous funding. While both academic and commercial research often have fundamentally different objectives and risks, unfortunately they are at present obliged to comply with the same standards of Good Clinical Practice (GCP), including relevant adherence to national and EU legislation. The result of such a “one-size-fits-all” approach to regulation is a fundamental mismatch between risk and risk management, in which academic-led studies lose out due to soaring administration and compliance costs. It is hoped that a new Clinical Trial Regulation (Regulation [EU] No 536/2014), scheduled for application either this year or next, should redress the current imbalances. It will be clear to most practitioners in the field of clinical studies that academic trials and commercial trials generally have quite different objectives - academic trials are often focused on real-world outcomes and routine clinical management, while commercial trials generally focus on assembling data to secure product approval and market authorisation. Such distinct objectives often lead to different study designs and different risk profiles, in turn leading to a potential wastage of scarce resources when the rules become misaligned. While all stakeholders readily agree with the foundational principles of patient protection and safety, as articulated in the Declaration of Helsinki, differences often arise in how best to deliver such protections. The current obligations for initiating, conducting, monitoring and reporting a clinical trial in the EU are set out in EU Directive 2001/20/EC, and laterally, EU Directive 2005/28/EC, and within the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (ICH-GCP E6 R1, 10 June 1996). The purpose of the EU Directives on clinical trials is to set out the regulations and administration of GCP in the conduct of trials undertaken within the 28 Member States. However, a number of practices, including Guideline ICH-E6, detailing the expected clinical practice for human trials, have attracted significant criticism, as have additional obstacles which unnecessarily hinder the progress of non-commercial academic-led studies. In particular, concerns have arisen that ICH-E6 lacks transparency on the identity of the authors and the evidence-base upon which the guideline rests. The most recent version of the guideline, from June 1996, has not been updated in years, rendering it out-of-date (although work on a draft addendum is under way). It creates costly and complex approval procedures and is principally written with industry in mind, having had little or no input from the academic research community. In addition, monitoring is criticised as disproportionately focused on minutiae of trial conduct rather than centralised oversight, while drug safety appears more focused on individual case reports than on the more material consideration of overall rates of adverse events. CORE CHALLENGES While each of these criticisms is well-founded, they overlie three core methodological challenges which need to be addressed if application of the new regulation is to be a success: 1) Recognition that current rules deal with different processes. Academic and commercial trials are not the same, however current regulatory frameworks do not appropriately acknowledge the clear distinctions. A top-down imposed “one-size-fits-all” approach attempts to shoehorn one constituency of the research community (academic researchers) into a process designed for a different constituency (the pharmaceutical industry). While these constituencies have much in common, they differ in respect of why they do research. Academic research is primarily conducted to drive improvements in patient care and treatment, while pharmaceutical research is primarily driven by commercial interests. This is no slight on the pharma industry, as their drive to license and market new products is similarly directed at improving patient care even if the path to such a goal is driven by the required profit-motive of any industrial pursuit. However, if current regulations persist in applying the same audit and management processes on both constituencies, then a significant body of research, of benefit to patients, clinicians and society, will increasingly struggle to find sufficient funding. 2) Risk management needs to be proportionate. It must be proportionate to the actual risk. Any reasonable assessment of risk must acknowledge the differences between, for example, an aspirin study conducted across a number of rural populations, versus a virally delivered experimental gene therapy study in an orphan neurological indication. Current EU regulations (and interpretations thereof) generally fail to accommodate such a distinction. Clearly, the actual risks of aspirin use and gene therapy are logarithmically different, however a voluminous body of documentation is required for both studies. Significantly, finding the funding required for an academic-led aspirin study in rural communities can be close to impossible, while funding a gene therapy study would likely attract several commercial players. More importantly, the beneficiaries of the aspirin study may far outnumber the beneficiaries of the orphan gene therapy study, resulting in a negative selection pressure against academic investigator-led research. Without academic-led research there would be an enormous gap in the evidence-based medicine upon which clinicians in ophthalmology and all other medical disciplines depend. 3) All stick, no carrot. Finally, there appears to be a fundamental contradiction in the basic message from the EU. The Commission stresses the importance of patient safety and validity of data, but remains silent on how to deliver same and on who is going to pay for it. The process appears to be all stick and no carrot. If the EU wishes to impose homogenous regulations for the control of clinical trials, regardless of risk and costs, and then enforce such regulations through national legislation obliging governments to uphold them, then such obligations should come with the necessary resources to meet those obligations. Academic funding for administration and compliance is close to non-existent and so, ultimately, the message from the EU becomes both contradictory and confusing as it simultaneously seems to say: patient safety and validity of data are important, but not important enough to be paid for. The result is that patient welfare – positioned at the core of the Declaration of Helsinki – may become corroded. The core criticisms of GCP derive from a misunderstanding of risk management, coupled with the ever-increasing costs required for full compliance. The costs of such compliance are far from trivial and can quickly mount up to a significant proportion of the funding required to fund even the most simple and straightforward of studies. Access to funding is materially different in academic and commercial environments, leading to an uneven playing pitch where universities and hospitals are being priced out of the clinical trial field due to increasingly burdensome obligations designed for industry. If such a trend remains unchecked, clinical trials may only be conducted by those with the deepest pockets, potentially resulting in an erosion of unbiased studies due to the inevitable conflicts of interest that may arise. A rebalancing of processes, risks and resources is required to produce a framework that maintains patient safety and data validity, but incorporates realistic management systems that protect and sustain a vibrant and independent clinical research environment. Gearóid Tuohy: gearoid.tuohy@escrs.org

Tags: European Union, research