Governing mechanistic studies to understand human biology

Abstract

Mechanistic studies may be defined as ‘an experiment, using an intervention in healthy subjects or patients, to better understand human biology and/or disease’. Such studies provide useful physiological insights into clinical conditions in humans and expand our knowledge of physiology in health and disease. Well-planned mechanistic studies are therefore a vital step in progressing drug discovery in humans. It is important in such studies that the rights and safety of research participants are preserved, while at the same time not allowing lengthy and complex approval procedures to stifle and potentially prohibit this type of research.

Introduction

Although there is no universally accepted definition of a mechanistic study, for the purposes of this article it is defined as ‘an experiment, using an intervention in healthy subjects or patients, to better understand human biology and/or disease’. The term mechanistic derives from the purpose of the research, to acquire new knowledge about human biological mechanisms. These studies represent a vital step in translating findings from preclinical science to humans. They are typically undertaken in an academic setting, and many universities (often in partnership with hospitals) have clinical laboratories that have performed these curiosity-driven projects for generations. An exemplar of this approach is the discovery of Helicobacter pylori as a cause of peptic ulceration; the key experiment being the administration of the bacteria to healthy volunteers, who subsequently developed features of the disease (Marshall, 2002). The experiment transformed understanding of peptic ulceration as a bacterial infection, led to an antibiotic-based cure for the disease, and a Nobel prize for the investigator. As long as animal models remain poor substitutes for homo sapiens, there will be a requirement to perform these studies or miss out on transformative discoveries.

The need for governance

Whether the object of the research is to understand the biology of healthy subjects, or patients with disease, it is unarguable that the volunteer is exposed to potential risks of the intervention and the assessment procedure, without any prospect of potential medical benefit (Miller, 2003) (as can be seen from the example given above). The need for protection of the rights and safety of research participants is paramount. Mechanistic studies clearly need oversight from an appropriate sponsoring body that is proportionate to the risks. The sorts of interventions that have been used include lifestyle change, diet, or physical exercise. Very commonly the intervention includes the administration of pharmacologically active substances, including licensed drugs. The use of a drug adds a dimension of complexity, resulting from the application of the EU Clinical Trials Directive (see below). Assessment procedures to measure the underlying biology range from the entirely non-invasive (questionnaire studies), imaging, blood and tissue sampling and (in the example given above) admission to hospital and endoscopic examination of the stomach.

EU Clinical Trials Directive

Introduced in 2001, this Directive (amongst other things) formalized the requirement that all clinical trials of drugs or pharmacologically active substances (hereafter referred to as Investigational Medicinal Products – IMPs) required approval from the relevant drug-licensing authority (in the UK this is the MHRA) (European Parliament & Council, 2001). Prior to this, the licensing authority had reserved its interest for later-phase therapeutic drug trials (Phase 2–4). Studies in healthy volunteers, even those using novel medicines for the first time in humans, were deemed non-therapeutic trials and outside the remit of the licensing authority. The adoption of the Directive by many EU member states meant that all studies involving IMPs required approval by the licensing authority. The consequence was an increase in cost, time to set up, unnecessary pharmacovigilance and overall complexity, with a consequent reduction in the numbers of mechanistic studies performed in many EU member states. In the UK, it was argued successfully that mechanistic studies should remain exempt, and accordingly the MHRA has powers to differentiate between mechanistic studies of IMPs and clinical trials of IMPs. This is based on the intention of the research. In a clinical trial of an IMP, the intention will be to determine the efficacy and/or safety of a drug under development, or a novel aspect of an established drug. In a mechanistic study, the intention is different; rather than being designed to better understand the molecule, the approach is to use the molecule to better understand human physiology or pathophysiology. However, a person’s intention is hard to prove, some projects will inevitably be ambivalent, and the ‘translational agenda’ generates an environment where every interventional study in humans is increasingly being viewed as an opportunity for drug discovery and development. The recent announcement that the Directive will undergo revision offers hope for a more flexible approach. Nonetheless, the classification of mechanistic studies as non-CTIMPs often causes confusion among sponsoring organisations, leading to lengthy approval processes. By their nature, mechanistic studies are often small-scale and often form part of closely supervised postgraduate research where time is short and lengthy approval procedures may make a study impossible.

Under the Directive, all clinical trials of IMPs must be reviewed by an ethics committee ‘recognised’ by the Member’s competent or licensing authority. However, once the licensing authority has established that a study is mechanistic, then the researchers are not bound by the Directive.

Research Ethics Review

The UK National Research Ethics Service (NRES) requires that all research on individuals identified by their use of the NHS requires the approval of an authorised research ethics committee (REC). Most of these are NHS RECs as few Universities have sought NRES authorisation for their RECs. Where a mechanistic study is being undertaken on patients, ethics review must be undertaken through NRES. In contrast, if healthy volunteers are being recruited, then university RECs are permitted to review the proposed research, and have processes that are more appropriate for the needs of the university sector. A recent welcome development has been the statement by NRES that that REC approval is not required for university studies of healthy volunteers, even if NHS premises are being used to carry out the research. However if ionizing radiation is being used, or the study will harvest tissues or cells (or other ‘relevant material’ as defined by the Human Tissue Act), then review must be undertaken by an appropriately flagged REC.

Minimizing risk

‘Would I volunteer for this study? Would I advise my daughter/son to volunteer?’

One way of minimizing risk is to design a protocol so the answer to these sorts of questions would be yes. Of course, the degree to which we as individuals are risk-averse (or otherwise) is variable, so this question is best asked of an independent REC. Since their inception in the 1960s, RECs have been reviewing mechanistic studies, providing necessary governance to allow safe prosecution of this type of research. The usual judgements on risk–benefit that apply to all human research apply to mechanistic studies, but there are obvious additional considerations. Many of the interventions and assessment procedures listed above are benign, but real uncertainties arise if the outcome is difficult to measure (e.g. it requires ionising radiation) or if a drug with a poorly established safety record is to be administered. Protocols that cause significant discomfort or carry a risk of tissue injury that is substantial or prolonged are unacceptable. Where drugs are involved, preferred options are molecules that occur endogenously in humans, so that risks of allergy and potential for long-term toxicity are practically zero. Where the substance is a licensed drug with good safety record, then this gives much reassurance. The substance needs to be manufactured to a standard that supports its use in humans (free from adulterants and sterile). Additional safety is generated by using low doses or local administration (e.g. into the skin). A sound principle is to avoid infusing any such agent in women, to avoid the risk of harm in early pregnancy.

Conclusion

Mechanistic studies provide useful physiological insights into clinical conditions in humans and as such expand our knowledge of physiology in health and disease. Such studies can also provide a useful bridge between basic science and early phase clinical trials in humans, and can be used to identify novel therapeutic indications for existing drugs. Well-planned mechanistic studies are therefore a vital step in progressing drug discovery in humans.