Is the legal protection for the foetus adequate in clinical trials?

In 2009 and 2010, the major drug regulatory bodies, the European Medicines Agency and the Food and Drug Administration in the USA, issued requests for the generation of information relating to the absorption, distribution, metabolism, excretion, efficacy and safety of investigational drugs in pregnant women prior to approval. In the wake of thalidomide, research involving pregnant women other than for obstetric or gynaecologic purposes became rare, and studies of investigational drugs practically unknown. Consequently, none of the legislation applicable in the UK and few of the guidelines introduced in the last 40 years properly addresses the conduct of clinical trials of investigational drugs in this population. This thesis questions whether the legal protection for the foetus is adequate in clinical trials. The answer appears to be a qualified “no”. Arguments persist regarding the moral standing of the foetus, particularly regarding abortion. That will not be the intent of such trials, and a moral case is made for the conduct of clinical trials in this population by analogy with the neonate, and the pregnant woman’s autonomy. Legally, we already recognise the foetus has ‘interests’ which crystallise upon live birth, and that compensation is recoverable for harm inflicted in utero manifesting as congenital injury. The essence of research is quite different from medical practice, and the extent to which this is understood by trial participants is unclear. The approvals processes contain a number of inadequacies which have the potential to expose the foetus to harm and affect the consent of the pregnant woman. The recovery of compensation in the event of children born injured following clinical trials during pregnancy in many ways may be more complex than other personal injury cases.. The conclusions of this thesis are that the existence of a foetus does merit recognition by the law in this setting and that morally such studies are justifiable. However, the present legislation and approval processes potentially expose the foetus to avoidable risk and may not be appropriate to enable the recovery of compensation, thereby creating potential to deter future trial participants. A proposal is made regarding an approach to simplify the process for recovery of compensation, and thereby strengthen the approval and consent processes.

Ecology, physiology and performance in high-rate anaerobic digestion

The design demands on water and sanitation engineers are rapidly changing. The global population is set to rise from 7 billion to 10 billion by 2083. Urbanisation in developing regions is increasing at such a rate that a predicted 56% of the global population will live in an urban setting by 2025. Compounding these problems, the global water and energy crises are impacting the Global North and South alike. High-rate anaerobic digestion offers a low-cost, low-energy treatment alternative to the energy intensive aerobic technologies used today. Widespread implementation however is hindered by the lack of capacity to engineer high-rate anaerobic digestion for the treatment of complex wastes such as sewage. This thesis utilises the Expanded Granular Sludge Bed bioreactor (EGSB) as a model system in which to study the ecology, physiology and performance of high-rate anaerobic digestion of complex wastes. The impacts of a range of engineered parameters including reactor geometry, wastewater type, operating temperature and organic loading rate are systematically investigated using lab-scale EGSB bioreactors. Next generation sequencing of 16S amplicons is utilised as a means of monitoring microbial ecology. Microbial community physiology is monitored by means of specific methanogenic activity testing and a range of physical and chemical methods are applied to assess reactor performance. Finally, the limit state approach is trialled as a method for testing the EGSB and is proposed as a standard method for biotechnology testing enabling improved process control at full-scale. The arising data is assessed both qualitatively and quantitatively. Lab-scale reactor design is demonstrated to significantly influence the spatial distribution of the underlying ecology and community physiology in lab-scale reactors, a vital finding for both researchers and full-scale plant operators responsible for monitoring EGSB reactors. Recurrent trends in the data indicate that hydrogenotrophic methanogenesis dominates in high-rate anaerobic digestion at both full- and lab-scale when subject to engineered or operational stresses including low-temperature and variable feeding regimes. This is of relevance for those seeking to define new directions in fundamental understanding of syntrophic and competitive relations in methanogenic communities and also to design engineers in determining operating parameters for full-scale digesters. The adoption of the limit state approach enabled identification of biological indicators providing early warning of failure under high-solids loading, a vital insight for those currently working empirically towards the development of new biotechnologies at lab-scale.