The future of neonatal therapeutic trials

Abstract

Neonatology has undoubtedly benefited from clinical trials. Nevertheless, more treatments based on inadequate experimental evidence are given than those that are supported by a validated evidence base. Clinicians seeking the basis for their current and future clinical practice are faced with challenges in the shadow of recent UK legislation and government recommendations. All patients must be protected from inappropriate research, but the benefits of regulations must be appropriately balanced with those of properly conducted clinical trials. It is ethically difficult both to persist with treatments of unproven benefit and unknown harm and to deny infants potentially valuable therapies. It is important that trials are conducted within the new legislative framework, but their future may rest with innovative solutions and the determination of all involved in the process.

Neonatology has undoubtedly benefited from clinical trials. Nevertheless, more medicinal treatments are given each day on European neonatal intensive care units without adequate experimental evidence than those that are given with the support of a validated evidence base.1 Clinicians caring for newborn infants, in seeking the basis for their current and future clinical practice, are, however, faced with challenges in the shadow of recent UK legislation and government recommendations.

Challenges to neonatal clinical research

The Medicines for Human Use Act

One challenge to new therapeutic research is the Medicines for Human Use (Clinical Trials) Act,2 which implements the European Clinical Trials Directive3 and which came into force in May 2004. The act provides a statutory basis for all aspects of clinical trial management, applying to all medicinal trials. The stated objectives of these new regulations are to simplify and harmonise clinical trials across the European Union while protecting participants and public health.

The Act requires all clinical trials to obtain the approval of the Medicines and Healthcare Products Regulatory Agency (MHRA).2 Investigators are required to report adverse reactions to medicinal products, share study outcomes through publication, and facilitate changes in prescribing practice. Clinical researchers share these beliefs in the principles of research governance with structured well planned clinical trials, conducted safely. The emphasis on reporting study results for peer scrutiny is crucial whether they are positive, neutral, or negative.

The act2 defines the sponsor required for each clinical medicinal trial as “an individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial” and details their legal responsibilities. Sponsors are responsible for the design, conduct, recording, and reporting of clinical trials. Importantly, although not obliged to provide indemnity for the research themselves, the sponsor and lead investigator must ensure adequate insurance and indemnity arrangements. By putting in place agreements that clearly define and allocate research roles, the risk of anything going wrong, and of research partners being sued inappropriately, should be reduced. Research ethics committees are responsible for reviewing the adequacy of these arrangements. In addition, host NHS Trusts must also check that the sponsor has confirmed what arrangements are in place, as part of their role in providing Trust permission for research to proceed.

Indemnity arrangements and negligent and non‐negligent harm

Indemnity arrangements within public bodies, especially the NHS, can address only negligent harm. This is the legal liability that arises from the NHS Trust's duty of care towards patients. Where an individual is harmed in the context of research and development (R&D) and harm can be demonstrated to have occurred because of negligence through, for example, not following an agreed protocol, then that would be deemed negligent harm. Therefore, if an NHS patient is harmed in the course of research as a result of negligent actions on the part of staff (including university staff working under honorary contracts), the NHS Trust is liable. For studies involving their employees, universities could also potentially be liable and could be counter‐sued by an NHS Trust. The additional cover for risks that are excluded under a university's general policy for negligent harm, such as studies involving children, can be expensive.

NHS Trusts in England belong to the Clinical Negligence Scheme for Trusts (CNST), run by the NHS Litigation Authority, which pools the risk of clinical negligence claims. The Trust may subsequently take disciplinary action against the individual responsible for the negligence which caused the harm. To protect themselves in the event of this happening, individual clinicians may elect to hold personal cover for this—for example, through a professional organisation such as the Medical Defence Union/Medical Protection Society. For researchers not employed by the NHS and without honorary contracts covering that clinical work—for example, clinical trainees or university scientists undertaking invasive studies on healthy volunteers—their employers are liable for their negligent acts and are responsible for holding adequate professional liability insurance.

Indemnity arrangements, however, do not extend to non‐negligent harm. NHS bodies cannot give advanced undertaking to pay compensation where there is no negligence and cannot obtain commercial insurance for this purpose. Organisations such as university bodies normally purchase professional indemnity cover for non‐negligent harm from clinical research, but this may become increasingly difficult and financially prohibitive. Although ethics committees can decide that a study can go ahead without a scheme of compensation for harm caused where there is no negligence, to continue to produce most neonatal clinical trials under university, charitable, or NHS supervision, these organisations must be willing to take on the financial exposure that non‐negligent indemnification for neonatal clinical trials brings.

Despite the financial pressure of such indemnification, clinical investigators must guard themselves against inappropriately limiting the number of study participants, as it would be unethical to contribute to the raft of studies of differing design and entry criteria that expose participants to trial treatments but are inadequately powered to determine relevant outcomes. Although the aims of new regulations in terms of safety, pharmacovigilance, and accountability are shared by those conducting clinical research, attempts to reassure that they will not hamper the discovery of new medicinal treatments4 have not quelled concerns5,6 that, for example, advancements may be hampered by lack of financial gain in a small commercial market and the reluctance of non‐commercial sponsors to take on indemnification.7 As obstacles such as free market economics already deter research in children,8,9 there could be major implications for neonatal medicine if the effect of new regulations is to generate a perception of further hurdles.5

Other legislation and proposals

For clinicians and researchers, the future holds the implementation of the Proposal of the European Commission on Medicinal Products in Children10 (at the earliest in late 2006). Its measures for children's medicines include:

• a requirement for industry to submit previous study reports

• an EU network of investigators and trial centres conducting research

• incentives for pharmaceutical companies studying new medicines, and producing orphan medicines, of potential paediatric benefit

• a new type of licence, the Paediatric Use Marketing Authorisation (PUMA), for existing medicines which new research, or research not currently in the public domain, shows are of paediatric benefit.

The statutory implementation of the Medicines for Human Use Act2 and the Proposal of the European Commission on Medicinal Products in Children10 join an explosion of other recent recommendations facing neonatal researchers, including those from the Griffiths report,11 Department of Health Recommendations on Research Governance,12 and the Human Tissue Act.13 The Department of Health acknowledges that such factors have led to a bureaucracy that is stifling many researchers and proposes14 to amend the approach to clinical research in the NHS.

This strategy recognises that:

• NHS R&D currently is neglected and under‐funded

• few incentives exist for staff to conduct and develop careers in health research in the NHS

• applied research has been viewed as being of less worth than pure research, although both ultimately benefit patients.

Nevertheless, the virtual “National Institute for Health Research”, in which it is proposed that as few as 10 centres of clinical research in the United Kingdom would have a funding and coordinating role for the whole country for certain research activities, may be potentially divisive.

Responses to the new challenges

In the United Kingdom, the current situation has been highlighted15 and there is increased awareness of the problems of prescribing for children and the disadvantage children may suffer.16,17,18,19 More than 90% of neonatal intensive care patients will receive at least one unlicensed or off‐label medicine.1 Many may also be deprived of valuable treatments, yet unproven. Neonatal prescribers face such dilemmas each working day. Is it ethical to use treatments without comprehensive information on benefits and risks, and yet, in the absence of alternatives, is it ethical to withhold them? Children's medicines have been targeted as one of the first areas to be taken forward under the umbrella of the new UK Clinical Research Collaboration (UKCRC), which will provide infrastructure and networks to assist clinical research,20 and the recently established Medicines for Children Network (MCRN) has started to develop Clinical Study Groups (CSGs).

Within the new regulations, some have already responded to facilitate research. For example, to balance the limitations placed on secondary studies of stored samples following the Human Tissue Act,13 with the beliefs of many of those parents who consent to clinical studies on behalf of their newborn children (namely that maximum benefit should be gained from their participation), some local ethics committees are permitting broader prospective consent for the future use of stored samples.

All patients must be protected from inappropriate research. In our future studies we must, however, appropriately balance the benefits of these regulations and those of properly conducted clinical trials. It is ethically difficult both to persist with treatments of unproven benefit and unknown harm and to deny infants potentially valuable therapies. This is the challenge to which neonatal investigators, ethics committees, charities, universities, the NHS, and public funding bodies must rise. It is beholden on government, institutions, and individuals to determine that important trials are conducted in the future within the new legislative framework. For those who care for newborn infants, evidence based practice is a daily difficulty. In the current regulatory climate, the future of neonatal clinical trials may rest with innovative solutions and the determination of all involved in the process.