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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2015 Feb 20;79(3):370–378. doi: 10.1111/bcp.12467

Clinical trials of medicines in neonates: the influence of ethical and practical issues on design and conduct

Mark A Turner 1,✉
PMCID: PMC4345948  PMID: 25041601

Abstract

In the past, there has been a perception that ethical and practical problems limit the opportunities for research in neonates. This perception is no longer appropriate. It is now clear that research about the medicines used in neonates is an ethical requirement. It is possible to conduct high quality research in neonates if the research team adapt to the characteristics of this population. Good practice involves respecting the specific needs of newborn babies and their families by adopting relevant approaches to study design, recruitment, pharmacokinetic studies and safety assessment. Neonatal units have a unique culture that requires careful development in a research setting. Clinical investigators need to recognize the clinical and ethical imperative to conduct rigorous research. Industry needs to engage with neonatal networks early in the process of drug development, preferably before contacting regulatory agencies. Follow-up over 3–5 years is essential for the evaluation of medicines in neonates and explicit funding for this is required for the assessment of the benefit and risk of treatments given to sick newborn babies. The views of parents must be central to the development of studies and the research agenda. Ethical and practical problems are no longer barriers to research in neonates. The current challenges are to disseminate good practice and maximize capacity in order to meet the need for research among newborn babies.

Keywords: clinical trials, ethics, neonate, patient and public involvment, pharmacokinetics, regulatory affairs

Introduction

Neonates deserve medicines that have been appropriately tested [1]. Appropriate testing yields an appropriate formulation, an appropriate dose and information about safety and efficacy. This information is lacking for most medicines given to neonates [2]. Therefore we need to conduct clinical trials about medicines in neonates.

The perception that ethical and practical problems limit the opportunities for research in neonates is no longer appropriate. Most issues that arise during clinical trials in neonates have been managed successfully in clinical research networks. The European Network for Paediatric Research at the European Medicines Agency (EnprEMA) provides a ‘one-stop shop’ for contacting neonatal (and other paediatric) networks (enprema@ema.europa.eu) [3]. The Global Research in Paediatrics (GRiP) Network of Excellence has developed a list of neonatal networks outside Europe [4]. In the United States the Pediatric Trials Network [5] and the Consortium Child Health Oversight Committee of the Clinical and Translational Science Awards support and conduct neonatal studies [6]. This review aims to give an overview of the practical and ethical issues that influence the conduct of clinical trials in neonates. This review is targeted at people with experience in trials who do not have experience of neonatal care (e.g. people who work in industry) and at neonatal professionals who do not have experience of trials. The situation in the USA has been summarized recently [7] so this contribution focuses on Europe. Key messages are summarised in Box 1

Box 1: Key messages about clinical trials in neonates.

  • Sponsors: engage early with investigators and networks, ideally before discussing development plans with regulators.

  • Protocol developers: develop trials intelligently, focus on filling the key gaps in knowledge rather than trying to answer all the questions in a single trial.

  • Neonatal units: be prepared to adapt to trials – they are needed and exceptions to guidelines can be justified by extra scrutiny that comes with trial participation.

  • All: listen to parents.

  • Funders: take account of need for medium-term follow-up (3–5 years).

  • The health economic savings from successful interventions will accrue from life-time reductions in usage of health, educational and social services.

Definitions and scope

A neonate is a person within 28 days of their expected date of delivery (due date). A baby born at 24 weeks gestation is a neonate for 20 weeks, while a baby born at term is a neonate for 4 weeks. Neonates vary in weight between 500g and 5 kg, a 10-fold difference. Preterm babies are extremely vulnerable and have a significant mortality and morbidity [8]. It is important to take account of preterm birth when expressing age. Standardized terminology has been proposed to do this during follow-up studies [9]. For some studies (for example when defining age groups for pharmacokinetic, PK, studies) it can be simpler to post-menstrual age [10]. Post-menstrual age is the best marker for many aspects of ontogeny, for example glomerular filtration rate (GFR) [10]. However, some aspects of drug handling alter in the days after birth [11]: the influence of post-natal age should also be considered for the first month after birth. Fetuses and neonates are adapted to exposures to specific xenobiotics. This means that they handle some situations well and others badly. The disposition and effects of drugs can differ with age [12], [13].

Neonatal Good Clinical Practice (GCP) in research

Introduction

Regulatory guidelines capture many aspects of best practice in research 14–16. The European Medicines Agency (EMA) has published guidance about the conduct of clinical trials in preterm and term babies [17]. A range of other regulatory developments has facilitated neonatal research [18]. It is important to ensure that data from clinical trials of medicines can be included in labelling changes whenever possible.

In the following sections we will examine neonatal-specific aspects of headings from ICH E6 [16].

Independent Ethics Committee

Ethics Committees need expertise in neonatal clinical trials. Some ethics committees can be over-protective because of inadequate awareness of international ethical norms or because they underestimate the willingness of parents to contribute to research.

Investigator

Clinical competences do not guarantee research competences. Investigators are responsible for ensuring that adequate resources are available for the study at their site. This includes considering the impact on clinical routines of preparing medicines and collecting data. Units differ markedly with respect to how medicines are administered (syringe driver, filtration policies, approach to infusing multiple medicines, dead spaces in complex infusion setups) and this can affect the implementation of the study [19]. Failure to appreciate the details of care can delay site opening by several months. Experienced neonatal nurses and pharmacists should review the protocol in detail as soon as possible during protocol development and implementation.

Consent and recruitment

There is a body of evidence to support best practice regarding consent and recruitment to neonatal trials 20–23. Trials that recruit in the days after birth benefit from strategies to inform parents about the trials before birth 24–26. Consent for neonatal interventions is best taken after birth to avoid including complications of labour and birth in the safety reporting of a neonatal trial, particularly for trials that will be submitted to regulatory authorities in support of drug licensing.

Given the stress surrounding the birth of a sick baby it is best to use a process of continuous consent in the days and weeks after the baby is born [20]. This involves repeated discussions with the family about their baby's progress including the opportunity to confirm or withdraw consent. Experienced research nurses do this unobtrusively. Parents may be happy to give initial agreement to the inclusion of their baby in a study but value ongoing discussion during the study, and beyond. This is particularly true if a baby dies after enrolment in a study [27].

The recruitment rate depends on the nature of the study and the condition of the baby. A pragmatic study of an attractive intervention may have more than 60% of parents consenting [28], [29]. A PK study of existing medicines embedded in clinical practice with dried blood spots taken with routinely indicated samples, or scavenged samples, may also recruit well 30–33. A first-in-human study or a PK study involving extra blood tests may recruit < 10% of families who are approached depending on the circumstances [http://clinicaltrial.gov/ct2/show/NCT01651637]. Nurses and pharmacists can take consent for recruitment to medicines trials involving neonates [28], [29]. This is compatible with the Helsinki Declaration, GCP and professional codes of practice, is acceptable to ethics committees and regulators and is valued by parents. A physician is responsible for the medical assessment of eligibility for a trial.

People not familiar with the neonatal units may assume that parents are present with their baby most of the time. However, parents often have other children to look after and/or do not live close to the hospital and/or have other commitments (particularly fathers who are often still working when babies are born). If a baby has been transferred to a specialist centre the parents may not be able to travel independently and can arrive on the unit at irregular hours. Some parents immerse themselves in the care of the baby. Other parents retreat as they come to terms with what has happened. All these factors mean that introducing a study and taking consent require persistence. In the UK it is possible to take telephone consent for neonatal medicines trials [34].

Trust between parents, the clinical team and the research team is central. This trust needs to be actively nurtured and supported. People who are not familiar with neonatal units can take for granted the considerable effort needed to develop and maintain the trust needed for clinical research in this setting.

Protocol: trial design and drug development in neonates

In the past, neonates have often been the last patient group to be exposed to a new medicine because stakeholders want medicines to have a well-defined safety profile before they are given to neonates. Neonates have the greatest to gain from some new medicines. Given the need for medium term follow-up over a number of years the neonatal component of a development programme can take a relatively long time. This means that if neonates are likely to gain substantial benefit from a medicine, neonates should not be the last population to be addressed in a drug development programme. The key issue is to gather sufficient information to plan a safe programme with a well-reasoned dose-finding strategy. A good example of rational drug development in neonates has been published for neuraxial analgesia [35]. A rational drug development plan does not have to expose large numbers of neonates to a drug, for example vancomycin, see below [36].

Neonatologists are faced with a large number of pressing therapeutic uncertainties. They tend to design trials that try to resolve each therapeutic uncertainty with a single, pragmatic trial. However, this approach has extended some of the therapeutic uncertainties. One example is inhaled nitric oxide in preterm neonates. When reviewing six large clinical trials about this intervention Sosenko & Bancalari noted: ‘although inhaled nitric oxide might be promising in specific subgroups of infants, more work is needed to define the optimum dose and duration, and the target population in terms of maturity, severity of illness, race and age at enrolment at which the infant would potentially be most responsive to intervention with inhaled nitric oxide’ [37]. Similarly, fundamental uncertainties remain about the treatment of patent ductus arteriosus despite decades of research into this condition [38]. Randomized controlled trials about antibiotics in neonates have generally been poorly designed and underpowered [39], [40].

Rather than designing a single trial that can answer a therapeutic question, neonatologists need to take a phased approach that builds up an integrated picture of the formulation and dosage regimen before testing efficacy and starting to evaluate safety. All phases of drug development can be undertaken in neonates if necessary and appropriate. Phase 0 (microdosing) studies are feasible in this age group. Neonatal phase 1 studies may be necessary when the condition only occurs in neonates and administering the drug to healthy volunteers in other age groups would be unethical (e.g. http://clinicaltrial.gov/ct2/show/NCT01651637). Innovative designs for phase 2 PK studies will improve the yield of drug development in this group [41].

The total circulating volume of a preterm neonate may be 50 ml. The EMA suggests that ‘Per individual, the trial-related blood loss (including any losses in the manoeuvre) should not exceed 3% of the total blood volume during a period of 4 weeks and should not exceed 1% at any single time … The total volume of blood is estimated at 80 to 90 ml kg−1 body weight; 3% corresponds to about 2.4 to 2.7 ml blood kg−1 body weight’ [17]. For a 750g baby this equates to 1.9 ml of whole blood over 4 weeks. There is some evidence to suggest that working within these limits does not have a short term impact on clinical indicators [42]. In specific circumstances it may be possible to argue for a larger sample volume. The welfare of the baby also needs to be ensured. Skilled neonatal units are able to provide appropriate care during sampling [43].

The blood sent to laboratories often exceeds the requirements for analysis because it is difficult to be precise about the volume required when taking samples and because variations in haematocrit lead to variations in the amount of plasma. Any excess (usually circa 100 μl) is retained because laboratories need some material for quality control. If there is an excess and it is not required for quality control then the excess can be ‘scavenged’ for research if the drug is stable under the conditions in which the sample is handled. Metronidazole concentrations from scavenged samples were 30% lower than study-specific samples but this did not affect the parameters in PK models [31]. During a study of piperacillin 15% of scavenged samples were not usable because of lack of information about the sampling times and the timing of flushes [30]. Variation in storage may also cause problems. Using scavenged samples is easy for the baby but needs just as much work by the investigators as other techniques.

Dried blood spots are widely used to collect samples in other age groups and can be valuable in neonates because of the minimal sample volume required (10–20 μl per sample). Their utility is limited to chemical entities that do not evaporate or pose other technical challenges before or during the assay. Under ideal conditions good correlation between concentrations measured in conventional and neonatal dried blood spot samples has been reported (r 2 = 0.95). The absolute values of the concentrations are affected by whether or not the substance partitions into red blood cells. Concentrations measured from dried blood cells were 15% lower for metronidazole and 50% lower for piperacillin [32], [33].

Dose finding and dose ranging is possible, e.g. for melatonin [44]. Sophisticated designs based on Bayesian reasoning to minimize the number of participants, e.g. the continual reassessment method, have been conducted in neonates [45]. These studies inform subsequent development, e.g. azithromycin where PK studies [46] have informed the drug development plan [47] or fluconazole [48], [49].

Trials of efficacy may not be needed if efficacy can be extrapolated to neonates from other age-groups. This can be done if the condition is found in other age groups and the disease course and concentration−effect responses for the drug are similar (e.g. infection) [50]. One example is the paediatric investigation plan for vancomycin in neonates which will determine whether an optimized dosage regimen (based on in silico and animal studies) attains PD endpoints in a timely way [36]. This approach avoids a large non-inferiority trial of efficacy. Extrapolation is not possible for conditions that are unique to neonates or for safety.

Multiple births (twins, triplets and higher order multiples) need to be accounted for. Hibbs et al. conducted a systematic review about how multiple births were handled in clinical trials. Fourteen trials met their entry criteria and explicitly included multiple births of which six indicated how multiples were randomized. Five of these six trials randomized multiples to the same allocation [51]. Statistical models can handle the ‘clustering’ arising from twins [52]. Our experience is that parents prefer to treat twins and higher order multiples in the same way so we allocate them to the same arm in a RCT.

Composite outcomes are commonly used, e.g. a composite of death or disability [53]. This is conservative because death may have nothing to do with the intervention. On the other hand, it is often impossible to exclude the possibility that a trial intervention contributed to death. There have been efforts to validate composite outcomes in neonatal cardiac surgery [54] and to validate and qualify composites in neonatal pulmonary hypertension [55]. A staged approach with a short term outcome at hospital discharge followed by 2 year outcomes can be used, for example, in the paediatric investigation plan for dopamine [56]. Two by two factorial designs have been used but require careful design to avoid overlapping primary outcomes [57]. It is important to record biological safety outcomes. Gestational age-adjusted norms have been reported for GFR [58] and creatinine [59]. The variation in liver enzyme concentrations seen in standard practice across the gestational age range has been reported [60].

Neonates can participate in more than one study at the same time as long as the families are willing, the welfare of the participants is not compromised and the study designs do not lead to problems with scientific interpretation [61]. There are some indications which will be impossible to study if babies cannot be recruited to more than one study (e.g. phase 3 studies of retinopathy or prematurity).

Practical aspects of neonatal trials

The culture of neonatal units

Neonatal unit culture is the product of integrating the care of sick newborn babies with the needs of families and staff who are frequently exposed to life changing events – birth, death, disability, grief [62]. Many neonatal units have strong routines to minimize medication errors, avoid infection, promote rational prescribing, optimize nutrition and reduce other threats to high quality care. These routines are tempered by the flexibility needed to manage critical illness and support family centred care (time for breastfeeding, skin-to-skin care, quiet time etc.). This means that the ability of a unit to adapt to trials may be limited and needs to be carefully negotiated. Central to implementing research projects is careful process mapping, taking account of all aspects of the unit, the specificities of each trial and the perspective of families and staff who are not specialist researchers. A structured approach to trial design and implementation increases recruitment and cuts down delays, for example a RCT can be preceded by work to elicit the views of parents and staff and by a pilot study 63–65. Apparently small changes to unit routine to accommodate a trial may have a big impact on the provision of care or may be difficult to implement. For example a trial of parenteral nutrition required extensive restructuring of unit routines [28]. The optimal solution is for dedicated research staff to develop and maintain procedures that can be easily implemented by families and frontline staff. Neonatal research nurses need careful support and development, as in other clinical areas [66]. Another complementary approach is to recruit ‘Research Champions’ from within the clinical team who can promote the importance of the study and troubleshoot obstacles from within the clinical team. Clinical staff are busy and their involvement in research needs to be limited to the activities that must be done by them. Their contribution to data collection sheets must be limited to the data that cannot be collected in other ways. We use very short paper sheets at the bedside to ensure that clinical staff gather the correct information and perform trial procedures with precision supplemented by comprehensive workbooks for research staff [28], [29]. Early phase treatment studies require close attention by dedicated staff because front line clinical staff are too busy to deliver complex and time-critical study procedures reliably. As with all trials, careful management of every step is essential [67], [68].

Clinical staff need to avoid throwaway comments about research ‘guinea pigs’. Staff need to be briefed about each project. We do not open a trial until 80% of the staff on the unit have been briefed about it. This can take several weeks. Centres that participate successfully in clinical trials are not necessarily the units that lead academic research so that academic credentials should not be the only criteria for site selection.

Clinical networks

In some health care systems babies receive inpatient neonatal care in specialist centres far from the family home. As a baby recovers from critical illness they often move from a specialist centre to a hospital close to home. This requires arrangements for continuation of trial medication and outcome reporting. It may be necessary to limit the data collected in continuing care sites. Safety reporting is needed as a minimum. Both recruitment and follow-up in other sites lead to complex governance arrangements. Research journeys should be mapped to clinical journeys with full descriptions of roles and responsibilities before a study opens [69].

Follow-up

The central importance of follow-up to neonatal research has recently been described by Marlow who also summarizes the content and methodology of contemporary follow-up studies [70]. Medium-term follow-up (1.5–3 years) is essential given the weak nature of most surrogates at term equivalent for safety and efficacy in neonates. Examples of misleading surrogates include adverse effects of intervention at term equivalent but benefit at 2 years (DRIFT) [71], difference in mortality/morbidity at term equivalent but no difference in disability at 7 years (ORACLE I) [72], no difference in mortality of morbidity at term equivalent but difference in rate of CP at 7 years (ORACLE II) [73] and benefit with surrogate was not sustained on follow-up (TTIP) [74].

Safety reporting

Acute toxicity is common in neonates and needs to be captured during clinical trials [75], [76]. Acute safety issues can be difficult to identify because of the physiological variation arising from preterm birth and its consequences. For example, acute alterations in oxygen saturation or heart rate that would be adverse events in other age groups are very common in preterm neonates and may not be noteworthy in this group. Additionally, serious adverse events are relatively common among all neonates irrespective of allocation within a trial. Pharmacovigilance benefits from a specification of the events that are anticipated from the natural history of the newborn period and previous experience with the medicine in neonates [24]. When it is not possible to anticipate adverse events of interest it is important to maintain a high index of suspicion. Methods to ascertain the causal relationship between an intervention and an adverse event have been proposed [77]. Causality assessment can be difficult at the level of individual babies. Alternatives are to describe events without inferences about causality to give prescribers information to make individualized benefit-risk assessments. Adverse events can be assessed for groups of babies using trials or observational studies enriched with propensity scores, for example morphine [78]. An alternative is to take a toxicological risk management approach, integrating data from multiple sources [79].

The potential impact of drugs administered during the neonatal period has been summarized for the kidney [80], [81], cardiovascular system [81] and the brain [82]. Biomarkers for significant renal impairment have been proposed [83]. It is not usually feasible to power a neonatal study to detect that a harm is associated with a treatment. Registries, cohort studies and other designs may be useful but need to be carefully designed. Confounding by indication is a particular problem in neonatal intensive care. The impact of the European pharmacovigilance regulation on neonates is not clear at present. Regulators have the ability to impose risk management plans on Marketing Authorization Holders. Realistic risk management plans, will enhance neonatal pharmacovigilance [http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000360.jsp]. The European Regulation on pharmacovigilance makes it clear that responsibility for safety reporting relating to off-label use lies with Marketing Authorization Holders [http://ec.europa.eu/health/human-use/pharmacovigilance/index_en.htm]. This also increases the likelihood that neonatal PV will be done well.

Patient and public involvement

It is absolutely essential that families are consulted about individual studies and that families and wider society are consulted about the direction and nature of research on neonates. There is an increasing awareness of the need to keep in touch with families after the initial involvement in the trial [27]. This will require significant effort, similar to that required for follow-up, but is important in its own right and not just a method of optimizing follow-up [70]. It is also important to develop the research agenda. This can be done by consulting experts [84] and clinicians [85] but parents and other stakeholders are important contributors [86].

Finance

The UK has a standardized costing template for trial-related activities and industry is prepared to meet the costs of their trials [http://www.crn.nihr.ac.uk/can-help/life-sciences-industry/setup-service/], including in neonates. The income from trials can be sufficient to support the specialized nursing staff who are required. In our experience a number of companies are committed to conducting research in neonates and are prepared to invest the necessary time, effort and money to address the issues described here. Costs not covered in the template include time spent on screening and recruitment. An interview about study recruitment may take 20 min. However, to set up the interview may require that the study team are available all day because of the unpredictable availability of parents. Staff often find that it is more difficult to make contact with parents in neonatal units than other settings. The costs of doing clinical trials properly in neonates will be offset by the savings to the health sector and society in general if interventions are successful. Hospital stays during the neonatal period may cost in excess of £100 000 and neurodisability and other adverse outcomes as children grow up, are expensive [87].

Conclusion

Neonatal clinical trials are an ethical necessity if we are going to use existing and novel treatments effectively in the newborn period. Effective trials depend on a range of factors including a rational choice of design to account for current knowledge gaps and the adaptation of protocol and unit routine to each other. Clinicians need to accept that current practice is predominantly not evidence-based so that rigorous research is needed and justified. Optimal trial conduct involves appropriate use of contemporary PK tools and strong governance arrangements when babies are transferred between units. Adequately funded, well-organized follow-up is required.

Ethical and practical issues are no longer barriers to research in neonates. The challenges now are to disseminate good practice and meet the needs for research among newborn babies.

Competing Interest

The author has completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Mark Turner's work on clinical trials in neonates is supported by the Medical Research Council grant G1100158, European Commission Network of Excellence Grant Agreement 261060, (Global Research in Paediatrics), and FP7 grants TINN (223614), TINN2 (260908), and NeoCirc (282533). He has benefited from discussions with a large number of people, particularly Patrick McGowan, Helen Hill (Liverpool); Ed Juszczak and Ursula Bowler (Oxford).

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