Drug Development Guidance Published by EMEA on New Medicinal Products for Term and Pre-term Neonates

EMEA publishes “GUIDELINE ON THE INVESTIGATION OF MEDICINAL PRODUCTS IN THE TERM AND PRETERM NEONATE”. This guideline addresses the considerations and requirements for the design and conduct of clinical trials in premature and term neonates using medicinal products of relevance for the use by this population. It includes background information on the maturation of organs and of body functions.

Introduction to EMEA Guidelines

Neonates are the group of children from birth up to and including the age of 27 days, including term and preterm neonates. They represent a particularly vulnerable subgroup of the paediatric population. Whilst they account for a low percentage of the total use of medicines in childhood, up to 90 % of medicinal products are used unauthorised or off-label in this population, especially if treated on Neonatal Intensive Care Units (NICUs).

There are several reasons as to why few clinical trials of medicinal products have been performed in neonates (e.g. feasibility difficulties linked to: age, small patient group and uniqueness of their diseases.) The Regulation on Medicinal Products for Paediatric Use (Regulation (EC) 1901/2006) creates obligations with regards to conducting clinical trials in paediatric patients including neonates in order to meet the recognised need for authorised medicinal products and the information on the use of medicinal products in children. Therefore clinical trials to investigate medicinal products in the neonatal population have to address the needs of this population (section 9.1).

Scope of EMEA Guidance

The guideline aims to provide guidance for the development of medicinal products for use in the neonatal period, defined as from birth up to 27 days post-natal age in term neonates and from birth up to a post-menstrual age of 40 weeks and 27 days in preterm neonates.

Organ Maturation in the Neonate

Most organ functions are physiologically immature in the neonatal period. The degree of immaturity may be aggravated due to prematurity, intrauterine growth retardation or any potential pathologic condition affecting the neonate. Functional immaturity of physiological processes and organ function predispose neonates to altered pharmacokinetics and pharmacodynamics, leading to potential inefficacy or reduced safety of a medicinal product in the neonate.

Maturational changes are rapid in the post-natal period, and the resulting high variability of the neonates (both inter-individually and intra-individually) has to be considered when investigating medicinal products for use in the neonatal population. Additionally, any medicinal product administered to the neonate may affect the ongoing maturation processes. Major developmental changes should be identified that could significantly influence exposure, safety and efficacy for a given medicinal product. If adequate and possible, not only pharmacokinetic changes due to ongoing maturation but also pharmacodynamic changes as a function of maturation itself should be investigated.

Heart and Lung

The post-natal cardiopulmonary system adaptation marks the most prominent changes during and after birth. Some of these changes occur instantaneous with the first breath, whereas others occur within hours or days after birth. In general, the impact of lung and heart maturation on PK/PD relationship (e.g., closure of the ductus arteriosus) has to be considered.

Cardiopulmonary monitoring of hospitalised neonates is carried out on a routine basis and these findings should be used and documented for the purpose of a clinical trial as appropriate. Less or non-invasive measures should be used whenever possible (e.g., measurement of blood pressure, heart rate, respiratory excursions and rate; pulse oximetry in at least one site, transcutaneous pO2 and / or pCO2 measuring, electrocardiogram [ECG], echocardiography, and Doppler sonography). Radiologic (e.g. X-ray, MRI) and laboratory (e.g., blood gases, haematocrit) assessments may additionally be required and would need to be synchronised with routine assessments and limited as much as possible.

Central Nervous System (CNS)

Critical processes of brain development consist of neuronal proliferation, migration, organisation and myelination. Two main phases can be distinguished with the first occurring between the 8th and 16th week of gestation, consisting of neuronal proliferation and generation of radial glia, and the second phase between 5 months and 1 year of life, consisting of glial multiplication (with neurogenesis and neuroproliferation continuing).

Even if a medicinal product is not primarily developed for an indication related to the CNS, the distribution and penetration into the CNS and the potential effects and neuro-developmental sequelae should be addressed.

Hypoglycemia is an important risk factor for perinatal brain injury. Due to the high metabolic rate and the dependence on glucose as unique source of energy of the brain, any medicinal product affecting glucose metabolism in the neonate may have an effect on the developing brain. This should be carefully taken into consideration when planning a neonatal study.

Measures to monitor brain function include EEG (electroencephalography), amplitude-integrated EEG (aEEG), ultrasonography, Doppler sonography, auditory and visual evoked potential measurements (AEP, VEP), cerebrospinal fluid (CSF) sampling, near-infrared spectroscopy (NIRS), (functional) magnetic resonance imaging (MRI) and positron emission tomography (PET). These measures have different utility, e.g. NIRS allows to continuously assess brain perfusion and oxygen consumption in neonates.

Kidney and Renal Function

Renal clearance mechanisms include glomerular filtration (GFR), tubular secretion and reabsorption. Glomerular filtration matures faster than the tubular function, and both depend not only on age and maturational status but also on adverse factors occurring in the pre- and post-natal period, including for example intrauterine growth retardation or administration of nephrotoxic drugs to the mother and the neonate.

Serum creatinine is elevated in the first days of life and reflects maternal creatinine and low GFR in the neonate. In premature neonates, the persistence of an elevated serum creatinine during the first weeks of life is the result of a transitory process of tubular creatinine reabsorption. Therefore, to monitor renal function serum creatinine is used after the first week of life in term neonates and after 4 weeks in premature neonates. Before these times, intra-individual changes (related to post-menstrual age) in serum creatinine are used as a guide to renal function.

Liver and Hepatic Function

Hepatic blood flow, plasma protein binding and intrinsic clearance determining hepatic clearance undergo significant post-natal changes. Most enzymatic microsomal systems responsible for drug metabolism are present at birth and their activities increase with advancing post-natal and gestational age. Rapid maturational changes occur during the first weeks of life. Hepatic clearance may be influenced by premature birth, pathologic conditions of the neonate or administration of drugs to the mother or to the neonate.

To predict the exact nature of these consequences requires an understanding of post-natal maturation and main involved enzymes. The ontogeny of specific enzymes is partly described in the scientific literature and may allow estimations of drug metabolism in the neonate. These data should be considered when planning neonatal studies.

If the medicinal product investigated is likely to be eliminated mainly through hepatic metabolism, markers of reduced/normal hepatic function could be included as covariates in the pharmacokinetic data analysis (e.g., in population PK analysis) as well as included in the safety assessment. Monitoring could include standard laboratory and imaging procedures.

Gastrointestinal System

Data concerning maturational changes of the neonatal gastrointestinal tract that may influence bioavailability are still limited.

Immune System

Lymphoid stem cells develop from precursors and differentiate into T, B or NK cells, as well as Antigen presenting cells (APCs) depending on the organs or tissues to which the stem cells traffic. Indeed, both the initial organogenesis and the continued immune system cell differentiation occur as a consequence of the interaction of a vast array of lymphocytic and microenviromental cell surface molecules and proteins secreted by the involved cells. De novo T-cell generation requires a functional thymus. The current paradigm is that the human T-cell repertoire is established during late foetal development and that, by the time of birth, thymectomy does not cause immediate immune deficiency. Thymic epithelial cells – the component of the thymus relevant for T-cell production and selection – involute rapidly after birth. Compared with adult T cells, neonatal T cells secrete increased levels of interleukin-10 (IL-10) following stimulation, but reduced levels of many other cytokines, including IL-2, IL-4, IL-8, interferon gamma (IFN-gamma), transforming growth factor beta (TGF-beta) and tumor-necrosis factor alfa (TNF-alfa).

Antibody response can readily be detected upon challenge in neonates provided to take into account the presence of interfering maternal antibodies. Modern multiparameter cytofluorimetric technology can be employed to assess not only the number of immune cells but also some immune functions such as cytokine production or cytolytic activity. However an effort to develop microassays has to be done to truly assess the different pattern of immune responses in the neonate and in infants in the first years of life. Molecular techniques such as spectratyping for T and B cell repertoire assessment can also be of value.

Body Composition

Changes in body composition during the neonatal period are important factors for altered pharmacodynamic and pharmacokinetic characteristics. Body composition correlates with both gestational and post-natal age, and it continues to change significantly during the first years of life. Age related changes in fat, muscle and total body water composition may produce significant quantitative changes in pharmacokinetic parameters such as volume of distribution. For instance, total body water is highest in the newborn and decreases substantially in the first 4 months of life therefore high water soluble drugs will present a larger Volume of Distribution in the neonatal period potentially requiring larger doses than older children in order to achieve the same desired therapeutic plasma concentrations. On the contrary, the amount of body fat is low at birth and increases progressively in the first months of life. Iatrogenic interventions in neonates could also significantly shift body composition characteristics.

Conditions Affecting Specifically the Neonatal Population

Neonates frequently suffer from conditions that are specific for this subset of the paediatric population, for example respiratory distress syndrome (RDS) or patent ductus arteriosus (PDA). In addition, neonates hospitalised on NICUs often suffer from multiple concomitant conditions, requiring administration of a combination of medicinal products resulting in a high risk of drug interactions. Additionally, adverse reactions in neonates, especially in preterms may trigger specific complications, as for example in relation to susceptibility to necrotising enterocolitis (NEC) or retinopathy of prematurity (ROP). As a further complicating factor, in utero growth retardation may affect pharmacokinetics and pharmacodynamics of drugs at birth and therefore may change the safety and efficacy profile of drugs used in the neonatal period.

Timing of Development of Medicinal Products in Neonates

The timing of studying a medicinal product in the neonate will depend on the seriousness and uniqueness of the condition to be treated as well as on the availability of alternative treatment options, the potential benefit of a new product, and the target population. Sponsors should refer to ICH Guideline E11.

Data Required Before the First Administration to a Neonate in a Clinical Trial

If possible, clinical data should always be obtained in the least vulnerable population. Depending on the condition, the new product, the target population and further factors according to section 2.1 of the ICH Guideline E11, initial tolerability, PK and safety data should be collected in adults before initiating studies in the neonatal population.

If older children are affected by the same disease or another disease for which the medicinal product may be of use, in general older (less vulnerable) paediatric age groups should be studied before studying the product in the neonatal population.

For conditions exclusively found in neonates, the development should primarily be made in neonates. However, also in such condition, the first studies in man should, if possible, be done in healthy adult volunteers. Sponsors should refer to the ICH Guideline E11.

In-Vitro Data

In order to predict the in vivo situation as much as possible (i.e., as regards efficacy, pharmacokinetics, safety), in vitro studies on human biomaterial, (e.g., on human non-terminally differentiated cells or, if relevant, foetal or neonatal cell cultures) may provide relevant additional information. Examples include enzyme activity, receptor expression and mediator modulation.

Animal Data

The conventional nonclinical studies should be performed including pharmacokinetic, primary pharmacodynamic, safety pharmacology, single- and repeated dose toxicity, genotoxicity, reproductive and developmental toxicity, including peri-/post-natal toxicity testing (e.g., transplacental exposure) and local tolerance studies.

In addition to these conventional non-clinical studies, juvenile animal data should be provided if needed. Juvenile toxicity studies will be necessary if available human safety data and previous animal studies are considered insufficient for a safety evaluation in the intended paediatric age group. If such studies are considered to be not relevant or not feasible, a scientifically data based justification should be provided.

Formulation and Route of Administration

The choice of formulation and route of administration depend on the condition to be treated and the clinical state of the neonate. Age-appropriate formulations and strengths using appropriate excipients must be developed to avoid extemporaneous preparations, even more so for neonates. Novel formulations should be evaluated through preclinical studies and in adults or older children as appropriate before consideration for administration to neonates.

Intravenous (IV)

The intravenous route will normally be used in clinically unstable term and preterm neonates. Neonates have a fragile vasculature system, and it may be very difficult to obtain appropriate peripheral or central access. Most common IV routes are peripheral veins (limbs, feet, hands or scalp), umbilical vein, or “long” peripheral lines that can be considered central, whereas internal jugular vein or femoral vein access is uncommon. Neonates may only have a small number of IV lines to administer all medicines as well as blood products, total parenteral nutrition (TPN) and fluid maintenance.

Oral

Oral administration should be used when possible and appropriate in the neonatal population, but there is still lack of data on absorption and safety. The way of enteral feeding (e.g., feeding tube, sucking), the time intervals (e.g. continuous, hourly feeds) and amounts of feeding have to be considered and specified.

Rectal Use

Rectal administration is not commonly used in this age group, and it is associated with erratic absorption. If considered it must be fully evaluated for safety and efficacy in addition to the appropriate bioavailability studies.

Topical Use

Topical administration may be necessary or suitable for local or systemic effect. Account must be taken of skin immaturity, especially in preterm neonates, and the large and more permeable and moisturised surface area to weight ratio which all predispose to an increased systemic absorption that could lead to toxicity.

Intramuscular (IM) use

Intramuscular administration is not usually a route of choice for neonates because absorption may be slow and unpredictable, varying with postnatal age and clinical state; injections may be painful and cause tissue damage. If the intramuscular route is considered its use must be justified.

Other Routes

Other routes of administration may be required or may be suitable (e.g., endotracheal, inhalation etc). Their use should be justified.

Dose Finding

In general, most drugs are developed for adults and older children before they are developed for the neonatal population. All relevant pre-clinical and clinical data in adults and children, or in adults and juvenile animals, should be taken into consideration to find a safe starting dose in neonates. PK / PD modelling techniques, using age appropriate and validated biomarkers, need to be considered to find the optimal dose. For a new medicinal product, the optimal dose has to be clinically verified. Existing physiologically based pharmacokinetic models to predict pharmacokinetic characteristics in the neonatal population may be considered if appropriate.

Pharmacokinetic Studies and PK/PD studies

Pharmacokinetic information is important to support adequate dosing in subpopulations of the clinically studied population and to assess the potential for clinical relevance of toxicity findings in the preclinical studies. However, pharmacokinetics alone is of limited value for extrapolating efficacy and safety from other patient groups, and extrapolation of efficacy will in general need pharmacodynamic data and PK/PD monitoring.

A population PK approach is preferable due to the importance of finding covariates related to dose-individualisation between individuals and over time in the maturating individual. The analysis can be made on rich and/or sparse data depending on the number of patients available and the possibility of developing highly sensitive analytical methods where very small sample volumes could be used.

Specific Aspects of Clinical Trial Design in Neonates

As for all clinical trials all measures to avoid bias should be included in trials performed in neonates. Therefore uncontrolled trials should be avoided in principle for demonstration of efficacy. They have limited usefulness for the demonstration of safety. On the other hand for randomised trials, in particular those using a placebo, there should be equipoise (genuine uncertainty) at the beginning of the trial and no participants should receive care known to be inferior to existing treatments.

The size of a trial conducted in neonates should be as small as possible to demonstrate the appropriate efficacy with sufficient statistical power. Adaptive, sequential, Bayesian or other designs may be used to minimise the size of the clinical trial. However, a balance between the need to stop recruitment early and the need to obtain reliable safety information should be aimed at.

In addition, clinical trials in neonates should be carried out in experienced neonatology centres with relevant expertise and with appropriate resources, in order to ensure optimum professional conditions for the protection and medical support of the neonates.

Age and Further Stratification Criteria

Taking into account age classes is of particular importance when recruiting patients within the clinically relevant age interval to optimise the evidence the potential influence of maturation. However, during data analysis, the use of age as a continuous co-variable is recommended whenever possible for the same reason.

The following subgroups within the neonatal population should be recognised as distinct, and the use or not-use of these criteria for stratification should be justified accordingly.

• SGA or not; hypertrophy or not
• ELBW, VLBW, and LBW
• GA (for example, < 26 weeks, 26 – 29 weeks, 30 – 33 weeks, 34 – 36 weeks, >= 37 weeks)

Endpoints and Outcome Measures

For use in clinical trials in neonates, there is a need to elaborate clinically relevant primary endpoints, linked to the conditions and prospects specific to preterm and term neonates. In addition, the need for establishing age appropriate surrogate endpoints should be considered.

Pharmacogenetics and -genomics

The relationship between phenotype and genotype may be completely different in the neonate as compared to other patient groups. Genetic testing like other tests is subject to prior informed consent. If target genes of interest can be identified, pharmacogenetic analyses of these genes are encouraged. If there are important pharmacogenetic differences affecting pharmacokinetics, efficacy and safety of the medicinal product in the adult populations, pharmacogenetic analysis of the target genes is recommended in neonates. In such cases, the time-dependency (maturation) of the relationship between genotype and phenotype may need to be described.

Dosage Adjustment over Time

Within days in the life of preterm and term neonates, there may be large physiological and / or pathological changes in body weight, BSA, and body composition, as indicated above. For example, physiological post-natal weight loss may be more than 10 % of birth weight, and body weight in preterm neonates may increase rapidly, up to threefold during post-natal medical care.

Consequently, there is a need to continuously re-calculate and adjust dosages of investigational medicinal products on the basis of actual weight (or other relevant covariates) or on the basis of results from therapeutic drug monitoring, because fixed or perpetuated dosages are most probably inadequate in terms of efficacy and safety.

Placebo and Active Comparator

Use of placebo in neonates is more restricted than in adults and older children, as neonates are even more vulnerable. Placebo can be used on top of best standard of care, as placebo use does not imply the absence of treatment. The use of placebo may be needed for scientific reasons, for example to quantify variability and to determine treatment effects. Placebo may be warranted in children as in adults when evidence is lacking. As the level of evidence in favour of an effective treatment increases, the ethical justification for placebo use decreases. In all cases, placebo use should be accompanied by measures to minimise its use and to avoid irreversible harm, especially in serious or rapidly evolving diseases.

Blood Sampling

Preterm and term neonates have very limited blood volume, are often anaemic due to age and frequent sampling related to pathological conditions. The fact that they receive blood transfusions (or iron or erythropoietin supplementation) must not be used as a convenience for increased volume or frequency for blood sampling. The number of samples and/or sample volume should be kept to a minimum.

Study Analysis

As in any clinical trial, the study analysis should be carefully planned in advance, taking into account the limited amount of data that may be available with this patient population. The Guideline on Clinical Trials in Small Populations (CHMP/EWP/83561/2005) is fully applicable to studies with term and preterm neonates, and it therefore needs to be taken into consideration for the planning of the study and of the analysis.

Pain and Distress

As most investigations and procedures carry the risk of pain for the neonates, pain should be prevented, and if unavoidable evaluated, monitored and treated appropriately. Evaluating and monitoring the level of pain may be difficult in the neonate, as scales are based on physiological parameters that can be affected by concomitant diseases and procedures. However, the development and / or use of validated scales is recommended, for example, the Premature Infant Pain Profile (PIPP) or the Neonatal Infant Pain Scale (NIPS) scale for the assessment of pain.

Safety Monitoring

As a general recommendation for hospitalised neonates in a trial, vital signs should be monitored continuously, and related events should be registered according to neonatal definitions (apnea-bradycardia; sustained bradycardia, tachycardia, desaturation, hypotension; fever, hypothermia etc.). Specific age and/or gestation appropriate (e.g., laboratory) reference values and ranges should be used.

Pharmacovigilance and Long-Term Follow up of Safety

The challenging task of pharmacovigilance and follow-up in terms of duration and type depends on the product itself, the target organs, the duration of exposure and other risk factors for sequelae. The potential for adverse drug reactions occurring later in life should be monitored as neonates may have been exposed to medicinal products at a sensitive period in terms of organ maturation. Only a small number of neonates is likely to be included in rather short term trials, thus long-term adverse reactions may not be detected and would require additional appropriate pharmacovigilance approaches and particularly pharmacoepidemiological studies.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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