A review of paediatric injectable drug delivery to inform the study of product acceptability – An introduction

Aim: The EMA defines acceptability as “ the overall ability and willingness of the patient to use, and their caregiver to administer, the medicine as intended ” [1]. This paper seeks to outline issues of acceptability in relation to injectable therapy, namely intravenous (IV), intramuscular (IM) and subcutaneous (SC) administra- tion routes


Introduction
Oral administration of drugs is a convenient and widely used route of drug delivery, but the oral route may not always be practicable or desirable. Parenteral routes of administration help circumvent issues such as dysphagia, gastrointestinal disease, low enteral absorption, high first pass metabolism, instability or degradation in the gastrointestinal tract [2,6]. Injectable routes constitute one of the main modes of therapy in hospitals and emergency care especially when the oral route is not feasible, such as in neonatology and critical care of children, impaired consciousness, trauma, and when there is a need for rapid onset of drug action. Injectable routes are also used for intermittent or continuous infusion of drugs; for maintaining consistent blood levels via depot formulations; and for maintaining nutrition in severely ill patients. Although injectable drug delivery offers several advantages, it also has drawbacks in terms of higher costs, training (including avoidance of sharps injury), specialized equipment and the need to avoid microbial contamination [2,6,7,8].
Innovations in injectable formulations, devices and clinical practice have permitted sustained, targeted and controlled therapy in addition to reducing frequency of administration and adverse events thereby improving patient acceptability [2,6,9].
In the outpatient and domiciliary settings in several countries, developments in practice include the increasing use of injectable antimicrobial therapy (OPAT) for paediatric and adult patients. Injectable administration can be achieved by visiting a healthcare facility, self-administration by the patient, administration by a caregiver/family member or with the help of a visiting health practitioner [10,11,12].
As further discussed below, the concept of acceptability is a complex one. In order to help focus the contents of this paper a summary of the 'knowns' and 'unknowns' with regards to paediatric drug product acceptability assessment has been compiled and is presented in Table 1.

The terminology of acceptability
In relevant papers discussing 'acceptability' a variety of terminology is used and often reflects the overall acceptability of an intervention, including safety and efficacy and other components relating to overall quality of life such as convenience to both patient and carer, feasibility and cost. Several other terms used to discuss outcomes may cause confusion when determining what to measure when demonstrating 'acceptability' of a pharmaceutical product ( Table 2). These include adherence, compliance, concordance [13,14], preference, quality of life, safe practice, benefit-risk profile, comparative acceptability. Acceptability of the drug product will be important in achieving these broader outcomes, but should be measured discretely.

Table 1
Gaps in acceptability information.

What do we know?
Information about the potential acceptability of an injectable product and its route of administration (IV, IM, SC) is important for product design and development. Paediatric patients and caregivers may have perceived preference for a route of administration. Regulatory authorities expect discussion of the acceptability of proposed dosage forms to be included in paediatric investigation plans and confirmation of acceptability from clinical studies. There is useful information in guidelines about product attributes that should contribute to product and patient acceptability but no regulatory guidance on how acceptability should be determined. The definitions of 'acceptability' in European guidelines concerns product and patient or caregiver acceptability but the term is also used in relation to overall acceptability of healthcare interventions. Product acceptability may involve the child patient, parent or caregiver, and the health professional caregiver with different importance or priority for different aspects of acceptability. For example, the child patient may prioritise avoiding pain on injection but the caregiver may have to contend with a complex administration technique. There is a growing amount of scientific literature on patient and caregiver acceptability of oral dosage forms and products for children. There is sparse literature directly concerned with the range of outcomes that might be measured to study acceptability of injectable products and no published tools that might be used. However, some features that make up 'acceptability' have been well studied and reported in different contexts. For example, pain scoring in different age groups for assessing the efficacy of analgesia. Companies and regulators should have information about the studies required to confirm patient and caregiver acceptability of injectable products but information and outcomes have not been published. Acceptability should be measured discretelywithdrawal from a clinical trial could be as a result of pain of administration but there are other reasons for withdrawal that may not be related to the drug product. What do we need to know? What information about acceptability is required for a paediatric investigation plan? What developmental changes in anatomy, physiology and psychology in childhood may affect the acceptability of an injectable product? What are the attributes of an injectable product for children that should make it acceptable for patients and caregivers? Is it possible to extrapolate from acceptability demonstrated in studies with adult patients? What should be studied in clinical trials/studies to demonstrate acceptability to patients and caregivers, of an injectable product? Can the experience of companies and regulators about methodology and outcomes of studies on acceptability of injectable products for children be harnessed to provide guidance? Can studies be designed to measure acceptability related specifically to characteristics of the drug product and discriminated from other aspects of the intervention? Table 2 Terminology.

Acceptability
The quality of being tolerated or allowed. [15] Acceptability (patient; care giver) The overall ability and willingness of the patient to use a medicinal product as intended and its care giver to administer the medicine as intended. [1] Acceptability (patient; care giver) The ability and willingness of a patient to self-administer, and also of any of his/her lay or professional caregivers, to administer a medicinal product as intended.
[ 16] Acceptability (cost) The ability and willingness of the provider to pay for the treatment [17] Acceptability

(intervention)
The term is also used in relation to overall health care interventions [14] Adherence The extent to which the patient's behaviour matches agreed recommendations from the prescriber. Adherence emphasises the need for agreement and that the patient is free to decide whether or not to adhere to the prescriber's recommendation. [18] Appropriateness A set of pharmaceutical design characteristics of a drug product that determines within a specific target patient population if a patient and/or its caregivers can use the pharmaceutical drug product as intended. [19] Benefit-risk In relation to pharmaceutical dosage forms, consideration of the advantages and disadvantages of the product in relation to efficacy and safety. [20] Comparative acceptability The attributes determining acceptability of two or more dosage forms or interventions are ranked and may allow preference to be expressed [14] Compliance The extent to which the patient's behaviour matches the prescriber's recommendations. [18] Concordance This is a recent term whose meaning has changed. It was initially applied to the consultation process in which prescriber and patient agree therapeutic decisions that incorporate their respective views, but now includes patient support in medicine-taking as well as prescribing communication.
Concordance reflects social values but does not address medicine-taking and may not lead to improved adherence. [18] Health-related quality of life The patient's ability to enjoy normal life activities.
Quality of life is an important consideration in medical care. Some medical treatments can seriously impair quality of life without providing appreciable benefit, whereas others greatly enhance quality of life. [21] Medicines optimisation A person-centred approach to safe and effective use of medicines, to ensure people obtain the best possible outcomes from their medicines. Medicines optimisation applies to people who may or may not take their medicines effectively. Shared decisionmaking is an essential part of evidencebased medicine, seeking to use the best available evidence to guide decisions about the care of the individual patient, taking into account their needs, preferences and values. [22] Preference Something one would like to have or do rather than something else. May be used when comparing the attributes of drug [15,23] (continued on next page) F. Ruiz et al.

Literature review
Much of the literature relevant to assessment of product acceptability relates to products used for adults and may not be directly relevant to children. Some of the literature and discussion concerns the overall acceptability of a health care intervention and quality of life.

Summary of method and results (see further information in supplementary material S1)
From mid-August to mid-September 2020, Pubmed was searched with the following keywords (acceptability [Title/Abstract]) AND (parenteral [Title/Abstract]) and 76 results were obtained.
On screening, 10 papers were judged relevant, with 4 concerning paediatrics. This search was verified on 25-Apr-22. 82 results were obtained, without finding any additional papers of interest for this review. Further searches were carried out on Google scholar. The search was widened to include all age groups. Detailed information on search terms is provided in supplementary material S1. Cited references of the selected studies/systematic reviews were hand-searched for any additional relevant articles. In addition, citation chaining searches were undertaken on Google Scholar using the "Cited By [# results]" link below the link to the paper.
A first table with 194 references was constructed. When the abstract mentioned "acceptability" but only concerned adults the reference was kept (to be able to compare children vs adults methods). When it was collected from "preference" or "pain" search terms, only references related to children were kept unless there was no access to the full article to check if it also concerned children. At the end of the process, 105 references were selected and are tabulated in supplementary material S2. The table provides summary information under the following headings: title; drug/device/acceptability factor studied; device/route, or formulation; age and age group; acceptability objective; method or tool used; summary of results.

Results
None of the studies directly addressed the issue of drug product characteristics in relation to acceptability which might be required by regulators for drug products early in their authorisation life cycle. However, there is information of relevance to preparing guidance within the references such as the use of pain scoring tools when comparing routes of administration; collection of data from lay and professional carers; importance of factors like convenience and care setting.

Age groups
Where the age of participants was defined in the paper, the data was coded into six categories shown in Table 3. There were 29 papers where the age of the participants was not included in the paper and 29 papers where adults only were studied. Five papers included information from parents or carers; one of which included preference for route of administration used for morphine for their baby from their perception of the effect on breast feeding.

Types of studies
Twenty reviews of the literature were found, including 4 systematic reviews. There were many clinical studies including randomised controlled trials where the aim was to compare the efficacy of the active drug by different routes of administration or injection device -acceptability or preference was determined by a variety of methods as a secondary objective. Inspection of the summaries shows the diversity of study types.

Focus of papers
When the papers are divided into study areas the main areas of focus are shown in Table 4. The majority of studies examined the acceptability of different devices used in the administration of drug products. Examination of the acceptability of or preference for different routes of administration was also frequently studied. Many of the selected papers concerned insulin or growth hormone and a comparison of different injection devices (pens) or were recording preferences for different routes of administration such as SC versus IV. Others concerned overall health care interventions such as OPAT and methods of achieving safe but convenient homecare, e.g., for rheumatoid arthritis, febrile neutropenia.

Conclusions
The literature review confirmed that there are few publications of direct relevance to determining what studies should be undertaken to describe the acceptability of individual injectable products for children. Regulatory guidance [1,16,26] and experience of the authors shows that information about injectable products relevant to acceptability is required in applications for marketing authorisation and that acceptability should be confirmed during clinical studies. Further work is required to gather information from pharmaceutical companies and to propose structures for pre-clinical and clinical studies to guide pharmaceutical development and product registration.

What is 'acceptability' in the context of an injectable medicine?
The EMA guideline on the pharmaceutical development of formulations for paediatric use [1] defines 'patient acceptability' as 'the overall In relation to pharmaceutical dosage forms, consideration of the attributes of the product and the way it is used and actual or potential effects on accepted standards of practice and harm to the patient. [24,25]   ability and willingness of the patient to use a medicinal product as intended and its care giver to administer the medicine as intended'. The guideline explains that 'the suitability of the chosen method to test the patient's acceptability and the appropriateness of the limits to be applied should be discussed and justified in terms of risk to benefit considerations, including risks at population level (e.g. emergence of microbiological resistance due to poor acceptability of different preparations with antibiotics). The characteristics of the target age group(s), the condition relevant to the paediatric medicine, single or multiple use, the duration of treatment and any comedication should also be considered'. The guideline frequently uses the terms 'acceptability, acceptance, suitability' and the requirement to discuss attributes of the pharmaceutical product in relation to them but does not attempt to quantify or to discuss methods for determining the acceptability of injectable products. In a recent Reflection Paper on the pharmaceutical development of medicines for use in the older population [16], patient acceptability is similarly defined as 'the ability and willingness of a patient to selfadminister, and also of any of his/her lay or professional caregivers, to administer a medicinal product as intended'. Much of the information in the reflection paper is also applicable to paediatric patients. It goes on to say that 'patient acceptability is likely to have a significant impact on patient adherence,

which can have an impact on the (perceived) patient and caregiver quality of life, institutional or hospital medication safety systems and/or the medicine's benefit-risk profile. Patient acceptability is mainly determined by the interplay of the multi-dimensional requirements of the medicinal product (design) and the characteristics of the patient and, where relevant, his/her caregiver (patient product interface)'.
Examples of product characteristics influencing patient acceptability are given which are generally applicable to the paediatric situation but again there is no focus on injectables. The reflection paper notes that 'adequate patient acceptability can be demonstrated by different means (e.g. using data from clinical trials, representative simulated use studies, human factor studies with healthy volunteers or patients, market experiences, literature)' and that 'selection of the method and acceptance criteria is left to the company.'.
These two EMA definitions of acceptability link the drug product characteristics and those of the patient and/or caregiver, indicating the multi-dimensional evaluation required and that this product-patient interaction is but part of an intervention to achieve health and wellbeing of the patient (and carer) and contributes to the acceptability of the overall intervention. Injectable drug products should be acceptable to the paediatric patient but should also be acceptable to the carer (professional or relative) since many injections will be administered by a carer rather than the patient.
Using the EMA guidelines and the Reflection Paper [1,16] and Kozarewicz's paper outlining regulatory perspectives on acceptability of dosage forms in children [26], Table 5 below outlines potential acceptability characteristics.

Interplay of product characteristics for patient and care givers
The characteristics of the injection dosage form such as pH and osmolality may have a direct bearing on patient acceptability if, for example, it irritates at the site of injection and causes pain. However, the technique of administrationfor example, by repeated direct venepuncture versus injection into an indwelling catheter -may not be within the control of the manufacturer yet the former injection technique is likely to be more painful than the latter. Equally, if pain on direct injection is predicted or observed the manufacturer may recommend dilution before administration or injection into a fast-flowing intravenous infusion or injection through a central venous catheter only and include this information in the SmPC and patient/carer information. Patient acceptability may be improved (as measured by pain on injection for example) but acceptability to the carer may decrease because of increased complexity and the benefit-risk profile may be decreased if central venous catheterisation is obligatory.
Many IV injections are not given by direct injection through a needle into a vein. When several injections are required over a period of time (which may be over minutes, hours, days or months) or infusion of injectable products is indicated, a short cannula into a peripheral vein, a longer catheter into a central vein or a subcutaneous reservoir linked to a central vein via a catheter can be used. If possible, the decision over which device will be used should be the focus of a discussion between the health care practitioner and the family or carer of the child. The injectable product is then administered into tubing or taps attached to the catheter or via special needles into the subcutaneous reservoir. Such administration techniques are commonly used in treatment of cystic fibrosis, in cancer care, for postoperative analgesia and for intravenous feeding but may be preferred for short courses of treatment in many children because of the preference over repeated direct venepuncture or IM injection [27,28]. Advantages and disadvantages of different approaches to reducing the need for direct venepuncture is beyond the scope of this article but further information is available [4]. Pharmaceutical developers should be aware of these techniques of intravenous administration and take steps to ensure that adequate product information is made available to enable safe and effective administration to the child, which is acceptable to the practitioner. Examples will include minimum and maximum concentrations, suitable carrier fluids, potential for interaction with administration apparatus, Table 5 Potential acceptability characteristics derived from paediatric guideline on pharmaceutical development of medicines [1], older people reflection paper [16] and Kozarewicz [26]. stability of diluted product, duration of injection or infusion, suitability of peripheral versus central venous administration and compatibility information where available.

Acceptability challenges and considerations
During formulation development the desired PK profile, biopharmaceutical considerations and/or physicochemical properties of the active drug may drive selection of one injectable route over another.
For the product developer there are challenges in paediatric formulation development such as avoidance of potentially toxic excipients [29] compounded by the lack of knowledge concerning acceptability and safety of medicines with respect to the age and developmental status of children.
Confirmation of the acceptability of a pharmaceutical product is a critical feature in the pharmaceutical development of all medicines. Acceptability needs to be evaluated in a manner that assures patient compliance in taking their medicine and will be a significant feature in developing concordance between patient, family carers and health care practitioners. Table 6 below outlines some of the main challenges and considerations related to paediatric injectable drug product development, including potential impact on product acceptability.

Acceptability assessment
In accordance with the guideline on pharmaceutical development of medicines for pediatric use, applicants must demonstrate to the regulator the acceptability of their new product in the targeted population [1]. In the context of injectable treatment, the drivers of acceptability are heterogeneous in terms of product and patient characteristics and of clinical practice. Local policies and practice may influence injection and administration technique (including direct SC or IM injection, venepuncture, IV or SC cannulation and use of indwelling catheters). For a new drug product relatively early in its clinical studies the criteria may relate to that specific product with standardized method of administration but later in the product life cycle, for those assessing the risk and benefit of health technologies, acceptability may be judged within broader health care interventions where other factors such as cost and quality of life are introduced, as well as acceptability compared to that of other products. Having an acceptable pharmaceutical product is an important contribution to the overall acceptability of health care interventions and hence on overall therapeutic outcomes.
Under these conditions, the selection of a harmonized set of judgment criteria to objectively measure acceptability will be challenging, particularly in the youngest populations. In addition, as acceptability is a multi-faceted concept and the analysis of the measures observed could be complex, the criteria should be analyzed in all these dimensions. Otherwise, the establishment of clearly defined algorithms would be required to manage cases where criteria, such as reduced pain or discomfort versus need for frequent hospitalization, might give opposite signals [23].

Conclusion
In addition to the challenges associated with the development of medicines for children there is a distinct lack of guidance or internationally agreed harmonized methodologies for determining the acceptability of injectable products. This brief review is intended to flag some of the issues in this area and to start a conversation on the development of such guidance.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence Table 6 Drug product development considerations related to acceptability of injectable drug delivery for paediatric patients.

Considerations
Impact on Product Acceptability

Product Design
Physicochemical properties of active the work reported in this paper.

Data availability
No data was used for the research described in the article.