Module 5: Acceptability

MODULE 5: ACCEPTABILITY

©WHO/Sergey Volkov

84 1. INTRODUCTION

In all disease areas, despite the availability of already authorized that are no longer covered effective molecules, formulations adapted for by patents. This includes over-the-counter children are still lacking and their development products for which safety and acceptability may falls behind that of formulations for adults. be problematic. With the incentive of additional Children are often either not treated or, based on data and marketing protection, the paediatric- anecdotal paediatric evidence, treated off label use marketing authorization aims at transforming or off licence with formulations for adults(1–5) . off-label use of drugs into safer and better circumscribed authorized use. Similarly, the Best During the past two decades, new legislation Pharmaceuticals for Children Act in the United and regulation-related guidance from the States provides incentives to encourage the United States Food and Drug Administration performance of studies involving children that (FDA) and the European Medicines Agency provide data on the effectiveness, safety and (EMA) are progressively changing this situation appropriateness of medicines already on the with the mandated concurrent development of market for same or expanded indications. formulations for adults and for children (6–11). Although determining the formulation type, Other countries have introduced policies to dose and intake frequency that provide adequate enhance the labelling of products for children drug exposure across all age or weight bands is (12): in Japan, by extending a product’s re- an essential component of developing drugs for examination period; in Canada, through a six- children, the acceptability of the formulation month extension of data protection providing itself also needs to be maximized, since it partly acceptability and efficacy data for children; and, conditions adherence and ultimately treatment in Switzerland, through the obligation to submit effectiveness and safety(14). paediatric plans and incentives for including data in the medicine label in accordance with The objective of this module is to discuss issues the agreed plans. India and China are becoming around formulation acceptability and to assist important pharmaceutical industry actors, and scientists and organizations confronted with their legislation is being revised to include specific the development of age-appropriate medicines provisions for developing drugs for children. for children. The module focuses on product development strategies for oral dosage forms Pharmaceutical companies are now required to – solid and liquid – although other forms, consider very early in a new drug’s development such as long-acting injectables or inhalants, the specific needs of children(13) in terms of may play an increasing role in therapy for therapeutic indication and the appropriateness children. Importantly, although the theme of of the envisioned drug formulations for the this initiative is developing better antiretroviral relevant target populations. (ARV) formulations for children living with In parallel with regulations mandating the HIV, the scope of the discussion extends to development of formulations for children for new other therapeutic fields, such as antibiotics and or innovative medicines, the EMA paediatric- antituberculosis drugs, medicines for diseases of use marketing authorization is a dedicated the blood and blood-forming organs and cancer marketing authorization covering indications and and malaria therapy, where acceptability may be appropriate formulations for medicines that are key, as well as medications for chronic conditions. developed exclusively for children, for products

85 2. BACKGROUND

The EMA defines acceptability as “the overall In commentary on the EMA guidelines (11), Piotr ability and willingness of the patient to use Kosarevitz (22) states: and its caregiver to administer the medicine As a general rule, acceptability aspects should be as intended” (11). The word “medicine” refers embedded in the development programme and here to the therapeutic entity as it is to be evaluated, (preferably) during the clinical study delivered to the end user. This includes the type (preferably) with patients from all target age of dosage form, its formulation: composition group(s). …The choice of the acceptability testing and appearance (tablet size, shape and colour), method and acceptance criteria (to determine the dose of its specific active substance, dosing whether the medicine dosage form is considered acceptable or not), should be described and justified, frequency, packaging, medical device, dosing taking into account the characteristics of the target devices, container closure system together with age group, the condition relevant to the medicine, written user’s instructions (product label and incidental and multiple use, co-medication and package leaflet)(15) differences between countries

Acceptability, in this context, is essentially a In compliance with regulators’ requirements, characteristic of the product and of how it is pharmaceutical companies must submit their delivered. Acceptability may significantly affect initial paediatric investigation plans (for the EMA) adherence – behaviour rather than a characteristic or paediatric study plans (for the FDA) early of the patient or caregiver – and may secondarily in the drug development process. Paediatric affect efficacy and safety. However, the precise investigation plans are submitted slightly earlier contribution of acceptability to adherence is than paediatric study plans, and both need to difficult to establish(16,17) . However, from an be agreed on with regulators before approval of ethical viewpoint that considers the inherent products for adults. Plans describe and justify vulnerability of children and adolescents, the age appropriateness of the formulations acceptability needs to be maximized regardless envisioned for the relevant children (and justify of how it affects clinical outcomes. waivers for specific groups of children).

Clinical appropriateness is a somewhat broader Although they may be modified during drug concept than acceptability, referring to the development, paediatric investigation plans (and medicine characteristics that determine whether, paediatric study plans) should provide sufficient in their personal environment and life situation, data to enable the assessment of the medicinal children and/or their caregivers can use the product quality (including acceptability), safety medicine as intended. For example, the need for and efficacy in children and thus its benefit–risk refrigeration is a major economic and practical profile for children (23). obstacle to the use of some liquid formulations in Moreover, if formulations already exist for tropical climates. Appropriateness for children is the subsets of the children in question, their discussed in detail in several reflection papers by suitability should be discussed. WHO, the EMA and the International Conference on Harmonisation of Technical Requirements for In its published scientific document template Registration of Pharmaceuticals for Human Use for a paediatric investigation plan application, (10,18–20). The FDA and the EMA (11,18) have also the EMA specifies further its expectations for issued various recommendations on designing formulations adapted for children. age-appropriate medicines for children (21).

86 The section of the paediatric investigation (15), which tend to replace liquid dosage forms: plans and paediatric study plans on developing syrups, solutions, emulsions and suspensions formulations for children should address critical (Table 5.1) (26). issues, such as: To achieve the targeted drug exposure, ■■ the need for a specific formulation, more than one dosage form and/or strength pharmaceutical form, strength or route of may be needed to cover the range of ages and administration in relation to the chosen weight bands as children grow and mature. subsets or age groups of children and Alternative administration strategies with the benefit of the chosen formulation, flexible formulations may be considered for pharmaceutical form, strength or route of children who cannot be accommodated by a administration; specific dosage form: such as segmenting or ■■ potential issues related to excipients and crushing tablets, co-administration with food children’s (anticipated) exposure levels; or liquids or multi-use formulations such as

■■ the administration of the medicine to subsets dispersible chewable tablets (11). of children, including acceptability, use of Although children and caregivers have an specific administration devices, ability to mix opinion about what are the most desirable with food and possible use with a nasogastric types of formulations, preference does not tube; and equal acceptability (27). For older children ■■ the precision of dose delivery and/or dose and adolescents, for example, lifestyle and accuracy for any pharmaceutical form for the peer pressure greatly influence medication anticipated dose for children and indicated preferences. age range.

If, based on scientific justifications, a formulation or pharmaceutical form relevant and acceptable for children cannot be developed on an industrial scale, the applicant should state how it intends to facilitate the industry-verified or extemporaneous preparation of an individual ready-for-use formulation for children.

Despite little empirical evidence, it is generally accepted that the availability of better age- adapted formulations would reduce the risk of medication and dosing errors and increase the overall safety and effectiveness of treatment (14). Although they may still play an important role in the drug development approaches, traditional liquid formulations present important limitations in terms of stability, palatability and costs. For children, the development of liquids has shifted to solid formulations in the past two decades (24,25). Children and caregivers prefer solid oral dosage forms, including tablets, capsules, mini-tablets or pellets and chewable, dispersible and multi-particulate dosage forms

87 Table 5.1. Advantages and disadvantages of various oral formulations for children

Development and Oral dosage forms Dose flexibility Dose preparation Ease of ingestion Tolerability and safety Risk of incorrect dosing Stability – shelf life in use Supply chain Relative cost manufacturing complexity Syrup, solution, High (with limits Need for measuring Easy to swallow; palatability and May require buffers, co-solvents, Incorrect use of Less stable than solids; Simple development, routine Bulky and heavy for Low drops for drops) device volume are possible issues flavours, sweeteners; multidose measuring device microbiological contamination in manufacturing and packaging transport and storage; containers may need preservatives use; compatibility with primary may need refrigeration packaging Emulsion High Requires measuring Easy to swallow; palatability and May require flavours, sweeteners; Incorrect use of Less stable than solids; Development can be complex; Bulky and heavy for Medium to high device and shaking for volume are possible issues multidose containers require measuring device; microbiological contamination; routine manufacturing and transport and storage; homogeneity preservatives and surfactants shaking for homogeneity thermodynamic instability packaging may need refrigeration and dose uniformity Suspension High Requires measuring Easy to swallow, uncertain Multidose containers require Incorrect use of Less stable than solids; Development can be complex; Bulky and heavy for Medium device and shaking for palatability, consider volume, preservatives and may require measuring device; microbiological contamination; routine manufacturing and transport and storage; homogeneity gritty sensation possible buffers, surfactants, flavours or shaking for homogeneity physical instability packaging may need refrigeration sweeteners and dose uniformity Effervescent or Low Suitable volume Easy to swallow; palatability and May require flavours, sweeteners; Need to absorb full Moisture sensitivity; solution or Simple development; routine Easier transport and Low to medium dispersible tablet and quality of water volume are possible issues consider sodium, potassium and dispersion volume dispersion of limited stability manufacturing and packaging; storage for dissolution and bicarbonate content and residue low-humidity conditions and dispersion modified tooling Multi-particulates, Medium to high Appropriate use of Easy to swallow; from birth on if Risk of aspiration or choking Risk of incorrect dosing Good stability; compatibility with Complexity depends on Easier transport and Low to medium granules, powders measuring device or dispersed in liquid, from six months when not dispersed for products requiring food or beverage vehicle to be technology; routine packaging storage packaging; may need on with semi-solid food; dose, dose measurement; verified with standard equipment; can food or liquid vehicle volume, texture and palatability incomplete dosing if serve as intermediate for other require consideration the food or beverage dosage forms vehicle is incompletely consumed; reconstitution errors for powder for suspensions Tablets Low No preparation Difficult to swallow for younger Risk of aspiration or choking; Low risk of incorrect Good stability Not complex; routine packaging Easier transport and Low children, depending on size and ability to swallow limited for dosing, except if tablet with standard equipment storage shape; limited organoleptic issues younger children; lack of data on manipulated age versus suitable size Hard gelatin Low May need preparation Difficult to swallow for younger Risk of aspiration or choking; Low risk of incorrect Good stability Non-complex development Easier transport and Low capsules if administered with children, depending on size; risk of gelatin shell sticking to dosing and incorrect use process; routine manufacturing storage food or liquid limited organoleptic issues gastrointestinal mucosa; gelatin and packaging process may not be acceptable in some cultures – alternatives exist Soft gelatin capsules Low No preparation Difficult to swallow for younger Like hard gelatin capsules; Low risk of incorrect Potentially less stable than Requires specialist development Easier transport and High children, depending on size; potential risk of chewing dosing and incorrect use tablets; may be sensitive to high and manufacturing processes; storage; may be sensitive limited organoleptic issues temperature and humidity routine packaging with standard to high temperatures equipment and humidity Mini-tablets Medium Multiple mini-tabs Easier to swallow than Risk of aspiration or choking, Risk of incorrect dosing Good stability Non-complex development Easier transport and Low (1–4 mm) may require counting; conventional tablets; limited especially for children younger if multiple mini-tablets process; routine manufacturing storage device or packaging – organoleptic issues than two years if coated required per dose and packaging process; content manual dexterity uniformity a challenge Oro-dispersible Low No preparation; water Easier to swallow than Risk of aspiration or choking; may Low risk of incorrect Good stability; may require Complexity depends on Easier transport and Low to high tablet or melt not necessary conventional tablets; taste require flavouring or sweeteners dosing and incorrect use moisture protective packaging technology; routine packaging storage and grittiness are the main with standard equipment; considerations or specialist process and equipment (lyophilizates) Chewable Low No preparation Should be chewed and not Risk of aspiration or choking; may Low risk of incorrect Good stability; may require Complexity depends on Easier transport and Low to medium dosage forms swallowed; palatability may be require flavouring or sweeteners; dosing and incorrect use moisture protective packaging technology; routine packaging storage an issue risk of intestinal obstruction if with standard equipment; swallowed whole or specialist process and equipment (deposited formulations and softgels) Oral films Low No preparation, Easy to swallow May require plasticizers, flavours or Low risk of incorrect Good stability; requires Requires specialist Easier transport and Medium to high (dispersible) water not necessary – sweeteners dosing moisture-protective packaging development, manufacturing storage manual dexterity and packaging processes

Source: reprinted from Int J Pharm., 536, Walsh J, Ranmal SR, Ernest TB, Liu F, Patient acceptability, safety and access: a balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations, 547–62, Copyright (2018), with permission from Elsevier. (26)

88 Table 5.1. Advantages and disadvantages of various oral formulations for children

89 3. CHALLENGES

There are multiple challenges in developing How acceptability is understood and defined better acceptable formulations for children. obviously depends on the question asked. Here Most obvious is the lack of consensus around the essential question is to determine whether what acceptability means and consequently a formulation proposed for registration is the lack of guidance from regulators on how acceptable for the relevant target populations it should be evaluated. Another difficulty of children: can the claim for age-appropriate arises from the fact that acceptability is only medicines for children be effectively one attribute of formulations appropriate substantiated? However, published studies show for children. Other considerations include extreme variation in how acceptability is defined stability, absorption, disease, safety and cost. and assessed. Formulations for children are often considered late in development, when efficacy and safety In the most recent reviews examining various for adults begins to be known and when stability aspects of acceptability of pharmaceutical and pharmacokinetic data have already started dosage forms, the multiplicity of keywords used to be accumulated. Another difficulty is that to identify relevant literature confirms this acceptability is not an inherent property of variation and confusion around the concept the product; it is also defined by the end- of acceptability. Published literature searches users: the children and their caregivers. Finally, most often include such words as acceptance, standardized methods and quality assurance adherence, tolerability, satisfaction, preference, are lacking for assessing the acceptability of palatability, taste and swallowability (28). formulations ranging from solid oral dosage Because paediatric investigation plans and forms such as tablets, capsules, mini-tablets paediatric study plans must be submitted at and pellets, to chewable, dispersible, multi- the very beginning of clinical development of particulate dosage forms and liquid dosage the medication (for adults: Phase I in Europe forms such as syrups, solutions, emulsions and and Phase II in the United States), at the time suspensions. The following sections describe of these first trials, the real constraints of the these difficulties in greater depth and explore formulations for children are not yet known. what solutions can be found. Pharmaceutical companies may therefore not want to or be able to describe the envisioned dosage form for children in a detailed manner. 3.1 Lack of guidance from regulators and varying definitions of acceptability Following the submission of the paediatric investigation plans and paediatric study plans, European and United States regulators require regulators may request clarification about the that pharmaceutical companies describe and target group or the choice of formulation. justify in their development plans the choice Although interactions between regulatory of their formulations for all target populations agencies and pharmaceutical companies and require that they document and report the are not public, a review by the EMA of the acceptability of their formulations, but they paediatric investigation plans submitted to the offer little guidance on what studies should be Paediatric Committee during the first years of performed and reported to comply with this implementation of the paediatric regulations requirement. indicated that in 82% of the cases, the excipients were questioned (their justification, dosage

90 and the possibility of avoiding them through 3.2 Dosage forms for children are a alternative formulations); in half the cases, necessary compromise between stability, testing for palatability and acceptability was absorption, disease, safety, cost and discussed; and in 23% of cases, formulations and acceptability practical issues related to manipulations or small volumes were considered problematic (13). The ideal formulation should have flexible dosage In another review covering 2007– 2011 (29), increments and minimal excipients, be palatable, 150 paediatric investigation plans were examined safe and easy to administer and be stable with (16 therapeutic areas and 220 oral dosage forms regard to light, humidity and heat (Fig. 5.1) (32). in 431 strengths and compositions). One third However, as stated by Walsh et al. (26), “a single of the paediatric investigation plans involved ideal dosage form does not exist”. tablets, 20% liquids and 16% dosage forms stored as a solid but swallowed as a liquid, such as The development of age-appropriate medicines dispersible tablets. According to this report, the for children is constrained (33) by the Paediatric Committee review and interactions characteristics of the target population of children with pharmaceutical companies resulted in an (age group) and by the characteristics of the increase in the number of oral dosage forms molecules (solubility, stability and taste), their age- or a modification of their specific composition and development-dependent pharmacokinetic or strength. For many paediatric investigation profiles (absorption, distribution, metabolism plans, the target age range was widened and and excretion), their pharmacodynamic profiles the excipient composition and usability aspects (therapeutic window, mode of action and modified(30,31) . toxicity), the disease and the disease stage

Fig. 5.1. Medicine formulations: a compromise between stability, absorption, disease characteristics, safety and cost

Definition of acceptability, Patients and disease Product formulation data collection and outcome ■■ Age ■■ Molecules: solubility, criteria ■■ Inherent ability stability, taste ■■ Clinical trials: from dose ■ ■■ Prior experience ■ Excipients finding studies to post- ■■ Developmental marketing ■■ Disease type and state pharmacokinetic profile ■■ Sociocultural context of use ■■ Human factor studies –absorption, distribution, ■■ Direct observation of metabolism and excretion children Acceptability dimensions ■■ Pharmacodynamics ■■ Questionnaires and diary ■■ Palatability ■■ Intellectual property entries for children and ■■ Swallowability landscape caregivers ■■ ■■ Dose size and volume and flexibility Manufacturing complexity ■■ ■■ Ease of use, manipulations and device Product shelf life and storage conditions ■■ Impact on lifestyle and dosing frequency ■■ Market size and supply chain ■■ Aspects of packaging ■■ Cost ■■ Transport and storage conditions

91 (forgiveness and acute versus chronic condition), the paediatric investigation plan or paediatric the circumstances of use (clinic, home, nursery, study plan is submitted, and it is only when the school or other), the intellectual property first formulation prototype is available that landscape, the manufacturing and packaging acceptability can be truly evaluated in the target complexity, the product shelf life and storage population and the formulation possibly modified. conditions, the market size and the supply chain The prototype formulation can be intermediate and cost, which ultimately determines access. of the intended final formulation for children or derived from the existing formulation for The characteristics of the final product adults. Using such a prototype often requires therefore represent a compromise between performing a bioavailability study to ensure that multiple constraints (Fig. 5.1). When suboptimal it leads to the same active ingredient exposure formulations are finally obtained, mitigation as the final commercial formulation (unless a strategies can be developed to minimize the biowaiver is granted based on the solubility and impact on acceptability. Risk-based strategic permeability properties of the active ingredient). approaches to innovation could guide the Produced under good manufacturing practice selection of formulations (27,34), but within this standards that ensure reproducible bioavailability, process, acceptability has often been considered it can later be bridged to the final commercial an adjustment variable resulting in pharmaceutical preparation (38,39). products that remain poorly adapted to children.

3.5 Standardized methods and quality 3.3 The influence of the user and the assurance for assessing acceptability medicinal product cannot be studied are lacking separately After almost 10 years of implementation of the The characteristics of the user and those of the paediatric regulations, both in the United States medicinal product drive acceptability (35,36). and in Europe, many experts have investigated Although distinguishing what relates to the user how the acceptability of formulations for children and what relates to the dosage form is useful, is assessed and reported. All reviews stressed the they cannot be disentangled since acceptability lack of standardized methods for assessment and is precisely what links formulation characteristics of quality assurance (13,14,28,36,40–45). with specific target groups. In the studies that are published, the domains of acceptability explored vary considerably, 3.4 Acceptability studies are often carried with palatability being, by far, the most common out late attribute measured. Little to no information is provided about how data capture tools are Although the development of formulations developed and validated or the precautions taken for children can still continue after products to avoid interviewer bias. Hypotheses tested and for adults have been registered along a criteria for acceptability are rarely clearly stated. timeline based on agreed commitment to the Research reports hardly ever define what EMA and FDA, and acceptability questions is considered “acceptable”. Although the can be addressed during the whole duration acceptability threshold used in veterinary of development, in practice the window of research (44) is relatively unambiguous, no such opportunity during which acceptability can be criteria are available for humans. Percentages assessed and the formulation modified is short or scores based on ad hoc summarized or (37). As explained above, the characteristics regrouped direct or proxy measurements of of the product only begin to be known when

92 acceptability reported in published studies However, the more potent option for newborn cannot be readily interpreted. infants, lopinavir/ritonavir solution, was a heat- unstable, foul-tasting solution with 45% alcohol However, most of the acceptability studies for and 17% propylene glycol. It was only in 2015 that a product registration have not been published. better adapted multi-particulate lopinavir/ritonavir In a review of the studies involving children listed solid-pellet formulation received regulatory in the clinicaltrials.gov database in preparation approval. Nevertheless, this formulation cannot be for a symposium, Pinto & Selen (46) note that the given safely to newborns, is difficult to administer results of palatability and swallowability studies by caregivers and is poorly accepted by children are simply not communicated. Of 7259 studies because of its remaining bitter taste. listed, 874 provide study results, but none on swallowability and only two on palatability (46). In a report of the M-CERSI paediatric formulation development workshop in 2016 Published articles report few aspects of through the University of Maryland’s Center of acceptability, with limited evaluation of Excellence in Regulatory Science and Innovation, acceptability dimensions, limited categories Robert Ternik and colleagues have compiled the of information providers and large variation in various approaches used to assess and document assessment approaches and tools (42). palatability and swallowability (34). As explained above, as a result of the incentives and mandatory requirements from stringent Palatability regulatory agencies, the development of drugs for children is systematically initiated in parallel Many approaches have been used to assess to the development of drugs for adults, and more palatability in children (47–49). formulations for children will become available, With the rank order or preferential method, although their acceptability does not or perhaps the subject is asked to place products in order cannot take precedence over other key attributes of preference or choose the one they prefer. such as efficacy, pharmacokinetics or stability. Evaluation is brief and does not involve sustained ARV medicines clearly exemplify this situation. attention and is therefore suitable for young The first anti-HIV molecules marketed in the children. early 1990s had severe toxicity and limited With the facial action coding system, children efficacy and formulations for children comprised are exposed to stimuli and the facial expressions at best liquid forms that were difficult to procure, are videotaped; however, this approach is time store and administer. In many low- and middle- consuming and costly (50). income countries where the HIV epidemic was most severe, the only way to keep children with With scaling methods, subjects older than five HIV alive was to treat them with a mix of syrups years are presented samples and asked to select and solutions and fractions of adult tablets. the likeness of sensation on a scale (51,52).

The first palatable, easy-to-take fixed-dose Scaling methods include: combination became available in 2007. Triomune ■■ facial hedonic scales: these are a scale from 2 Baby® (6 mg stavudine + 30 mg lamivudine + to 10 with pictorial descriptors (43) that can 50 mg nevirapine) and Triomune Junior® (double be used with children as young as three years these concentrations) were the first fixed-dose old, but cognitive maturity may influence the combinations licensed for children younger than results (52,53); 12 years. They were scored so that they could ■■ visual analogue scale: a scale from 10 to 100 easily be broken in half, allowing use within a points on a horizontal 10-cm line, anchored simple weight-band dosing table. with word descriptors at each end (43,52)

93 ■■ Likert scale: it assigns 5–11 points to verbal understand the information in the packaging and descriptors, ranging from “extremely weak” labelling. Formative studies may be conducted to “extremely strong”; and during the iterative product development process

■■ labelled magnitude scale (54), a hybrid scale to assess user interaction with the product and with verbal descriptors on a quasi-logarithmic identify potential difficulties or errors in use. They vertical scale, suitable for describing the taste are followed by human factor (simulated or actual- intensity of highly divergent samples because use) validation studies to demonstrate that the of its broad scaling (54) intended users can use the final product without serious errors or problems under the expected Finally, with verbal response (descriptive use conditions. In situations when understanding methods), children are asked to rate preference the information provided in the labelling of a using verbal descriptors such as “no taste” combination product is critical to using a product to “very strong taste”. This method is more safely and effectively, a study to assess the user’s discriminating than scaling methods (34) but is understanding of such information is appropriate. not suitable for younger children who cannot Knowledge task studies may be carried out as visualize and accurately use the descriptors. part of the formative or validation process. Use- related risk analysis helps to identify the critical Swallowability tasks to be evaluated in a human factor study, inform the priority for testing the tasks and Palatability is subjective, but swallowability is determine whether specific use scenarios should more objective since it describes an ability be included in testing. The analysis should consider of children rather than an appreciation. Most all the intended uses, users and use environments; studies used direct observation, investigating therapeutic or diagnostic procedures associated children’s mouths after administration. Few with the use of the product; similar products studies used questionnaires or diary entries used within the environments; and any associated to provide parents’ reports of the outcomes medical factors that may affect the safe and of swallowing or whether or not a problem in appropriate use of the product. swallowing the product occurred (28,29,55,56. The difficulty lies in defining the outcome: There is considerable need for developing “everything swallowed”, “smooth swallowing”, an operational and pragmatic definition of “swallowing with a choking reflex or cough” and swallowability and palatability and for establishing “biting or chewing followed by swallowing” (34). a simple, standardized method for evaluating For palatability, children’s cooperation highly all dimensions of acceptability, swallowability, influences the assessment. palatability and ease of use. Researchers in the field stress the need to bridge in vitro and in Ease of use vivo data and to develop new technologies for assessing palatability and caution about using adult Ease of use is a third major component of the panels to predict palatability among children. acceptability of a medicine. Human factor studies are designed to evaluate the user interface of a Alignment between stakeholders in defining product (57). Drug development should consider acceptability, assessment methods and criteria the user interface and factors that can reduce would clearly foster much better understanding the risk of medication errors. Since children are of the relationships between acceptability, often dependent on a caregiver for preparing swallowability and adherence to therapy. This and taking the drug, such studies may not involve relationship is essential to understand risks and young children. Human factor studies are typically develop appropriate mitigation strategies to conducted with representative users to evaluate achieving the desired therapeutic outcome. the ability of the user to perform critical tasks to

94 4. SOLUTIONS

This section outlines some potential solutions for Opportunities for scientific advice from the addressing the challenges described. FDA are similar. Most importantly, a parallel mechanism has been put in place for EMA and FDA reviewers to concurrently exchange 4.1 Seek advice from regulators as early with pharmaceutical companies their views on as possible in the process of developing scientific issues during the development phase formulations of new medicinal products. This increases the dialogue between agencies and pharmaceutical Building the much-needed consensus between companies from the beginning of the life cycle of regulators and the pharmaceutical industry a new product, provides a deeper understanding around what is meant by age-appropriate of the basis of regulatory decisions, optimizes medicines for children, what acceptability is product development and avoids unnecessary and how acceptability should be assessed and testing replication or unnecessary diverse testing reported will likely take considerable time. methods. Parallel EMA and FDA advice can be Nevertheless, before and during a marketing obtained at the request of the developer. authorization procedure for a medicinal product, pharmaceutical companies have various 4.2 Clearly define the characteristics of opportunities to discuss critical issues in the drug development process with regulators. users and products

Part of this dialogue is scientific advice, an As explained above, the final formulation opportunity for (early) communication between is necessarily a compromise between the a company and a regulatory authority (the EMA constraints of the molecules and the specific and/or national competent authorities) on quality needs of children. Although at the planning and both clinical and nonclinical aspects of drug stage of developing formulations for children, development, such as study design, choice of when early clinical studies involving adults have endpoint and indication (see http://www.ema. just been completed, little is known of what europa.eu/ema: Scientific advice and protocol these constraints are. Carefully considering assistance). the characteristics of the target populations of The EMA scientific advice is open to children and caregivers in their environment as pharmaceutical companies, academia and other well as those of the medicinal product is very parties developing medicines and is free of important when establishing the target product charge for questions related to children. The profile (59). number of companies requesting scientific The following characteristics of the user should advice related to medicines for children has be considered: increased every year. In 2007, only 7.6% of ■■ age: relative arbitrary characteristic of scientific advice was related to children versus the classically defined age groups given 24.4% in 2016. Companies conducting clinical the variability and non-linearity of body development in accordance with scientific composition and physiological maturation; advice recommendations are more likely to be granted marketing authorization (58). ■■ inherent ability: neurocognitive development and dependence on the caregiver;

95 ■■ previous experience of the child with the ■■ the actual mode of administration that reflects formulation, ability to learn how to take a understanding user instructions and the given product (60) specifically, immunologic feasibility of following them and the device– functioning (CD4+ T-cell%and/or the ability of user interface, such as dial, touch screen, the caregiver to prepare the product or use a indicators, operating instructions, packaging device (short- versus long-term acceptability); etc.; and

■■ disease type and state: acute versus chronic, ■■ associated adverse reactions, tolerability and disease type and state that may affect the risk of misdosing. ability to take the product; need for multiple active pharmaceutical ingredients or co- treatments, such as for HIV, tuberculosis (TB) 4.3 Consider all acceptability attributes or malaria therapy and previous knowledge of simultaneously and study them the dosage form; and systematically ■■ the sociocultural context of medicine use (40,61). All the elements of acceptability should be systematically explored among children of the The following characteristics of a medicinal relevant age groups and appropriately reported. product should be considered: This applies to questions of taste, smell and ■■ palatability: the most frequently measured texture but also the swallowability of less attribute of acceptability; traditional solid forms, such as pellets of different ■■ appearance: for example, colour, shape, sizes with or without coating, granules and mini- embossing etc.; tablets (dispersible or not). ■■ swallowability: size, shape and integrity of the In terms of palatability, it is important to dosage form, such as film coating; determine to what extent the results obtained in ■■ the complexity of modification before the laboratory (such as electronic taste sensing administration if required: determining the systems and cell models), in animal models and dose, weight band width and frequency through adult taste panels or evaluations by of dose adjustment; over time, shift of healthy adult volunteers can be extrapolated to responsibility from caregiver to children; children (17). ■■ fixed-dose combinations; It is also necessary to determine whether ■■ the required dose: for example, the dosing the results of acceptability studies among volume, number of tablets, break marks etc.; children can be extrapolated to children in different age groups, or for different types of ■■ the need for a vehicle: soft food or liquid, diseases, considering the volume of liquid to culturally and financially determined; be administered or the size of multi-particulate ■■ the required dosing frequency and duration of granules, for example (42). The research carried treatment; out in recent years around the acceptability ■■ the selected administration device (62), if any; of mini-tablets or pellets is an example of this approach (63–70). ■■ the primary and secondary container closure system; weight and bulkiness; need Box 5.1 lists acceptability domains, providers of for refrigeration and physical, chemical information and data capture tools, with selected and microbial stability; specific storage articles and reports to which the reader can refer. requirements;

96 4.4 Plan acceptability studies as early Box 5.1. Acceptability domains, providers of information and data capture tools as possible

What aspects and dimensions of At the earliest conception of the strategy for acceptability are measured? developing formulations for children, all the dimensions of acceptability listed above must ■■ Taste, swallowability, other (34,71–74) be considered. The need for data to inform ■■ Ease of use, need for device or for vehicle the biopharmaceutical risk assessment should (62,75–79) be identified early so its collection can be ■■ Accuracy of the dose administered and synchronized with the programme for developing completeness of dose intake (5,80) formulations for adults. For example, these may include evaluating potential taste issues using Who is providing the information on animal models and trained adult taste panels. acceptability? When the adult dosage is being developed, ■■ Health-care professionals (80,81) an exploratory formulation is usually used for the Phase I and IIa studies. Based on these, ■■ Educated panels of adult testers or evaluators (82) a commercial formulation for adults may be developed. The development of a formulation ■■ Caregivers: observational versus proxy for children starts much later (Fig. 5.2). When measures (27,61,83,84) the paediatric investigation plan is submitted to ■■ Children: issue of outcomes reported regulators, the formulation for children can only by children (85) be broadly described based on the exploratory formulation for adults used at the time. What tools are used to capture and report Acceptability for children can first be assessed acceptability? during the initial dose-finding or population pharmacokinetic studies. All components of ■■ Hedonic scales, Likert scales or visual- acceptability in the target populations must analogue scales: the complexity must be be evaluated to minimize the risk of delays in age appropriate (41,53,86–89) developing the final commercial formulation ■■ Direct observation or recorded reaction: for children. closing mouth, pushing the product or vehicle away, crying or spitting out; refusal Acceptability in the target populations can thus to take the medicine; inability to swallow be directly assessed and documented early when (41,85) the formulation is being developed at the time of the initial dose-finding pharmacokinetic studies ■■ Time taken by the nurse or caregiver to involving children. Using prototype formulations administer the medicine may limit the delays incurred if the formulation ■■ Other tools, such as electronic tongue, design needs to be modified based on the animal models, etc. evaluation of acceptability.

Acceptability can still be further assessed in Adherence and effectiveness as indicators pre-registration or in post-marketing studies, but of acceptability (60,81,89,90) this would likely be too late to effectively inform the development of formulations for children. The data generated may only lead to modifying the product labelling or to amending the dosing instructions.

97 Fig. 5.2. Evaluating all aspects of acceptability in the first pharmacokinetic studies involving children

Developing formulations for adults

Preclinical Phase 1 Phase IIa Phase IIb Phase III Registration

Exploratory formulation for adults Commercial formulation for adults

Commercial formulation for children

Preclinical Pharmacokinetics Phase II Phase III Registration

Developing formulations for children

4.5 Capitalize on existing scientific 4.6 Harvest what is already available networks Regulators, in collaboration with both the If several hundred paediatric investigation plans innovator and generic pharmaceutical companies, or paediatric study plans have been submitted, should work to identify opportunities to share it is only now that they start to result in key lessons learned and best practices based registered products. It is therefore too early to on their interactions. The types of information draw the lessons learned from the first decade most valuable to developers should be reviewed of implementation of the regulation of the and discussed, with agreement on the types of development of formulations for children. Issues information that could be shared without disclosing of stability, bioavailability and dose determination the confidential proprietary data. Routinely making and the safety of excipients have largely this information available to companies throughout dominated the scene and taken precedence over the course of developing a paediatric investigation the question of acceptability. Nevertheless, the plan or paediatric study plan would facilitate the regulation of the development of formulations efficient development of a formulation for children. for children has set in motion considerable The publication of best practices for evaluating interest and debate around acceptability, acceptability by regulators would be helpful in as shown by the work of scientific networks planning and implementing the development of regrouping academics and formulation scientists tailored formulations. The publication of best such as the European Paediatric Formulations practices has been applied for Phase I studies, Initiative and the IQ Consortium Drug Product population pharmacology, efficacy and safety, Pediatric Working Group. All stakeholders agree extrapolation of data collected for adults and on the need to systematically incorporate post-registration studies. Similar to the above, acceptability considerations within drug if alignment can be reached on what constitutes development without delaying the availability of precompetitive sharing of best practices, this therapies for children. would greatly facilitate formulation assessments.

98 Although regulators should require that involving children, in pharmacological studies the essential elements that constitute the to determine the dose that ensures optimal acceptability of a product in the various target exposure across all age and weight bands and in groups be evaluated clinically in children, the the subsequent efficacy and safety studies. These pharmaceutical industry should re-evaluate their evaluations are essential to better understand the publication strategies with respect to the clinical longer-term acceptability of the drugs developed results related to assessing the acceptability as well as the impact of acceptability on of drug products and devices in these trials. A adherence and the outcomes of major interest: strategy that mirrors the publication of clinical effectiveness and safety (15,91). safety and efficacy endpoints could serve this purpose (25). This will progress biopharmaceutical Children and their caregivers must be involved science and minimize registration delays. as early as possible in developing the medicines that are safe and designed for them. The Regulatory agencies provide the opportunity participation of children and caregivers in clinical for free scientific advice; pharmaceutical trials can contribute in a meaningful way. In many companies are therefore strongly advised to instances, the lack of children to participate consult with regulators periodically or as needed in trials can slow recruitment and hinder the to ensure strategic and technical alignment. This completion of clinical studies. This reality is a is especially true for the generic pharmaceutical meaningful obstacle to developing products for industry, since it is playing an increasingly children. This same reality makes it even more important role in providing medicines for important that drug product and formulation children. The creation of fixed-dose combinations elements are considered from the earliest stages of several molecules poses problems that of developing formulations for children to avoid transcend the already complex issues of stability, changes late in development that further slow compatibility and bioequivalence. Scientific the registration of medicines for children. advice and early interactions with regulators can help to minimize biopharmaceutical risks and speed up product registration. 4.8 Broaden acceptability studies to include cultural elements and involve social scientists 4.7 Start to collect data systematically Not only children and their parents, but Without unnecessarily increasing the complexity families and the broader community, health and duration of developing formulations for professionals, public health stakeholders and civil children, all the components of acceptability society organizations should be more involved should be evaluated among the relevant users in studying the acceptability of formulations for all paediatric subsets of interest. This requires (see the module on community engagement). that the team in charge of interacting with Geographical and cultural environment should the regulators, the scientists responsible for be considered, especially in countries in developing formulations and the clinical teams which patients have limited access to health within a company work in close collaboration care (15,40). Parents are often not frontline from the onset of the programme for developing caregivers, either because they have health formulations for children. problems themselves or because they are absent. Paediatricians and paediatric research networks The extended family of brothers and sisters or should systematically include in research grandparents are in turn responsible for ensuring protocols a module for assessing the acceptability that children receive the medications they need. of formulations for children in any clinical trial The conditions for delivering and storing drugs and the availability of foods and vehicle types

99 vary considerably from place to place. The design multi-dose studies) and their standardization, the of formulations, packaging and instructions evaluation of the reliability and reproducibility to users must take these circumstances into of the results and the analysis of the data. The account (57,92). tools for collecting acceptability data need to be validated according to age groups, the greater or Social scientists must be involved in this research lesser involvement of parents or guardians and the to better understand the use of drugs in the economic and cultural context in which children economic, geographical and cultural context of live. The methods, strengths and limitations of their use. This goes beyond the supposed but very patient-reported outcome studies that collect data poorly documented variation in taste preferences to support claims in medical product labels need to across cultures. For example, the ability of be assessed. Standardized methods would enable parents or caregivers and children to use a drug comparisons across studies and define which depends in part on the community’s perception products are better accepted in which populations. of the disease in question and the expected role of the therapy and of the health-care system Standardized, universal, objective, simple metrics that makes it available (90). The stigmatization must be developed and validated to evaluate of HIV infection has raised public awareness of the acceptability of existing formulations for these issues, but the same considerations apply to children and optimize that of formulations under managing other diseases, whether TB, malaria or development. This research must necessarily chronic diseases among children. involve the concerned populations, researchers and regulators. Multicomponent referential models to assess acceptability are currently being 4.9 Encourage methodological and evaluated (mapping and clustering models) (80). translational research This research must also be translated to enrich decision-making models that would allow, at the Academia and formulation scientists must planning stage of the development of formulations undertake more primary fundamental and for children, the best options for dose forms for translational research, with the support children to be determined with the best degree of government organizations such as the of reliability. These models should accelerate the United States National Institutes of Health or development of appropriate formulations for philanthropic organizations such as the Bill & children with the effect of increasing efficiency for Melinda Gates Foundation, in addition to or all stakeholders and delivering optimized medical even in collaboration with the work being done outcomes to children. in the pharmaceutical industry.

Methodological research is needed. It should cover the study designs (validated scales for endpoint assessment, children versus adults as assessors, power analyses and sample sizes, use of controls and need for randomization and single-dose versus

100 5. CASE STUDIES

This section describes two examples of situations developing a taste-masked formulation with solid where acceptability was considered in developing granules that associates four drugs LPV, ritonavir, pharmaceutical products. abacavir and lamivudine, a 4-in-1 with the aim of resolving the limitations of the pellets and simplifying therapy for infants (93). 5.1 Developing ritonavir and lopinavir/ ritonavir for treating children with HIV Finally, AbbVie has successfully developed and commercialized a solid powder formulation of ritonavir to replace the liquid formulation, which Ritonavir and lopinavir (LPV) are very potent ARV needs refrigeration for storage and is therefore drugs that have been widely used in combination difficult to use in the tropical climates of Africa, with various nucleoside reverse-transcriptase where more than 95% of children living with HIV inhibitors for treating people living with HIV since reside. Ritonavir is used as a booster for other the early 2000s. One important characteristic protease inhibitors. is that they present a solid barrier to the emergence to resistance mutations. They have The publication of this development by AbbVie therefore been extensively used as a second-line is forthcoming. Indeed, the case of LPV and regimen for adults and as first- and second- ritonavir exemplifies the complexities of line regimens for children whose initial viral developing age-appropriate medicines for load is very high compared with that of adults. children when the chemistry of the active However, both drugs are insoluble and poorly ingredients severely limits formulation options. absorbed. The initial formulations developed by the innovator pharmaceutical company AbbVie were complex solutions presented in soft-gel 5.2 Example of acceptability evaluation capsules for both adults and children or as liquid embedded in a Phase II comparative formulations for children with excipients, which bioavailability study of a generic versus an made their taste difficult to bear. In the late innovator product 2000s, AbbVie subsequently developed a solid formulation using the melt-extrusion technology WHO and national guidelines recommend that resolved taste and excipient issues, LPV/r for children younger than three years presented in the form of tablets for adults and initiating first-line antiretroviral therapy (ART) smaller tablets for older children. and older ones requiring second-line ART. The generic company Cipla has more recently Whereas older children (older than five years) developed a pellet formulation of the LPV/ who can swallow tablets may have minimal ritonavir (LPV/r) combination for infants and problems taking their medications, the younger young children in resource-limited settings (with ones would need a syrup, pellet or mini-tablet tentative approval by the FDA), but as shown or dispersible formulation. Although currently in the study summarized below, taste remains licensed formulations of LPV/r syrup and pellets a significant challenge for younger children, taste bitter, in the CHAPAS-2 trial in Uganda and swallowability creates difficulty in using comparing solid and liquid formulations, the this formulation for infants younger than three pellets were more acceptable than syrup months of age. Cipla in collaboration with the largely because they were easier to store and Drugs for Neglected Diseases initiative is further transport, since they are heat stable and hence

101 do not require refrigeration. However, the formulation remains less than ideal because it acceptability of the pellets waned over time, tastes bitter. In CHAPAS-2, the older children with the reported challenges being the need preferred LPV/r tablets to pellets, and taste was to mask the bitter taste with food, increasingly the main factor. An LPV/r formulation suitable refused by the children, and the caregivers for younger children with improved taste worrying about ensuring that the child is taking masking therefore still needs to be developed. In the whole dose. The requirement that the LPV/r the meantime, ongoing caregiver support needs syrup be refrigerated makes the formulation less to be embedded in national programmes in the acceptable than heat-stable pellets in low- and countries in which the LPV/r pellets have been middle-income countries, although the pellet rolled out (94–96).

6. SUMMARY

The acceptability of a drug formulation to in the drug development timeline, and there the intended users may have a significant is little consensus about how acceptability impact on treatment adherence and ultimately should be defined, measured and reported. safety and efficacy. As a result of recent This may contribute to unnecessary delays in paediatric regulations in the United States making new medicines available to children. The and the European Union, considerable effort considerations below aim to promote clearer and has been made to improve the acceptability more systematic evaluation of the acceptability of drug formulations for children. However, of new formulations for children to facilitate acceptability studies are often carried out late their development.

7. KEY CONSIDERATIONS

■■ Consensus around assessing the acceptability ■■ Regulators should make available existing non- of formulations for children should be proprietary data on acceptability.

established among key experts. ■■ Acceptability data should be collected ■■ Standard criteria for measuring acceptability systematically.

should be developed. ■■ Acceptability studies should be broadened to ■■ Risk-based strategic approaches should be include cultural elements, and social scientists used to guide the selection of formulations. should be involved.

■■ The characteristics of users and products ■■ Methodological and translational research should be clearly defined and considered relating to the acceptability of formulations simultaneously. should be encouraged.

■■ Acceptability studies should be planned early in the process of drug development.

102 8. USEFUL RESOURCES

■■ European Paediatric Formulations Initiative: ■■ Global Research in Paediatrics (GRIP) www.eupfi.org work package 5: Paediatric Formulations:

■■ IQ Consortium Drug Product Pediatric www.grip-network.org Working Group: www.iqconsortium.org ■■ Pediatric Formulations Task Force (American

■■ United States Pediatric Formulations Initiative: Association of Pharmaceutical Scientists) www.bpca.nichd.nih.gov/prioritization/ researchandcollaborations/Pages/pediatric- formulations-initiative

9. ACKNOWLEDGEMENTS

Author: Marc Lallemant1,2

Contributor: Victor Musiime3,4

Reviewers: Janice Lee5 and Diana F. Clarke6

1 Program for HIV Prevention and Treatment, Institut de Recherche pour le Développement, Marseille, France 2 Chiang Mai University, Thailand 3 Makerere University, Kampala, Uganda 4 Joint Clinical Research Centre, Kampala, Uganda 5 Drugs for Neglected Diseases initiative, Geneva, Switzerland 6 Boston Medical Center, MA, USA

The authors are grateful for the input received from the European Paediatric Formulations Initiative and the IQ Consortium Drug Product Pediatric Working Group, especially Catherine Tuleu (University College London, Chair, European Paediatric Formulations Initiative) and David Cheng Thiam Tan (AbbVie, Co-Chair, IQ Consortium) as well as Trupti Dixit (independent), Eleni Dokou (Vertex), Elizabeth Galella (Bristol- Myers Squibb, Co-Chair, IQ Consortium Drug Product Pediatric Working Group), Melissa Keeney (Eli Lilly), John Morris (AbbVie), Yogesh Patil (Amgen), Fabrice Ruiz (Clinsearch), Smita Salunke (University College London), Daniel Schaufelberger (Janssen), Julia Schiele (AbbVie) and Robert L. Ternik (Eli Lilly).

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