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