What are some of the current critical issues facing the industry with respect to delivering dosages to various populations – and why is it so important?
Improvements in standards of living mean we are living longer, but as our bodies age it is most likely that we need to take medications for our ailments. The growing global population and the industrialization of developing nations means that the patient pool is increasing. The large age range, increasing patient pool, and the geographic and cultural diversity within the patient pool are some of the challenges to deliver dosages to populations. There is a great deal of activity within the industry to provide medicines which take patient circumstances into consideration, essentially making medicines more “patient-centric.” The growing demand for patient-centric medicines requires consideration of all potential patients when developing new medicines. A disturbing fact is that more than half of the drugs prescribed to children have never been formally clinically evaluated in children. Regardless of the patient group, adherence to medications for both acute and chronic therapies continue to be a major challenge in pharmacotherapeutic treatment of diseases. Adherence is strongly correlated with improved outcomes.1 It is important to ensure that the medicines are easy to take (e.g., easy to open packaging, easy to swallow tablets). Successfully administering medicines to pediatric patients also depends heavily on patient-centricity.
Regarding pediatric dosage forms, what are some unique problems or challenges that manufacturers might face when developing a product from scratch? Is the pediatric market a growing one?
Initial questions to ask are “what is the intended age range?” and “what is the dose range?” Understanding the age range is central to developing an age-appropriate dosage form. With oral medicines, the dosage form needs to be acceptable and practical for the child to take (e.g., ease of swallowing and palatability are important). For respiratory medicines, consideration needs to be given to coordination difficulties when children use inhalers. There are also changes in physiology during the early years of childhood (e.g., transit time, pH range throughout the gastrointestinal tract (GIT), metabolizing enzyme expression). The appropriate format, size, and volume of the dose depend on the child’s age and weight. Building a Target Product Profile (TPP) is helpful for developing a pediatric product from scratch and particularly valuable when comparison to marketed products for the same indication(s) and feedback from stakeholders such as caregivers is included.
What are some concerns a pharmaceutical company might have when reformulating an adult product into a pediatric dosage form? Is this approach viable?
The biggest concern is whether the drug will be as safe and effective in children as in adults. Importantly, children are not simply small adults. Rather, physiology can be significantly different when comparing children, especially neonates, to adults. In particular, large physiological differences include expression of metabolizing enzymes, gastric pH, and transit time. All of these factors affect drug solubility or bioavailability which impacts what the appropriate dose would be for a given patient (adult vs. child). Furthermore, it is unlikely that the adult medicine is available in a dosage form that can be easily administered to children (e.g., tablets). In fact, tablets formulated for adults can pose a safety hazard for children who have difficulty swallowing. Therefore, alternative dosage forms designed for children are preferred for increased safety and more convenient administration. Additionally, an adult dosage form cannot simply be converted to a pediatric-friendly dosage form as unlike adult dosing, pediatric dosing is weight-based. Hence, to better serve pediatric patients, a wider variety of dosage strengths, or the ability to measure and administer precise doses is needed. Moreover, excipients that are allowed for use in adult dosage forms may not be acceptable by regulatory authorities for use in pediatric patients. All of these aspects must be taken into consideration when reformulating an adult dosage form product into a pediatric dosage form product plus the formulator must ensure the stability, quality, and pharmacokinetics of the drug product. To address these concerns, pharmaceutical companies should work with stakeholders (e.g., caregivers, nurses, pediatricians, regulators, drug delivery technology companies) to design and develop pediatric-friendly dosage forms.
When a pharmaceutical company is choosing a company to help them develop a new pediatric dosage form, what questions should they ask? What qualities and expertise should pediatric dosage form developer/manufacturer/service provider have to ensure that their client gets the best quality product?
How many pediatric formulation projects has the company supported? What types of dosage forms have they developed? What types of technologies do they have at their disposal (and have experience with)? Drug delivery technology companies that have worked on many drugs for pediatric patients are able to bring lessons learned to new projects. At Catalent, we have significant experience developing pediatric dosage forms and offer a wide range of technologies that can be used for pediatric patients including multiparticulates, orally disintegrating tablets, mini-tablets, and mini-soft gelatin capsules. We work with customers globally and are familiar with regulatory requirements worldwide.
Does the company use a decision map to guide its formulation strategies and determine the most appropriate one for the pediatric patients? It is important to understand the age range. If there is a large age range, there may be changes in preference and unique medication administration challenges that impact the design of pediatric dosage forms.
Are there different and perhaps conflicting requirements for pediatric dosage forms worldwide? How can a pharmaceutical company plan for these differences to ensure a quality product and a smooth product launch?
Although regulators strive for worldwide harmonization, there are still some differences in regulatory requirements for pediatric dosage forms. Additionally, there are differences in culture and healthcare delivery across the globe. In particular, environmental factors impact the provision of medicines for children in developing countries – cost of goods, packaging (for Zone 4), ease of transportation/storage (solid dosage forms are preferable to liquids), and being able to administer without water (as potable water may not be readily available). All these factors may affect the design of pediatric dosage forms and should be taken into consideration to ensure a smooth product launch.
Looking ahead do you see the pediatric market as a growing one? Should pharma companies devote the time and resources to develop pediatrics forms of all future products?
The pediatric market is a growing one. More drugs are emerging from discovery pipelines for treatment of cancer and genetic disorders in patients that are applicable to pediatric patients. Treatments for childhood ailments beyond infections, asthma, and allergies are available. Specifically, treatments are now on the market or in late stage clinical trials for conditions that manifest during childhood including cystic fibrosis, sickle cell disease, spinal muscular atrophy and Duchene’s muscular dystrophy. Additionally, governments have introduced legislation, such as the EU Pediatric Regulation, to facilitate the availability and development of pediatric medicines with some regulatory authorities requiring clinical trials to be conducted as a prerequisite for initial approval of an adult dosage form. In fact, legislation in the US has closed loop holes for pediatric study exemptions for drugs that are indicated for treatment of orphan and rare diseases in patients. Accordingly, pharma companies should expect to develop pediatric dosage forms to address the growing pediatric market for all future products.
References
- Boswell KA, et al. Am J Pharm Benefits. 2012; 4: e97-e108