What are some of the current critical issues facing the industry in regard to delivering dosages to various populations – and why is it so important?
In drug product manufacturing, it is critically important to adequately treat each patient based on their individual needs. Pediatric populations require special considerations when formulating drug delivery methods.
The pediatric population covers a vast age range from infants to teenagers, and in some cases, pediatric dosage forms are also administered to those who have difficultly consuming traditional solids, such as stroke patients or those with degenerative diseases for example Parkinson’s and Alzheimer’s. Each age subgroup has different pharmacokinetic responses, dosage requirements, swallowing abilities and taste preferences, which are all important factors in the ultimate success of a formulation.
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?
Specifically knowing which APIs are stable and in what form (liquid versus solid) is a start. For example, there are many benefits to a liquid delivery however a shortened shelf-life and refrigeration requirements should be taken into consideration when compared to solid forms. If you decide to formulate solid doses, knowing your patient population’s ability to take solid medications is key. Other considerations include taste, solubility, and the required measurable dose form based on mg/kg of body weight.
The important questions to ask during the dosage form process should include:
- Can the patient swallow a tablet? If not, a liquid formulation should be considered.
- Is the API stable in the liquid formulation? If not, a solid formulation should be considered.
- Can the taste be masked?
- Is a flexible dosage formulation required to cover all age populations?
All these factors can pose their own unique challenges when developing a new drug product.
The global pediatric dosage form market is expected to reach $110 billion in 2019. This represents around a 5% year on year growth from three years ago, when the market was valued at $95 billion. The US occupies approximately 44% of this $110 billion, EMEA 33%, and APAC 22%. Some areas of the market grow slightly more than 5%, while some areas grow just under 5%, with the average being approximately 5%. This market presents exceptional opportunities with growth expected to remain at this rate until 2021.
In the last 20 years pediatric drug approvals increased five-fold, with an average of 10-20 approvals per year to 50-60 approvals annually today. Oncology, central nervous system (CNS), and infectious disease applications are three areas which lead the pediatric dosage trends in clinical trials, and of more than 1,000 pediatric trials currently ongoing, half of them are small molecules.
What are some concerns a pharmaceutical company might have when reformulating an adult product into a pediatric dosage form? Is this approach viable?
From the pediatric patient perspective, this group is unique. People often assume that pediatric dosing is straight forward and that the adult formulation is suitable, however this is not the case. For example, with an adult dosage tablet, it is not as simple as cutting the dose into a smaller size for a pediatric patient. In addition to the different age/dosage correlation, consideration must be given to the difference in preferences, abilities and body weights, making their pharmacokinetic profiles different.
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?
The questions to ask for any drug formulation include the “five right” drug development paradigms:
- Right Drug
- Right Dose
- Right Population
- Right Trial Design
- Right Endpoints
When seeking a supplier to work with, asking if the company has a designated subject matter expert (SME) is a start, as is ensuring that the company has the right facilities and equipment to accommodate production. Due to the delicate nature of pediatric formulation, having someone who is dedicated in this area and well-versed with adequate experience in coordinating age, dosage forms, and taste preferences is important.
Also knowing whether the company has complied with any regulatory approvals is another important consideration. In the US, pediatric drug development laws are covered by the following:
- The Pediatric Research Equity Act (PREA)
- Best Pharmaceutical for Children Act (BPCA)
- Title V of FDA safety and innovation Act (FDASIA)
The Pediatric Research Equity Act (PREA) is triggered by an application of at least one of the following criteria:
- new indication
- new dosage form
- new dosing regimen
- new route administration
- new active ingredient.
The act requires companies to conduct studies for drugs and other biological products that will be used in younger populations to determine if they are compliant with regulations or guidance on formulation by age. This goes alongside adequate labelling for each product to ensure they are given properly, both in form and regimen.
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?
Different regulations come from different regions, including the US Food and Drug Administration (FDA), European Medicines Agency (EMA), Health Canada (HC) and the Australian Therapeutic Goods Administration (TGA), to name a few.
There can be regulatory challenges stemming from the different pediatric drug development regulatory programs. For example, in the EU, pediatric regulations have been enforced from 2007 (EC No1901/2006) while the US follows the BPCA and PREA acts, and Canada has no specific requirement to conduct pediatric studies under their current food and drug regulations.
Harmonization among different regions has been discussed for many years, and some regions such as Canada, support international harmonization efforts. If a company developed a pediatric drug product and received approval from a US regulatory agency and then wants to expand to Europe, it will be required to make a separate submission for EMA regulatory agencies for approval. Even if most of development and validation data to support US requirement may be used for other regional submissions, it is highly recommended to discuss the details with local regulatory agencies.
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?
As mentioned previously, the pediatric market was discounted for a long time, but in the past decade, we see it is growing quickly.
There are close to 1,300 clinical trials underway investigating over 600 drug substances, so it is safe to say that it is beneficial for pharma companies to at least consider exploring. With the additional opportunity to adapt these methods to patients with degenerative and long-term diseases, such as Parkinson’s and Alzheimer’s disease, there is even further opportunity for pharma companies that are looking to generate reliable sources of income, while addressing critical needs in the industry.