PAEDIATRICS: CONSEQUENCES OF THE EU REGULATION
The Regulation (EC) No 1901/2006 on Medicinal Products for Paediatric Use has been effective since December 2006. And this regulation is mandatory for all pharmaceutical companies developing new products.
Key elements of the regulation are for one the obligation to develop paediatrics according to a Paediatric Investigation Plan (PIP) agreed upon by the PDCO1 (with possible deferrals or waivers). It is further mandatory to submit paediatric data when filing new applications - unless the waiver or deferral has been approved by the PDCO. Other important elements are the new Marketing Authorisation Procedure for off-patent products (PUMA) as well as incentives (six months patent extension).
The paediatric development must be conducted according to a Paediatric Investigation Plan (PIP), which includes the timing of planned studies for all paediatric population subsets (neonates, infants, children, adolescents) and must take into account the development of paediatric formulations, the pre-clinical studies such as juvenile toxicity and the clinical studies in children.
Deferral A so called Deferral allows the company to provide paediatric data at a later stage of the overall development. Reasons for a Deferral could be:
- scientific or technical
- related to public health
- studies in adults should be finalised and evaluated before starting studies in paediatric population
- studies in paediatric population will take longer and possibly delay the Marketing Authorisation for adults
The PDCO determines the schedule and the deadlines for deferred studies. Also partial Deferrals are possible and can cover a subset of paediatric populations or defined indications. The holder of the Marketing Authorisation must than submit annual progress reports or a deferred PIP to EMEA as soon as the (adult) medicinal product has reached the market.
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Waiver
For specific medicines or classes of medicines, a Waiver can be granted when a product is likely to be ineffective or unsafe for part of or for the complete paediatric population, the disease occurs only in adult population or no sufficient therapeutic benefit over existing treatment for paediatric patients could be achieved. If a Waiver has been granted, no paediatric data has to be provided. As with Deferrals, full and partial Waivers can be granted.
PIPS are not requested for medicines for conditions where a class waiver exists (e.g. Alzheimer's Disease).
The request for an agreement on a PIP, Deferral or Waiver has to be submitted upon completion of the pharmacokinetic studies in adults (often understood as end of Phase 1). Based on the assessment and opinion of the PDCO, EMEA decides upon the validity of the requests and agrees (or not) on the proposal.
According to the Paediatric Regulation, if a PIP for a medicine intended for children is agreed, the pharmaceutical company will have to follow that plan. Once the plan is complete, EMEA or the applicable authorities in the Members States will check that all studies required have been performed. This compliance check is necessary before an application for Marketing Authorisation can be considered valid.
Pharmaceutical Development
The pharmaceutical industry needs to integrate all the paediatric aspects in the complete development process and has to assess the paediatricuse for both products in early and late development and already authorised products. Data needs to be generated for Marketing Authorisation of all new products since July 26, 2008 and new indications, pharmaceutical dosage forms and routes of admission since January 26 2009. And pharmaceutical industry needs to develop new paediatric formulations. So, a sound paediatric development strategy is needed, where various challenges are considered and addressed. The mandatory activities implemented by the Regulation will lead to additional efforts and costs with increased pressure in a competitive environment. The efforts range from small additional developments activities to full development programs, which can be very time consuming also due to low recruitment rates and staggered development in the different age groups. And depending from the envisaged marketing strategy, global paediatric legislation needs to be considered and followed. For the U.S. FDA for example, the paediatric program (called BPCA and PREA) is usually first discussed at the end of Phase 2 before initiation of Phase 3. However an earlier interaction may be advisable to discuss for example epidemiology, therapeutic needs and the clinical development concept. It is also recommendable to submit the same PIP to FDA and PDCO. But because of other differences between the European and the U.S. concept, it may be necessary to implement separate clinical development programs.
So what paediatric formulations should be developed? Many children have problems swallowing tablets. But this is also true for certain liquid formulations. Suppositories might be an option in countries like Germany or some Mediterranean states but will face ethical resistance in the U.K. or the U.S. Other possibilities for paediatric formulations could be for example:
- coated (taste-masked) particles in suspensions
- coated particles in tablets for preparing suspensions
- granules, sprinkles and pellets
- mini tablets in capsules
- oral lyophilisates or disintegrating tablets
- oral strips and buccal wafers
But no matter what formulation seems to fit best, it has to be kept in mind that a possible optimal paediatric formulation may not be feasible because of stability issues or problems of a later manufacturability of a marketed product. Unsolved questions like acceptable daily intake, taste masking, flavours, dosing accuracy, overall compliance or prolonged release require thorough pre-clinical research. And it has always to be kept in mind that children and adolescents are no small adults. They have to be distinguished regarding anatomy, physiology, pharmacology and psychology. That does also apply to some excipients leading to intolerances, diarrhoea, allergic reactions or even CNS depression (for example propylene glycol in children under 4 years).
How to plan a Paediatric Clinical Trial
Vulnerable patient groups such as children and pregnant women are protected by legislation, GCP and various guidelines. This limits pre-authorisation clinical research in these populations. But the same ethics require that new drugs demonstrate quality, safety, efficacy and a positive risk benefit balance in these populations and now children have to be exposed to Investigational New Drugs. Therefore, only children should participate in clinical trials that will directly benefit from them. That means that the research activity should relate directly to the clinical condition from which the child suffers. The respective paediatric clinical trials are often difficult, time consuming and expensive. So there is a high need for comprehensive and sound planning. Besides the differences in physiology mentioned above, children have limited capacities in understanding what's happening and limited or no competence to make decisions. And compliance is also often depending on the parental supervision. Any concerns about conducting trials in the paediatric population should therefore be well-balanced by the ethical concerns of giving medicinal products to a population in which they have not been appropriately tested2. When planning the trial it is necessary to minimise the risk and increase the benefit for the individual child. Blood samples should be kept to minimum. The child (or parent) must also have the option to refuse or back out without penalty. And procedures should be stopped in the case of distress and dissent. Poorly written information sheets for children and parents might also cause difficulties. When preparing this information one should think about that parents may not understand the information in detail and that the child might not understand anything. So clear and unambiguous writing and layout is as necessary as the integration of pictures and schematic processes.
Conclusion
There is an obligation to integrate paediatric aspects in the development of all new products. The Paediatric Regulation and guidelines in the EU but also the U.S. require pharmaceutical companies to review their research and development strategies and their allocation of resources. An active dialogue between sponsors, regulators and CRO s is essential for a successful implementation of the Guideline. The submission of paediatric developments plans like PIP but also Deferral and Waiver proposals need to be planned, agreed and implemented early in the research and development process. The development of paediatric formulations requires specific knowledge and skills combined with dedicated pre-clinical work and the flexibility to introduce new and sophisticated dosage forms to both development and production.
Author:
Wolfgang Schmitt
CONCEPT HEIDELBERG
Source:
1 PDCO: Paediatric Committee at EMEA (advisory board to EMEA an its executive role)
2 see also 1901/2006/EU, page 2 #7
