Frequently, proven medications in adults and their formulations are used to treat pediatric conditions; thus, the reported rates of the off label (up to 78.7%) or unlicensed (up to 35) drugs for children are high in different settings.¹ In 2000, a survey revealed that ~50% of all drugs prescribed to hospitalized children in the European Union are administered either in an off label or an unlicensed manner.² This trend can reach up to 90% of the medications given to neonates and infants, particularly in Pediatric Intensive Care Units.³ However, it is well known that children are not small adults, in fact, they are a heterogeneous group requiring different pharmacotherapies.⁴

In general, the absorption, plasma protein binding, metabolism and excretion levels of children are reduced, whereas the volume of distribution is increased. Furthermore, it is commonly assumed that the same plasma concentration of a drug and/or its metabolites in pediatric population and adults is responsible for the same pharmacological effect. Nevertheless, children may differ from adults in several receptor characteristics (quantity and affinity) and variable concentration reached at the site of action, as well as in different membrane permeation and plasma protein binding.⁵ All these pharmacokinetics and pharmacodynamics differences must be taken into consideration when determining the dose (mg/kg) for children, since the doses may be higher, lower or similar than those used in adults.

In addition, depending on the age of children, the route of administration may be different than the one used in adults. Likewise, medications should have a pleasant taste and the excipients must be chosen carefully since some of them may be toxic for children.^6,7 Considering the pharmacological and pharmaceutical particularities of children, the aims of this article are reviewing issues involved in the development and approval process of drugs for pediatric use, as well as describing the current status of pediatric drug development in Mexico.

Background

Drug approval for pediatric patients involves the use of clinical pharmacology information available to determine the effectiveness, safety, and dosage in children. However, only a few studies show pharmacokinetic and pharmacodynamic data to decide the appropriate dose for each of the pediatric phases. Therefore, studies in pediatric populations are necessary.

Efforts to encourage the development of medicines for pediatric use began about twenty years ago. The Food Drug Administration (FDA) has worked to address the problem of inadequate pediatric testing and inadequate pediatric use information in drug and biological product labeling. Consequently, through the Modernization Act of 1997, the FDA established incentives for conducting pediatric studies on drugs with exclusivity or patent protection.⁸ In addition, Best Pharmaceuticals for Children Act (BPCA) in 2002 and the Pediatric Research Equity Act (PREA) in 2003 were approved.^9,10 BPCA establishes that drug sponsor may obtain an additional six-month exclusivity if the sponsor submits information of the use of a drug in the pediatric population. PREA considers that the sponsors of certain applications that might be used in children are required to submit pediatric assessments unless they receive an applicable waiver or deferral of this requirement.¹¹

In 2006, the European Union approved the law in order:

1. to enable the development and accessibility of medicinal products for the pediatric population;
2. to ensure that such products are subject to high-quality ethical research and appropriately authorized to be used in the pediatric population, and
3. to improve the information available on the use of medicinal products in several pediatric populations.¹²

Under this legislation, all studies conducted in compliance with an agreed pediatric investigation plan, the holder of the patent or supplementary protection certificate will be entitled to a six-month extension. In addition, a one-year extension of the period of marketing protection for drug concerned, on the basis that this new pediatric indication brings a significant clinical benefit in comparison with existing therapies. In the case of orphan drugs, the manufacturer can obtain an extra two-year exclusivity on the market.

Furthermore, in order to reduce the time for obtaining approval for marketing pediatric medicines, the clinical studies design should adhere to the guideline E11 of the International Conference of Harmonization to demonstrate the efficacy of drugs in children.¹³

Age Considerations

The physical, metabolic and psychological processes inherent to growth from birth into adulthood reveal that children are far from being a homogeneous group. Changes in physiology (and consequently in pharmacology) influence the efficacy, toxicity and dosing regimens of drugs used in children. As a result, clinical trials in adults are not necessarily predictive for children; thus, they will be needed in children of different ages in order to demonstrate that a pediatric drug is safe and effective in all of the target age group(s).¹⁴

Moreover, acceptability and preference among the different pediatric dosage form(s) are known to vary among children. Hence, the child’s age, individual health status, behavior, disabilities, background, and culture are currently considered as the main parameters determining the child’s acceptability and preference. However, the initial pharmaceutical development of pediatric medicinal products should focus on a minimum number of acceptable dosage forms that may meet the needs of most children in the target age group(s). This can be achieved by developing dosage forms that facilitate the administration of a range of doses and that are acceptable to different children ages.¹⁴

Through international agreement (and to some extent arbitrary), classification of the pediatric population is as follows:

1. preterm newborn infants;
2. term newborn infants (0 to 28 days);
3. infants and toddlers (> 28 days to 23 months);
4. children (2 to 11 years);
5. adolescents (12 to 16 to 18 years, depending on the region).¹⁵

It is important to describe the exposure-response relationship (pharmacokinetics/pharmacodynamics) of a drug or biological in the pediatric population it will be used.¹⁶

Clinical Pharmacology Considerations

Depending on the status of the drug, there are several recognized approaches providing substantial evidence to support its safety and effectiveness in pediatric populations.^16,17 In a first approach, a drug is developed through adequate and well-controlled investigations for a pediatric indication that differs from the indications approved for adults. Regularly, this situation involves diseases that are biologically different in adults and children; the burden of disease is distinct or only exists in children; thus, the development of a complete research program is required.

A second approach uses evidence from adequate and well-controlled investigations in pediatric populations to support the same indication approved for adults. In this case, previous information on the disease and exposure-response knowledge from studies in adults and relevant pediatric information is used to design and, in some cases, analyze new pediatric studies.

On a third approach, the assumption is that the course of the disease and the effects of the drug are sufficiently similar in the pediatric and adult populations to extrapolate the adult efficacy data to pediatric patients.¹⁸ Thereunder, a pediatric study is conducted to determine if drug exposure is similar to effective exposure in adults. If there is a concern that exposure is different in pediatric patients, relevant pharmacokinetic and pharmacodynamic studies beyond the clinical outcome desired for the drug in the pediatric population may also be important.¹⁶

In terms of safety, data can be extrapolated from pediatric safety studies conducted with similar medications in pediatric populations and from adverse events reported in adults. If this information is not available, it is necessary to evaluate the feasibility of conducting studies in pediatric patients.

Pharmacokinetic Considerations

During childhood, changes in the development of body composition and proportions occur, as well as in the function of the organs during growth and maturation. All of them affect the pharmacokinetic characteristics of drugs at different ages. Typically, drug pharmacokinetics is evaluated over the entire pediatric age range in which the agents will be used.¹⁹ Nevertheless, a review performed on International Clinical Trials Registry to identify trials in children younger than 12 years reported that pharmacokinetic data were only collected only in 24% of all eligible trials, and of this 77% were conducted in North America, while 2% were performed in Latin-American and the Caribbean. In addition, most trials included children older than over 2 years.²⁰

There are numerous pharmacokinetic differences between children and adults, especially in newborns and infants. For example, total body water, expressed as a percentage of body weight, decreases with age, from approximately 80% in newborns to 60% by 1 year of age.²¹ Conversely, body fat increases with age, from 1%-2% in a preterm neonate to 10%-15% in a term neonate, and 20-25% in a 1-year-old.²²

Moreover, a reduction in the number of total plasma proteins (including albumin) in the neonate and young infant increases the free fraction of drug; thereby, influencing in drug bioavailability.^23,24 Other factors associated with the development of the disease —such as variability in regional blood flow, organ perfusion, permeability of cell membranes, changes in acid-base balance, and cardiac output— may also influence drug binding and distribution.²⁵

Delayed maturation of drug-metabolizing enzyme activity may account for the marked toxicity of drugs in the very young. Important developmental changes in the biotransformation of drugs prompt the need for age-appropriate dose regimens for many drugs commonly used in neonates and young infants.²⁵ Expression of phase I enzymes —such as the P450 cytochromes— changes intensely during early childhood.^26,27 Similarly, substantial changes in phase II enzyme expression occur during development, which will have a profound impact on xenobiotic disposition and clinical outcome.²⁸

In contrast, neonates rapidly eliminate micafungin and require nearly three times the normal adult dose to achieve comparable levels of systemic exposure. Likewise, acyclovir dosing regimens may not act in therapeutic central nervous system concentrations and more frequent dosing may be required for neonates.²⁹

Developmental changes in renal function can dramatically alter the plasma clearance of compounds with extensive renal elimination and; thus, constitute a major determinant of the age-appropriate selection of a dosing regimen. Therefore, for drugs eliminated primarily by the kidney, physicians should individualize treatment regimens in an appropriate manner that reflects changes in maturation and in the treatment of renal function.²⁵

Pharmaceutical Considerations

Children treatment implies specific pharmaceutical problems that have not been reached the same extent in adults, and whose occurrence may be age-dependent. For example, infants are simply unable to swallow conventionally-sized tablets, safety issues with certain excipients that are acceptable in adult formulations, and adherence problems with unpalatable drugs. Neonates may require very small volumes of a parenteral medication to avoid volume overload. Therefore, children should be treated with drugs whose pharmaceutical design is appropriate to be used in them.¹⁴ Moreover, to ensure adequate treatment of all children, different routes of administration and dosage forms may be required. However, lack of pediatric formulations often leave health care professionals no alternative but using the adult medication in an off-label or unlicensed manner.³⁰

Ethics in the Development of Pediatric Drugs

Up to 1980s, it was often argued that children should be protected from clinical research for ethical reasons. Since then, there has been a gradual shift to the current consensus that children merit the same level of health care as any other age group, including evidence-based prescribing drugs.³¹ Nevertheless, any concerns about conducting trials in the pediatric population should be balanced by the ethical concerns about giving not-appropriately-tested medication to a population. Public health threats from the use of untested medicinal products in the pediatric population can be safely addressed through the study of medicinal products for the pediatric population, which should be carefully controlled and monitored through the specific requirements for the protection of the pediatric population who take part in clinical trials with implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.¹²

Application for Pediatric Medicine Approval

A fundamental step to apply for a drug or biological product approval is taking into account every single consideration mentioned above in order to work out a strategic plan for pediatric medication. This plan is developed to ensure that the necessary data on the use of the drug in children will be obtained safely. In the USA, the plan is known as pediatric study plan (PSP), while in the European Union (EU) it is known as the pediatric investigation plan (PIP).

For investigational new drug (IND) application —which may involve a new active ingredient, new indication, new dosage form, new dosage regimen or a new administration route—, the FDA required to submit an initial pediatric study plan (iPSP). A biosimilar product that has not been determined to be interchangeable with the reference product is considered to have a new active ingredient.³² The iPSP should be submitted no later than 60 calendar days after the end-of-phase 2 studies. If there are no phase 2 studies, it should be submitted as early as practicable, but before the initiation of any phase 3 studies, or any combined phase 2 and phase 3 studies. The iPSP should include an overview of the disease in the pediatric population, overview of the drug or biological product, overview of planned extrapolation of effectiveness to specific pediatric populations, drug-specific waiver (if applicable), plan to request deferral of pediatric studies, tabular summary of planned nonclinical and clinical studies, age-appropriate formulation development, nonclinical studies, clinical data to support design and/or initiation of studies in pediatric patients, planned pediatric clinical studies (including pharmacokinetics, clinical effectiveness and safety studies), timeline of the pediatric development plan and agreement for pediatric studies with other regulatory authorities (e.g. EMA). The agreed iPSP (or amended agreed iPSP), including any requests for waivers or deferrals under PREA, will be reviewed by the Pediatric Review Committee (PeRC), and a decision about granting or denying any such requests will be made during the review of the marketing application.

The purpose of a PIP is supporting the authorization for the use of a drug in children. Once the plan is accepted, it is kept up to date through a modification procedure. The PIP should contain needs of all childhood age groups, general description of the disease and its diagnosis and treatment (highlight differences between children and adults), information on the chemical characteristics of the current formulation, data from non-clinical and clinical studies, a proposed strategy (including additional non-clinical studies, plans for pediatric formulation, etc.), and a description of planned clinical trials. If development is performed in parallel with adults, details of the chronological development of studies in children compared to the adult population should be included. If the studies with children are not conducted in parallel, a postponement may be requested for the completion of the PIP.

EU legislation stipulates that PIP should be submitted to the Pediatric Committee (PDCO) no later than the end of pharmacokinetic studies with adult humans. Normally, the PIP is presented once there is clinical experience with adults. If a PIP is completed and the pediatric data is included in the product information for the EU, a six-month extension period is given for the granting of a supplementary protection certificate as compensation. The PIP procedure takes between 9 and 10 months, from presentation to decision making.³³ All marketing authorization requests for new drugs must include the results of the studies described in an agreed PIP unless the medication is exempt due to a deferral or waiver. This requirement also applies when the holder of a marketing authorization wishes to add a new indication, pharmaceutical form or route of administration for a drug that is already authorized and covered by intellectual property rights.³⁴

In addition, Pediatric-use marketing authorizations (PUMA) are granted by EMA for drugs that are intended exclusively for pediatric use. The PUMA process was established to make it more profitable for pharmaceutical companies to market drugs for children. For this purpose, new data used for PUMA approved drugs are protected for 10 years, and the applications are partially exempt from fees. A PUMA development must follow a pediatric investigation plan (PIP) and be agreed by the PDCO.³⁵ In both Mexico and Latin America, it is necessary to make legislative efforts to encourage the development of drug formulations designed specifically for the pediatric stage.

Drugs for Children in Mexico

Most of the Mexican population is the result of crossbreeding between Amerindians, Europeans, and West Africans. Accordingly, Mexican mestizo patients might have pharmacological peculiarities that may lead to changes in absorption³⁶, distribution^36,37, drug metabolism^37-44, and the occurrence of adverse reactions.⁴⁵ Unfortunately, there are just a few studies exploring pharmacokinetics and pharmacodynamics in Mexican children, mainly in those with kidney transplant.^46-51 Similarly, only four clinical trials including pediatric patients have been registered in the Mexican Registry of Clinical Trials.⁵² In contrast, 38 clinical trials with completed status involving pharmacological interventions designed and funded by Mexican institutions are registered in ClinicalTrials, while another 12 studies are ongoing.⁵³ Even so, more research is needed to develop medicines for Mexican pediatric patients.

Ignoring the physiological differences of each pediatric stage and the pharmacokinetic features of the Mexican population may lead to therapeutic inefficiency or the occurrence of adverse reactions in Mexican children. For this reason, it is necessary to replicate the findings in other populations to guarantee that the drugs administered to Mexican children have the same effectiveness and safety as those observed in children from other populations. Furthermore, it is necessary that Mexican regulatory authority encourage the development of pediatric drugs including Mexican children.