The pediatric population has suffered from Adverse Drug Reactions (ADRs) from medicinal formulations that are intended for adults. This practice of unlicensed and off-label prescription is most widespread in children, especially in neonates and cancer patients. This is due to the insufficient drug development and clinical trials conducted in children to produce age-specific formulations. Pharmaceutical companies face ethical, technical and commercial challenges.
Following the development in pediatric healthcare in the international scene, particularly in the United States, the European Commission has created and strengthened regulations governing drug development and clinical trial designs in children. The Paediatric Regulation took effect in January 2007 to stimulate quality and ethical pediatric drug development without conducting unnecessary clinical trials and without delaying authorization in adults.
Through a review of documentary secondary data and available information from regulatory agencies, this dissertation will examine the directives of the legislation vis-à-vis clinical trial designs as a pediatric drug development response, and how it has influenced the industry as a whole. Recommendations on the improvement of the legislation and of drug development trial designs will be presented.
The lack of drug development for the pediatric population has resulted in several problems; among these are Adverse Drug Reactions (ADRs) and the unavailability of quality, safe and effective drugs for the treatment of diseases in children. This is the primary reason why the practice of unlicensed and off-label prescription has become widespread, from hospital wards to community clinics. Prescribers merely rely on their experience in prescribing medicines to children at doses and administrations that are only being scaled down as they are applied in adults. Based on research, however, this practice is highly unadvisable due to pharmacokinetic and pharmacodynamic differences between children and adults (Collier, 1999).
Because of these concerns, the Pediatric Regulation was put into action in 2007 to encourage quality and ethical research for the development and availability of medicines and information for use in the pediatric population. In this regard, unnecessary trials and delays in authorizing medicines for adults should be avoided. In the background, the regulation has been largely influenced by the policies developed in the United States, the outcomes and learning derived from it, and the changes in the political, technological and commercial environment in both regions. Correspondingly, the regulation is found to be able to influence these environments and instigate conditions by which developments will be geared towards the improvement of pediatric healthcare. Databases gathered by the authoritative bodies and resource networks established by the US were a rich resource for the adaptations, deviations and overall direction of the European legislation. Incentives, rewards, punishments, and legal obligations are a huge part of the intensity and expediency of pediatric drug research and clinical trials (Rocchi, 2010).
After four years of implementation, an increase in pediatric drug development has taken place. Pharmaceutical companies are obliged to conduct parallel drug developments in children as adults while publicly funded organizations participate in a newly incentivised development of medicines that are beyond their patent or market protection. Off-patent drugs are given specific and proven safe and effective pediatric applications. Information is also being made available to frontline healthcare professionals and to patients through a standardized labeling system (Roberts, 2011). Consolidated guides have supplemented available drugs and common practices in medicine administration in order to lessen incidences of ADRs caused by off-label and unlicensed prescriptions. These have also proposed further research recommendations that are necessary for pharmaceutical companies and in measuring the impact of their activities. Most importantly, the legislation defined measures in regard to clinical trials performed in children, taking into account the differences in pharmacokinetics and pharmacodynamics between children and adults. The networks established across international borders helped reduce unnecessary and duplicate trials, and made sharing of findings and facilities more efficient and effective.
However, questions remain whether the whole industry is truly responsive to the virtues of the legislation and whether the legislation is properly guiding the direction for a total greater benefit. The legislation has created huge financial incentives for pharmaceutical companies that would include developments for the pediatric population. The measures and controls bordering these incentives are not yet proven to be valuable in ensuring that the legislation is not being circumvented and used for the mere creation of ever bigger profits. Potential loopholes lie in the legislation itself, for instance, waivers and deferrals. Statistics will show a possible correlation between the legislation’s directives and the actual products and information derived from the industry’s response.
Do children really benefit from this legislation and the developments in drug development? Are they protected from potential harms from participating in the numerous clinical trials being conducted? These and other questions regarding clinical trial designs vis-à-vis the Pediatric Regulation will be explored in this dissertation. The investigation will look into the evolution of the pharmaceutical and healthcare industry in the face of the new regulation. Recommendations on possible improvements in the legislation as well as to the response of pediatric drug development will be presented, in consideration of their strengths, shortcomings and drivers to success and failure.
Background: Pediatric Medicine
On the 18th of December 1997, the European Medicines Agency (EMEA) together with the European Commission, summoned pediatric experts for a discourse concerning issues on pediatric drug development, specifically on the use of new medicines. Some groups were invited such as the European Federation of Pediatrics Physicians, the Committee of European Doctors, European Patient Organizations, and the European Federation of Pharmaceutical Industries. They were tasked to recommend improvements on the then-existing regulatory framework that had failed to address increasing cases of maladministration, the lack of drugs specifically formulated for the pediatric population, and the lack of useful information.
This problem was currently being addressed in the United States through a ruling by the Food and Drug Administration (FDA). In August 1997, manufacturers were required to supply data as regards drugs that were expected to be used frequently by children. At that time, the European Union simply encouraged pharmaceutical companies to investigate the effects of new medicines in children and to develop formulations to cater to different subgroups.
This guideline was not sufficient to make informed and appropriate drugs more available to children. In fact, this resulted from a lack of clinical trials and specialized formulations. Reflected in practice, this was the widespread off-label and unlicensed prescriptions leading to moderate to serious health problems.
After deliberations on ethical, technical and practical matters, the group agreed that old drugs be reviewed for stringent labeling and networks be made on the international level to assure efficiency. They also approved of encouraging clinical trials and pharmaceutical formulations, supported by several incentives (The European Agency for the Evaluation of Medical Products, 1998).
Typical Pediatric Drug Development Programme
Through the changes implemented out of the pediatric convention, there has been an increase and improvement in pediatric drug development in recent times. Although the subject matter involves a lot of complex steps and stages, the industry and other stakeholders such as regulatory agencies have adopted a simplified, general procedure.
As in any other market initiatives, developers first look at the potential response of target patients to a new drug or a new feature. Once this has been spelled out, ways how to minimize the need for clinical trial are discussed. Available procedures include replacing studies and reducing number of patients involved through extrapolation, modeling and simulation. This is due to ethical, technical and economical challenges that clinical trial is faced with. Nevertheless, due to the limitations of these techniques, pharmacokinetics and safety studies must be conducted, at the minimum (Campbell et al., 1998). In studies that concern neonates, microsampling techniques and sensitive analytical methods have been developed in order to address the relatively more delicate needs of neonates participating in research. Sparse sampling and other pharmacokinetic models have also been developed (James & Ito, 2009).
In some cases, a feasibility study is done before the actual trial. Evidence must support that the proposed clinical trial can be completed substantially. Sometimes, a waiver can be granted, eliminating trials in pediatric population subgroups. Finally, a clinical trial will be designed, one that is specially tailored to the need, capacity and safety of children. A number of controls and other specifics may not work in children as they do in adults. Also, the recruitment of children to participate in research raises more ethical questions than in adults. These being said, the unavailability of eligible participants and the size of the study population affect the capacity of the research to make sound, measurable and relevant conclusions (James & Ito, 2009).
Recommendations in pediatric pharmacology were initiated through extrapolation of therapeutic research and practices in adults, wherein dose and duration of treatment are adjusted and scaled-down based on age- and development-specific effects. This methodology has been predominantly successful because most drugs are relatively non-toxic. There is also a wide margin between therapeutic and toxic doses. In his thesis (published in 2005), Prof. Stephenson stated that most basic processes and receptors on the cellular and physiological level are common to all mammals, regardless of age and developmental stage; resulting in minor differences in the response to drugs between children and adults. According to him, two reasons for the perceptions of differences in pharmacodynamics are: the possible differences in pharmacokinetics that have not been adequately studied across subgroups and various diseases; and the difficulties in measuring the effect (Stephenson, 2005). Most pharmacokinetic and pharmacodynamic studies are conducted in adults, thus limited in elucidating drug action in pediatric populations.
This lack of information must be carefully treated so as not to lead to hasty conclusions. As is affirmed by the World Health Organization (WHO) in its “Model Formulary for Children” (2010) (World Health Organization, 2010), differences in physiology between children and adults, including organ maturity and body composition, significantly alter medicines’ efficacy and safety. Extrapolation is often limited to exactly similar diseases, and with those having the same pathological processes. Stephenson recognized true age-depended pharmacodynamic differences. While some of these can be reversed by withdrawing the drug applied, some do cause permanent and profound effects when applied to a sensitive point in development.
What’s noteworthy however, is that both Stephenson and WHO recommend, if not explicitly, that more extensive and intensive research on pediatric pharmacology and drug development be performed. As WHO declared, the “Model Formulary for Children” not only aims to assist prescribers by making drug dosage information accessible, but also to show where research is inadequate. Accordingly, collaboration and regulation on the international level have resulted in an improvement in clinical trials and generation of new information on medicine use, such as the EU pediatric legislation.
Recent Advances in Pediatric Medicine
The United States has continuously taken the lead in creating an environment that fosters development of quality, safe and effective medicines for children. Through its Drug Amendments of 1962, the US Congress mandated that drug safety and effectiveness be first established before marketing. However, there was no sufficient attention given to the pediatric population, as reflected by disclaimer labeling by pharmaceutical companies. Since not all pediatric needs are addressed by the available drugs on the market, physicians had no choice but to prescribe drugs in doses and other administration based only on experience and estimates (Collier, 1999). Despite the wide use of certain drugs, they were still not authorized for use in children, such as morphine and anesthesia, commonly used in pain medication and in surgeries respectively (Gluck, 2009). In 1994, where there is apparent pediatric application for a drug, pediatric testing was encouraged. In 1997, the FDA enacted the FDA Modernisation and Accountability (FDAMA) Act (Matsui et al., 2003). It lessened pharmaceutical companies’ practice of putting disclaimers on labels (i.e. a drug is not proven safe and effective for use in children). One important section of this legislation was the Better Pharmaceuticals for Children Act (BPCA), a ruling that offered the incentive of a 6-month extension on marketing exclusivity upon conducting pediatric trials on new drugs, as well as to those that are already marketed for the purpose of getting better information concerning their use in children. In 1998, FDA’s Pediatric Rule mandated clinical trials in the pediatric population. But it was suspended when the Association of Physicians and Surgeons sued the FDA, ruled by US District Court for the District of Columbia as having exceeded its statutory authority. Advocates for children’s health then protested, hence the administration enacted the rule as a separate legislation, the BPCA 2002. The Pediatric Rule was codified as the Pediatric Research Equity Act (PREA) of 2003, requiring the conduct of pediatric drug trials. Both of these took effect in 2007 under the FDA Amendments Act (Benjamin et al, 2009).
The intensification of clinical trials is subject to the availability of suitable facilities and well-trained investigators and pediatricians who possess specialized expertise. The UK, in its anticipation of an increase in clinical trials to be performed due to regulatory developments, has created national networks that will support pediatric research and will remove all foreseeable barriers.
The National Institute for Health Research is aimed at hosting revolutionary collaborative and multi-centered research focused on the needs of patients and the public by supporting outstanding individuals and providing world-class facilities (The National Institute for Health Research, 2011). To support this goal, a part of this institution, the UK Clinical Research Network (UKCRN), is tasked to provide the infrastructure needed to create new and better treatments. They help researchers in setting up clinical studies and also provide training to health professionals (Clinical Research Network, 2011). In December 2005, the Medicines for Children Research Network (MCRN) were launched. Funded by the Department of Health, it enhances the clinical research conditions for the growth and safety of effective medical drugs for children in UK. Its mandate is to improve the coordination, speed and quality of randomized controlled trials (RCT) and other well-designed studies. Its infrastructures include the “MCRN Coordinating Centre in Liverpool, 6 local Research Networks (LRNs), 13 Clinical Studies Groups (CSGs), a Clinical Trial Unit (CTU) and a Neonatal Network” (The European Agency for the Evaluation of Medical Products, 1998). These help them support non-commercial, pharmaceutical/biotech-sponsored and investigator-led studies across England (Medicines for Children Research Network, 2011).
Through the collaboration among the BMJ Group Ltd, the Royal Pharmaceutical Society of Great Britain, the Royal College of Pediatrics and Child Health, and the Neonatal and Pediatric Pharmacists Group, comes an essential resource for clinical use of pediatric medicines. The British National Formulary for Children (BNFC) is the standard UK pediatric reference that aids pharmacists and healthcare professionals in prescribing, dispensing and administering medicines for children. One of its bases is the Medicines for Children by RCPCH Publications and the information validations against emerging evidence, best-practice guidelines, and from a network of clinical experts (British National Formulary for Children, 2011).
The insufficiency of safe and effective medicines for 20% of the population of the 27 Member States of the EU has brought about the implementation of the Pediatric Regulation on January 26, 2007. It was developed by the European Parliament and the Council of the European Union whose main objective is to stimulate quality and ethical research for the development and availability of medicines and information for use in the pediatric population. In this regard, unnecessary trials and delays in authorizing medicines for adults should be avoided.
The need for a system of incentives was concluded upon in the round table of experts in pediatric medicines at the EMEA, organized by the European Commission in 1997. The commission also initiated international discussion on the performance of clinical trials through the International Conference on Harmonisation (ICH).
“In April 2001, a Clinical Trials Directive 2001/20/EC on Good Clinical Practice for Clinical Trials were adopted, and came into effect in May 2004” (Benjamin et al, 2009). It is aimed at protecting children in the conduct of clinical trials.
On January 26, 2007, the Pediatric Regulation, Regulation (EC) No 1901/2006, was finally implemented, in which EMEA was made responsible for the implementation thereof. One of its directives was the formation of the Pediatric Committee (PDCO) that was supposed to be operational on July 26, 2007, six months after the commencement of the legislation (Benjamin et al, 2009).
The key to the legislation’s success was the cooperation of different agencies in creating joint action plans. These agencies include EMEA, the European Commission, PDCO, and all Member States of the European community.
The Pediatric Regulation: Procedure and Regulating Bodies
According to Article 6 of Directive 2001/83/EC (Boots et al, 2007) all new applications for marketing authorization become valid only if they comply with an agreed Pediatric Investigation Plan (PIP), unless granted a waiver or a deferral by EMEA. The same applies to those that are already on the market but with a proposed new indication, forms and/or routes of administration. The PIP ensures that pediatric drug development becomes as beneficial as that for adults, and that overall efforts are geared towards addressing unmet children’s needs and not towards mere profitability. The PIP should be able to define which subgroup it will cover in the study, as well as its means and timing. According to Regulation (EC) No 1901/2006, the PIP (or the application for a waiver or deferral) should be submitted no later than the completion of pharmacokinetic studies in adults (Biotechnology Industry Organization, 2011).
The EMEA is responsible for verifying the validity of PIPs submitted and preparing a report for the PDCO within 30 days, who will then issue an opinion within 60 days. This validation concerns the ability of the studies to generate data and conditions for the treatment of children, and whether the benefits justify the studies and outweigh the risks. The PIP can be later modified and supplied with further information as requested by EMEA. This also allows the PDCO to give its assessment in additional 60 more days (Benjamin et al., 2009) through an assigned Rapporteur. After the PDCO accomplishes its opinion, EMEA should forward it to the applicant in 10 days. Given adequate justifications, the applicant may request for reassessment within 30 days, after which the PDCO will assign a new Rapporteur who will be given the same duration to confirm or revise the previous opinion with a statement of reasons for the conclusion. If no request for reexamination is submitted, the decision will be definitive after another 30 days. Ten days after receipt of the definitive opinion, EMEA will make a decision to be published without any confidential commercial information. The whole procedure normally takes about 140 to 200 days, not including possible appeals (Watzl, 2007).
Stephenson (2005), in his work indicates that PDCO members should not have conflicting interests, such as affiliations with pharmaceutical companies that could affect their impartiality. Members are further required to declare their financial interests annually. Its most important tasks are outlined in Article 6: evaluation of PIPs and requests for waivers and deferrals, and of the research proceedings; provide support and advice for pediatric research; and keep a database of pediatric medicinal products.
The Pediatric Regulation: Incentives and Obligations
Based on Regulation (EEC) No 1768/92’s (Aagaaard & Hansen, 2009), a patent or supplementary protection certificate (SPC) holder will be granted a 6-month extension of such upon its compliance with an agreed PIP. Other prerequisites apply such as the product’s authorization in all Member States and the disclosure of relevant information from the studies performed to patients.
The application for these incentives does not come free of obligation to actually place the products on the market together with the pediatric indication. Marketing Authorisation Holders (MAHs) have a period of two years after the approval to accomplish this (Watzl, 2007). And in case a MAH intends to discontinue supplying a medicinal product to the customers, they have to notify the EMEA no less than 6 months before their prior to the supply termination. They are then required to transfer the marketing authorization or to allow a third party to use the pharmaceutical, pre-clinical and clinical information obtained by them (Clinical Research Network, 2011).
As for off-patent medicines in which safety and efficacy of pediatric application need to be established, the Pediatric Use Marketing Authorisation (PUMA) was initiated. It provides incentives exclusively for drug developments that are relevant for safe and effective treatment for children. A 10-year period of data protection will be given to MAHs, thus no generic medicine can enter the market until that period expires. That period can be further extended to a maximum of 11 years, if during the first 8 years; the MAH proposes new and better therapeutic indications. The difference between PUMA and patent protection is that market exclusivity is not guaranteed by data protection. Research can still be conducted by competitors on the same active substance. When authorized for pediatric indication, a medicine may leverage the brand name used for adults (Gluck, 2009), but with a corresponding symbol that will signify that the medicine has been proven safe and effective for the pediatric population. This kind of labeling aims to make medicines approved for children more visible. The symbol and its explanation will be included in the labeling and the package leaflet (Biotechnology Industry Organization, 2011).
As part of EMEA’s pharmacovigilance efforts, the applicant must describe the measures by which possible ADRs will be monitored in the long term as well as its efficacy follow-up. When necessary, the applicant may also be required to set up a risk management system that contains pharmacovigilance activities and other measures of managing risks associated with the product (The National Institute for Health Research, 2011). Here the EMEA will provide a detailed guide for the benefit of the applicant.
Since the Pediatric Regulation aims to increase information on proper drug use for children, research bodies are requested to submit all information obtained on clinical trials they have conducted, which will be assessed by competent authorities (James & Ito, 2009). The information provided may be used to update package leaflets and to affect marketing authorization.
The Pediatric Regulation: Procedure and Regulating Bodies
The Pediatric Regulation aims to stimulate drug development for children without delaying authorization for other populations such as adults. Deferrals can conduct research programs when it is more feasible to carry out studies in adults before the pediatric population, or when it is estimated to take longer to conduct clinical trials in children as compared to those in adults. Another reason is when children’s safety is at risk because of incomplete or unavailable pediatric formulations (Zucker & Rago, 2007). With this, companies that are granted with deferrals should submit an annual report to the EMEA every year after the marketing authorization, in order to give updates on the progress of the deferred studies (Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006).
In addition to preventing delays, the Pediatric Regulation also aims to discourage unnecessary clinical trials in children especially when no foreseen significant benefit will result. Article 11 lays out the grounds for obtaining a waiver. The application should be supported by proof that the medicine is expected to be unsafe and ineffective for children. The medicine should also be for the treatment of diseases that are only prevalent among adults or only in a specific age subgroup (when a waiver is only for a subgroup). The medicine under question should also not address an unmet therapeutic need nor have an added value over existing treatments. The PDCO will create a list of waivers of medicinal products so that pharmaceutical companies will easily know for which products the requirements will be waived and which clinical studies have already been waived (Steinbrook, 2002).
The Pediatric Regulation: Authority Obligations
The EMEA will give free scientific advice on aspects related to the design and conduct of clinical trials in the pediatric population, specifically on the quality, safety and efficacy of the products under development. The request for advice is not mandatory and is not binding on PDCO. It may also be obtained at any stage of the development, before submitting a PIP or during the compliance for it. If the request is beneficial both, for the adult and the pediatric population, then a fee will be determined.
A community funding program will be in places such as the Seventh Framework Programme for Research and Technological Development (FP7). It is Europe’s main instrument for funding research in the region. For the period between 2007 and 2013, its budget is as much as 53.2 billion Euros, the biggest among its kind. One of its priorities is the clinical studies for drugs that are currently used off-label. Others are for the development of vaccines, medicines for mental disorders, HIV, malaria, tuberculosis, diabetes, and pre-natal and maternal care. It is open to applicants worldwide to such organizations as universities, research centers, multinational corporations, SMEs, public administrations, as well as to individuals.
Review of Related Literature
Yellow Card Reporting: UK
The Medicines and Healthcare products Regulatory Agency (MHRA), an executive agency of the Department of Health, is dedicated to safeguarding public health by ensuring that medicines and medical devices in the market work safely. One mechanism created to facilitate this mission is the Yellow Card Scheme (October 2005) (Yellow Card, 2011), pledging to help make medicines safer. This is achieved through analysis of reports submitted by patients and healthcare professionals that enables the agency to discover previously unidentified side effects or adverse drug reactions (ADR).
Despite the rigorous tests and licensing system that drugs go through before being allowed to be sold in the market, there are still limitations as to the identification of side effects, and so in the provision of information and warnings. Clinical trials for these medicines take place in controlled environments and among an average of 1,500 participants only. This is far from the conditions in which the medicines are actually used – by people across age groups, diseases, environments and lifestyles. The size of study population may not be amply large to observe side effects and measure its correlation with the medicine. Some side effects also become perceptible only at a period after the administration. Lastly, the fact is that all effective medicines have one or more side effects, minor or serious. Drugs are given a license because their benefits outweigh the side effects. That is why the agency emphasizes the availability and accessibility of correct information so that the public can exercise discretion as regards the benefits and potential risks of using medicines.
The Yellow Card alone, however, will not be sufficient to make recommendations. These data will be analyzed vis-à-vis clinical trial data and other information from worldwide databases. This is carried out by experts constituted of doctors, pharmacists and scientists. Reporting can be done through an online site, at pharmacies or by calling the agency’s hotline. These data are then made available for public viewing through Drug Analysis Prints (DAPs) with an accompanying interpretation guide.
On top of allowing informed decisions, the agency also takes action in order to ensure the public’s safety. When a new side effect has been identified, the medicine’s profile will be compared to its alternatives. Several information and warnings have been added to medicines, and some drugs have already been pulled out of the market through the use of this system. The public, including patients and healthcare professionals, is encouraged to report observed side effects, though they are yet to be confirmed. A huge amount of data from various sources, more than 20,000 reports per year, will give statistical power to the agency to draw reliable and valid conclusions (Yellow Card, 2011).
Together with the Commission on Human Medicines (CHM), MHRA publishes a monthly Drug Safety Update to guide professionals on the use and safety of medicines. Similarly, the British National Formulary regularly publishes up-to-date information that is accessible through the internet and in hard copies found in libraries and pharmacies. Instructions and other information that come with every medicine, called the Patient Information Leaflet (PIL), are also made accessible online. The agency also has a “learning package on pharmacovigilance” so professionals can better protect patients from avertable harm. Finally, the agency welcomes queries about side effects even though patients have no intention of submitting a report.
On the more sophisticated end, EMEA devised EudraVigilance in December 2001. EudraVigilance acts as a central server that collects information from all organizations legally obliged to record serious adverse drug reactions. These include EU regulatory agencies and pharmaceutical companies responsible for a particular medicine licensed across EU (EudraVigilance, 2011). Regulatory authorities in the EU continuously supervise and monitor medicine use in all EU countries for the purpose of supplying this information for scientific assessments. Unlike the Yellow Card Scheme, it aims to detect possible safety signals early on. It also serves as useful to pharmaceutical companies to see what other information must be furnished.
The facilitation of information exchange and the secure, automated submission of regulatory pharmacovigilance reports work through an electronic system called EudraVigilance Gateway. Different from submitting a Yellow Card, users are required to register and identify themselves, for which their eligibility for access rights will be evaluated. EudraVigilance also monitors individual user interactions and the exchanges of safety, acknowledgment and medicinal product reports.
With its knowledge of medicines’ adverse reaction profiles, it performs a vital role in the European Risk Management Strategy. Its decision-making authority lies in its ability to detect, assess, minimize and communicate risks.
In the future, EudraVigilance aims to make its database public to improve treatment and help prevent side effects. More sophisticated technology will be employed to automatically extract statistical trends in detecting safety issues. Other functions will also be added, such as gathering data on medicine usage practices and the usage rate of individual medicines.
Drug Use in Pediatric Population
The lack of medicines specifically formulated for children that have been proven safe and effective through clinical trials has posed valid concerns for the pediatric population. This branches off to several interrelated areas of discussion such as adverse drug reactions (ADRs) that are probably a consequence of imprecise and erroneous formulation, maladministration, and off-label and unlicensed prescription (Aagaaard & Hansen, 2009).
Unlicensed and Off-label Prescribing in Children
A common practice among professionals including pediatricians, general practitioners, neonatologists and pharmacists is unlicensed and off-label prescriptions. Unlicensed prescription concerns drugs that are not specifically licensed for use in children (James & Ito, 2009). Off-label drugs are those used outside of the terms for which they are licensed, frequently involving deviations from specified dosage, age group, indications, or route.
Data available on cases of unlicensed and off-label prescription for a review of its scale are concentrated between 1985 and 2004, preceding the inception of the EU legislation. In a review done to make comparisons among three different settings – pediatric hospital wards, neonatal hospital wards, and community settings – it has been shown that the practice is prevalent, in varying degrees (Barker et al, 1987).
Among the three settings, neonatal hospital wards consistently had the highest recorded incident ranging from 16% to 62% of total prescriptions. Of all children being prescribed with, 36% to 92% receive off-label or unlicensed drugs, even higher in premature babies. The lowest incident is found to be in community settings which include pediatric and family practice clinics, and pediatrician offices, with a prescription rate of only 11% to 37%. Based on studies conducted between 1999 and 2000, the share of drugs used off-label in UK is 11%, 29% in Netherlands and 33% in France (Barker et al, 1987).
Fungal infections which occur at a 16% rate among low-birth-weight neonates remain to be one of the major causes of death in this pediatric subgroup. In the United States, the common treatment includes amphotericin B deoxycholate, lipid complex amphotericin, or fluconazole. The Food and Drugs Administration (FDA) has not approved the use of any of these drugs for neonates. The industry is left to speculate as to which medicine is more effective and safer to use based on prior knowledge of their adverse effects. However, no precise studies confirm the recommended dosage and duration of treatment. They are limited to sparse sampling strategies and pharmacokinetic studies (James & Ito, 2009).
The most common drugs used in pediatric wards are acetaminophen, cisapride, chloral hydrate, and salbutamol; caffeine, ampicillin, dopamine, Phenobarbital, morphine, sodium chloride, theophylline, and vit K and E in neonatal hospital wards; while in community settings, they are salbutamol and amoxicillin. In another study, the most common drugs used off-label in community pharmacies are antibiotics, analgesics and antihistamines (James & Ito, 2009).
Pediatricians’ viewpoint has been considered in the subject of prescribing unlicensed and off-label drugs. Alarmingly, only 50% of them believe that this practice is potentially detrimental to patients, despite a large safety and efficacy concern as reflected by reports of high levels of treatment failure and ADRs. Moreover, only a third seek parental consent or give information on potential risks (Barker et al, 1987).
On the other hand, only 36% of neonatologists expressed concern about efficacy while 52% about safety. The report of treatment failures was also at a low of 24%, and zero observed ADRs. A discrepancy can be observed especially since this setting has been shown to have the highest incidence of the practice. It could mean that there are no effective means to measure these outcomes. The relatively small fraction (one-third) of neonatologists who thought that formulations should be more specific for the pediatric population could suggest the need for data on drug efficacy and safety.
Referred to as the gatekeepers of medicine, pharmacists have been identified to have a key role in the proper dispensing of medicines. However, only a minority takes the subject at hand seriously. They are also not educated on the reasons for such occurrences. In fact, they learned about it through experience and not during their formal training. What is more, only half see the need for medicines to undergo trials in children because of the existence of “significant levels of empirical knowledge” (Stewart, 2007). This discovery calls for a thorough renewal and revalidation of the educational system.
In practice, they find it acceptable to resort to such prescription when alternatives are not available. They also think that they are responsible for informing parents regarding the unlicensed or off-label use. However, the Royal College of Pediatrics and Child Health recognizes that it could cause confusion among patients and parents, and put both prescriber and pharmacist in an unfavorable situation. Thus the rational buffer is to contact the prescriber, which pharmacists have affirmed. However, when given hypothetical scenarios, only a minority will confirm with the prescriber. Perhaps a facilitative system can foster the kind of synchronization necessary (Stewart, 2007).
A few industry-wide support has been instituted such as the British National Formulary for Children (BNFC), which together with pack inserts, are the most common source of information on pediatric prescription among pharmacists. These will be distributed to community pharmacies free of charge. Formularies, however, should only be temporary and supplementary. As of 2004, a list of high-priority drugs for children created by the National Institutes of Health contained only one of the aforementioned commonly prescribed off-label drugs. The list evidently had to be expanded. In 2010, WHO released its Model Formulary for Children, positively containing all those listed above. It means that formularies and drug development should complement each other down a continuous development.
One of the difficulties experienced in assessing the scale and pervasiveness of unlicensed and off-label prescriptions was the absence of a single evaluation criterion. Studies conducted across countries, hospitals wards and community clinics were using different definitions and measures. Given the current limitations in pediatric drug development, these practices remain to be the most rational; hence understanding it in light of the bigger system is indispensable. There has to be a unified method to gather and analyze data in order to devise policies and interventions that address the problems right at the center. Time-based studies will also help measure the effectiveness of specific policies implemented or new materials distributed. Communication, education and proper information dissemination remain to be the key success factors in keeping pediatric drugs safe and effective (Stewart, 2007).
ADRs in Children
Given the scale and pervasiveness of unlicensed and off-label prescription, it can be deduced that the consequence of this practice is also widescale. At the more serious end, adverse drug reaction (ADR) has been found to occur across different settings, age groups and diseases. Defined by W.H.O., it is a drug response that is harmful and unintended, as a result of dosages consumed by humans to prevent, diagnose treat, or alter any physiological functioning of the body.
Most ADRs involve anti-infective, anti-asthmatic and gastrointestinal (diarrhea and vomiting) reactions. The skin is also observed with rashes as well as systematic reactions such as those linked with the central nervous system. The main causes are accidental ingestion, damaged and inconvenient packaging, and label-related maladministration (Napoleone, 2010).
In a study conducted in different children’s hospital wards in UK over a period of 13 weeks, 11% of all admissions were associated with ADR. Around 4% was associated with licensed drug prescription, while 6% was with unlicensed and off-label (which constituted 35% of all prescriptions). In pediatric offices, ADR incidence is only at 1.4% (Napoleone, 2010).
Based on EMEA’s database, starting from December 2001, ADRs have been reported and are directly associated with unlicensed and off-label prescriptions. Sixteen percent (16%) of all serious ADRs are reported to be fatal.
These cases are more severe in the pediatric population under the age of 2. In a 38-month long study of FDA reports, an average of 243 drug-related deaths per year are accounted for. In a separate study of death incidents, 41% occur during the first month of life and 84% during the first year. Between 1997 and 2000, out of all the ADR reports received by FDA for children under 2 years old, 61% resulted in either death, disability, congenital anomaly, hospitalization, etc. It appears that younger children are more susceptible to ADR because there are more variations in dosage and indications among age subgroups, and also because their detoxification mechanisms are not yet fully developed. Moreover, of all these cases, 24% was passed on to the infant through the mother, with outcomes as grave as congenital anomaly or disability. Numerous cases were linked to drugs that prevent the transmission of HIV (Moore et al., 2002).
One important case to consider is that of tolazoline, a drug that was widely used in the treatment of pulmonary hypertension, hypoxemia refractory and mechanical ventilation in newborns. It was only 15 years after that safety and efficacy studies were conducted, and dosing recommendations were made available. Prior to that, not even randomized or placebo-controlled studies would support the medicine’s therapeutic claims. The only information available to patients and healthcare professionals was that the drug demonstrated some normalization of abnormalities and that no gastrointestinal difficulties were caused. In a later study, it was found to decrease renal function, gastrointestinal hemorrhage, and duodenal perforation. Other reports of ADR such as high incidence of bleeding and the development of extracorporeal membrane oxygenation, without sufficient efficacy, resulted in tolazoline’s withdrawal (Giacoia & Mattison, 2005).
In the same study done in 5 hospitals in UK, 4 out of 183 drugs accounted for 38% of all drug-related deaths. One of these is cisapride, a non-FDA-approved drug for infants that was typically used to treat gastroesophageal reflux. Due to reports linking it with cardiac arrhythmia and sudden death, it was pulled out of the market in 2000.
The primary challenge in gathering sufficient data on ADR that would allow for policy and systems improvements is underreporting, more so in unlicensed and off-label drug use. Underreporting is found to be at high rates in spontaneous reporting, which relies on healthcare professionals’ and patients’ reports of suspected ADR, such as the Yellow Card Scheme. In Italy for example, spontaneous reporting in children stands at an average of 1.7%, compared to 8% of total reporting (Napoleone, 2010). It understates the spread and gravity of incidents because people are not compelled to submit reports and some symptoms might come unnoticed. Others do not see the value of a single report, especially when that information has been previously known. They might not understand the importance of this system in minimizing risks thus creating a safer environment for patients. Probably healthcare professionals are anxious in reporting because as curricula show, not enough emphasis is given on pediatric pharmacology and pharmacovigilance. Anyhow, spontaneous reporting remains to be an important component of pharmacovigilance. For instance, WHO’s Database grows annually by about 250,000 reports. Agencies made a commendable move in standardizing reporting and making it more accessible to healthcare professionals and patients through the internet. A more unbiased method of getting information is prospective monitoring, such as that done in the five hospital wards in UK. Not surprisingly, most of these studies are done on hospitalized patients, fairly skewing observations.
On top of these issues, the above-mentioned studies and data pertaining to short-term ADRs. Long-term ADR is even more difficult to measure. Additionally, some serious ADRs may manifest at a much later time after the administration, or even after the drug has been granted marketing authorization.
Although a series of clinical trials, assessments and risk management provide efficacy profiles, drugs may demonstrate ADRs only after being used by a large, ordinary market. Some ADRs appear only in small fractions in patients, thus a clinical trial with a relatively small study population will not be able to detect such phenomenon instantaneously. An alternative signal detection approach available but not widely explored is data mining. Examples of this method are cumulative techniques, time scans, proportional reporting ratios, Poisson methods, and Bayesian data mining (Aagaaard & Hansen, 2009).
Special Pediatric Disease Area
Pediatric malignancies occur rarely in children, accounting for only 1% of all cancers in humans or a total of 15000 cases diagnosed yearly in Europe. Despite the small percentage, it remains to be the leading cause of death among children. One of the reasons is the lack of appropriate treatments given to patients, or 50% being unauthorized to be marketed for children, and 75% of medicines used in chemotherapy are old off-patent drugs. Also because of this small number of disease incidence, pharmaceutical companies find little interest in developing medicines for cancer, thus developments in this area are largely carried out through the efforts of pediatric oncology networks and cooperative groups. The clinical studies they perform make use of medicines in the market that is intended for adults. Series of pharmacological trials have proven the efficacy of these medicines and the overall outcome has improved outcomes in children and healthcare standards. However, the medicines’ summary of product characteristics still does not provide information for pediatric application.
In 2003, the European consortium for Innovative Therapies for Children with Cancer (ITCC) was created and now serves as a major resource for everything that pharmaceutical companies would need to obtain knowledge and expertise. Nine years after its establishment, 29 anticancer drugs were developed. Of the 21 diseases that they address, only 7 occur in both adults and children, while only 6 drugs have full pediatric indication. After considering all factors in applicability to the pediatric population, summary of product characteristics shows that 78% of these drugs have no data to support recommendations use in children (Valles, 2009).
As defined by the National Institute of Neurological Disorders and Stroke (NIH), epilepsy is a brain disorder of recurring seizures that are caused by wrong signals sent by the brain’s nerve cells. Symptoms include strange sensations, emotions and behaviors, as well as violent muscle spasms and unconsciousness (NIH, 2011). Identified causes are illness, brain injury and abnormal brain development. But most of the time, the cause is not identifiable. This disease is diagnosed through brain scans and other tests, yet drug development has not been successful in finding a cure for epilepsy. The medicines available are only for controlling seizures. When these do not prove to be effective, doctors resort to surgery and device implantation (U.S. National Library of Medicine, 2011).
Because of these research and drug development limitations, many government and non-government organizations have set up their own means to minimize the difficulties being experienced by patients and their parents. For instance, Epilepsy.com provides information to the community on how to take control of their epilepsy and seizures. They also launched the Epilepsy Therapy Project which aims to raise funds that will translate promising research into better treatments (Epilepsy.com, 2011). Founders state that research on the disease is underfunded and thus the medicines available cause ADRs including fatigue, abdominal discomfort, dizziness and blurred vision. More serious ones include inflammation or failure of the liver or pancreas, serious reduction in the number of white blood cells and platelets, aplastic anemia, excessive bleeding and unusual infections. Since seizure medicines reduce the nerve cells’ excitability, they may impair cognitive functions, attention and concentration, memory, energy level, mood, drive, and mental and motor speed (Schachter, 2006). Another branch of this organization is the Epilepsy Professionals that guides healthcare professionals in giving better care to epileptic patients. Under its initiatives is the listing of clinical trials available to patients, looking into new therapies, medications, medical devices and surgical procedures. Another relevant organization is Epilepsy Research which aims to boost publication in both experimental and clinical epileptology, prioritizing those that offer novelty, significant relevance, and interest to a multidisciplinary field (Pitkanen and Theodore, 2011).
At a June issue report in Archives of Internal Medicine, a pharmaceutical company was found to conduct a clinical trial of the epilepsy drug gabapentin as a seeding or marketing trial. This technique is used by companies to introduce a pharmaceutical drug or medical device to physicians in the guise of testing a scientific hypothesis, to increase prescribing (Peart, 2011). Joseph Ross, M.D., an assistant professor of medicine at Yale University, concluded that the clinical trial entitled “Study of Neurontin: Titrate to Effect, Profile and Safety (STEPS)” was conducted as a marketing strategy without informing the trial patients and investigators, rendering it unethical (Ross et al, 2011). The shortcomings of drug development supplemented by pharmaceutical companies taking advantage of uninformed patients and healthcare professionals add to the hindrances to the acceleration of drug development. As of the present, doctors no longer prioritize controlling seizures at any cost (ADRs), but now match the capacity of patients to live a functional life. For instance, findings from a double-blind, randomized, comparative clinical trial on childhood absence epilepsy (also known as “petit mal”) were published in the New England Journal of Medicine. The research identified important differences between the medicines used to control seizures and their side effects (Glauser et al, 2010). This is expected to give physicians more information as to the selection and monitoring of their prescribed therapies and eventually produce better treatment.
In the US, 6.8 million children under the age of 18 have asthma. This disease ranks third among hospitalization causes, and ranks first among children between 3 and 12 years old. 14 million school days missed are attributed to asthma, downgrading school performance. In a national survey conducted by the National Asthma Education and Prevention Program (NAEPP) among children with uncontrolled and controlled asthma, it was found that controls available for asthma symptoms are not sufficient in almost every goal as regards emotional and time-related activities, both on the patient and their caregivers. Those with uncontrolled asthma were more physically and psychosocially challenged to adapt. They had higher incidence of missing school, arriving late or leaving early, missing school-related activities, using rescue inhalers at school, and visiting the health office or school nurse. Greater work is also being demanded from their caregivers and they are found to have lower QOL for emotional activities and are being less productive (Dean, 2010).
Among all those affected, asthma is most prevalent in inner-city children with greater severity. This can be measured by the amount of medication that is needed to achieve control, the need for care, and the ease by which control is achieved. However, the population is faced with a huge difficulty in achieving the control that would allow them to live a normal productive life. Most especially among inner-city children, this has become a difficult challenge for drug developers because this population is supposed to have developed resistance to treatment or impaired responsiveness. The type of airway inflammation found in this population is greater compared to non-inner city children, although its implications on severity are not yet established. Socioeconomic factors and others add up to this difficulty such as environmental allergens, pollutants, infections, and stress (Busse, 2011).
Because of these difficulties and unmet needs, three distinct research networks were established by the National Institutes of Allergy and Infectious Diseases (NIAID) for the purpose of improving health care for this population at risk. They aim to understand difference between asthma occurring in inner-city children and those in other locales, the potentially unique contribution of environmental allergens to the condition, and to improve controls for this population by identifying the mechanisms that possibly limit the children’s response to treatment.
Attention deficit-hyperactivity disorder (ADHD) is a chronic condition whose symptoms are experienced over a lifetime; as being characterized by the inability to focus attention, modulate activity level and control impulses, resulting in maladaptive behaviors in relation to age and developmental levels. All of these affect the young person’s daily life as well as the quality of life of their families. Some of the causes of ADHD are low birth weight, environmental conditions and genetics. Criteria for diagnosis are provided by the Diagnostic and Statistical Manual of Mental Disorders. Of the three types of ADHD, 80% comprise the combination of inattentive, hyperactive and impulsive, 10% to 15% predominantly inattentive, and about 5% predominantly hyperactive and impulsive (Rappley, 2005).
In the area of drug development, one such multi-center, double-blind, randomized cross-over trial is the Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non-stimulant (ACTION). The medicine under investigation is Atomoxetine and its efficacy in improving cognition and emotional function of ADHD in children and adolescents. The most common treatment is stimulant medications with an efficacy rate of 60% to 90% on patients. However, there are times that these stimulants are not effective or some contraindications are present. At these occurrences, non-stimulants are considered as an alternative (Tsang, 2011).
As for stimulant medication, methylphenidate and dextroamphetamine have shown strong evidence of efficacy and safety when compared with placebo in randomized controlled trials. These drugs were tested on a 24-month period, with 68% to 80% percent of participants no longer meeting the criteria for ADHD diagnosis. The most common ADRs are mild, ranging from appetite suppression, stomachache, and headache. No strict dosage guidelines are being implemented, only the recommendations to start with lower doses.
Methylphenidate however, was voted in 2006 by the Drug Safety and Risk Management Advisory Committee of the FDA to recommend a black-box warning that would describe the associated cardiovascular risks in using this stimulant drug in the treatment of ADHD. They also included a guide for patients that should come with the prescription, containing non-technically written information on the potential hazards of the drug. A similar agent, methamphetamine, had been widely used but now poses a problem. When smoked or injected intravenously, was found to be associated with hyperthermia, rhabdomyolysis, myocardial infarction, stroke and sudden death (Nissen, 2006).
Clinical Trials in Children
Having discussed the appalling consequences of insufficient studies in pediatric drug development, clinical trials are markedly needed for the improvement of children’s health care. For a long time, pharmaceutical companies and research sponsors have not delved much into this sector due to a number of difficulties and lack of rewards. Because of that, government agencies established laws that would both incentivize and require pharmaceutical companies to conduct clinical trials in the pediatric population.
The importance of these studies is largely to provide necessary information for the correct labeling of drugs prescribed for children. Whereas prescribers commonly practice unlicensed and off-label prescriptions based on scaling down the size or surface area of medicines, this is proven disadvantageous to pediatric patients (Roberts et al., 2011). FDA only allows extrapolation of data from studies performed in adults for diseases and the drugs having the similar effects. Aside from that, pharmacokinetic studies and other relevant information should supplement the claims. As a drawback, the drug may emerge to be more or less toxic for children of different ages.
To begin with, children are not small adults – not only their body size and composition are different but also their physiology, cognitive and motor functions. High-toxic drugs may cause adverse drug reactions or can affect growth and development, such as corticosteroids (Steinbrook, 2002). That makes long-term follow-up ideal in clinical trials so as to identify and measure long-term effects on the participants’ growth and development.
Due to the complexities involved in this methodology, guidelines have been created such as the Pediatric Pharmaceutical Research Unit model which promotes understanding of financial advantages, as well as minimal exposure to physical and psychological harm. Its goal is to increase patient recruitment and the utilization of age-appropriate techniques (Steinbrook, 2002).
The incentives provided by law have moderated the hindrances to creating a constructive environment for clinical trials. The main barrier identified was ethical considerations regarding consent, risks and harms that children would go through during trials. Second is the commercial practicability of these studies since the pediatric population is significantly smaller than the adult population, and they consume much smaller amounts of medicine. Lastly, technical difficulties rank as one of the top barriers in conducting trials. Researchers find it difficult to measure endpoints such as pain and to require children to perform some activities. Frequent and relatively huge blood sample needs make it difficult to execute certain tests in younger children. As to logistics, performing multicentre trials is a challenge as eligible participants are hard to gather into one location due to few numbers of children are affected by some diseases. The news article “Desperately Seeking Kids for Clinical Trials” has revealed that a particular company’s research breakdowns are caused by inadequate recruitment (Sammons, 2011).
Clinical Trial Design
In order to protect Children’s Rights, the United Nations established four fundamental principles in pharmaceutical studies: 1) all human rights apply to children without exception; 2) all interventions must have the child’s best interest as a primary consideration of the highest priority; 3) children have the right to the highest attainable level of health and; 4) children have the right to obtain information and the right to respect of their opinion. Based on the recommendations of The Committee for Proprietary Medicinal Products (CPMP), the following product categories must apply to pediatric clinical trials: a) for diseases that exclusively affect children; b) for diseases that mainly affect children; c) for diseases without a cure, both occurring in children and adults; d) and for diseases that have a cure, but with sufficient information only available for adults (Clinical Research Foundation EEU, 2009).
The International Conference on Harmonisation of Technical Requirements for registration of Pharmaceuticals for Human Use (ICH), which coordinates the pharmaceutical stakeholders of Europe, US and Japan through resource-effective drug development, gives further guidelines regarding pediatric drug development. Clinical trials must be done entirely on children if and only if the disease in question affects children exclusively or predominantly. For diseases affecting both populations, and where there is no sufficient treatment, children should only participate after safety and tolerability studies have been conducted in adults.
The ICH provides Good Clinical Practice (GCP) guidelines and it is essential that studies are performed by GCP-adept medical personnel. They should be able to build a good relationship and open communication with the patients and their parents. Trials should be conducted in institutions that are suitable to the specific needs of children in terms of infrastructure, for instance.
It is important that clinical trial personnel are sensitive to the needs and fears of children, and to the basic differences between them and adults. Techniques involved in research procedures range from low-risk (e.g. questioning, observation, and measurement) to high-risk (e.g. chemotherapy and surgery). Types of studies may be on efficacy, pharmacokinetic, or safety. According to the FDA, out of 326 studies performed to obtain pediatric exclusivity, 62% aimed to determine both a drug’s safety and efficacy. While 45% studied pharmacokinetics and/or pharmacodynamics, 4% studied efficacy-only, and 12% studied safety-only (Boots et al., 2007). These figures are not far from the studies done during the first 10 years of the legislation.
In these 10 years, 95,000 children participated in 365 trials (Benjamin et al., 2009) proving that strict guidelines must be in place to protect children. Participants as young as newborns and premature babies take part in such trials. According to ICH guidelines, the pediatric population is categorized as neonates (birth to 27 days), infants (28 days to 23 months), children (2 to 11 years) and adolescents (12 to 18 years). As in adults, all clinical trials should first be tested on animals. When risks are increased upon withholding an effective treatment, placebo-controlled trials are deemed inappropriate. Finally, the success of these trials should be measured by how much has resulted in label improvements. For instance, in the 365 trials, only 38% has led to labeling changes.
Safety and Efficacy Issues
Despite the guidelines provided by several agencies to protect children from foreseeable harm, risks are still not completely removed. Since clinical trials are done to identify and probe into previously unknown drug effects, minor to critical ADRs may be observed. A case in point, the 365 trials involving 90,000 participants over a period of 10 years were to determine whether 153 medicinal products were qualified for pediatric exclusivity. FDA medical reviewers have found 12 drugs that increased or caused suicidal ideation, agitation, aggressive and hyperactive behavior, and even vision loss, stroke, and death. These outcomes appeared in lesser intensity and frequency in adults (Benjamin et al., 2009).
Additional 21 products were found to have growth-related effects such as suppressions in the hypothalamic-pituitary-adrenal axis and the musculoskeletal system. Some drugs even caused progression in the diseases being treated and therefore, early death (Benjamin et al., 2009).
In the European Union, the European Medicines Agency (EMEA) plays the key responsibility of evaluating medicines being developed for use in its member countries (European MEA, 2011e). One of its subdivisions is the Committee for Medicinal Products for Human Use (CHMP), (European Medicines Agency, 2011a) which prepares the Agency’s opinions on all matters within its scope. One of its key roles is to furnish scientific and regulatory guidelines for pharmaceutical companies, for which it consults with the Efficacy Working Party (EWP) (European Medicines Agency, 2011b). EWP’s main task is to provide recommendations on drug development’s clinical aspect.
To illustrate the intricacy of typical clinical trial procedures, two working examples of EWP guidelines will be looked into: on drug development for the treatment of ulcerative colitis (UC) (European Medicines Agency, 2011d) and on clinical investigation of treatments for juvenile idiopathic arthritis (JIA) (European Medicines Agency, 2011c). On one hand, UC is a chronic inflammatory bowel disease, usually involving the rectum but may extend to involve the colon. 15% of its occurrence affects children, of which majority involves older children and adolescents. It may also appear in newborns as young as 3 months old. On the other hand, JIA refers to arthritis starting to appear in children no older than 16 years old, and may affect any age group. It lasts for no less than 6 weeks. Though it is a major cause of child disability, its causes are unknown.
Taking the first guideline, its objectives, priorities, methods and measures will be examined. Some of its most important objectives were to clarify the requirements for the efficacy assessment methods and the safety aspects of the development. As part of its inclusion criteria and procedures, several assessments should be performed concerning osteoporosis, steroid dependency, metabolic disorders, etc. Emphasis was given on the evaluation of drug concentration for different ages. It encourages the development of a suitable oral and rectal formulation for young children. The aim of the treatment should be remission (the disappearance of signs and symptoms) without side effects on growth and maturation as well as normalization of body weight, growth and sexual development, if these are abnormal at the baseline.
As regards safety measurement, all adverse events (AE) have to be documented, including those expected by the pharmacodynamic properties of the investigational product. A risk management plan is required to anticipate risks of neoplasia, infections and autoimmune disease. They also advise that a Data Monitoring Committee may be necessary, to identify groups at increased risk, and to monitor study endpoints, duration, population, and available safety knowledge. Endoscopic follow-up may be omitted.
In the second guideline, clinical investigation for JIA, the objective is to provide guidance concerning the design of clinical studies related to the investigation of medicinal products to be used in JIA, particularly its therapeutic efficacy and clinical safety. Outlined in this document, the ultimate goal of treatment should be the induction of remission. As of yet, modern treatment has concentrated on the prevention of organ damage, maximization of physical function and promotion of normal growth and development through a rapid inflammation suppression. JIA is one of those diseases where off-label drug prescription is commonly practiced, relying on empirical experience because of a limited number of studies performed. The assessment of some medicinal products has been assessed based on their efficacy in the treatment of rheumatoid arthritis in the adult population. Extrapolation has mostly been inappropriate since JIA in the pediatric population comprises several categories of different diseases, each having different prognoses and variable clinical presentations.
As for recommendations for safety, investigation of the drugs’ pharmacokinetics should be investigated as subgroups may require age-appropriate formulations. Long-term safety monitoring requires follow-up in the post-marketing setting. This monitoring may have to be extended for a period longer than 12 months when parallel data in the adult population is not available. Even longer periods may be necessary to guarantee assessment of clinical safety in the pediatric population.
Because of the limitations of clinical trials as a function of drug development especially in the pediatric population, the safety and efficacy of medicinal products are compromised. Thus to further ensure the safety of patients, monitoring of a medicine’s effects has been extended beyond clinical trials and up until its post-marketing. This is called pharmacovigilance, define by WHO as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem” (World Health Organization, 2011).
Regulating agencies revolutionized their tools in countering and preventing the unacceptable implications of unsafe drugs. Two pharmacovigilance systems have been presented, the Yellow Card Scheme and EudraVigilance. A couple of cases that illuminate pharmacovigilance will help examine the extent and inadequacy of this system in terms of discovering ADRs that have not been exposed through clinical trials.
The first pharmacovigilance case is on the antiviral oseltamivir, also known as Tamiflu. This analysis covers the period 1 April 2009 to 11 July 2010, during the H1N1 influenza pandemic. Through the EudraVigilance database, a total of 1,135 reports were collected worldwide, majority of which are non-serious ADRs. More than 50% of the affected patients were 18 to 64 years old, while nearly 20% were between 3 and 11 years old (European Medicines Agency, 2010a). From the FDA database, only 1,805 reports were gathered from 1999 to 2007; while in Roche database, 2,466 reports were collected, 22.8% of which are serious (Jefferson, 2009). Based on all these reports, the most common suspected ADRs include vomiting, rash, headache, diarrhea, abdominal pain, as well as hallucination, confusional state, convulsion, nightmare, and suicidal tendencies.
The second case is that of selective serotonin re-uptake inhibitors (SSRIs) which are typically used to treat depression, anxiety disorders and some personality disorders. Reports pointed it to abnormal bleeding due to its platelet-blockade properties that cause platelet dysfunction (Medsafe Pharmacovigilance Team, 2006). In a review of 20 studies (late 1990’s onwards), the ADRs associated include changes in testosterone and natrium level, and liver damage.
Based on these 20 studies, it was deduced that cohort study was not the most appropriate approach to post-marketing surveillance of ADRs, as has been typically believed by healthcare professionals. Cohort studies lack randomization and were only able to detect type A (dose-dependent and predictable) and type B (dose-dependent and unpredictable) ADRs. Case reports on the other hand, which include spontaneous reporting, have provided data about patients, suspected ADRs, disease treated and medicines used. While they may not be the most accurate and research-based because of their retrospective nature, they provide new information about previously unknown ADRs. In particular, they are suitable for detecting type C (chronic effects) and type D (delayed effects) ADRs. In addition, their findings can indicate where systematic analysis should be done in larger populations so as to utilize and apply more accurate measurements.
ADRs detected both during clinical trials and in post-marketing settings are on the most basic level, caused by the lack of inappropriate formulations. Children are exposed to doses and ingredients that are originally developed for adults. The high incidence of unlicensed and off-label prescription in children further highlights the need for age-specific formulation. A hospital disclosed that it spends 11 hours in extemporaneous drug preparation every day, one of the major causes of ADRs (Dubin, 2008). Another major problem is the low compliance rate among pediatric patients because of medicines’ unpleasant attributes. Statistics show that rates of 50%-70% non-compliance apply to children because of drugs’ disagreeable taste and difficulties in administration, like swallowing tablets or capsules (Dubin, 2008).
The problem is further amplified in neonates. The lack of neonate-specific liquid oral formulations has resulted in parents and healthcare professionals’ practice of pulverizing tablets, opening capsules, and mixing these with other formulas or with food. Capsules are obviously not suitable for neonates as well. Moreover, injectable formulations that are being administered orally pose a problem since gastric acids distort and destroy some drugs’ efficacy. Extra caution should also be exercised because some toxic substances that cause ADRs may be contained in injections. In some cases, relatively diluted formulations may be mixed with other fluids at a volume that is too much for neonates. There is no sufficient data on whether the alternative and unproven administration of medicine are able to achieve the drug’s intended efficacy (Giacoia & Mattison, 2005).
The Best Pharmaceuticals for Children Act (BPCA) established a network of pediatric medical centers that aims to expand clinical trials in children, the Pediatric Trials Network (PTN) (Canavan, 2011). In addition to pharmacokinetic difference considerations, they are taking new heights into pharmacogenetics, the science looking into the effect of genetic factors on drugs. How can this knowledge of the pediatric population, drug properties and pharmacokinetics lead to practical improvements in pediatric drug development?
There are basic differences between children and adults that should be taken into consideration. These are absorption, distribution, metabolism and elimination of drugs relative to the body’s composition, maturity and response. Drug absorption may be oral, topical or rectal. Children under 3 years old have higher gastric pH which increases absorption of basic drugs and decreases the absorption of weak acids. This factor dictates what kind of medicine will be most effective and how its administration should be timed. For instance, some findings show that the best time to administer these drugs is with meals so as to avoid gastrointestinal irritation. Because of neonates’ relatively thinner epidermis with a poorly developed stratum corneum, topical absorption is more enhanced than it is in adults, and thus systemic effect can be achieved through transdermal route. Correspondingly, absorption of toxic is also enhanced through skin contact with agents such as hexachlorophene and methylated spirits. Other repercussions concerning this high permeability is a high transepidermal water loss that leads to difficulties in fluid balance and temperature control (Barker et al. 1987). For children who are experiencing vomiting, rectal absorption is recommended, but only for medicines with wide therapeutic margins (Pandolfini & Bonati, 2005).
A newborn is made of up 80% water, 65% at 12 months, while an adult is 60% water. This and the fact that neonates have less body fat composition indicate the need for larger volumes of water-soluble drugs. But before making dosage recommendations, hepatic function and renal elimination should be considered first. The binding of drugs with protein is diminished in neonates resulting in higher percentages of unbound active drugs in the plasma. Looking at drugs currently being used in children, few highly protein-bound drugs count. Finally, the blood-brain barrier of neonates is not yet fully developed. Therefore drugs’ lipid-solubility should be watched to prevent over-penetration of drugs into the brain (World Health Organization, 2010).
Even with reference to full-term infants, the newborn population is special in its maturational heterogeneity, distinct physiological and metabolic characteristics, as well as the diseases that are unique to this period of development. Deeper into the strata of developmental subgroups, low-birth-weight infants should be considered as a separate population with very special pharmacological requirements. The effect of drugs can be affected by their physiological characteristics and metabolism, as well as their pathophysiologic abnormalities. The differences in absorption, distribution, metabolism and excretion between preterm and term infants may be associated with the rapid and variable maturation and process during the first month of life, although no sufficient studies have been done in this respect (Giacoia & Mattison, 2005).
From the perspective of pharmaceutical companies, formulation for children is not simply altering those available for adults. Aside from technical factors, market needs have to be determined and addressed. For instance, the high non-compliance among children is due to bad taste. Unlike adults, children have very little tolerance for this. Drug developers have to consider a medicine’s taste, smell, texture, shape and mouthfeel, as well as children’s emotional state in taking these medicines. Recently, pharmaceutical companies have seen new commercial opportunities in focusing on respiratory/allergy, anti-infectives, and CNS (Dubin, 2008).
Pediatric Investigation Plan (PIP)
Before conducting pediatric drug development studies and clinical trials as required for the acquirement of marketing authorization, pharmaceutical companies should first submit a pediatric investigation plan (PIP). The PIP contains a description of the studies and a more suitable medicinal formulation for children. It ensures that authorisation of a pediatric medicine is supported by data gathered through safe clinical trials in children. PIPs submitted to the European Medicines Agency’s Pediatric Committee (PDCO) can be accepted or declined by them. As difficulties along the way render the plan unfeasible or inappropriate, it can be modified afterward.
When the PIP has been completely complied with, the pharmaceutical company will be granted a 6-month extension for the market protection of its product. Also contained in the PIP is a long-term follow-up procedure in case of ADRs. The applicant may also have to propose a risk management system or post-marketing studies. Where a study has resulted in an authorization of a pediatric indication for a product already marketing for other indications, it should be placed on the market bearing its pediatric information (including results of studies, the status of PIP, waivers and deferrals).
To ensure children’s safety, studies can be deferred until such time that it has been proven safe through tests performed in the adult population. For the development of diseases that do not affect children, a PIP needs not to be submitted.
The most basic guide in determining the ethical appropriateness of actions and decisions is whether these are acted upon on behalf of a child’s best interests (Sutcliffe, 2003). This includes both subjecting them to the potential risks of research, and prescribing drugs that have not been tested at all to the general pediatric population. Another dimension is respecting their autonomy through informed consent. To ensure scientific and social validity, proposals should be reviewed independently and verified against appropriate standards. However, the possibility of causing physical and psychological harm remains to be anticipated and difficult to measure.
Ethical concerns revolve around the appropriateness of clinical trials in children in opposition to the day-to-day practice of exposing the general population to treatments that have not been proven safe and effective for them. Authorities and regulatory agencies are one on the stand that for the most part, it is more beneficial not only to the general population but also to research participants to be tested and treated in a safe and controlled environment. In order to protect the rights of children who participate in such research, they created what is called the Clinical Trials Directive 2001/20/EC. Among its concerns is the consent given by patients’ legal guardians. Both parents and patients must be informed regarding the trial’s benefits and risks. Article 4(h) of the Directive defines the expertise needed in the Ethics Committee. Such experts must provide opinions on clinical trials to be performed in children from the time that the initial protocol is submitted and throughout the trial progress when amendments are being generated.
Since children’s capacity in performing certain tests and activities are limited, clinical trials should be appropriately designed according to their objectives and the scientific questions it aims to answer. It should also be adapted to the requirements and needs of each pediatric age group. For instance, the use of placebo is more limited in children than in trials performed in adults. Treatment should also not be withheld if proven to be beneficial, especially in cases of serious and life-threatening conditions. This is highly important when possible ADRs would affect a child’s growth and development. In all cases, age-appropriate formulations should be used whenever available. When not avoidable, pain should be minimized and treated effectively, including fear, distress and parental separation. The child’s comfort and reassurance should be top priority (Waller, 2007).
Complications arise when acquiring consent from very young children and neonates who may be affected by clinical trials and the drugs administered on them for the long term. The medicines that will be used during these trials had not been previously proven effective and safe. More seriously, they may cause long-term harm to the growth and development of the participating children. The question remains whether a few children may be sacrificed for the good of the whole population.
Finally, guardians who give consent on behalf of children may not understand well the risks associated with the clinical trial. Transparency of the procedures and possible effects should be priority. They may also perceive the trial to be the only way to cure the child’s disease, especially in terminal cases thus they might not consider the risks at all. Likewise, guardians possibly do not have the best interest of the child at heart, especially where research groups give tokens to participants (Wendler and Jenkins, 2008).
The multiplicity of forces that influence the issue of Pediatric Drug Development demands impartial consideration of various standpoints – science, politics, ethics and business. Conflicting principles, for instance, of science and ethics limits the freedom to investigate the quality, safety and efficacy of medicinal products; hence limiting the availability of empirical data that would shape and support designs of clinical trials (Sammons, 2011).
Descriptive research will be most suitable for the purpose of describing the nature of the legislation and drug development for pediatric population, and exploring the factors affecting the outcome of such legislation. Related literature will aid in critically evaluating previous research and multiple cases, and minimize possible bias. Documentary secondary data will also be largely used for its richness in observational, research-based data.
The researcher will primarily use the quantitative method in order to measure several issues at hand. First, pediatric pharmacology will be explored in terms of its scale (the number of drugs and usage information made available in the market relative to the total pediatric population) and depth (the development across different subgroups and the reliability of drug development procedures, particularly in the design of clinical trials). Pharmacokinetic and pharmacodynamic differences between children and adults will be highlighted as a prelude to the discussion. Given these, the sufficiency of drug development for the pediatric population will be put to question as is correlated to physicians’ dependence on off-label and unlicensed medication for children.
The following limitations in pediatric clinical trial design are already well documented:
- A cost-benefit analysis of drug development for this population has proven to be minimally profitable
- Trial designs are limited by the eligible patients and controls suitable for the age
- It takes longer to complete the development compared to that of adults
- Approval process also takes longer
The EU legislation has been brought forth as a response to mitigate these limitations. It placed emphasis on pediatric drug quality and efficacy, while boosting and maintaining clinical trial safety among participants.
Moreover, the researcher will explore and study the complexities and impact of factors such as ethics and politics. On one hand, a study shows that children and their guardians are more likely to be willing to participate in non-beneficial research in spite of the risks made known to them (Niles, 2003). The conditions that foster this will be examined, such as terminal illnesses, promises of recovery, and lack of alternative medication or therapy. Since children are considered to be more vulnerable in general, stricter observance is applied. Not only the consent of both participant and guardian are required, but also an institutionalized assessment of risks and benefits. However, interpretations are still needed for ambiguous terms such as “minimal” and “minor”. The institution’s credibility and authority on the matter will also be scrutinized. In addition to these ethical issues, physicians’ viewpoints will be considered since they are the ones directly involved in off-label and unlicensed prescriptions. A relevant question to be addressed is whether it is more ethical to prescribe a possible cure to patients, or to withdraw these potentials altogether (Collier, 1999).
On the other hand, influential companies and organizations have different, if not conflicting, interests that pull the development in various directions. Large investments, profits and reputations are at stake; thus careful consideration of publications, news and studies will still be observed. For instance, issues arise when research bodies offer tokens to participants, especially a significant amount of money offered to guardians.
Furthermore, clinical designs will be evaluated according to their consideration of age subgroups and the magnitude of variation in doses required. The researcher will inquire as to what extent these trials employ extrapolation, modeling and simulation. It has been previously cited that extrapolation from studies in adults is more often unadvisable than not. That is due to medication differences, age group differences, and high risks in growth and developmental aspects.
First and foremost, the researcher will look into the EU legislation, contextualize its development, and examine its assumptions and objectives. Each directive will also be scrutinized in terms of its targeted audience – how the legislation has benefited and incurred them additional costs, their mandated responsibilities, and the authority bestowed upon them. For example, how has the legislation affected pharmaceutical companies’ development of new drugs, operations and profitability, particularly for the pediatric population? How are sponsors of clinical trials and research bodies rewarded, and what measures do they take to ensure the safety of participants? What additional challenges do they face in the coming of this relatively new legislation? As for regulating bodies, the researcher will look into the scope of their authority and responsibility, as well as applicable controls against fraud. Have they been effective by far and what are their weaknesses? In general, are there responses and results that the legislation failed to anticipate, and with that, how can it be improved?
Documentary secondary data are subdivided into pre-legislation and post-legislation. The researcher will first examine those published before the EU legislation, covering the period 1999 to 2007. The common problems and concerns the industry faced in that period will be examined, followed by an inspection of their recommendations. It can be inferred that these situations largely affected the crafting of the legislation.
Post-legislation materials are those published after 2007, the year of the EU legislation’s implementation. By and large, these are observations and critiques of the principles, effects and responses of the different stakeholders. Included here are studies on issues surrounding clinical trial designs such as adherence to the directives, population representativeness, age-matched controls, safety measures are taken, patient consent, availability of eligible participants, pharmacovigilance and approvals of such designs or proposals.
Afterward, the researcher will look into the reports of successes and failures of clinical trials. Two illustrative examples will especially examine recent pediatric pharmacovigilance issues: tamiflu and SSRIs. Analyses will be formulated as regards tendencies in drug development, the type of diseases treated and the population size benefited.
Finally, these materials will be given an international perspective through comparisons vis-à-vis pediatric medicines regulation across nations (UK, EU, US and Japan); and advances in pediatric drug use in different governing bodies (UK, EU, FDA, ICH, WHO).
Presentation of Results
For the first objective of this dissertation, the various provisions and regulations in the EU legislation will be described. The risks, challenges and pitfalls involved as well as their benefits and achievements will be analyzed.
Secondly, data will be presented reflecting the implementation of study design and clinical response to the legislation. The representativeness of study population in terms of age-specific pharmacokinetics and pharmacodynamics will be a qualification. Accomplishments, improvisations, limitations and overall trends in clinical trial design will be presented. These will be supported by an analysis of the prerequisites, risks and effects of drug testing on children.
Finally, in order to draw conclusion on the success of the EU legislation, its provisions will be compared with the designs of clinical trials. This evaluation will be in terms of: the availability of high-quality drugs and public information; the effectiveness of such directives as Pediatric Use Marketing Authorization (PUMA), Pediatric Investigation Plan (PIP), and the European Network of Pediatric Research in conducting ethical research in children; authorization delays for use in adults; and the increase in drug development for neonates. Based on these conclusions, the researcher will present recommendations, both amendments to the legislation and improvements to clinical trial design. Above all, this entails analysis regarding the responsiveness of clinical trial design to the legislation.
Reliability and Viability
The secondary documentary data and related literature used in this dissertation are selected by the researcher based on several criteria: actual research was conducted and is supported by strong evidence; the publication’s relevance to related studies and review; representativeness of study population; at least 5 independent studies and research must confirm the findings; disconfirmation must be minor relative to selected sources, and must be refuted or explicated in any one of those sources; depth of issue examination; and any indications of possible bias such as background and affiliation of the author.
The researcher mitigates bias in data examination and in the presentation of conclusion and recommendation by ensuring that evidence are sufficient, clear and relevant to the findings.
As for the limitations of this project, the researcher relies upon the availability of the EU legislation directives and is limited to documented, publicly-available studies and findings in pediatric drug development and clinical trial designs. No judgments will be made in favor of any particular subgroup, disease category, procedure, culture, gender, nationality, or organization.
In order to assess the achievements and tribulations in pediatric drug development, the researcher must first explore complex issues that provided the backdrop of its formulation, influenced its directives, and verified its validity and relevance as legislation. This will be achieved through the use of documentary secondary data and reviews of related literature, in which several criteria will ensure reliability and validity. Data pertaining to the trends in drug development and clinical trial designs will be presented.
Conclusions on the legislation’s achievements and pitfalls will be drawn from an examination of its directives vis-à-vis the response of clinical trial designs. Finally, recommendations will be given, both as amendments to the legislation and improvements to clinical trial design.
Findings and Discussion
Pediatric Regulation: Context and viability
Data have been presented on the background of the Pediatric Regulation, the context in which it was created, its main objectives and the barriers it aims to remove for the achievement of those objectives. It can be deduced that efforts in creating better drugs for children and protecting their rights have gone a long way since the historical drug-related tragedies of the past had taken place (Gluck, 2009). These initiatives also span different nations and leverage collaboration among different expertise and experiences.
It has been found that most clinical trials and drug development are impeded because of commercial, ethical and technical difficulties. However, these may no longer be true and acceptable. Recent data show that more and more children are taking prescription medications. For example, a 12-month study in Canada on a private drug plan database showed that 30% of Canadian children claim a prescription drug. The same is true for the US. The annual growth of spending on prescription medication is greater in children than in adults (Boots et al., 2007).Thus it is now commercially rewarding for pharmaceutical companies to conduct major clinical trials and drug development in children. On top of that, the magnitude of profits that a pharmaceutical company gains from taking advantage of the incentives offered by regulating authorities are highly rewarding.
Aside from profitability, ethical concerns on performing clinical trials have confirmed that subjecting children to medication that had not been tested for safety and efficacy is more disadvantageous to the population at large. The common practice of unlicensed and off-label prescription resulted in minor and serious ADRs, including death. Moreover, research verifies that it is safer for clinical trial participants to be treated in controlled environments than to be prescribed drugs with doses that are based only on physicians’ and pediatricians’ experience and estimates. Finally, technical difficulties can now be combated through state-of-the-art technologies that regulatory agencies and research networks could effectively liaise among stakeholders. Guidelines have been provided by agencies in order to make it easier for research groups to conduct trials without sacrificing the rights of children. Secondary endpoints are also available as alternatives to primary endpoints that cannot be measured in children. Tools have been improved in order to assess pain and to measure quality of life among younger who is believed to be a more vulnerable group. The small number of eligible participants and patients affected by certain diseases that make recruitment a lot more challenging than in adults can be resolved through agencies such as the National Institute for Health Research which provides the infrastructure for multi-center research. Databases kept by authorities that detail the proceeding and outcomes of clinical trials give authorities the idea of which technologies and support materials need to be developed. One example is the pharmacokinetic assays used to acquire blood samples (Boots et al., 2007). These require samples that are too much for neonates, making the acquisition of blood samples highly discomforting. Hence, technological developments must be geared towards alleviating these kinds of difficulties.
The Legislation on Clinical Trials Outcome
In addition to the mitigation of the abovementioned barriers, authorities have created legislations that incentivize pharmaceutical companies to develop pediatric drugs. In the US for instance, the change in pediatric drug development between the periods 1991 to 2001 and 1999 to 2007 was a dramatic increase. Dr. Richard Gorman of the Committee on Drugs of the American Academy of Pediatrics claimed that “We are entering what could be the golden age for kids and pharmaceuticals” (Gluck, 2009). However, before hastily declaring the success of the legislation, the assessment must not be limited to how much drug development has flourished – but to how much the pediatric population’s unmet needs have actually been addressed.
First and foremost, the representation of pediatric subgroups is not well established in clinical trials. Whilst younger children use more medications, of which 90% are prescribed unlicensed or off-label, fewer trials have been conducted in this population. Only 14% of participants are represented by neonates, while 39% by infants. For instance, 37% of the respiratory prescription drugs used in children are still used unlicensed or off-label. In a study presenting the drugs that most children use, top of the rank are respiratory drugs, anti-infectives for systemic use and dermatological. However, the drugs that were granted pediatric exclusivity in 2005 include atorvastatin (Lipitor), simvastatin (Zocor), omeprazole (Nexium), lansoprazole (Prevacid), and sertraline (Zoloft), 5 among the 10 top-selling prescriptions in North America (Boots et al., 2007). Interestingly, Pediamed Pharmaceuticals announced that they were concentrating on developing respiratory/allergy drugs, anti-infectives and CNS for children (Dubin, 2008). Furthermore, only 38% out of 365 trials conducted among 95,000 participating children have resulted in labeling changes (see Clinical Trial Design). If a huge number of children are getting involved in these studies, it must at least result in a total good for the general population and not only gain the research sponsor some commercial reward. Regulating agencies have released several lists of priority drugs for children; however this does not guarantee the development of those drugs. Moreover, a study has exposed the inaccuracy and unreliability of such list released in 2004 (see Unlicensed and Off-label Prescribing in Children). Through the World Health Organisation’s (WHO) Model Formulary for Children 2010, huge improvements are seen in its listing. On top of laying down the drugs widely used without license and off-label, it guides healthcare professionals in prescribing and dispensing medicines that have not been tested in children. The Formulary also leads research where it is lacking. Nevertheless, Formularies must remain supplementary to information obtained through well-designed studies and clinical trials in order to ensure that medicines are formulated and administered age-appropriately. Ideally, the devaluation of such materials must be a real golden age in pediatric drug development.
In terms of monitoring and ensuring the safety of drugs prescribed to children, pharmacovigilance is set up and systematized. Most research and clinical trials are not able to entirely unravel all possible effects of a certain drug, both benefits and risks. Some effects have long gestation periods and appear only in a relatively small percentage of the total population. Thus unless it is released on the market, these ADRs can hardly be quantified, analyzed and corrected. This yet inevitable situation is strategically being managed through the reporting of ADRs in almost all stages of development and marketing. Included in this knowledge bank is information gathered during clinical trials which make possible the re-assessment of ADRs after the marketing. But by far, the most effective method of obtaining ADRs that are previously unidentified with some degree of statistical power is spontaneous reporting. This has been institutionalized and standardized by the UK through the Yellow Card Scheme. This system allows healthcare professionals and patients to report suspected ADRs. “Suspected” means that the reactions may or may not be associated with the medicine being reported, or what shows up is a symptom of another illness, or caused by another medicine. Yet the potential of this data gathering system remains fruitful compared to others, and that it can be enhanced by empowering and encouraging stakeholders regarding their role in fostering safer and more effective medicines for children. Its availability in community pharmacies and accessibility through a hotline puts it in an even better position. Perhaps one way of encouraging people to report more promptly is the availability of these reports publicly, either on the website or through scientific literature. Also, systematic analysis must follow constantly and continuously in order to generate conclusions on ADRs that have not been previously identified, with which spontaneous reporting has been proven to be effective.
On the level of legislative initiatives, the CNH guidelines advise that clinical trials be done in children after safety and efficacy have been established in adults. On the contrary, the Pediatric Regulation requires that the PIP be submitted early on, before the completion of pharmacokinetic studies (Watzl, 2007). This directive may not be totally beneficial to children notwithstanding its objective to give timely opinions on pediatric studies.
As regards the impact of the Pediatric Regulation, RAND (research and development) Corporation, a nonprofit institution that helps in the improvement of policies through research, was asked by the European Commission to assess the economic, social, environmental and sustainable impacts of the legislation. RAND judged that the legislation will achieve its overall objective of improving children’s health, at a net gain against total cost of money to the industry, the government and the consumers (Gluck, 2009).
Taking the legislation’s stakeholders one by one, it can be assessed whether the legislation derives a positive response from each. As for pharmaceutical companies, the rewards and incentives have significantly increased drug developments in the pediatric population. Usually a compound’s protection lasts for 7 years, after which generic medicine can enter the market. The incentive of an additional 6-month extension can be magnified considering the huge population in Europe. A pediatric study that costs around one million dollars can be turned into profits of $50 million through the protection of a 6-month patent extension (Gluck, 2009).
However, the incentives associated with Pediatric Use Marketing Authorisation (PUMA), or already off-patent drugs do not appear to be as attractive. Because of this, the Pediatric Committee (PDCO) launched a list of priority list of indications for children where public funding through the European Commission serves as the most viable vehicle since pharmaceutical companies have little interest in off-patent medicines. In the first exercise in 2007, six projects have already obtained funding. Additionally, the Seventh Framework Programme for Research and Technological Development (FP7) has called for proposals for studies on these drugs. Although PUMA is currently weak, authorities hope that new pediatric formulations can still be extracted from the old drugs.
Based on a report by EMEA, out of 629 validated applications from 2007 to 2009 only 21 applications (3%) referred to PUMA. The same goes on the report for 2010 (4 applications constituting 3%) (European Medicines Association, 2011f). On the other hand, there were a total of 9 projects funded by the EU Framework Programme between 2007 and 2009 (European Medicines Association, 2010b), and 3 projects in 2010.
The Pediatric Regulation also resulted in the establishment of the European Network of Pediatric Research which will drive the generation of new information through pediatric research. They will establish a network of existing networks to facilitate trials that require specific expertise, facilities, and methodologies, to carry out its objective of avoiding duplicate studies and testing in children. They will build the necessary scientific and administrative competencies to capacitate other agencies to serve their function (Rocchi et al, 2010).
The whole system is supported by the European Medicines Agency (EMEA) by providing free pediatric and scientific advice, and information tools that include an inventory of therapeutic needs, new product labeling information requirements, and a database of clinical trials that is available to the public (EudraCT). This aspect appears to be one of the European legislation’s advantages over the implementation in the US (Sinha, 2008). The research community is able to leverage an efficient and profitable use of resources, as well as share improved methodologies on the conduct of clinical trials. Recruitment of participants has also become more efficient. For the pediatric population’s safety, EMEA provides guidelines on safety monitoring and long-term follow-up on ADRs, as well as other post-marketing requirements like a risk management system.
In order to assure transparency, all information and research progress are published, from planning and recruitment to the final results. All EMEA’s decisions on PIPs and their corresponding waivers and deferrals are being made public through the website. Moreover, all information related to the granting of a marketing authorization is included in the Summary of Product Characteristic and the Patient Leaflet that goes with the medicinal product. In addition to this, the European Medicines Association (2004) obliged the Commission to publish a list of companies and products that have benefited from any of the rewards and incentives in this Regulation, as well as the companies that have failed to comply with the Pediatric Regulation. Benefits include advice from the Agency and the National Competent Authorities, PIP waivers, extension of SPC or market exclusivity, marketing authorization, reimbursement, and research incentives (European Medicines Association, 2010b).
Finally, the European Commission is tasked to write a report on all the aspects of the Pediatric Regulation’s implementation, whether good or bad. The most important considerations are the economic and public health impact of the legislation against its objective of providing safer medicines to children while protecting their rights in clinical trials and studies.
The EU pediatric legislation has introduced revolutionary changes in the pharmaceutical industry. Its mandates and incentives are expected to create a paradigm shift in the development of new medicines. Europe is largely utilizing the learning and databases derived in the US in its decade-earlier implementations such that the trickling of effects in Europe is more intense and faster. However, the new EU legislation’s foundations cannot wholly leverage the experiences of the US. Unlike in the US, pediatric development is mandatory in EU for all new medicinal products, unless where a waiver is granted. Pharmaceutical companies are also required to submit a PIP as soon as it has finished pharmacokinetic studies in adults. During clinical trials, research should be able to identify the appropriate total daily dose and the frequency of medication, otherwise efficacy and safety might not be established. A consideration of pharmacokinetic parameters is necessary for a risk-benefit analysis. The anomalies of SSRIs mentioned above, for instance, were probably caused by dosing strategies that are unsupported by pharmacokinetic studies. Before conducting clinical trials in the pediatric population, pharmaceutical companies are encouraged to develop first an evidence-based dosing strategy. However, the challenge is that pharmacokinetic and dose-ranging studies are difficult to perform and ethically challenging, and do not offer prospective direct benefits (Auby, 2008).
With all these changes facing the industry, stakeholders face scientific, ethical, practical and financial difficulties. For instance, the use of a placebo in clinical trials raises ethical concerns among health authorities and ethics committees. One technical difficulty is the non-acceptance of current EMEA guidelines of comorbidity. Yet this case constitutes 40% to 70% in child and adolescent psychiatry (Auby, 2008). In the new environment resulting from the creation of the pediatric legislation, pharmaceutical companies would probably integrate the pediatric considerations at the very early stages of developing new chemical compounds. Drug development in adults will now be parallel to that in the pediatric population.
To counter the challenges, the European Commission published guidelines that imply the need for stakeholders’ cooperation and interaction. These new processes are very promising in leading to huge improvements in pediatric drug development and child health care. One of the legislation’s creations, the European Pediatric Committee (PDCO), could potentially offer greater support to new applicants through direct interactions with pharmaceutical companies. Dialogues around the common goal of developing better medicines for children would be imperative and beneficial to the improvement of the pediatric regulation.
As can be seen from the information presented in this dissertation, there are still a lot of information gaps that need to be addressed before the pediatric population can be given holistic protection on healthcare. Most studies are limited in terms of representativeness of the population especially in terms of age-specific pharmacokinetic and pharmacodynamic differences. Endpoints are more difficult to measure in children than in adults since they are not able to perform specific tasks and activities, and their ability to communicate perceptible pain and improvements is limited. This lack of scientific data, particularly on pharmacokinetics in children, should not lead prescribers and formulators to generalize that differences between children and adults are not sufficient to cause alarm in terms of unlicensed and off-label prescriptions. It must always lead to further developments on areas that are identified to be unintelligible or insufficient.
To mitigate the harm resulting from this widespread practice, authorities have come up with formularies specially made for children. This effort has standardized the guide for healthcare professionals and recommendations as to further research and has led to more coordinated studies and drug development efforts. Nonetheless, these materials should remain to be supplementary to evidence-based data and a guide as to which medicines need further research.
The strict guidelines being drawn by regulatory agencies call for quality research and drug developments, in turn creating safe and effective drugs for children. This environment that values pediatric health and information transparency promotes competition among pharmaceutical companies. In the long run, this will benefit the whole population in terms of health and sound decision-making. If information will be made available and accessible to patients and healthcare professionals, their decisions will be guided by an intelligent assessment of risks and benefits.
The networks established through the Pediatric Regulation have helped in establishing guidelines that simplify procedures, advising the research community as regards clinical trial designs, in making facilities and other resources available most efficiently and effectively. To maintain the integrity of these authoritative organizations, the impartiality of its members should always be prioritized. They must not have conflicting interests especially on the financial gains of pharmaceutical companies.
Taking this on to an international level, the sharing of resources such as funding, information, methods and expertise are made even more beneficial. For instance, drugs developed within Europe reach countries like Japan and US, where data can be gathered regarding its ADRs sequentially leading to possible improvements in formulation. Resource-sharing can be achieved at a bigger scale, while mistakes and precautions can be preempted as well. For example, much has been learned from the 10-year earlier implementation of the US of such legislation.
Such practices as unlicensed and off-label prescriptions that cause immense harm to children can be mitigated. Stakeholders remain ill-informed about the severity of the condition and their role in possibly eliminating the risks. They are also not able to identify the root cause which is the lack of age-appropriate formulation, a consequence of lack of clinical trials in pediatric drug development. Nonetheless, they see value in coordination between prescribers and pharmacists in the proper dispensing of medicines to patients. They also take responsibility in informing patients and parents of the potential risks of using medicines that have not been tested in children, but a system to guide them and facilitate this communication is lacking. This is one of the underlying issues that the EU legislation has failed to throw careful consideration into. Much effort has been concentrated on the drug development phase and less on the frontline turnover and dispensing of medicine.
At the bottom of this practice, the most vulnerable are neonates. Majority of medicine usage is prescribed for this age group yet the least research and clinical trial also occurs here (Giacoia & Mattison, 2005). As mentioned, endpoints are harder to measure in children in general, and even more challenging in the neonatal population. Facilities and technology available to measure drug efficacy are very limited. These could be the reasons why pharmaceutical companies are reluctant in conducting drug development research in this population, not to mention the ethical repercussions attached. Newborns and full-term infants are not able to give consent in participating in clinical trials where their growth and development are at risk at a permanent stage. Moreover, neonatologists do not seem equipped at observing and measuring ADRs. They are too confident in asserting that ADRs do not occur in their area of responsibility when in fact drugs are not intended and tested for neonates. This above all else, calls for a standardized measurement or monitoring body of the scale and scope of the practice, including the types of diseases, medicines and specific patient groups involved. Current statistics are only based on individual research that is highly limited.
As for the drug development of pediatric cancer patients, one of the limitations lies in the inaccessibility of innovative compounds developed for adults by pharmaceutical companies. In addition to cures for those currently suffering the disease, survivors of childhood cancer must be given more attention. Technology has increased understanding of tumor biology and design of anticancer compounds. New data are available on their mechanisms of action, antitumor activities and toxicity profiles. Moreover, greater attention has also been given to the efficacy of drugs than their safety. Long-term follow-ups are as important in this population as maladministration may result in lack of benefit, resistance development, and increased ADRs (Paolucci, 2007).
Limitations in research and development are more evident in the case of epilepsy, wherein no cure for the disease has been found yet. Only medicines to control seizures are present, which most of the time cause ADRs. Non-government and non-profit organizations largely influence the environment and their role is vital to increase quality, effective and safe drugs for their children suffering from epilepsy. Instead of focusing on authentic drug development, pharmaceutical companies may be inclined to use clinical trials as a marketing ploy since returns in this area are not that rewarding. As a conclusion to the STEPS case, the trial was deemed a seeding trial because of the involvement of the marketing team in data collection and because of the failure to disclose the real purpose to the stakeholders (Medical News Today, 2011).
In the case of asthma, despite the prevalence of the disease, there is still no existing treatment that effectively achieves control of symptoms. The disease is proven to be detrimental to physical, psychosocial, emotional, and educational performance, productivity and adaptability, especially in children with uncontrolled asthma. This ineffective drug development can be attributed to the lack of coherence in the efforts of different research networks and the lack of international cooperation. Standardized treatment is hardly seen among three countries surveyed in a study, including the Netherlands, Italy, and the United Kingdom. The use of asthma drugs varies widely among these countries, which even limits the comparison of data on outcomes (Sen, 2011).
As for the clinical trials presented in ADHD, ADRs are only minimized up to a certain level. Parents are well-advised to contact the Clinical Trial Coordinators (CTC) in the case of any physical, behavioral, psychological, or physiological anomalies attributable to the trial. The CTC will ask the parent to continue the treatment if the ADR observed is mild, and to monitor the development of the condition. In the case of emergencies, the parents should take the participant to the nearest Emergency Department, whom the CTC will inform regarding the treatments administered. All ADRs will be recorded. The research group will be responsible for monitoring the participants’ safety during and after the clinical trial.
Having pointed out the lack of age-appropriate formulations, pharmaceutical companies are called to design formulations and administration that are well-suited to children. Other companies have initiated using sweets, puddings and creative packaging that will distract children away from the bad taste of medicine. This step would highly decrease the currently high non-compliance rate among the pediatric population. However, the commercial and financial challenge remains as to the size of the pediatric population and its consumption of medicines, vis-à-vis the size of adult population and profitability of mainly serving this market. History proves that only market-based incentives and rewards for drug development can stimulate better healthcare since the costs and difficulties of conducting clinical trials are high.
The incentives offered to pharmaceutical companies seem adequate because of the upsurge of drug development in children. Besides, drug testing in children has been made mandatory by the European Commission. The stringent monitoring through the requirements of the PIP ensures that clinical trials will be free from causing harm to children, as much as possible. For instance, before studies can be approved, applicants must give a description of such studies as well as the implications for the pediatric population. The PIP aims to guarantee that all data gathered through clinical trials are done through safety procedures. For instance, most studies have to be performed in adults first to establish safety. Additionally, participants are required to carry out long-term follow-ups in order to monitor ADRs that are more observable in a relatively larger population. Others are required to present a risk management plan in order to mitigate the risks foreseen in the research. The resulting findings should be included in the labels such as the clinical trial results, PIP status, and all other information that will put healthcare professionals and patients in a better position in terms of decision making and assessing risks and benefits. However, despite the regulations, pharmaceutical companies could still circumvent the legislation right through the use of waivers that exempt applicants from conducting clinical trials specifically for the pediatric population. This is either because such indications are not present in children or that conducting such trials does not outweigh the risks posed for participants. This poses a concern especially for pediatric cancer patients where granting of waivers might be based on the histological type of cancer rather than its mechanism of action. For instance, drug development for breast cancer should not be automatically waived for children because even though breast cancer does not occur in children, the same compound can be targeted to cure leukemia (Vassal, 2009). Pharmaceutical companies have also been observed to develop drugs that are most commonly used in the adult population and extend these studies to children in order to acquire an additional six-month market protection. These drugs do not necessarily address the real needs of children. Lastly, the mechanism for developing off-patent drugs for pediatric indications, PUMA has not been a sufficient incentive or reward for pharmaceutical companies. The majority of the few studies filed under PUMA are funded publicly. This is because the 10-year data protection offered by the directive does not necessarily guarantee market exclusivity, thus other groups can conduct studies on the same active ingredients under question.
In any case, it may be too early to tell whether loopholes in the legislation are preventing the maximum benefit that could be achieved in pediatric healthcare. An important success factor in the legislation’s implementation and possible amendments is the close coordination among the different agencies, networks and authorities. Specialization and task delineation are also good sources of advantage. EMEA should be kept transparent and all the information that the public needs to make sound decisions.
In order to tackle the Pediatric Regulation in light of the issues present in clinical trials in children, one has to start at the concerns that are most familiar to its primary stakeholders. The side effects of medicines in children cause a variety of harm, from minor headaches to situations as dreadful as death. These occur because of the insufficient drug development for the pediatric population, leaving medicines on the market vulnerable to off-label and unlicensed prescription. Healthcare professionals are left with no choice in the endeavor to provide patients with potential cures to their diseases, despite these medicines’ efficacy and safety are not clinically proven. There is also a gap between this practice and the patients’ awareness of risks associated with their aspired benefits.
Adverse drug reactions (ADRs) are due to insufficient pharmaceutical studies, research and clinical trials conducted in the pediatric population. Because of this, not enough information is generated that will indicate the safety and efficacy of drugs as regards their use in children. There are no guidelines to help healthcare professionals in terms of dosage, timing, and route of administration. Prescribers have been limited to unlicensed and off-label drug use, the experience-based prescription of scaling down medicines intended for adults. However, aside from differences in size, body composition, maturation and functions, children have pharmacokinetic and pharmacodynamic differences from adults (Holford, 2010). This lack of development is a result of difficulties in conducting research and clinical trials in the pediatric population. Pharmaceutical companies have found it ethically and technically difficult, without enormous financial rewards to developing drugs for this small, complex and sensitive population.
With these at hand, it is important to examine actions to be taken at two levels: a short-term solution through the development of formularies and education for the stakeholders including healthcare professionals and patients; and a medium to long-term approach through legislation, establishment of networks and regulatory agencies, and the standardization of drug development procedures.
Since ADRs are not completely evitable at the present condition of appropriate-drug availability, access to information holds the key to intelligent decisions and the prevention of unnecessary harm. Those at the frontline must be equipped in handling problems where their judgment can cure or make a patient worse. Prescribers and pharmacists should be given refresher courses and seminars that will update them on the prevalence and seriousness that the practice causes. Furthermore, since information is not available on labels, a standard formulary must be made available to them, free of charge if possible. This will enable them to inform patients and parents of the risks and benefits associated with using unlicensed or off-label medicines. More importantly though, the process of informing patients or parents should be standardized as well so that confusion will not arise among people at different levels. Through this they can be empowered and own the responsibility to communicate. Technologies for measuring ADRs that minimize human error must be made accessible to them as well, especially to neonatal wards where neonatologists appear to be unable to observe ADRs in patients.
In addition to this, healthcare professionals should be made connected to patients. More than numerical and technical emphasis on ADRs and pharmacovigilance, they should hear stories of how reporting had saved lives in the past and what specific medicines had been pulled out of the market. This will create an impression among professionals that every action they take has a corresponding effect on another person’s life.
On the more holistic approach, where standardization, networking and sharing of resources are on the level of creating new legislation, there should be systems that are conducive, well-defined, easily understandable and measurable. Efforts become more effective and efficient when taken to a large-scale movement where resources and information can create ripples and become accessible to small research groups. Also, having a larger population participate in the implementation stage generates statistical power that is not available in sample populations that are imperfectly represented. Well-designed systems can lead to sophisticated analysis that will instigate improvements and mitigation of pitfalls. Moreover, collaboration reduces overlaps in function and authority, and will speed up the process with less bureaucracy. Excellent communication is fundamental to success since stakeholders understand well their areas of responsibility.
The authoritative bodies should also revisit their core organization, function and their aptitude in implementing the new regulations. Since the Pediatric Regulation is an entirely new initiative, they may have to invite new types of experts who understand well the pediatric population, especially the more sensitive areas of cancer and neonatal healthcare. They may also reorient their existing personnel and realign their technologies, facilities and procedures. The challenges that have occurred in the past should serve as basis in preventing these from happening in the pediatric population. For instance, the conflict of interest among pharmaceutical companies developing the same compounds at the same time, yet having different prospective benefits and risk levels must be looked into. Moreover, the staff of regulatory authorities should be quick in spotting seeding trials as in the case presented in the epilepsy drug gabapentin. Seeding trials destroy the integrity of the entire biomedical enterprise as it depends on good science and the transparency of its purpose. Authorities must be wary of the diversion of clinical studies from the values of well-designed and well-conducted phase 4 studies. Steps have already been outlined to reduce bias and unwarranted commercial influence in drug development, all it takes is firm implementation. Finally, the inventory of pediatric needs should also be strictly prioritized in order to make sure that the industry is going in this direction. Having a firm yet encouraging environment for the whole industry must begin with its implementers.
Procedure-wise, a standardized reporting system must be created in order to make an analysis of reports quicker, supplemented by tools that will help people in analyzing raw, large data and making decisions. Educating and empowering the most ordinary of consumers does not end in giving them information, but should extend to equipping them on how to best utilize the information. If the databases provided by the public will be made available to them, people will be better guided and cautious in their intake and administration of medicines; and they will have a better sense of purpose and responsibility in taking action.
On the level of the legislation’s directives, drugs that have been proven safe and effective for children but will no longer be manufactured by its Marketing Authorisation Holder (MAH), or has no intended party to transfer the authorization to, should be allowed for generic manufacturing. This serves the purpose of all the studies and trials conducted for that particular drug while both adult and pediatric populations will be benefited. Revolutionary information should not be rendered useless because of commercial constraints. Efforts should not only be geared towards the bigger populations’ needs (where the profits are), but also for whom needs them most.
For instance, pediatric cancer patients are disadvantaged compared to adults because of the rare incidence of the disease in children, compared to the whole cancer-affected population. Also, most drugs used for pediatric cancer patients are off-patent drugs intended for adults, further reducing the incentives for drug development in this area. Pharmaceutical companies thus find little interest in developing medicines that will address this niche. The most practicable drivers then are cooperative groups and publicly-funded organizations. The legislation must find a way to create an encouraging environment for these groups to boost research and development. One way will be for the European Commission to allow a larger budget to support these particular activities. Another will be to increase the incentives for benefactors who are involved in this endeavor. They could incentivize pharmaceutical companies and other for-profit companies to contribute to the funds of off-patent drug development since they do not want to undertake it themselves.
Given the short period of the legislation’s implementation, further studies and advanced investigation is still needed in order to draw sensible conclusions on the effectiveness of the Pediatric Regulation. Pediatric Use Marketing Authorisation (PUMA), for instance, must figure out where it wants to focus its efforts – whether in encouraging pharmaceutical companies to develop pediatric drugs by increasing financial incentives and rewards; or in making the environment more favorable for research conducted by cooperative groups and publicly-funded organizations that are more purpose-driven yet dependent on the availability of sponsorship. This way, the progression of the directives will be more concentrated and can achieve a greater impact on the targeted area. The acquirement of a waiver also calls for keen attention as this may be largely used by pharmaceutical companies to circumvent the Pediatric Regulation, or unintentionally hamper the development of drugs largely needed by small groups. For instance, indications that have been listed as automatically waived for studies in children may include diseases that are not obvious to occur in children. Yet upon closer studies, other categories put them in the same type as those occurring in children. On another note, the boundaries associated with the granting of a deferral must be clearly defined, more so the consequences that companies who fail to adhere to this agreement.
Finally, measuring the impact of the legislation on the different stakeholders – the pharmaceutical industry, regulatory authorities, healthcare professionals, health insurers, the government, the research bodies, and the general public – is as important as the pre-implementation studies. Monitors and indicators must be standardized and all-encompassing. It must be able to describe and quantify the effect and changes in terms of the procedures done in drug development, the resources used, partnerships entered into, international collaborations, technological advancements, economic growth, the support systems provided to prescribers and pharmacists, and the actual products and information made accessible and understandable to patients and their guardians. Until such time that these measures could demonstrate the goals aimed at by the legislation at a certain scale and scope, the judgment of success and pitfalls is not yet sufficient and thus improvements will not be adequately recommended.
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