Background There is often a lack of safety and efficacy data in the paediatric population at the time of drug approval. Legislative efforts have promoted clinical pharmacology research in this underserved population. We sought to determine the quantity and quality of paediatric clinical pharmacology data in US drug labelling at the time of initial approval and to evaluate trends over time.
Materials and methods The labelling data of 213 new molecular entities approved between 2003 and 2012 were systematically reviewed. The type of paediatric pharmacology data present at the time of approval was recorded and stratified by age group. Labelling revisions were analysed for updated paediatric data. The presence of paediatric-specific black-box warnings was noted.
Results Of the 213 drugs evaluated, 48 had adult-specific indications. Of the remaining 165 medicines, only 47 (28%) had paediatric study data at the time of initial labelling. The number of approved drugs with paediatric data was the greatest in 2005 (8, 44%) and was at its lowest point in 2012 (3, 11%). Only five medicines had neonatal data, with none of the anti-infective agents presenting neonatal information. Seven medications had a paediatric-specific black-box warning. Additional 16 medicines presented paediatric data during general labelling updates.
Conclusions Despite efforts to improve the quality of paediatric clinical pharmacology data, there was not a significant increase in drugs with paediatric data at the time of approval over this 10-year study period. Paediatric drug approvals and labelling revisions continue to lag behind their adult counterparts.
- Paediatric Practice
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What is already known on this topic
There is a lack of safety and efficacy data in the paediatric population at the time of drug approval. Legislative efforts have promoted clinical pharmacology research in paediatric population. The extent to which these initiatives have impacted paediatric information at time of new drug approval is not clear.
What this study adds
There has not been a significant increase in the number of drugs with paediatric data at the time of initial approval. Few of the medicines approved for use in paediatric patients were approved for use in neonates. Paediatric drug approvals and labelling revisions continue to lag behind their adult counterparts.
The past two decades have been marked by major policy changes and innovations in the field of paediatric pharmacotherapy. The US Food and Drug Administration's (FDA) Paediatric Labeling Rule of 1994 followed by the FDA Modernisation Act (FDAMA) of 1997 and the companion legislations of the Best Pharmaceuticals for Children Act (BPCA) in 2002 and Paediatric Research Equity Act (PREA) of 2003, have led to significant advances in the field of paediatric clinical pharmacology.1 This series of initiatives has resulted in approximately 780 paediatric clinical trials that have expanded existing knowledge of appropriate age for use, pharmacokinetics, pharmacodynamics, as well as safety and efficacy data.2 Over 100 drugs have been studied with more than 400 subsequent paediatric labelling revisions.3–5 In 2012, the BPCA and PREA were permanently reauthorised under the FDA Safety and Innovation act (FDASIA).3 ,4 This permanent status was a further step in promoting pharmaceutical research in this traditionally underserved population.6
The ultimate aim of these pharmaceutical policy initiatives is to provide the paediatric population with safe, effective and equitable drug therapy. The intent of these initiatives is to provide additional data on safety, efficacy and dosing of currently available medications, and also to stimulate routine testing leading to paediatric labelling at the time of the initial drug approval.7
Current legislation has stimulated paediatric labelling updates for drugs that are already on the market, but the extent to which these initiatives have impacted paediatric information at time of new drug approval is not clear. The objective of this study was to determine the quantity and quality of the paediatric clinical pharmacology data in US drug labelling at time of the initial drug approval and to evaluate change over time.
We performed a retrospective study of paediatric pharmacology data available for new molecular entities (NME) approved by the FDA between 1 January 2003 and 31 December 2012. The FDA maintains a publicly available online database of all drug approvals that includes the initial labelling information and subsequent label revisions. Labelling information for all recently approved NMEs was obtained from the FDA database at (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm). Drug approval reports were scanned in reverse chronological order by month, searching for original NME approvals. These new approvals included all newly approved drugs and selected new biologics. Only biologics that were listed on the FDA website under new drug approvals were included. Biologics used for research purposes, tissues, gene therapies, and vaccines were not included. Generic approvals, new formulations of existing drugs, abbreviated new drug approvals, and supplemental applications were also excluded, because these drugs were already present on the market.
As a primary outcome, the initial approval letter and label were reviewed in detail for presence of any paediatric information. Subsequently, as a secondary outcome, any supplemental data, including addition of new formulations, and all subsequent labelling revisions were also reviewed for an update on paediatric information. Paediatric data was described as any data relevant to paediatric population in the formal approval, dosing guidelines or the presented studies. Drugs with advice for no use in children because of unavailability of data were considered drugs with no paediatric data. The month and year of approval and the therapeutic category of each drug were recorded. Each drug label was reviewed for presence of any paediatric data at time of initial approval, in any of the prespecified paediatric age groups. The age classification was adapted from the Paediatric Exclusivity Study Age Group, which includes newborns (0–1 month), infants (1 month–2 years), children (2–12 years), and adolescents (12–18 years). Because of the major differences in metabolism, formulation and physiology during the early versus middle childhood period, we further stratified the 2–12-year age group into 2–6 years and 6–12 years.8 ,9 Any labelling update concerning the paediatric population and all paediatric black-box warnings were also recorded. It was also noted if the source of paediatric information in the labelling was from human studies, animal studies or other relevant resources, such as extrapolation from adult studies or drugs in the same therapeutic class. The therapeutic category variable was determined by the drug's primary indication or based on the mechanism of action. There were 19 therapeutic categories defined (table 1).
As the FDA database does not contain patient information and is publicly available, the study was not considered human subjects research.
Over the duration of the study, 213 NMEs were identified and 99% of them were approved for adult use (n=211). An insulin-like growth factor for treatment of growth hormone deficiency and a synthetic formulation of pulmonary surfactant for prevention of respiratory distress syndrome were solely approved in the children of 2–18 years old and neonates, respectively. Forty-eight of the identified new drugs were indicated for adult-specific conditions. Of all the others with potential paediatric indications (n=165), only 47 (28%) presented paediatric pharmacology data at the time of initial approval (see online supplementary etable 1). None of the drugs related to gastrointestinal, anaesthesia/analgesia, cardiology, rheumatology, urology or nephrology had any paediatric information despite the potential paediatric indications (table 1). The number of drugs with paediatric information per year did not follow any specific pattern over the study period, being highest in 2005 (n=8) and lowest in 2012 (n=3). The majority of paediatric data pertained to the 12–18 years age group (n=45, 96%). The amount of data available at approval decreased with age with only five drugs having neonatal data. Drugs used to treat infectious diseases (n=14) followed by neurologic (n=7) and endocrine/metabolic (n=5) conditions had the highest rates of presenting paediatric data in the initial labelling (7%, 3% and 2%, respectively). However, none of the drugs approved for infectious disease indications had data regarding use in newborns (table 2).
Of the 118 medicines without paediatric data at the time of initial approval, 16 presented labelling updates with paediatric data. Four of the 47 medicines with paediatric data at the time of initial approval, presented additional paediatric information. The details of updates were related to age range expansion (n=15) or non-age specific information (n=5). Labelling updates were mainly seen for medications related to HIV (n=6), cancer (n=4), diabetes (n=3) and allergies (n=2). New formulations of the NMEs were available for 14 drugs (6%) related to infectious diseases (HIV and hepatitis B), neurology (seizure, neuralgia), endocrine/metabolic (inborn errors of metabolism) and oncology (renal cell carcinoma). Oral suspensions (n=13) and oral capsules (n=1) were added to the initial formulations through the formulary update. Only five drugs had paediatric labelling update following the formulation change. The paediatric update belonged to drugs for treatment of renal cell carcinoma and HIV, with none of the seizure (n=4), neuralgia (n=1) or inborn errors of metabolism (n=1) medications providing any paediatric information despite appropriate formulation being available.
The mean time to the labelling update was 54 months (range 11–106), with 40 months for the six labelling updates related to HIV medications, and 43 months for oncology drugs. Seven medications had a paediatric-specific black-box warning, and one paediatric black-box warning was added as an update. Black-box warning data included suicidality (n=3), fetal and developmental adverse effect (n=3) and death (n=1). Of all the updated labelling with paediatric information including black-box warnings, only 56% quoted data from human paediatric studies (n=42).
Our results demonstrated that over 70% of the newly approved drugs do not have any information related to paediatric population despite having clear indication for paediatric use. If present, this data was mainly related to children above 12 years of age, while newborns and younger children were kept in a therapeutic orphan status. We observed obvious lack of paediatric data for drugs approved in adults for treatment of critical conditions like HIV, hepatitis C and cancer, with further lack of information for conditions such as mood disorders and hepatitis B in younger children. There were no new drug approvals or updates that were related to infectious diseases in the neonate, which is an area of significant therapeutic need in this population. This is consistent with previous evidence showing that availability of paediatric information directly correlates with the paediatric patient's age with the least available data in the newborn population.7 ,10 ,12
Presence of paediatric data at the time of the initial approval did not follow any specific pattern of advancement over the study period, with minimal formulation or labelling update related to paediatric population. FDA's analysis data has shown over 400 labelling updates as a result of paediatric pharmacotherapy initiatives in the past 20 years.4 At the same time, we found that only a very small number of these labelling updates belong to the newly approved drugs of the past 10 years.
Although no recent data are available, this pattern is in agreement with the 2006 report on newly licensed medication by European Medicines Agency (EMA) where only 74 out of a total of 222 newly approved active substances include information allowing paediatric use.13
As per FDA's guideline on the clinical investigation of medicinal products in the paediatric population, for drugs intended to treat serious or life-threatening diseases occurring in adults and paediatric patients, relatively urgent and early paediatric studies should be initiated. We observed a prominent lack of paediatric data for the majority of drugs approved in adults for treatment of such conditions, and also a considerable delay to paediatric labelling update for the few drugs available. Conditions such as melanoma or juvenile macular degeneration are now recognised entities in paediatric population. Irritable bowel syndrome and nicotine addiction are of increasing prevalence in preadolescent and adolescent age groups with substantial physical and emotional burden and, as a consequence, there is a need for therapeutic options. This lag in availability of paediatric pharmacotherapy data can result in a delayed paediatric access, which can be detrimental in such conditions with limited therapeutic options and potentially fatal outcomes.
Most newly approved anticancer drugs were indicated for conditions such as myelodysplastic syndrome, multiple myeloma and chronic lymphoid leukaemia, which are extremely rare in children. This pattern demonstrates how new drug approvals are mainly driven by adult indications. Furthermore, it has been shown that regardless of the indication, the mechanism of action of anticancer drugs may be of potential value for treatment of certain types of paediatric malignancies. This should be considered before calling for a paediatric study waiver solely based on the adult-focused indication.14 ,15
The BPCA has identified key areas in need for paediatric pharmacotherapy research, which includes infectious diseases, oncology and anaesthesia.16 Consistent with available evidence on European medicinal products, infectious disease had the highest percentage of drugs with paediatric data at time of initial labelling, while oncology and anaesthesia were among the lowest studied drugs. This substantially low degree of paediatric data in highly emphasised areas in need for research by the recent regulatory acts further highlights the limitations in current strategies in promoting paediatric research among relatively newly approved drugs.
The legislation passed during the past two decades have made significant strides in overcoming the substantial gap that exists in paediatric pharmacology data. As we move forward in enhancing our knowledge of drugs that are commonly used off-label in children, efforts should be also made to maintain research equity in newly approved drugs. This strategy is a key step in avoiding the expansion of the currently existing gap in the field of paediatric pharmacotherapy.
Although the potential barriers for conducting paediatric research have been addressed by multiple reports, and variable recommendations have been made to overcome the foreseen obstacles, our study shows the current efforts have not made a solid step in overcoming the existing challenges.7 The collaborative role of federal agencies, academic institutions and patient advocacy groups are needed to support the paediatric therapeutic legislations in an ethical framework and practical manner so that research equity and, as its result, safe and efficacious pharmacotherapy comes into a reality in this underserved population.17 ,18
There has not been a significant increase in the number of drugs with paediatric data at the time of initial approval. The lag in paediatric drug approvals and labelling revisions continue to be prominent compared to adults. This delay in providing paediatric pharmacotherapy data for the newly approved drugs will cause further expansion of the currently existing gap in the field of paediatric pharmacotherapy. The paediatric legislations should further pave the way for normalising the concept of research equity and demanding the paediatric data as a rule and not a mercy.
The authors would like to acknowledge Yao Iris Cheng for her contribution to conducting the statistical analysis of this work.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online supplement
This data was presented as an abstract at the European Society for Developmental, Perinatal and Pediatric Pharmacology (ESDPPP) meeting, Salzburg Austria, June 2013.
Contributors SS-Z: contributed in data interpretation and was the lead author of the manuscript, also approved the final manuscript as submitted. MM-Am: collected the data, contributed to the data interpretation and critical review of the manuscript and also approved the final manuscript as submitted. JNvdA: contributed in the critical review of the manuscript and also approved the final manuscript as submitted.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.