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Original article
Trends in paediatric clinical pharmacology data in US pharmaceutical labelling Samira Samiee-Zafarghandy,1,2,3 Maryann Mazer-Amirshahi,1,2,4 Johannes N van den Anker1,2,5,6,7 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ archdischild-2013-305605). For numbered affiliations see end of article.
Drug therapy
Correspondence to Dr Samira Samiee, Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, 111 Michigan Ave. NW., Washington, DC 20010, USA; [email protected] This data was presented as an abstract at the European Society for Developmental, Perinatal and Pediatric Pharmacology (ESDPPP) meeting, Salzburg Austria, June 2013. Received 2 November 2013 Revised 30 June 2014 Accepted 2 July 2014 Published Online First 25 July 2014
ABSTRACT 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 adultspecific 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 antiinfective 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.
INTRODUCTION
To cite: SamieeZafarghandy S, Mazer-Amirshahi M, van den Anker J N. Arch Dis Child 2014;99:862–865. 862
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
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.
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.
METHODS 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
Samiee-Zafarghandy S, et al. Arch Dis Child 2014;99:862–865. doi:10.1136/archdischild-2013-305605
Downloaded from http://adc.bmj.com/ on March 14, 2015 - Published by group.bmj.com
Original article 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 blackbox 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.
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
Over the duration of the study, 213 NMEs were identified and 99% of them were approved for adult use (n=211). An insulinlike 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 adultspecific 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
Therapeutic category of approved drugs during the study period
Therapeutic categories
Number of drugs
Number of drugs with paediatric data
Number of drugs without paediatric data*
Oncology Infectious disease Endocrine/metabolic Neurology Psychiatry Gastrointestinal
41 35 27 17 12 11
2 14 5 7 1 0
11 21 22 4 11 11
Cardiology Urology Diagnostic imaging Haematology Dermatology Ophthalmology
10 10 9 7 6 6
0 0 2 1 2 3
6 5 4 4 4 3
6 4 3 3 2 2 2 213
2 3 0 3 0 2 0 47
4 1 3 0 2 0 1 118
Pulmonology Allergy/immunology Anaesthesia/analgesia Toxicology Nephrology Obstetrics/gynecology Rheumatology Total
Examples of usage of drugs without paediatric data PH+ AML, melanoma, thyroid cancer HIV, multidrug-resistant TB DM, IEM, dyslipidemia MS, partial seizure MDD, schizophrenia, insomnia, smoking cessation IBS, SBS, HIV-associated Diarrhoea, chemo-associated nausea HTN, PAH Over active bladder CNS or cardiac vascular imaging Iron overload, anaemia, thrombocytopenia Actinic keratosis, dispersion of injected drugs Macular degeneration, OAG, postoperative inflammation Obstructive pulmonary disease Hereditary angioedema Sedation, analgesia, refractory pain – Hypercalcemia, ESRD – DMARD
*Drugs with paediatric indication but no paediatric data. CNS, central nervous system; DM, diabetes mellitus; DMARD, disease modifying antirheumatic drug; ESRD, end-stage renal disease; HTN, hypertension; IBS, irritable bowel syndrome; IEM, inborn errors of metabolism; MDD, major depressive disorder; MS, multiple sclerosis; OAG, open-angle glaucoma; Drugs with paediatric indication; PAH, pulmonary arterial hypertension; PH+ AML, Philadelphia positive acute myeloid leukaemia; SBS, short bowel syndrome; TB, tuberculosis.
Samiee-Zafarghandy S, et al. Arch Dis Child 2014;99:862–865. doi:10.1136/archdischild-2013-305605
863
Drug therapy
Table 1
RESULTS
Downloaded from http://adc.bmj.com/ on March 14, 2015 - Published by group.bmj.com
Original article
Drug therapy
(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
Table 2 Paediatric drug approval by indication Therapeutic categories
12– 6– 2– 18 years 12 years 6 years
Original article
Trends in paediatric clinical pharmacology data in US pharmaceutical labelling Samira Samiee-Zafarghandy,1,2,3 Maryann Mazer-Amirshahi,1,2,4 Johannes N van den Anker1,2,5,6,7 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ archdischild-2013-305605). For numbered affiliations see end of article.
Drug therapy
Correspondence to Dr Samira Samiee, Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, 111 Michigan Ave. NW., Washington, DC 20010, USA; [email protected] This data was presented as an abstract at the European Society for Developmental, Perinatal and Pediatric Pharmacology (ESDPPP) meeting, Salzburg Austria, June 2013. Received 2 November 2013 Revised 30 June 2014 Accepted 2 July 2014 Published Online First 25 July 2014
ABSTRACT 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 adultspecific 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 antiinfective 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.
INTRODUCTION
To cite: SamieeZafarghandy S, Mazer-Amirshahi M, van den Anker J N. Arch Dis Child 2014;99:862–865. 862
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
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.
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.
METHODS 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
Samiee-Zafarghandy S, et al. Arch Dis Child 2014;99:862–865. doi:10.1136/archdischild-2013-305605
Downloaded from http://adc.bmj.com/ on March 14, 2015 - Published by group.bmj.com
Original article 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 blackbox 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.
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
Over the duration of the study, 213 NMEs were identified and 99% of them were approved for adult use (n=211). An insulinlike 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 adultspecific 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
Therapeutic category of approved drugs during the study period
Therapeutic categories
Number of drugs
Number of drugs with paediatric data
Number of drugs without paediatric data*
Oncology Infectious disease Endocrine/metabolic Neurology Psychiatry Gastrointestinal
41 35 27 17 12 11
2 14 5 7 1 0
11 21 22 4 11 11
Cardiology Urology Diagnostic imaging Haematology Dermatology Ophthalmology
10 10 9 7 6 6
0 0 2 1 2 3
6 5 4 4 4 3
6 4 3 3 2 2 2 213
2 3 0 3 0 2 0 47
4 1 3 0 2 0 1 118
Pulmonology Allergy/immunology Anaesthesia/analgesia Toxicology Nephrology Obstetrics/gynecology Rheumatology Total
Examples of usage of drugs without paediatric data PH+ AML, melanoma, thyroid cancer HIV, multidrug-resistant TB DM, IEM, dyslipidemia MS, partial seizure MDD, schizophrenia, insomnia, smoking cessation IBS, SBS, HIV-associated Diarrhoea, chemo-associated nausea HTN, PAH Over active bladder CNS or cardiac vascular imaging Iron overload, anaemia, thrombocytopenia Actinic keratosis, dispersion of injected drugs Macular degeneration, OAG, postoperative inflammation Obstructive pulmonary disease Hereditary angioedema Sedation, analgesia, refractory pain – Hypercalcemia, ESRD – DMARD
*Drugs with paediatric indication but no paediatric data. CNS, central nervous system; DM, diabetes mellitus; DMARD, disease modifying antirheumatic drug; ESRD, end-stage renal disease; HTN, hypertension; IBS, irritable bowel syndrome; IEM, inborn errors of metabolism; MDD, major depressive disorder; MS, multiple sclerosis; OAG, open-angle glaucoma; Drugs with paediatric indication; PAH, pulmonary arterial hypertension; PH+ AML, Philadelphia positive acute myeloid leukaemia; SBS, short bowel syndrome; TB, tuberculosis.
Samiee-Zafarghandy S, et al. Arch Dis Child 2014;99:862–865. doi:10.1136/archdischild-2013-305605
863
Drug therapy
Table 1
RESULTS
Downloaded from http://adc.bmj.com/ on March 14, 2015 - Published by group.bmj.com
Original article
Drug therapy
(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
Table 2 Paediatric drug approval by indication Therapeutic categories
12– 6– 2– 18 years 12 years 6 years
