Pediatric exclusivity and other contemporary regulatory changes: impact on pediatric drug study, labeling and safety

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1 Pediatric exclusivity ad other cotemporary regulatory chages: impact o pediatric drug study, labelig ad safety Cli. Ivest. (2013) 3(3), Historically, most drugs have bee used off-label i childre due to a lack of specific iformatio o dosig, safety ad efficacy. This practice risks adverse evets, leadig to serious public health cosequeces. Regulatory chages have attempted to address such issues by madatig ad icetivizig the study of drugs i childre. By all accouts, these regulatory chages have bee eormously successful i stimulatig >400 pediatric cliical trials erollig >170,000 childre over the last 5 years. These trials ad others coducted over the precedig 15 years have resulted i >400 pediatric-specific labelig chages. While these labelig chages have improved pediatric drug safety, critics voice cotiuig cocers about the fiacial widfall for idustry, relative lack of study of off-patet agets ad cotiued eglect of several importat pediatric subpopulatios (e.g., eoates). Kevi D Hill*, P Bria Smith, Michael Cohe-Wolkowiez, Daiel K Bejami Jr & Jeifer S Li Departmet of Pediatrics & the Duke Cliical Research Istitute, Duke Uiversity Medical Ceter, Durham, NC 27705, USA *Author for correspodece: Tel.: Fax: kevi.hill@duke.edu Keywords: Best Pharmaceuticals for Childre Act pediatric cliical trials pediatric drug safety pediatric exclusivity pediatric labelig Historically, childre are uderrepreseted i drug trials; cosequetly, most drugs are used off-label i this populatio [1 3] by extrapolatig dosages from cliical trial data i adults. This practice is iappropriate because childre have uique differeces due to developmet: these differeces affect both pharmacokietics ad disease pathophysiology whe compared with adults. Recogizig these differeces ad the importace of coductig trials i childre, the US Cogress has eacted, over the last 15 years, several regulatory iitiatives aimed at stimulatig pediatric drug developmet ad research. These iitiatives have icluded a pathway for Natioal Istitutes of Health (NIH)-sposored pediatric drug research, as well as icetives ad madates for idustry the so-called carrot ad stick approach [4 6, ]. Pediatric research has bee successfully fostered by these programs as evideced by 405 labelig chages sice their iceptio. However, some limitatios ecoutered thus far iclude the cost of the programs stemmig from prologed patet protectios, few studies of off-patet therapeutics ad cotiued eglect of certai pediatric subpopulatios [6,104,105]. The purpose of this article is to review the history of pediatric drug prescribig, the impact of recet regulatory chages, ad the successes ad failures of these efforts. Off-label pediatric prescribig Off-label drug use occurs whe a drug is used i a differet way tha is described i the US FDA-approved drug label. This typically meas that the drug is used i a ustudied or uderstudied patiet populatio or for a ustudied or uderstudied idicatio. Off-label drug use is commo i childre. I a review of 2000 drugs i /CLI Future Sciece Ltd ISSN

2 Hill, Smith, Cohe-Wolkowiez, Bejami & Li the 1973 Physicia s Desk Referece, 79% of drug moographs lacked sufficiet iformatio or labelig regardig pediatric use, while a similar review i 1991 foud o chage, with 81% of drugs lackig pediatric iformatio [2,3]. A review of 350,000 pediatric hospital discharges at 36 tertiary care childre s hospitals foud that 79% of pediatric i-patiets received a off-label drug [1]. I childre, off-label drug use ca lead to efficacy failures or udesired toxicities. Despite umerous otable historical examples [7,8], safety cocers remai commo. I a cotemporary aa lysis evaluatig previously off-label pediatric drugs studied uder the auspices of pediatric exclusivity, serious safety cocers were idetified i 33 out of 137 (24%) products. These icluded 12 products with europsychiatric adverse evets, icludig suicidal ideatio (ribavari ad iterfero a), aggressive behavior (tolterodie) ad stroke, visio loss ad death (sumatripta). There were also safety evets related to growth (betamethasoe, mometasoe), musculoskeletal evets (ciprofloxaci, levofloxaci), iadequate atibiotic CNS peetratio (liezolid, ertapeem), ad icreased mortality (propofol) [9]. These examples illustrate that, although off-label drug use is a commo practice i pediatrics, there is clearly a risk of iadequate efficacy or potetially serious adverse evets. Furthermore, off-label use of multiple agets risks uaticipated drug drug iteractios that ca affect dosig, safety, or efficacy. Regulatory history & the process of pediatric drug study Despite recogitio of the dagers of off-label drug prescribig i childre, for may years drug testig was ot required i childre, ad maufacturers could claim efficacy based o adult data (Figure 1) [6]. I 1979, the FDA made its first attempt to limit these claims ad required that drugs marketed to childre iclude pediatric iformatio o the label [6,10]. This policy did little to icrease the study of drugs i childre as most pharmaceutical compaies chose istead to iclude a disclaimer statig that safety ad efficacy had ot bee established i childre [6]. The FDA respoded by issuig the Pediatric Rule, which allowed the labelig of drugs for pediatric use based o extrapolatio of efficacy from adults ad additioal pharmacokietic, pharmacodyamic ad safety studies to pediatric populatios. Although cotrolled pediatric efficacy studies were ecouraged uder this rule, they were ot required by law, ad cosequetly this volutary program did ot result i a icrease i the umber of pediatric studies [10]. Of the 430 drugs for which labelig supplemets were submitted, oly 23% supplied sufficiet pediatric iformatio for labelig, ad most of these submissios targeted arrow age rages (e.g., studies limited to adolescets) [11] I 1997, respodig to the cotiued lack of pediatric data, Cogress passed the FDA Moderizatio Act icludig sectio 505A, kow as the pediatric exclusivity provisio [106]. The exclusivity provisio grated a additioal 6 moths of marketig exclusivity (the carrot ) for coductig pediatric studies i respose to a FDA writte request. The pediatric exclusivity provisio fudametally chaged the pediatric cliical trials ladscape. Now the fiacial icetive for idustry was potetially large, ad the regulatios esured that the risks of failure were low as log as sposors adhered to the FDA s stipulatios. The pediatric exclusivity provisio was broadly popular amog the pediatric commuity as it resulted i a icrease i pediatric drug studies [5,107,108]. The major limitatio, however, was that there was o icetive for pharmaceutical compaies to study off-patet drugs. Therefore, drugs commoly used i childre still lacked critical dosig, safety ad efficacy iformatio. The 2002 Best Pharmaceuticals for Childre Act (BPCA) addressed this problem by establishig the Program for Pediatric Studies [102]. Uder this program, the Natioal Istitute of Child Health ad Huma Developmet (NICHD) ad the FDA were tasked with developig a priority list of off-patet drugs (Table 1) [12]. The FDA could the issue a writte request for study of a drug o the priority list. If the request was declied by the drug sposors (oly oe such request has ever bee accepted), the the FDA could publish requests for study to third parties, icludig academic istitutios. Other importat amedmets uder the BPCA icluded: Clear laguage idicatig that the FDA ca request studies i differig pediatric subpopulatios (icludig eoates); A requiremet for review of safety evets for 1 year after gratig of exclusivity [13]. The 2002 BPCA required review ad reauthorizatio i At that time, Cogress further refied the process for the study of off-patet drugs by requirig that the priority list focus o therapeutic areas of eed rather tha specific drugs. The 2007 reauthorizatio also established a process whereby the NIH (i additio to the FDA) could iitiate the study of a off-patet drug, provided that the drug was eeded i oe of the priority therapeutic areas [101]. Fially, i the summer of 2012, Cogress permaetly reauthorized BPCA with further refiemets to the process. Some of the more importat chages are summarized i Box 1 [109]. While the pediatric exclusivity provisio iitiated a volutary testig program for o-patet ad subsequetly off-patet agets, critics had log argued that drug study should also be a requiremet for all ew

3 Pediatric exclusivity & other cotemporary regulatory chages US FDA Moderizatio Act Provides market exclusivity for drugs studied i childre The Pediatric Rule FDA allows pediatric labelig based o extrapolatio of efficacy from adults + PK/PD data i childre Best Pharmaceuticals for Childres Act Re-authorizes pediatric exclusivity with provisios for study of off-patiet drugs icludig developmet of the priority list Pediatric Research Equity Act FDA Safety ad Iovatio Act Cogress codifies the BPCA/PREA re-authorized Fial Rule requirig pediatric without suset study of ew products The Fial Rule A federal judge strikes dow the FDA requires pediatric Fial Rule decidig that FDA does studies of ew products, ot have authority to require idicatios, dosig regimes testig i childre ad so forth FDA Amedmets Act Re-authorizes pediatric exclusivity ad revises priority list to emphasize therapeutic areas of eed Figure 1. Timelie of recet regulatory chages. BPCA: Best Pharmaceuticals for Childre Act; PD: Pharmacodyamic; PK: Pharmacokietics; PREA: Pediatric Research Equity Act. pediatric drug applicatios as it already is for adults [6]. To regulate pediatric study for ew drug applicatios, Cogress passed the Pediatric Research Equity Act (PREA) i This act required that, for all applicatios submitted to the FDA for ew drugs (icludig ew idicatios or dosage forms), sposors must iclude data that: Assess safety ad effectiveess of the product i pediatric subpopulatios; Support dosig ad admiistratio of the product for each relevat pediatric age group [13,103]. New drug applicatios ca also qualify for pediatric exclusivity but oly if the FDA issues a writte request ad the sposors effectively meet the requiremets [4,102]. Together, BPCA ad PREA have established mechaisms for study of three broad classificatios of pediatric therapeutic agets: Drugs that are still o patet; Drugs that are off patet; Drugs ot yet approved for marketig (Figure 2). Measurig the success of regulatory chages I a 2001 status report to Cogress, the FDA oted that the pediatric exclusivity provisio had doe more to geerate cliical studies ad useful prescribig iformatio for the pediatric populatio tha ay other regulatory or legislative process to date (Box 2) [108]. This assessmet was based largely o the umber of pediatric-specific labelig chages, ad by this metric, there has bee cotiued progress. Betwee 1 Jue 1998 ad 25 October 2011, the FDA approved 425 pediatricspecific labelig chages as a result of studies coducted uder BPCA or required by PREA [4]. Labelig chages have added sigificatly to our kowledge of safety ad dosig of may drugs i childre. I a aalysis of the first 108 products with labelig chages i respose to a writte request, Rodriguez et al. [14] foud that: Twety three cotaied ew or revised pediatric iformatio such as ew dosig, dosig chages, or pharmacokietic iformatio; Thirty four icluded ew or ehaced safety iformatio; Nietee icluded iformatio o lack of efficacy; Sevety seve exteded age limits for the product. Overall, >50% of products studied had substative differeces i dosig, safety or efficacy. Approximately 20% of the labelig chages highlighted age-related chages i drug absorptio or elimiatio. For example, clearace of the commoly used attetio deficit hyperactivity disorder medicatio Cocerta (methylpheidate HCl) i childre ages 6 12 years was approximately 50% lower i compariso with adolescets or adults, while the opposite relatioship was see for clearace of the atihypertesive Lotesi (beazapril HCl), where clearace i the 6 12-year-old age Cli. Ivest. (2013) 3(3) 229

4 Hill, Smith, Cohe-Wolkowiez, Bejami & Li Table 1. Priority list of eeds i pediatric therapeutics. Therapeutic Areas Drugs Ifectious disease Methicilli-resistat Staphylococcus aureus ifectios Clidamyci, trimethoprim sulfamethoxazole Ifectios Bezathie peicilli G, acyclovir, doxycyclie Tiea capitis Griseofulvi Atituberculous drugs No specific drug Atiparasitic drugs Albedazole Iflueza Oseltamivir Cardiovascular disease Hypertesio Hydrochlorothiazide, lisiopril, b blockers, amlodipie Hypotesio Sodium itroprusside, dopamie Dyslipidemia Statis Respiratory disease Asthma Therapeutics i youg childre, drug-delivery systems, albuterol Pulmoary hypertesio No specific drug Itesive care Ketamie, ihaled aesthetics/isofluorae, lorazepam Aesthesia/sedatio Biodefese research Nerve aget exposure Drug delivery systems, midazolam Cyaide toxicity Hydroxycobalamie Orgaophosphate poisoig Praladoxime Pediatric cacer Neuroblastoma 13-cis-retioic acid Leukemias ad solid tumors Methotrexate, vicristie, dauomyci, actiomyci-d, 6-mercaptopurie Psychiatric disorder ADHD Methylpheidate Bipolar disease Psychosis/aggressio Lithium Atypical atipsychotics Neurological disease Cerebral palsy Lorazepam Seizures Fospheytoi Neoatal research Neoatal BPD/lug developmet Betamethasoe, azithromyci (itraveous) Pai Morphie Neoatal abstiece sydrome Methadoe Ifectios i eoates Metroidazole Necrotizig eterocolitis Ampicilli, meropeem Adolescet research OTC drug use No specific drug Adolescet pharmacology No specific drug Drug ad idicatios ewly added to the Best Pharmaceuticals for Childre Act list from the 2010 prioritizatio process or other sources idetified by the NICHD as a priority. ADHD: Attetio deficit hyperactivity disorder; BPD: Brochopulmoary dysplasia; OTC: Over the couter. Adapted from [111]

5 Pediatric exclusivity & other cotemporary regulatory chages Table 1. Priority list of eeds i pediatric therapeutics (Cot.). Therapeutic Areas Drugs Hematologic disease Sickle cell aemia Hydroxyurea Thrombosis ad thromboprophylaxis No specific drug Edocrie disease ad diseases with limited alterative therapies Fragile X MGluR5 atagoists Type I diabetes No specific drug Dermatologic disease Atopic dermatitis Hydrocortisoe valerate Severe iflammatory ski disease Methotrexate Gastroitestial disease Gastroesophageal reflux Cyclic vomitig ad weight gai Cholestatic disease Prokietic drugs, H2 blockers Cyproheptadie Ursodeoxycholic acid Real disease Chroic kidey failure Devices used i dialysis Aemia of chroic disease Agets to stimulate erythropoiesis Rheumatologic disease Coective tissue diseases Hydroxychloroqui Special cosideratios Therapeutics i childre with itellectual ad physical disabilities No specific drug or idicatio Pediatric formulatios Multiple drugs ad idicatios Pediatric devices Geeral issues Drug ad idicatios ewly added to the Best Pharmaceuticals for Childre Act list from the 2010 prioritizatio process or other sources idetified by the NICHD as a priority. ADHD: Attetio deficit hyperactivity disorder; BPD: Brochopulmoary dysplasia; OTC: Over the couter. Adapted from [111]. group was approximately 50% higher i compariso with adults [14]. Aother importat assessmet of the success of BPCA ad PREA is the umber of pediatric cliical trials coducted i childre. Over a 6-year period before passage of the pediatric exclusivity provisio ( ), drug sposors promised to complete 71 postmarketig studies, but oly 11 were actually completed [108]. I the first 2 years after passage of pediatric exclusivity ( ), sposors completed 58 pediatric studies that resulted i 25 grats of pediatric exclusivity [108]. This tred has cotiued, ad over the 5 years sice reewal of the pediatric exclusivity program, >400 studies have bee coducted i childre uder the auspices of PREA ad BPCA, erollig >170,000 study subjects [110]. Icreasig trial experiece ad moetary ivestmet has resulted i importat itellectual gais. Trials i childre are particularly challegig because of specific cocers related to ethics, dosig, outcome measures, low blood volume ad difficulty aalyzig small samples, assessmet of log-term effects o growth/ developmet, ad the iability to use healthy voluteers for early-phase studies. Cosequetly, more tha half of all trials coducted uder BPCA have bee cosidered failed trials [111]. However, icreasig trial experiece has improved our uderstadig of the specific differeces betwee pediatric ad adult trials, ad these itellectual gais will ehace future trials ad improve child health. As a example, a aa lysis of ati-hypertesive trials completed for pediatric exclusivity highlighted pediatric-specific factors that cotributed to the iability of several dose-ragig trials to demostrate a effective dose respose relatioship [15]. I this aa lysis, failed trials ofte used a arrow dose rage, failed to use weight-based dosig, or did ot use liquid-based formulatios. These fidigs ad others have resulted i substatial chages to the FDA s writte request, icludig a requiremet that a age-specific formulatio be developed alog with age-specific erollmet criteria. Cli. Ivest. (2013) 3(3) 231

6 Hill, Smith, Cohe-Wolkowiez, Bejami & Li Box 1. Summary of pediatric drug provisios icluded i the 2012 US FDA Safety ad Iovatio Act. Permaetly reauthorizes pediatric drug laws PREA ad BPCA reauthorized without suset Requires earlier ad better pediatric study plaig Drug compaies must submit pediatric study plas at the ed of Phase II trials i adults The FDA ad drug compaies must meet to discuss pediatric studies The FDA must publish, withi 1 year, a proposed rule detailig the pediatric study plaig process Adds ew eforcemet tools The FDA must issue public o-compliace letters to compaies that do ot fulfill PREA requiremets Allows compaies to request a extesio for good cause if PREA studies are delayed Icreases focus o eoatal drug studies Requires all writte requests to iclude studies i eoates or to outlie reasos for ot doig so Requires that a eoatologist sit o the FDA s iteral Pediatric Review Committee Requires the FDA to hire a eoatologist to assist the agecy i eoatal applicatio of BPCA ad PREA Icreases trasparecy Requires the FDA to release data reviews of BPCA studies submitted betwee 2002 ad 2007 that have ever bee made publicly available Improves accoutability Requires PeRC review of deferral extesio requests Requires the FDA to publish a publicly available report o BPCA ad PREA every 5 years Other improvemets Exteds the madatory reportig of adverse evets period from 1 year to 18 moths Reews the authorizatio of appropriatios for the NIH BPCA program for 5 years at US$25 millio per year Requires the FDA to hold a public meetig o acceleratig developmet of therapies for pediatric rare diseases ad develop a strategic pla BPCA: Best Pharmaceuticals for Childre Act; PeRC: Pediatric Review Committee; PREA: Pediatric Research Equity Act. Adapted from [109]. There have bee importat cliical trial ifra structure improvemets as well. The 2002 BPCA required the NIH to establish a program for pediatric drug testig ad developmet. The NICHD was charged with implemetig this pla ad therefore developed the Obstetric ad Pediatric Pharmacology Brach (OPPB), which was established i The aual budget of the OPPB has raged from US$29 37 millio with $25 millio aually from BPCA grats ad cotracts [16]. The OPPB has provided a cetral orgaizig brach at NIH dedicated to the study of pediatric ad obstetric therapeutics ad also to the traiig of idividuals with a focus i pediatric/obstetric cliical pharmacology. The OPPB is also required to develop the priority list of off-patet therapeutic agets that require study [16]. The BPCA also required the FDA to establish the Office of Pediatric Therapeutics withi the FDA. The Office of Pediatric Therapeutics s primary missio is to esure access for childre to iovative, safe ad effective medical products. The creatio of these defied braches withi the NIH ad FDA that are dedicated to the study of pediatric therapeutics has bee eormously importat to cetralizig ad coordiatig pediatric trials. Cetralized oversight has allowed the developmet of a strategic focus ad has helped map out commo goals ad objectives to esure that relevat stakeholders are ivolved at all levels of coordiatio, plaig ad implemetatio of pediatric study. A good example is the developmet of the priority list (Table 1). This list of off-patet drugs is revised every 3 years uder the guidace of the OPPB ad ivolves iput from pediatricias ad subspecialist providers, pharmacologists ad basic scietists, as well as idustry ad advocacy represetatives. The process to develop the priority list is cotiually refied ad curretly focuses o distict areas of therapeutic eed, with priority areas of study idetified every year. To facilitate study of therapeutics o the priority list, the NICHD has supported over 60 research etworks or cosortia [112]. Two examples related to BPCA iclude: The Pediatric Pharmacology Research Uit Network, which existed from ad was desiged to

7 Pediatric exclusivity & other cotemporary regulatory chages Off-patiet drugs/biologics O-patiet drugs/biologics New drugs/biologics NIH works with pediatric experts ad US FDA to develop a list of therapeutic eeds Process ca be iitiated by either NIH or sposor Studies are required for all ew drugs or biologics FDA determies whether to issue a writte request ad what to iclude Sposor declies writte request FDA ca decide to refer the request to FNIH to cosider fudig the studies Sposor receives writte request ad has 30 days to accept Sposor ca request that studies be coducted uder BPCA as well ad be eligible for pediatric exclusivity Sposor accepts writte request Sposor coducts required studies ad submits data to FDA for review Sposor ca request a waiver if the drug is felt to be ieffective or usafe i childre Pediatric Review Committee provides recommedatios to FDA FDA determies whether to approve the applicatio ad grat pediatric exclusivity. FDA ad sposor reach agreemet o labelig chages Figure 2. Process for study of drugs or biologics uder Best Pharmaceuticals for Childre Act ad Pediatric Research Equity Act. New drugs/biologics have: ew active igrediets; ew idicatios; ew dosage forms; ew dosig regimes; or ew reoutes of admiistratio. FNIH is a idepedet, oprofit corporatio. The majority of fuds that the FNIH receives are from the private sector. The FNIH has partially fuded two prior studies, but has ot fuded ay studies sice More recetly, a study of most o-patet agets has bee picked up by the Pediatric Trials Network. BPCA: Best Pharmaceuticals for Childre Act; FNIH: Foudatio for the Natioal Istitutes of Health. facilitate collaboratio amog the NIH, academia, ad idustry ad to develop a comprehesive program i pediatric cliical/developmetal pharmacology. The Pediatric Pharmacology Research Uit coducted over 250 studies ad cotributed to labelig chages for 23 differet therapeutic agets [113] ; The Pediatric Trials Network (PTN), which was iitiated i 2010 by the NICHD as the primary aveue for study of off-patet agets after a writte request has bee declied. Although still i its ifacy, the PTN curretly has 30 molecules uder active study ad icludes a etwork of 60 participatig sites across the USA. The PTN has iitiated study of 16 off-patet agets curretly listed o the BPCA priority list [114]. I additio to ifrastructure improvemets i the USA, BPCA ad PREA regulatios have cotributed to a icreased global emphasis o pediatric drug study. I 2006, the Europea Parliamet followed the US example, passig legislatio requirig pediatric-specific study of drugs. I respose, the Europea Medicies Agecy has developed pediatric ivestigatio plas [115]. Likewise, i 2007, the WHO iitiated its Make Medicies Child Size program [116]. Globally, pediatric-based practitioers have bee ispired by the icreased commitmet to pediatric drug study. A example is the Stadards for Research i Child Health Iitiative a global iitiative supported by the FDA, the Europea Medicies Agecy ad the WHO, that aims to improve the quality of desig, coduct, ad reportig of pediatric cliical research by Cli. Ivest. (2013) 3(3) 233

8 Hill, Smith, Cohe-Wolkowiez, Bejami & Li Box 2. Results of studies coducted uder Best Pharmaceuticals for Childre Act ad Pediatric Research Equity Act. Madated (ew drug/biologics applicatios) 134 products studied sice BPCA reauthorized i studies coducted sice BPCA reauthorized i pediatric-specific labelig chages Icetivized (primarily o-patet drugs/biologics) 57 products studied sice BPCA reauthorized i studies coducted sice BPCA reauthorized i pediatric-specific labelig chages Prioritized (primarily off-patet drugs/biologics) 17 off-patet products referred to NIH for study 5 studies with results submitted to NIH for review 0 labelig chages The US FDA has bee required to track products studied ad studies coducted sice BPCA was reauthorized i September A total of 30 products, 82 studies ad 59 labelig chages were coducted uder both Pediatric Research Equity Act ad BPCA ad were thus madated ad icetivized. Data take from [119]. Data take from [120]. Data take from [121]. A 2012 Istitute of Medicie Report [4]. BPCA: Best Pharmaceuticals for Childre Act. promotig the use of moder research stadards [17]. There have also bee global ifrastructure gais. I a aalysis of published trials completed uder the pediatric exclusivity provisio betwee 1998 ad 2007, trials were coducted i over 50 differet coutries, icludig more tha a third with sites i developig atios [18]. While there certaily are ethical ad quality cocers related to the globalizatio of pediatric research, it is likely that such a global ivestmet i pediatric trial ifrastructure will improve the ability to coduct future trials. Critiques Cost While few would debate the importace of ivestig i pediatric trials, the public cost of pediatric exclusivity has bee criticized. Six moths of patet extesio ca result i tremedous ecoomic gai for pharmaceutical compaies whe the patet extesio is for a blockbuster drug (defied as a drug with aual sales exceedig $1 billio). For example, a public watchdog group estimated that the added reveue for 6 moths of patet extesio for Prilosec would exceed $1.4 billio [105]. This cost is passed o to the geeral public as these drugs will ot be available i geeric form util the patet extesio expires. I a cost aa lysis of 14 drugs grated pediatric exclusivity i three blockbuster drug classes ACE ihibitors, statis, ad serotoi selective reuptake ihibitors extrapolated cost to the US Medicaid program was estimated at $340 millio for the 6 moths of patet extesio [19] It should be oted that there is a upfrot cost for study sposors with o guaratee of a positive profit margi. I a aalysis of drugs across ie differet pediatric subspecialty areas, the media cost per writte request for studies performed uder the pediatric exclusivity program was $12.3 millio (rage: $ millio). Whe accoutig for ecoomic returs resultig from patet extesio (8/9 drugs studied received patet extesios), the media et beefit was $134.3 millio (rage: -$ millio), ad the et beefit/cost ratio raged widely from to [20]. By chace, this aa lysis was atypically weighted towards blockbuster drugs, which represeted five of the ie drugs studied. Noetheless, these data highlight the variability i both cost ad beefit, ad also demostrate that there may be some risk to pharmaceutical compaies of a egative profit margi for the study of less ecoomically viable products. However, it is also importat to recogize that 80% of writte requests issued by the FDA have bee sposor-iitiated. While the FDA must first determie if there is a eed to study these drugs i the pediatric populatio, sposors obviously prefer to study drugs with the greatest potetial fiacial gai. Cosequetly, blockbuster drugs may have bee disproportioately represeted, at least i the early years of the program. A aalysis of trials coducted betwee 2002 ad 2004 uder the pediatric exclusivity program oted that 13/59 (22%) products studied were blockbuster drugs [20]. Although the fiacial beefit to pharmaceutical compaies has bee sigificat, it is also importat to cosider the overall cost beefit of improved pediatric drug dosig ad safety. Cost savigs to the health care system solely from a modest 2% reductio i adverse evets for childre have bee estimated to be i the rage of $ millio aually, based o the overall aual cost of adverse evets ad the icidece of adverse evets i childre [5]. To further quatify these gais for Cogress, the FDA examied hospitalizatio rates for five serious illesses (asthma, HIV/AIDS, cacer, peumoia ad kidey ifectios) ad foud sigificatly higher rates for childre tha for middle-aged adults. The agecy hypothesized that some of the differece i hospitalizatio rates might be due to fewer iformed drug therapies ad less adequate data o drug dosages i childre. The FDA calculated that elimiatig 25% of these differetials for just these five illesses would lead to direct medical cost savigs of $228 millio aually, ad would accout for approximately a third of the total costs of the exclusivity program over the ext 20 years, with icreased gai likely beyod that time frame [108]. Thus, the potetial fiacial gai from improved pediatric drug dosig, safety ad efficacy is likely sigificat. The fact that the BPCA program received ear uaimous cogressioal support ad was reewed without suset i 2012, despite the fiacial ad

9 Pediatric exclusivity & other cotemporary regulatory chages political climate, highlights the major importace of drug ad device developmet for child health ad suggests that there is broad agreemet amog stakeholders that the log-term fiacial ad public health beefits outweigh the associated costs. Misaliged objectives Aother criticism of the BPCA program is that labelig chages are ot the best meas to improve safety ad effectiveess of drug therapy. Physicias ofte do ot use the drug label, typically preferrig prescriber drug refereces icludig the Harriet Lae Hadbook or Neofax. Neither of these resources idicate whe dosig is recommeded for off-label idicatios or age groups. I a limited aalysis for a Istitute of Medicie report, these prescribig resources ofte did ot iclude the latest labelig iformatio [4]. Furthermore, there is a evidet discrepacy betwee labelig chages ad actual eed withi the field. This is because study is oly madated for ew igrediets, idicatios, regimes, or routes of admiistratio ad because there is oly fiacial icetive to study opatet drugs. Cosequetly, oly oe study sposor has ever accepted a FDA-issued writte request to study a off-patet drug; therefore, some of the most commoly prescribed pediatric drugs are eglected. As a example, i 1994 whe the pediatric rule was first proposed by the FDA, te drugs were idetified as the most commoly prescribed off-label pediatric medicatios [108]. Four of those te drugs clotrimazole/betamethasoe, fluoxetie, cromoly sodium, ad sertralie remaied o-patet, ad all four were quickly studied followig passage of the exclusivity provisio. By the time of the FDA s first status report to Cogress i 2001, all four had bee grated patet extesio [108]. The remaiig six drugs were all off-patet ampicilli, albuterol (for use i ages <2 years), atipyrie/bezocaie otic, promethazie, methylpheidate, ad metaprotereol sulfate. To date, oly methylpheidate has received a labelig chage, ad this was accomplished via a applicatio for a ew dosig regime for a extededrelease capsule [117]. Therefore, the sposor qualified for patet extesio. I a 2010 aalysis, the Govermet Accoutability Office reported that 17 off-patet writte requests had bee declied by sposors ad therefore referred to the NIH for further study. The NIH has fuded studies of 11 of these agets, but at the time of the 2010 review, oe of the studies had yet satisfied the requiremets of their writte request, ad to date oe of these studies has resulted i a labelig chage [104,117]. The reasos behid this limited ability to study offlabel therapeutics are primarily fiacial. The aual budget for the NICHD was $1.1 billio whe Prilosec received its patet extesio, resultig i a estimated $1.4 billio i additioal profits to AstraZeeca. Cosiderig the fiacial implicatios, it is clear that uder the curret system, o-patet agets, ad particularly more profitable agets, will be prioritized by study sposors. As a example, of the 192 drugs listed o the FDA website as havig received pediatric exclusivity through July 2012, 20 (10%) are atihypertesive agets icludig six differet ACE ihibitors ad four differet agiotesi receptor blockers. May of these agets are rarely prescribed by pediatric providers. Meawhile, three commoly prescribed off-patet atihypertesive agets sodium itroprusside, furosemide ad spiroolactoe were icluded o the iitial BPCA priority list i 2003, ad a fourth aget, hydrochlorothiazide, was added with the first update i Noe of these off-patet agets have received labelig chages. I the iterim, other drugs that have received pediatric exclusivity iclude eight cholesterol-lowerig agets (icludig six differet statis), six ati-reflux agets (icludig four differet proto pump ihibitors), ad four differet atidepressats (three serotoi selective reuptake ihibitors ad a serotoi orepiephrie reuptake ihibitor) [118]. No allocated fudig for off-label drugs I the absece of a fiacial icetive to study off-patet agets, it is clear that fuds must be allocated or privately raised. I 2002, with passage of BPCA, Cogress authorized appropriatio of $200 millio for the fiscal year dedicated to the Program for Pediatric Studies of Drugs ad for such sums as are ecessary for the five succeedig fiscal years [102]. I essece, this was the moetary estimate that they felt would be ecessary to study off-patet agets (for which the Program for Pediatric Studies of Drugs was desiged). These fuds were iitially to be raised by the Foudatio for the Natioal Istitutes of Health, a private, ot-for-profit foudatio established by Cogress [102,104]. However, the foudatio has ot provided fuds for study of ay off-patet aget, ad they are o loger tasked with raisig fuds related to BPCA. I fact, o fuds have ever actually bee allocated by Cogress for the BPCA program, ad istead the fuds must be provided from the iteral NIH budget, therefore decreasig the pool of moey available for study i other pediatric iitiatives. Limited eoatal studies Aother criticism of pediatric studies coducted uder BPCA ad PREA is a relative lack of eoatal trials [21]. By the ed of 2011, oly 6% of labelig chages eacted uder BPCA applied to eoates [4]. Neoates (age <28 days) are the most eglected of all pediatric subpopulatios, ad by some estimates over 90% of medicatios are used off-label i this group [4]. The 2007 BPCA reauthorizatio icluded laguage to ecourage eoatal Cli. Ivest. (2013) 3(3) 235

10 Hill, Smith, Cohe-Wolkowiez, Bejami & Li study ad required a subsequet review of eoatal studies [101]. Of 37 writte requests issued after 2007, oly oe required a eoatal study while three requested eoatal studies but gave the sposors the optio of excludig eoates. Sice 2007, oly eight drugs with writte requests issued prior to 2007 have received eoatalspecific labelig chages, ad of these, oly two have bee for ew drug applicatios [104]. There are several reasos for the relative paucity of studies i eoates. New drug studies are ofte ot required by the PREA madate because the requiremets apply oly to the specific idicatio icluded i the applicatio, ad this idicatio typically applies to adults ad/or older childre. Similarly, the icetive structure has also bee less successful i eoates. This is because pediatric exclusivity is ofte grated after study of the drug i childre ages >1 moth. Oce exclusivity has bee grated, there is o remaiig icetive for sposors to go back ad coduct eoatal trials. I additio, the FDA has sometimes agreed to waive eoatal study requiremets because there have bee safety or ethical cocers with coductig these studies. There are, i fact, uique challeges to cliical trials i eoates. These iclude scietific challeges relatig to: The ovel diseases ad physiology of eoates; The heterogeeity of diseases ad drug resposes betwee eoates of differig gestatioal ages; The eed for log-term ad therefore costly follow up to assess drug effects o eurodevelopmet; Limited availability of blood for samplig. There are also uique ethical challeges. For example, balacig risk ad beefit is complicated i a extremely premature eoate for whom ay form of uecessary itervetio could be costrued as harmful. I additio, there may be ethical cocers with obtaiig iformed coset ad erollig eoates i cliical trials as parets are uder duress with limited time betwee presetatio ad iitiatio of drug therapy [21,22]. These ethical ad scietific challeges have historically limited eoatal cliical trials ad serve as a major barrier to improved drug study. However, importat stakeholders ow recogize that it is also uethical to practice eoatal medicie without adequate data o drug safety or efficacy. I a ope letter to US seators i April 2012, the America Pediatric Associatio, America Pediatric Society, Associatio of Medical School Pediatric Departmet Chairs, ad the Society for Pediatric Research all strogly ecouraged regulatory provisios to advace eoatal drug studies i the 2012 BPCA/PREA reauthorizatio. I the same letter, they recommeded that a eoatologist be permaetly added to the FDA Office of Pediatric Therapeutics [107]. These chages were recetly icorporated ito the 2012 reauthorizatio, but it remais to be see if they will help circumvet some of the uique challeges iheret to eoatal cliical trials. Lack of publicatio Publicatio of trial results esures trasparecy ad is also the most effective mechaism for dissemiatio of iformatio to the greater pediatric commuity. While publicatio is the traditioal bechmark for trial completio i academic circles, it is ot a critical performace ed poit for idustry. This may explai why relatively few trials coducted for pediatric exclusivity have bee published i peer-reviewed jourals. I a aa lysis of trials coducted betwee 1998 ad 2004, oly 44% were ultimately published, icludig oly 33/100 trials that resulted i a importat labelig chage. This practice has bee challeged as ethically uacceptable [23]. Coclusio Sice the 1990s, there has bee a icreasig awareess of the public health cosequeces of iadequate pediatric drug study. Regulatory chages have attempted to address these cocers by providig icetives as well as madates to icrease study ad to improve labelig of agets for use i eoates, childre ad adolescets. By all accouts, these efforts have bee eormously successful at stimulatig pediatric research. Idustry has ijected much eeded capital ito pediatric trials, ad, as a result, >400 labelig chages have bee made. Udoubtedly, these efforts will improve the safety of pediatric medicie. However, the fiacial widfall for idustry remais a sigificat criticism. This fiacial gai comes largely at the expese of the US taxpayer. While the public health cost will ultimately be offset by savigs as a result of improved pediatric drug dosig, safety ad efficacy, may feel that idustry should ot be the ultimate fiacial beefactor. Furthermore, the moey ivested could potetially have achieved greater et-beefit, particularly i the realm of off-patet drugs, which are some of the most frequetly prescribed pediatric drugs ad yet remai vastly uderstudied. Noetheless, after decades of relatively futile efforts to improve pediatric labelig, there have fially bee substative gais. Future perspective After decades of relative stagatio, it is clear that legislatio is a effective meas to stimulate chage. Idustry has respoded to legislative madates ad icetives, ad the resultat ivestmet has led to greater progress tha at ay other time i the history of pediatric drug research. Early legislative shortfalls have bee addressed durig the reauthorizatio process, ad the FDA ad Cogress have cotiually refied their efforts to appropriately stimulate pediatric drug

11 Pediatric exclusivity & other cotemporary regulatory chages study. These refiemets have bee importat ad have resulted i critical improvemets, icludig developmet of the priority list, establishmet of braches at the NIH ad FDA, ad a reewed iterest i traiig a future geeratio of cliical pharmacologists. However, pediatric drug study remais limited relative to that see i adults. For example, there is o mechaism or icetive to ecourage ew drug developmet specifically for childhood diseases. Istead pediatric providers must cotiue to rely o trickle dow from the adult armametarium. Now that the 2012 BPCA reauthorizatio has bee approved without suset, there is o loger a automatic timelie for future refiemets. Therefore, the ous will fall o the pediatric commuity to esure cotiued procedural improvemets to optimize aligmet of ivestmet ad objectives. To this ed, pediatric specialists should be icluded i key decisiomakig roles (e.g., at the FDA ad NIH) ad should have iput ito trial desig, objectives, iterpretatio of results, ad decisios regardig labelig. The most importat future priority should be to improve study of off-patet agets. To this ed, the icetive structure is limited, ad, despite greater eed, off-patet drug study has bee relatively eglected. Recet efforts by the NIH are ecouragig particularly ivestmet i ifrastructure such as trial etworks (e.g., Pediatric Trials Network) devoted to pediatric drug/device study. It is importat to capitalize o these ifrastructure gais but, more importatly, to ecourage further Executive summary Off-label drug use i childre Historically, approximately 80% of drugs have ot bee labeled for use i childre. There are umerous examples of serious adverse evets as a result of drugs used to treat childre without prior study of dosig, safety or efficacy. Despite widespread recogitio of this problem, prior to the 1990s there had bee little improvemet i pediatric drug labelig i over two decades. Major regulatory chages madatig or icetivizig pediatric study US FDA Moderizatio Act (1997) Itroduced pediatric exclusivity providig a potetial 6-moth patet extesio for studies i respose to a FDA-issued writte request. Best Pharmaceuticals for Childre Act (2002) Reauthorized pediatric exclusivity ad iitiated a process for study of off-patet agets, icludig developmet of a priority list. Pediatric Research Equity Act (2003) Madates pediatric-specific study of all New Drug Applicatios, icludig submissios for ew igrediets, ew idicatios, ew dosage forms, ew regimes ad ew routes of admiistratio. The curret process for pediatric drug study O-patet agets The FDA issues a writte request ad, if sposor accepts ad completes the required studies, the it ca qualify for pediatric exclusivity. Off-patet agets Rarely studied by the sposor as there is o fiacial icetive ad therefore typically referred to the NIH (Natioal Istitute of Child Health ad Huma Developmet) to iitiate study. New Drug Applicatios Pediatric Research Equity Act regulatios require pediatric study for the specific drug idicatio icluded i the applicatio. Major successes over the past 15 years as a direct result of regulatory chages Over 700 cliical trials coducted i childre. Over 400 pediatric-specific labelig chages that have improved dosig, ehaced safety, exteded age idicatios or icluded iformatio o efficacy. Itellectual gais, icludig improvemets i pediatric trial desig ad coduct, as well traiig of cliical pharmacologists with pediatric expertise. Ifrastructure gais icludig establishmet of the FDA Office of Pediatric Therapeutics ad the Obstetric ad Pediatric Pharmacology Brach at the NIH. Trial etworks (e.g., Pediatric Trials Network) developed to study off-patet drugs. Critiques Patet extesio is a fiacial widfall for drug compaies. O-patet agets have bee disproportioately prioritized with less study of importat off-label agets. Although eoates are perhaps the most vulerable pediatric populatio, oly 6% of all labelig chages have icluded eoatal iformatio. Future perspective Regulatory chages have improved safety ad labelig of pediatric therapeutics; however, the process ca be refied to achieve a better cost beefit margi. Cli. Ivest. (2013) 3(3) 237

12 Hill, Smith, Cohe-Wolkowiez, Bejami & Li ivestmet i pediatric research. Billios of idustry dollars were required to stimulate the >400 labelig chages for o-patet agets. A similar ivestmet will be eeded to ecourage similar gais for off-label therapeutics. Ackowledgmets The authors would like to thak A McMilla of the Duke Cliical Research Istitute for her editorial assistace. Fiacial & competig iterests disclosure K Hill has received a research grat from Pfizer Ic. PB Smith has served as cosultat for Pfizer Ic., Astellas Pharma ad GlaxoSmithKlie ad has received a research grat from Cubist Pharma. MC Wolkowiez has received a research grat from Pfizer Ic.; he has also served as cosultat for Pfizer Ic. ad Johso & Johso. DK Bejami serves as a cosultat (geeratig persoal icome) to Astellas Pharma US, Biosyexus, Cubist Pharmaceuticals, Refereces Shah S, Hall M, Goodma DM et al. Off-label drug use i hospitalized childre. Arch. Pediatr. Adolesc. Med. 161, (2007). Wilso JT. A update o the therapeutic orpha. Pediatrics 104(3 Pt 2), (1999). 3 Gilma JT, Gal P. Pharmacokietic ad pharmacodyamic data collectio i childre ad eoates. A quiet frotier. Cli. Pharmacokiet. 23, 1 9 (1992) A aalysis of off-label drug prescribig habits amog hospitalized childre i the Pediatric Health Iformatio Systems database. 2 Istitute of Medicie. Safe ad Effective Medicies for Childre. Pediatric Studies Coducted Uder the Best Pharmaceuticals for Childre Act ad the Pediatric Research Equity Act. Field MJ, Boat TF (Eds). The Natioal Academies Press, Washigto, DC, USA (2012). A Istitutes of Medicie review of aspects of pediatric studies ad chages i product labelig that resulted from Best Pharmaceuticals for Childre Act ad Pediatric Research Equity Act ad their predecessor policies. Ward RM, Kauffma R. Future of pediatric therapeutics: reauthorizatio of BPCA ad PREA. Cli. Pharmacol. Ther. 81, (2007). Breslow LH. The Best Pharmaceuticals for Childre Act of 2002: the rise of the Medicie Forum o Drug Discovery, Developmet, ad Traslatio. The Natioal Academies Press, Washigto, DC, USA (2008). volutary icetive structure ad cogressioal refusal to require pediatric testig. Harvard J. Legis. 40, (2003). Papers of special ote have bee highlighted as: of iterest 1 Johso & Johso Pharmaceutical research ad developmet, Merck ad Co., Pfizer Ic. ad The Medicies Compay. He has research grat from Astellas Pharma US, AstraZeeca ad UCB Pharma. He also receives support from the US govermet for his work i pediatric ad eoatal cliical pharmacology (1R01HD , 1R01FD , 1U10-HD , 1K24HD , ad Govermet Cotract HHSN C uder the Best Pharmaceuticals for Childre Act), the o-profit orgaizatio Thrasher Research Foudatio for his work i eoatal cadidiasis, ad from idustry for eoatal ad pediatric drug developmet (For more iformatio see: J Li does ot have ay coflicts of iterest to report. The authors have o other relevat affiliatios or fiacial ivolvemet with ay orgaizatio or etity with a fiacial iterest i or fiacial coflict with the subject matter or materials discussed i the mauscript apart from those disclosed. No writig assistace was utilized i the productio of this mauscript A excellet review of the history of pediatric drug legislatio. Chooara I, Rieder M. Drug toxicity ad adverse drug reactios i childre a brief historical review. Paediatr. Periat. Drug Ther. 5, (2002). Weiss CF, Glazko AJ, Westo JK. Chlorampheicol i the ewbor ifat. A physiologic explaatio of its toxicity whe give i excessive doses. N. Egl. J. Med. 262, (1960). Bejami DK Jr, Smith PB, Su MJ et al. Safety ad trasparecy of pediatric drug trials. Arch. Pediatr. Adolesc. Med. 163, (2009). US FDA. Specific requiremets o cotet ad format of labelig for huma prescriptio drugs: revisio of pediatric use subsectio i the labelig. Fed. Regist. 59(238), (1994). 11 Departmet of Health ad Huma Services US FDA. Regulatios requirig maufacturers to assess the safety ad effectiveess of ew drugs ad biological products i pediatric patiets: FDA fial rule. Fed. Regist. 63(231), (1998). 12 NIH. Best Pharmaceuticals for Childre Act (BPCA) priority list of eeds i pediatric therapeutics. Fed. Regist. 776(63), (2011). 13 Vachieri C, Butler AS, Kutse A. Addressig the Barriers to Pediatric Drug Developmet: Workshop Summary. Istitute of Rodriguez W, Sele A, Avat D et al. Improvig pediatric dosig through pediatric iitiatives: what we have leared. Pediatrics 121, (2008). A review of the various labelig chages that resulted from the study of drugs i respose to a US FDA-issued writte request. Bejami DK Jr, Smith PB, Jadhav P et al. Pediatric atihypertesive trial failures: aalysis of ed poits ad dose rage. Hypertesio 51, (2008). A aalysis of factors cotributig to success or failure of trials of pediatric atihypertesive agets that were coducted i respose to a writte request. 16 Euice Keedy Shriver Natioal Istitute of Child Health ad Huma Developmet, Natioal Istitutes of Health, Departmet of Health ad Huma Services. Obstetric ad Pediatric Pharmacology Brach (OPPB), Natioal Istitute of Child ad Huma Developmet, Report to the Natioal Advisory Child Health ad Huma Developmet Coucil, Jauary US Govermet Pritig Office, Washigto, DC, USA (2008). 17 Hartlig L, Wittmeier KD, Caldwell P et al. StaR child health: developig evidece-based guidace for the desig, coduct, ad reportig of pediatric trials. Pediatrics. 129(Suppl. 3), S112 S117 (2012).