Crisis Convulsivas 2008

 

C l in in ic ic a l T h e r a p e u t i c s /V /V o l u m e 2 7 N u m b e r 6 2 0 0 5

N e w b o r n s a n d D r u g S tu t u d ie ie s: s: T h e N I C H D F D A N e w b o r n Drug D evelopm ent Initiat Initiatii ve G e o r g e R G i a c o ia i a M D ; a n d D o n a l d R. R. M a t t i s o n M D Obstetric and Pediatri Pediatricc Pharmacol Pharmacology ogy Branch Cen ter or R esear esearch ch or Mo thers and Children Na tional Institute o f Child Institute Child Health and H uma n Devel Development opment National Insti Institut tutes es o f Health Health Dep artment of Health and Human S e r v ici c e s , R o d v i i~i ~ e , Maryland ABSTRACT B a c k gr ound : P r ogr e ss ha s be e n m a de in r e se ar ar c h on the e f f e c ts of dr ug the r a py on pe dia tr ic pa tie nts, but n e o n a t e s a r e s ti ti llll a n u n d e r s t u d i e d p o p u l a t i o n . T h o s e most f ike ly to r e c e ive dr ug the r a py ( e g, pr e te r m infants) are least likely to be studied. O b j e c ti ti v e s: s: T h e p u r p o s e s o f t h i s a r t i cl cl e a r e t o s u m ma r iz e a n initia tive tive de ve lope d jointly jointly by the N a tiona l Institute of Child Health and Human Development ( N I C H D ) a n d t h e U S F o o d a n d D r u g A d m i n i s t ra r a t io io n ( F D A ) a nd to intr odu c e a se rie rie s of a r tic le le s de ve lope d as a result of this initiative. M e t h o d s : I n f o r m a t i o n f o r t h i s a rt rt i cl cl e w a s g a t h e r e d from the proceedings of a wo rksho p cosponso red by the NICHD and the FDA that took place March 29 a n d 3 0 , 2 0 0 4 , i n R o c k v i ll ll e , M a r y l a n d . R e sults: D osing ba se d on use in a dults a nd olde r c hildr e n ha s r e sulte d in a dve r se e ve nts a mon g ne w bor n inf a nts, a n d ma y ha ve long- te r m e f fe fe c ts. ts. M or e ove r , f orormula tions a ppr opr ia te f or use in ne ona te s a r e of te n una va ila ble ble , a nd c o mp e nsa tor y e ff ff or ts suc h a s m ixing c r ushe d ta ble ts ts into f or mula m a y inte r f e re re w ith a c c urate dose delivery. delivery. Unde r the Best Pharm aceuticals for

i es es in in t h i s v u ln ln e r a b l e p o p u l a t i o n . T h e N I C H D a n d F D A d e v e l o p e d t h e N D D I a s a n o n g o i n g p r o ce ce s s t o ide ntif y a nd sugge st str a te gie s f or a ddr e ssing obsta c l es es t o c o n d u c t i n g d r u g t r ia ia l s i n t h e n e w b o r n . Clin Tber. 2005;27.-796-813) Copyright © 2005 E xc e r pta Me dic a , I nc . Key words: neonate, National Institute of Child H e a l th t h a n d H u m a n D e v e lo lo p m e n t , U S F o o d a n d D r u g A d m i n i s t r a ti ti o n , N D D I .

C hildr e n A c t of 2002 , gov e r nm e nt a genc genc ie ie s w or k w ith e xpe r ts in pe dia tr ic s a nd pe dia tr ic r e sea sea r c h to de v e lop a nd pr ior itiz itiz e a li list st of of f - pa te nt dr ugs f or w hic h pe diatric studies are urgently needed. Four such listings w e r e publishe d in the Federal R egister f r o m J a n u a r y 2 0 0 3 t h r o u g h J a n u a ry ry 2 0 0 5 . T h e N I C H D a n d F D A have also initiated the Newborn Drug Development I nitia nitia tive ( N D D I ) , a m ultipha se pr ogr a m to de te r m ine g a p s i n k n o w l e d g e c o n c e rn rn i n g n e o n a t a l p h a r m a c o l o g y a nd c linic linic a l tr ial ial de sign a nd to e x plor e nove l study de signs for for use in ne w bor ns, w ith th e ultima te goa l of inc r e a sing sing our know le dge a bou t th e sa f e ty ty a nd e ff ff ic ic a cy cy of dr ugs use d to tr e a t ne w bor ns. Conclusions: M ost drug s used to treat newb orns stil st illl la c k a ppr o pr ia te dosing , e ff ff ic ic a cy, cy, a nd sa f e ty stud-

of 2002 ( B P C A ), ),3 an d the Pediatric Pediatric Research Equity Act o f 2 0 0 3 . 4 F D A N IA IA p r o v i d e d a c a r r o t o f 6 m o n t h s of ma r ke t e xc lusivity lusivity f or on- pa te n t dr ugs in r e tur n f or studie s in c hildr e n, r e sulting sulting in a nu m be r of stud ie s in in olde r c hildr e n. T h e n u m b e r o f d r u g s s tu tu d i e d i n n e w b o r n s , h o w e ve ve r, r, h a s r e m a i n e d v e r y s m a l l a n d , f o r t h e m o s t p a r t , t h o s e s t u d i e d w e r e f u l l -t -t e r m i n f a n ts ts . I n c o n t r a s t , t h e population of infants receiving neonatal intensive

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INTRODUCTION More than 40 years ago, Harry Shirkey coined the t e r m t h e r a p e u t i c o r p h a n s , r e fe f e r ri ri n g t o t h e p l i g h t o f c hildr e n r e c e iving dr ugs w ithout the be ne f it of pe dia tr ic d r ug studie s to c ha r a c te r iz e sa f e ty a n d e ff ff ic ic a cy, cy, t G r e a t str ide s ha ve be e n ma de in dr ug te sting in c hild r e n s i n c e t h e rnid-1990s, w i t h t h e e s t a b f is is h m e n t o f the National Institute of Child Health and Human D e v e l o p m e n t ( N I C H D ) P e d i a t r i c P h a r m a c o l o g y Research Network, passage of the US Food and Drug Administration (FDA) Modernization Act of 1997 ( F D A M A ) , 2 the B e st P ha r ma c e utic a ls f or C hildr e n A c t

A c c ept epted ed or publ i c ati~ ati~ M a rc h 20 2005 . doi: 10.1016/j.climhera.200S 10.1016/j.climhera.200S .06.008 0149 29181051519. 00

P r im im e d i n th e U S A . R e p r o d u c titi o n i n w h o l e o r p a r i s n o t p e r m i tte tte d . Copyright © 2005 Excerlxa Medica Inc.

V o lu lu m e 2 7 N u m b e r

 

G R G i a ~ a a nd nd D R M a t l i s o n care is primarily preterm infants, and most of the d ru g s g i v en i n t h i s s e t t i n g h a v e n o t b ee n t es t e d ; as a consequenc e, they are no t labeled for use in this age group,s This problem is com pound ed by the frequent o f f - la la b e l u s e , in in n e o n a t e s , o f d r u g s t h a t h a v e b e e n a p proved for adult indications. In addition, polypharm a c y i s c o m m o n d u r i n g h o s p i t a l s t a y s .6 I t i s o f i n -

U s e o f D r u g s in in N e w b o r n s T r a d i t i o n a l ly ly , d r u g s h a v e b e e n i n t r o d u c e d t o t h e n e o n a t a l i n t e n s i v e c are s e t t i n g o n t h e b as i s o f e ffi ca c y i n a d u l t s , s i n g l e ca s es , o r s m al l c as e s e ri e s . As a c o n s e q u e n c e , p e d i a t r i c d o s e s a r e e m p i r i c a ll ll y d e r i v e d , safety is unk now n, and efficacy is presumed but not demonstrated.

terest that most of the adverse drug events frequently m e n t i o n e d t o s u p p o r t t h e n e e d f o r m o r e d r u g t e s t in in g i n ch i l d re n o c cu rre d i n t h i s m o s t v u l n erab l e o f t h e p e d i a t r ic ic p o p u l a t i o n s - - t h e t e r m a n d p r e m a t u r e n e o n a te te . 7, 7 ,s T h e p u r p o s e o f t h i s a r t ic ic l e i s t o s u m m a r i z e a n i n i t ia ia tive developed jointly by the NICHD and the FDA a n d t o i n t r o d u c e a s e r ie ie s o f a r ti ti c l e s d e v e l o p e d a s a r e sult of this initiative.

M a t u r a t i o n a l heterogeneity distinctive p h y s i o l o g i c a n d m e t a b o l i c c h a r a c t e ri ri s ti ti c s , a n d c o n d i t i o n s o r d i s . e a s e s t h a t a r e u n i q u e t o t h i s p e r i o d o f l if if e c h a r a c t e r i z e t h e n e o n a t e a s a s p ec i al p o p u l a t i o n . C o n d i t i o n s a ffec t i n g p r e t e r m i n f a n t s a r e d i f f e r e n t f r o m t h o s e t y p i c a ll ll y a ffe ct i n g fu l l -t e rm i n fa n t s . Ho wev er, t h ere i s a n o v e rl ap i n c ert ai n c o n d i t i o n s (e g , n ec ro t i zi n g en t ero c o l i t is is ) ; t h e r e f o r e , t h e r a p ie ie s m a y n e e d t o b e e v a l u a t e d i n n e o n at es at a ran g e o f g es t a t i o n al ag es . No t i n freq u en t l y , d i fferen t co n d i t i o n s co ex i s t i n t h e s i ck n eo n at e , m a k i n g i t d i ffi c u lt lt t o ev al u a t e t h e e ffi ca cy o f u s i n g

T h e i n t r o d u c t i o n o f t o l a z o li li n e f o r t h e t r e a t m e n t o f p u l m o n a r y h y p e r t e n s i o n o f t h e n e w b o r n s i l l u st s t r at at e s the problem of drugs becoming widely used without a p p r o p ri a t e effi c ac y an d s a fe t y s t u d i e s . Th e fL fLrS rStt rep o r t o f t h e u s e o f t ol o l a z o li li n e i n n e w b o r n s w a s p u b l is is h e d a s a l e t t e r t o t h e ed i t o r. 3 z Th e d ru g w as u s ed i n 5 p ret e r m n e w b o r n s w i t h p u l m o n a r y h y p o p e r fn fn s i o n c o m plicating hyaline membrane disease. The dose was e m p i r i c al al l y d e r i v e d (2 (2 m g / k g) g) . T h e a u t h o r s t a t e d , n o s ev ere g as t ro i n t es t in in a l d i ffi c u l t i e s a s t h o s e re p o rt e d i n adults were found , and considerable norma lization o f v a r i o u s a b n o r m a l i t i e s o c c u r r e d . 32 In t h e en s u i n g years, tolazoline became widely used for hypoxemia ref rac tory to me cha nica l venti ventilat lation. ion.3~, 3~, ~4 Patie nts in a n u m b e r o f s t u d i e s w e r e f u l l -t -t e r m i n f a n ts ts a f f e c t e d b y p u l m o n a r y h y p e r t e n s i o n .3 . 3 s Effi c ac y wa s b as e d m o s t l y i n i m p r o v e m e n t s in in a r t e ri ri a l o x y g e n a t i o n a n d n o t o n o u t c o m e .~ . ~ N o r a n d o m i z e d , p la la c e b o - c o n t r o l l e d s t u d i es es w e r e c a r r i e d o u t . I t t o o k m o r e t h a n 1 5 y e a r s o f u s e b e f o r e d o s i n g r e c o m m e n d a t i o n s b e c a m e a v a i la la b l e . 3 7 A s t u d y p u b li li s h e d in in 1 9 8 6 d e m o n s t r a t e d a p r o l o n g e d h a l ff- l if if e in in p a t i e n ts ts w i t h d e c r e a s e d r e n a l f u n c t i o n a n d s u g g es t ed t h at t h e i n fu s i o n rat e s b e s u b s t an t i a l l y reduced.3s.339 Ad v e rs e e v e n t s , i n cl u d i n g g a s t ro i n t e s t i n a l duced.3s. h e m o r r h a g e a n d d u o d e n a l p e r f o r a t io i o n , w e r e r e p o rt rt ed.4°.441 T h e d r u g w a s l a b e l e d f o r u s e i n n e w b o r n s w i t h ed.4°. pulmonary hypertension despite the absence of con-

o u t c o m e m e a s u r e s s u c h a s m o r t a l it it y . T h e p h y s io io l o g ic ic a n d m e t a b o l i c c h a r a c t e r is is t i c s o f l o w - b i r t h - w e i g h t i n fa fa n t s , a s w e l l a s t h e p a t h o p h y s i o l o gi gi c a b n o r m a l i t i e s a s s o c i a t e d w i t h t h e v a r i o u s c o n d i t i o n s t h ey e x p e ri en c e , c an i n fl u en ce t h e b i o d i s p o s i t io io n a n d effec t s o f d ru g s t y p i ca l l y s e en i n t h e n e wb o rn p o p u l at i o n . Al t h o u g h n o t s u ffi c i en t ly ly s t u d i ed , t h e ra p i d a n d v a r i a b l e m a t u r a t i o n o f p h y s io io l o g i c a n d p h a r m a c o l o g i c p ro ce s s e s d u ri n g t h e fi rs t m o n t h o f l i fe re q u i r e s m o d i f y i n g tr tr e a t m e n t r e g i m e n s f o r s o m e d r u g s . I m m a t u r i t y o f p h y s i o lo lo g i c p ro ro c e s s es es a n d o r g a n f u n c t i o n~ n ~ -1 -1 6 m a y l e a d t o m a r k e d d i f f e re re n c e s in in a b s o r p tion, ~7 ~7-~ -~99 distribution,Z0, distribution,Z0, z~ me tabo lism , zz-~ an d/o r excretionZT,zz s b e t w e e n p r e t e r m a n d t e r m i n f a n t s a n d excretionZT, o l d e r i n f a n t s a n d c h i l d r e n ,z~-31 ,z~-31

t ro l l e d cl i n i ca l t ri a l s . Th e h i g h i n ci d en ce o f b l e ed i n g , l a c k o f e f f ic ic a c y , a n d d e v e l o p m e n t o f e x t r a c o r p o r e a l m e m b r a n e o x y g e n a t io i o n a n d t h e u s e o f n i tr tr o u s o x i d e42 e 42 r e s u l te te d i n t h e a b a n d o n m e n t o f t h i s t h e r a p y . T h i s e x a m p l e i l lu lu s t ra ra t e s a m a j o r p r o b l e m i n n e o n a t o l o g y : i t i s s t a n d a rd p rac t i c e fo r a d ru g t o b e i n co rporated into the therapeutic armamentarium before e f f ic ic a c y h a s b e e n d e m o n s t r a t e d . W h e n a d r u g t h e r a p y becomes the standard of care, ethical considerations p rev e n t t h e u s e o f p l ac eb o -co n t ro l l ed tri tri al s. s. Few drugs labeled for adult indications--and subs eq u en t l y u s e d o ff-l ab el i n t h e i n t en s i v e c are n u r s e _ n / have p r o v e d e f f i ca ca c i o u s. s. T h e n o t a b l e e x c e p t i o n s h a v e b e en d ru g s s p ec i fi ca l l y d es i g n ed fo r u s e i n t h e n e wb o rn p o p u l a t i o n (e g , s u rfac t an t fo r re s p i ra t o ry d i s -

METHODS Information proceedings NICH D and 30, 2004, in

for this article was gathered from the of a workshop cosponsored by the t h e F D A th th a t t o o k p l ac ac e M a r c h 2 9 a n d R o c k v il il l e, e, M a r y l a n d .

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Clinical Owrapma~ t r es es s s y n d r o m e , n i t r o u s o x i d e f o r p e r s i st st e n c e o f p u l mona r y f e ta l c ir c ula tion) . T he sc a r c ity of a de qua te c linic linic a l tr ia ls in in ne w bor n s c a n be a ttr ibu te d to se ve r a l factors: (1) ethical con cerns , (2) (2) lack of ince ntives for p h a r m a c e u t i c a l s p o n s o r s , ( 3) 3) l i m i t e d n u m b e r s o f p a tie nts a va ila ila ble f or study, a n d ( 4) la c k of a ppr o pr ia te study de signs, pa r tic ula r ly f or dr ug studie s in pr e ma -

be the dif f ic ulty of distingu ishing be tw e e n dr ug e f f e c ts o n g r o w t h / d e v e l o p m e n t a n d a b n o r m a l i t i e s r el el a t e d t o p r e m a t u r i t y a n d c o n d i t i o n s a s s o c i a t ed ed w i t h p r e t e r m delivery. 47

t u r e a n d l o w - b i r th th - w e i g h t i n fa f a n t s. s. T h e u n i q u e n e s s o f n e o n a t a l c o n d i t i o n s a n d d i s ea e a s e s is is s u c h t h a t e x t r a p o la tion of e f fic fic a c y studie s f or a dult indic a tions is r a r e ly possible.43 possible. 43

B oth sho r t- a nd long- te r m toxic ity ( e spe spe c ia ia lly lly f unc tiona l a lte r a tions, w hic h m a y no t be e vide nt until la te r in lif e ) a r e ma jor c onc e r ns in ne w bor ns, pa r tic ula r ly in those de live r e d be f or e te r m. R e c ognitio n of a dve r se d r u g r e a c ti ti o n s i s h a m p e r e d b y t h e l i m i t e d r e p e rt rt o i r e o f s i g n s a n d s y m p t o m s e x h i b i t e d b y i m m a t u r e i n f an an t s . F o r e x a m p l e , n e o n a t a l t o x i c it it y p r o d u c e d b y c h l o r a m p h e n i c o l o r b e n z o ic ic a c i d m a y m a s q u e r a d e a s s e p s i s 4 4 Intoxication may occur as the result of many dif f e r e nt f a c tor s, inc luding limite d a c tivity of dr ugme ta bo liz ing e nz ym e s (D (D ME s) ( eg, eg, limite d gluc ur onid a t i o n o f c h l o r a m p h e n i c o l ) s o r d r u g i n h i b i ti ti o n o f a s p e ci ci fi f i c D M E a c ti ti v it it y s u p e r i m p o s e d o n a n a l r ea ea d y d e ve lopm e nta lly de c r e a se d e nz ym e a c tivit tivity. y. F or e xa m p i e, e , c o a d m i n i s t r a t io io n o f e r y t h r o m y c i n , a n i n h i b i t o r o f c y t o c h r o m e P 4 5 0 ( C Y P) P) 3 A 4 w i t h m i d a z o l a m , a C Y P 3 A 4 s u b s t r at at e , h a s p r o d u c e d d e e p e r a n d p r o l o n g e d s e dation in neonates compared with older infants and c hildr e n.4~ n. 4~ F a c tor s tha t inf lue nc e the lo ng- te r m e f f e cts cts of dr ug t r e a t m e n t o n t h e d e v e l o p m e n t a n d f u n c t i o n o f d i ff ff e rr-

tr e a tme nt of ne ona te s a r e not a va ila ble . T a ble ts a nd c a psule s a r e u nsuita ble , a nd th e la c k of liquid or a l f or mulations has led to the practice of crushing or pulv e r iz iz i n g t a b l et e t s o r o p e n i n g c a p s u le le s a n d m i x i n g w i t h formula or a solid food. There are no data docum enti n g t h a t t h e d e s i re r e d d o s e i s a b s o r b e d .48 . 48 Tab let splitting is a ssoc ia te d w ith su bsta ntia l va r ia bility bility be tw e e n dose s.° s. ° T h e o r a l a d m i n i s t r a t io io n o f i n j e ct c t a b le le f o r m u l a t i o n s can also be problematic. Some drugs are chemically de gr a de d by ga str ic a c id. I n othe r c a se s, the c onc e nt r a t i o n o f t h e f o r m u l a t i o n m a y b e t o o d i l u t e d , r e q u ir ir ing pr ohibitive ly la r ge f luid volume s f or sm a ll inf a nts. I nje c tions ma y a lso c onta in pote ntia lly toxic e xc ipie n t s a n d t h e t a s t e m a y b e u n a c c e p t a b le le to to n e w b o r n s . 4 T a ste pe r c e ption a nd pr e f e r e nc e s de ve lop e a r ly in f e ta l de ve lopme nt. S tudie s in pr e te r m inf a nts ha ve d o c u m e n t e d th th e i r p r e f e re r e n c e f o r s w e e t s a n d a v e r s io io n to bitte r ta ste ste , s° A lthou gh a me thod olog y is is a va ila ila ble f or te sting the ta ste pr e f e r e nc e s of ne w bor ns a nd inf a nts, st pa la ta bility bility studie s of c om me r c ia l or a l dr u g f o r m u l a t i o n s a r e n o t a v a il il a b le le . E xc ipie nts pr e se nt in the c omme r c ia lly a va ila ble pa r e nte r a l a nd to pic a l f or m ula tion s ma y le a d to se ririous a dve r se e ve nts. P r opyle ne glyc ol, be nz yl a lc ohol, a n d p o l y e t h y l e n e g l y c o l h a v e b e e n i m p l i c a t e d in in n e o n a t a l t o x i ci ci t y , a n d d i m i n i s h e d r e n a l f u n c t i o n i n

e nt or g a n syste ms inc lude ( in a ddition to the spe c if if ic ic action of a drug): duration of exposure, degree of imma tur ity, spe c if ic inte r a c tions be tw e e n dr ugs a nd o r g a n d e v e l o p m e n t , a n d e f fe fe c ts ts o n g r o w t h a n d d e v e llopment. Unraveling possible long-term effects on skeletal, behavioral, cognitive, immune, and pulm o n a r y d e v e l o p m e n t a n d f u n c t i o n w o u l d r e q u i r e e pi pi d e m i o l o g i c s t u d y o f a l a r ge ge n u m b e r o f n e w b o r n s coupled with mechanistic experimental and clinical studie s to de monstr a te a c a nse - e f f e c t r e la tionship. However, validation of biomarkers of development a n d f u nc tion , a s w e ll a s dr ug e f f e c t, w ill impr o ve tria tria l de sign, long- te r m sa f e ty e va lua tion, a nd inte r pr e ta tion. A ma jor c ha lle nge tha t is like like ly to pe r sist, sist, give n the inc r e a sing f r e que nc y of p r e m a tur e de live r ie ie s, w ill

pr e te r m inf a nts ma y inc r e a se the r isk of t o x i c i t y s 2 - s 9 H y p e r o s m o l a l i ty ty h a s r e p o r t e d l y r e s u l t e d f r o m I V a d ministration of multivitamin preparations containing pr opy le ne glyc ol,s2 ol,s2 T h e inc r e a se d pe r me a bility of the skin in pr e te r m inf a nts f a c ilita ilita te s the tr a n sde r m a l a bs o r p t i o n o f p r o p y l e n e g l y c o l;l; t o x ic ic i t y i n p r e t e r m i n fants has ncluded co m a an d incr increase ease in osm olal gap. gap.S2, S2,s5 s5 A g a s p i n g s y n d r o m e h a s b e e n d e s c r ib ib e d i n p r e m a tur e inf a n ts r e c e iving iving be nz yl a lc ohol a s a pr e se r va tive tive in pa r e nte r a l pr e pa r a tion s, s*. s*.s7 s7 M e ta bolic a c idosis ( pr e suma b ly f r om the be nz oic a c id m e ta bolite ) ha s inc r e a se d intr a ve ntr ic ula r he mor r ha ge , S s, 9 a n d mo r ta li ty ty h a s l e d t o t h e r e c o m m e n d a t i o n t h a t b en e n zy zy l a l c o h o l not be use d a s a pr e se r va tive in the f or mula tion of d r u g s t o b e u s e d i n n e w b o r n s ,s4-s7 , s4-s7

oxicky

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Formulations

I n m o s t i n s t a n c es es , f o r m u l a t i o n s a p p r o p r i a t e f o r

V o lu lu m e 2 7 N u m b e r

 

G P G i a c e ia ia a n d D R

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A m o n g t h e p r o v i s io io n s e n a c t e d b y B P C A i n 2 0 0 2 w a s the e sta blishm e nt of a pr oc e ss to stud y of f - pa te nt use o f d r u g s i n c h i l d r e n . N o t a b ly ly , t h e r e w a s a l s o a r e c o m m e n d a t i o n t o i n c l u d e n e w b o r n s i n t h e s e c l i n ic ic a l s t u d ies, ie s, w he ne ve r r e le va nt. T h e B P C A dir e c ts the se c r e ta r y

f o r c a r d io io v a s c u l a r co c o l l a p se se o r s h o c k / ~ T h e d e s i g n o f e f fic fic a c y tr ia ls ls f or dr u gs us e d o r t h e t r e a t m e n t o r p r e ve ntion of B P D is impa ir e d by the la c k of c r ite r ia to d i s c ri ri m i n a t e b e tw tw e e n p r o p h y l a x i s a n d t r e a t m e n t o f t h e condition. Diuretics such as spironolac~one or furosemide a r e use d f or the ir pulm ona r y e ff ff e c ts. ts. N on inva sive methods for pharmacodynamic measurements of the

of the Department of Health and Human Services, a c t i n g t h r o u g h t h e d i r e c t o r o f t h e N a t i o n a l I n s t it it u t e s of Health NIH) and in consultation with the comm iss i o n e r o f t h e F D A a n d e x p e r t s i n p e d ia ia t ri ri c s a n d p e d i a tr ic r e se a r ch) ch) , to d e ve lop a nd pr ior itiz e a list list of of f p a t e n t d r u g s f o r w h i c h p e d i a t ri r i c s tu tu d i e s a r e u r g e n t l y ne e de d. F ou r suc h listings ha ve be e n pub lishe d in the Federal Register T he initia l list w a s publishe d in January 2003, and others have been published in A u g u s t 2 0 0 3 , J a n u a r y 2 0 0 4 , a n d J a n u a r y 2 0 0 5 s ee ee the table for a summary of the drugs listed in the Federal Register as o f A p r i l 2 0 0 5 ) . ~ 6 s U n d e r B P C A , the de sign of c linic a l tr ia ls ls f or pe dia tr ic popu la tion s is is ba se d on ite r a tive tive c olla bor a tive a c tivitie tivitie s be tw e e n the F D A a n d t h e N I H t o d e v e l o p w r i t t e n r e q u e st st s W R s ), ), b y w h i c h t h e F D A n o t i f i es es m a n u f a c t u r e r s o f t h e n e e d t o o b t a i n a d d i t i o n a l c l in in i c al al i n f o r m a t i o n a b o u t d r u g s f or se le c te d indic a tions in spe c if ic ic popu la tions . 3 S e ver ver al al dr ugs o n th e p ublishe d list listss a r e f or ne ona ta l i n d i c at a t i o n s T a b le le ) . T h e y i n c lu lu d e d o p a m i n e a n d d o b u ta min e f or c a r diova sc ula r inte r ve ntions in pr e te r m inf a nts; lor a z e pa m f or se da tion; me toc lopr a mide f or ga str oe soph a ge a l re re f lux; diur e tics tics f ur ose mide ) f or b r o n c h o p u l m o n a r y d y s p la la s ia ia B P D ); ); a n d a z i t h ro ro m y c i n f or C b l a m y d i a inf e c tions. tions. E f for for ts to d e ve lop W R s f or the se dr ugs a nd indic a tions ha ve be e n f r ustr a te d by a num be r of sc ie ntif ntif ic is issue suess sum ma r iz e d in the p r e vious

e f fe fe c ts ts o f t h i s th th e r a p y o n p u l m o n a r y d e v e l o p m e n t a r e not a va ila ble , a lthough noninva sive f unc tiona l c ha r acterization and imaging may provide validated end points in the future. T h e de sign o f tr ia ia ls to te st the e f f ic ic a c y of se da tive s in new borns is problematic because of the lack of a validated scale to measure sedation. The Comfort S c ale ale,, va lida te d a nd w ide ly u se d in olde r c hildr e n, ha s n o t b e e n v a li li d a t e d f o r u s e i n n e w b o r n s .67 . 67 Th e definition and frequency of gastroesophageal reflux in preterm infants and the efficacy of drugs s u c h a s m e t o c l o p r a m i d e a r e a s o u r c e o f c o n t e n t io io n . Apnea of prematurity as a manifestation of gastroe s o p h a g e a l r e f lu lu x i n p r e t e r m i n f a n t s r e m a i n s c o n t r o versial,cc~ .67 T h e r e a r e n o v a l i d a t e d p h a r m a c o d y n a m versial, i c m e a s u r e m e n t s o f e f fi f i c ac ac y f o r p r o k i n e t i c d r u g s s u c h a s m e t o c l o p r a m i d e . S u r r o g a t e t e s ts ts t o q u a n t i f y r e f lu lu x s u c h a s e s o p h a g e a l s c i n t i g r a p h y a r e i n v a si si v e o r h a v e limita tions. 6 s . ° R e c e n t l y , 2 n e w m e t h o d s f o r r e f l u x d e t e c t i o n - - i n t r a l u m i n a l i m p e d a n c e a n d t h e 1 3 CCacetate breath test--have been described.6~o Both methods have advantages over the previously described surrogate methods: impedance measures m o t i l it it y a n d i s in in d e p e n d e n t o f p H , a n d t h e 1 3 C a c e ta te te st in c on tr a st w it h sc intigr intigr a phy) use s a sta b le le i s o t o p e . U n f o r t u n a t e ly ly , n e i th th e r m e t h o d h a s b e e n va lida te d a nd, the r e f or e , ne ithe r is use f ul in c linic a l

se c tion. A dd itiona l c onc e r ns a bout the de sign of the se tr ia ia ls w e r e r e la te d to th e c ond ition or dise a se , the indic a tion, the of f -la -la be l use of the dr ug , or the c om ple xitie s involve d in de sign ing a ppr opr ia te c linic linic a l tr ia ia ls in t h e n e w b o r n p o p u l a t i o n .43 .43 A n um ber of issues further complicate the design of c linic a l tr ia ls of inotr opic a ge nts in pr e te r m inf a nts: 1) the la c k of a w ide ly a c c e pte d ne ona ta l blo od pr e ssur e sta nd a r d, 2) the c ur r e nt pr a c tic e of tr tr e a ting hyp o t e n s i o n i n l o w - b i r th th - w e i g h t i n f a n ts ts w i t h o r w i t h o u t e v i d e n ce c e o f p o o r t i s s u e p e rf rf u s i o n , 3 ) p r o f o u n d h e m o dynamic alterations due to patent ductus arteriosus a n d de c r e a se d le le ft ft ve ntr ic ula r f unc tion , a nd 4) la c k of v a l i d a t e d m a r k e r s o f c a r d i ac a c o u t p u t , o r g a n p e r f n s io io n , a n d l o n g - t e r m o u t c o m e s in in r e s p o n s e t o i n t e r v e n t io io n s

trials. F e asi asibil bilit ityy issue s limit the de ve lo pm e nt of W R s f or d r u g s g i v e n t o p r e t e r m i n f a n ts ts . T h o s e i s su su e s in in c l u d e siz e a nd de sign of the study, e thic a l c onc e r ns, a nd s t a n d a r d s o f p r a c ti ti c e . A n u m b e r o f s t u d y d e s i g n i ss ss u e s t h a t h a v e n o t b e e n p r ev ev i o u s l y e v a l u a t e d m u s t b e c o n sidered in this fragile population. For some conditions, no unive r sa lly lly a c c e pte d de f inition e xists xists e g, a pne a of pr e m a tur ity) ; f or othe r s, no suf f ic ie ntly ntly c ha r a c te r iz e d de f inition e xists xists e g, B P D in the f ir st da ys of liff e) li e) . O the r im por ta nt de sign issue s inc inc lude the f ollow ing: str a tif ic a tion by ge sta tiona l a nd postna ta l a ge a nd de f inition of the study pop ula tio n; ide ntif ic a tion, c le le ffi n i ti ti o n , a n d r e l a ti ti o n s h i p o f e n d p o i n t s a n d c l in in i c al al s u r rogates to cli clinica nicall llyy relevant ou tcom es; choice of desig n

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C lili n ic ic a l l m ' a p m a ~ m o d e l ; t re r e a t m e n t c o m p a r a to to r s ; a n d d e v e l o p m e n t o f validated end p oint assessment tools. T o a ddr e ss issue s in the d e sign of c linic a l tr tr ia ls in term and preterm infants, the NICHD and FDA colla bor a te d w ith ne ona ta l e xpe r ts f r om indu str y a nd a c a demia in the Newborn Drug Development Initiative ( N D D I ) , a m u l t i p h a s e p r o g r a m t o d e t e r m i n e g a p s in in

T h e c a r d i o lo lo g y w o r k i n g g r o u p r e v i ew ew e d t h e u s e o f inotropic drugs in preterm infants for treatment of ne on a ta l posto pe r a tive c a r dia c f a ilur e . A f te r c onside r i n g t h e d i f f i cu cu l t ie ie s in in d e f i n i n g s h o c k a n d h y p o t e n s i o n in pr e te r m inf a nts, pa r tic ula rly rly dur ing the f a st 2 w e e ks o f l if if e, e, 2 p o t e n t i al al f r a m e w o r k s w e r e r e c o m m e n d e d : a p l a c e b o - c o n t ro ro l t ri r i a l w i t h r e s cu cu e f o r s y m p t o m a t i c in in -

knowledge concerning neonatal pharmacology and c linic linic a l tr ia l de sign a n d to e xplor e n ove l study de sign s f o r u s e i n n e w b o r n s , w i t h t h e u l t i m a t e g o a l o f i n c r ea ea s i n g o u r k n o w l e d g e a b o u t t h e s a f e ty ty a n d e f fi fi c ac ac y o f d r u g s u s e d t o t r e a t n e w b o r n s .43 . 43 The NDD I began in February 2003 with a planning session and the establishment of working groups in 4 t h e r a p e u t i c a re re a s : c e n t ra ra l n e r v o u s , p u l m o n a r y , a n d c a r diova sc u la r syste syste ms, a s w e ll a s pa in c o ntr ol. E a c h t h e r a p e u t i c a r e a w o r k g r o u p i n c l u d e d n e o n a t o l o g i s ts ts , subspecia subspe cialis lists ts in the des igned therapeutic area, p ediatric c lini linicc a l pha r ma c o logists, de ve lopm e nta l/f ollow - upc upc o n s u l t a n ts ts , a n d r e p r e s e n ta ta t i v es es o f t h e N I C H D a n d F D A . I n a d d i t i o n , w o r k i n g g r o u p s w e r e e s t a b li li s h e d t o d e v el el o p a n a p p r o a c h t o p r i o ri ri t iz iz i n g d ru r u g s t h a t r e q u ir ir e s tu tu d y in newborn conditions and to act as a resource on e t h ic ic a l i ss ss ue ue s. s. T h e e t h i c s g r o u p w a s c o m p o s e d o f n e o na tologists a nd pe dia tr ic ia ns w ith e xpe r tise in biome dic a l e thic s. ( A list list of p a r tic ipa nts is pr o vide d in the Appendix.) E a c h w or king gr oup ide ntif ie d spe c if ic topic s f or the focus of its discu discussi ssions, ons, as follows: pulm onary w orking group, apnea of prematurity and BPD; neurology w or king gr oup, se iz ur e s in te r m inf a nts a nd hypoxic i s ch c h e m i c e n c ep e p h a l o p a t h y ; c a r d io io l o g y w o r k i n g g r o u p , c a r dia c insta bility in pr e te r m inf a nts a nd postsur ge r y dysfunction in newborns; and the pain control word

fants and a trial based on a predefined targeted blood pr e ssur e . F or postope r a tive c a r dia c f a ilur e in ne w bor ns, 2 ge ne r a l f r a m e w or ks w e r e pr opos e d: a supe r iority trial comparing 2 currently used drugs and a random ized withdraw al study. The neurology working group proposed clinical tr ia l f r a me w or ks f or the tr e a tm e nt of se iz ur e s in in f ullullte r m inf a nts a nd a possible c linic a l f r a me w or k f or t h e s t u d y o f n e u r o p r o t e c t i v e t h e r a p i es es f o r n e o n a t a l e nc e p ha lopa t by. by. T h e p u l m o n a r y w o r k i n g g r o u p r e c o m m e n d e d c li li nni ca ca l t ri ri a l f r a m e w o r k s f o r s t u d y i n g d r u g t h e r a p y f o r t h e treatment of apnea of prematurity and the treatment o f B P D . T h e B P D c l i n ic ic a l fr fr a m e w o r k w a s s u b d i v i d e d a c c or din g to 3 dif f e r e nt the r a pe utic stra stra te gie s: pr e ve nt i o n , t r e a t m e n t o f e v o l v i n g BP BP D , a n d t r e a t m e n t o f e s ta blishe d B P D . T h e p a i n w o r k i n g g r o u p d e v e l o p e d c li li n ic ic a l t r ia ia l frameworks for evaluation of treatment of pain in 3 d if f e r e nt c linic linic a l indic a tions: pr oc e du r a l pa in, pos to p e r a t iv iv e a n a l g e si si a , a n d a n e s th th e s i a a n d p a i n c o n t r o l in me c ha n ic a lly ve ntila te d pr e te r m inf a nts. Members of the ethics working group were assigned to the 4 therapeutic work ing groups to provide b a c k g r o u n d o n t h e e t h i ca c a l c o n c e r n s re re l a t e d t o t h e p r o pose d c linic linic al al tr tr ia l f r a me w o r ks. I n a ddition , the e thic s w o r k i n g g r o u p i s c u r r e n t ly ly p r e p a r i n g a n a r ti ti c le le a b o u t

ing group, procedural pain, perioperative pain, and pa in a ssoc ia te d w ith me c h a nic a l ve ntila tion. W o r k i n g g r o u p s r e v ie ie w e d t h e e v i d e n c e u n d e r l y in in g t h e c u r r e n t t h e r a p y f o r t h e c o n d i t i o n s , c u r re re n t s t a t e o f k n o w l e d g e a b o u t p a t h o p h y s i o l o g y , a n d d e g r ee e e o f s i m iil a ri ri ty ty b e t w e e n t h e c o n d i t i o n s in in n e w b o r n s c o m p a r e d w i t h s i m i l a r d i s o r d e rs rs i n o l d e r c h i l d re re n a n d a d u l t s . T h e gr oup s pr e pa r e d ba c k gr ou nd pa pe r s a n d c linic linicaa l tr ia ia ls p a p e r s . T h e i n f o r m a t i o n g a t h e r e d in in t h e b a c k g r o u n d pa pe r s w a s c o nside r e d in the pr e p a r a tion o f the c linilinic a l tr ia ia ls pa pe r s, w hic h c o nta in a pr op ose d c linic linic a l tr tr ia ls ls f r a m e w o r k . T h e p r o p o s e d f r a m e w o r k i n c l u d e d s u g g e s t ed e d s t u d y p o p u l a t i o n , c h a r a c t e ri ri z a ti ti o n o f t h e c ondition, str a tif ic a tion c r ite r ia , use of bioma r ke r s, t r e a t m e n t e n d p o i n t s , a n d o u t c o m e m e a s u r es es .

t h e e t h i ca c a l p r o b l e m s o f c o n d u c t i n g d r u g t r i al al s i n t h e preterm population. F ina lly, the dr ug pr ior itiz a tion w or king gr oup de ve lop e d a syste m to ide ntif y the dr ugs o f highe st pr ior ity to ne ona te s. The papers produced by the various working groups were reviewed and discussed in a 2-day w orks h o p h e l d i n B a ltlt i m o r e , M a r y l a n d , M a r c h 2 9 a n d 3 0 , 2004 . A n a bbr e via te d ve r sion of the c linic a l tr ia l pa p e r s w il il l b e p u b l i s h e d a s a s u p p l e m e n t i n Pediatrics B e g i n n in in g w i t h t h i s i s s ue ue a n d c o n t i n u i n g i n s u b s e quent issues, Clinical Therapeutics w ill publish a r tic le s ba se d on the r e vie w s pr e pa r e d f or the B a ltimor e wo rksho p and the discussions that were stimulated by the se pa pe r s.

804

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G . R G i a c o ia ia a n d D.R. M a t d l m n

T h i s i s su su e o f Clinical Therapeutics inc lude s 4 a r tic l es es d e v e l o p e d b y t h e p a i n w o r k i n g g r o u p : A n a l g e s i a and Anesthesia for Neonates: Study Design and E thic a l I ssue s by A n a nd e t a l, A na lge sia a n d L oc a l A ne sthe sthe sia sia D u r ing I nvasi nvasive ve P r oc e dur e s in the N e o na te b y A n a n d e t a l , A n a l g e s ia ia a n d S e d a t i o n D u r i n g M e c h a n i c a l V e n t i l a ti ti o n i n N e o n a t e s b y A r a n d a e t a l ,

e v i d e nc nc e m a k e s i t a b u n d a n t l y c l e a r t h a t n e w b o r n s a n d p r e t e r m i n f a n t s a r e d i f f e re re n t f r o m o l d e r i n f a n t s a n d c h i ld ld r e n . T h e m a x i m c h i ld ld r en a r e n o t mi n i a t u r e a d u l t s ne e ds to be e xte n de d to inc lud e the c or olla r ie s a ne onate is not a miniature child a n d a very low b i r t h w ei g h t p r e ma t u r e i n / a n t i s n o t a mi n i a t u r e f u l l t e r m n e w b o r n . I t is hop e d tha t th is initia tive w ill r e -

a n d A n e s t h e s ia ia a n d A n a l g e s ia ia D u r i n g a n d A f t e r S ur ge r y in N e on a te s by B e rde rde e t a l. O th e r a r tic le le s to be pub lishe d in subse qu e nt issue s o f Clinical Therapeutics w ill a ddr e ss r e se a r c h on inotr ope s in pr e te r m inf a nts w ith c a r dia c insta bility, a framework for the treatment of electrographic seizures in newborns, treatment and prevention of n e o n a t a l e n c e p h a l o p a t h y , a n d a s y s t e m t o p r i o ri ri t iz iz e drugs for study in the newb orn po pulation.

suit in the deorphanizaton of newborn and preterm infants, and that the ukimate goal of providing t h i s p o p u l a t i o n w i t h s a f e a n d e f fe fe c ti ti v e d r u g s b e c o m e s a reality. ACKNOWLEDGMENTS

T h e vie w s pr e se nte d in this a r tic le le do not ne c e ssar ssar ily ily r ef ef le le ct ct t h o s e o f t h e F D A o r t h e N I C H D .

REFERENCES CONCLUSIONS T h e n e w b o r n p o p u l a t i o n i s c o m p l e x a n d h e te t e r og og e n e o u s . W e ll- de signe d c linic linic a l tr ia ls w i th c a r e f ul c ha r -

a c t e ri r i z a t io io n o f s a f et e t y a n d e f fi fi ca ca c y m u s t b e c o n d u c t e d b e f o re re t h e i n t r o d u c t i o n o f d r u g s t o t h i s f ra r a g il il e p o p u la tion. I nde e d, most a dve r se e ve nts r e sulting rom insuf f icie icie nt e va lua tion of of f - la la be l use of dr ug s in c hildren have been reported in neonates. T h e m o s t c h a l le le n g i n g a s p e c t o f p e r f o r m i n g c l in in i ca ca l tr ia ls in c hildr e n is de signing a nd c on duc ting saf saf e ty and efficacy studies in preterm and sick newborns. O n l y a f e w o f th th e > 1 0 0 d r u g s c u r r e n t l y u s e d i n n e w b o r n i n t en e n s i v e c a r e n u r s e ri ri e s h a v e b e e n d e m o n s t r a t e d t o b e e ff ff e ct c t iv iv e . M o s t d r u g s h a v e b e e n i n t r o d u c e d w i t h out a ppr opr ia te dosing, e f f ic a c y, or sa f e ty studie s. This population is the most vulnerable to adverse d r u g e f f e ct ct s b e c a u s e o f t h e i m m a t u r i t y o f D M E s a n d p a t h o p h y s i o l o g i c c h a n g e s t h a t a f fe fe c t d r u g d i s p o s i t io io n . D r ugs de ve lop e d for for spe c if ic ic ne w bor n indic a tions ( eg, eg, sur f a c ta nt f or r e spir a tor y distr e ss syndr ome , nitr ous oxide f or pe r siste nc e of pulmona r y f e ta l c ir c ula tion) have been well studied. However, although great str ide ide s ha ve be e n ma de in the study of dr ug s in c hildr e n overall, newborns--particularly preterm infants-r e ma in la r ge ly ly e xc lud e d f r om c linic linic a l dr ug tr ia ls. ls. The N ICHD and FDA developed the NDDI as an ongoing pr oc e ss to ide ntif y a nd sugge st str a te gie s to a d d r e s s o b s ta ta c l e s t o c o n d u c t i n g d r u g t r ia ia l s i n t h e n e w born. The NDDI workshop, herein described, is the f ir ir st st in a se r ie s of m e e tings tha t w ill e xa min e the sta te of the sc ie nc e a n d de f ine r e se a r c h pr ior itie s f or spe c ifific dise a se s or c onditions in ne ona te s. T he a va ila ble June 2

5

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Ped iatri iatricc Pl~rrr~c olo~: Therape utic Pr/nc~es/n Pr#ct/~. Pr#ct/~. 3rd e l. Philadelp h ia , Pa : L ip p in co r t Willia m s & Willd n s; 2 0 0 4 :1 1 1 - 1 1 8 . Horn LW, Kuhn RJ, Kanga SJ. Evaluation of the reproducibil reproducibility ity o f tablet splitting m provide accurate d o se s for the pediatric population. J P e d ~ P h a rm rm P r a ct ct . 1 9 9 9 ; 4 : 3 8 42. M a o n e T R , M a tte s RE) ,Be r b a u m JC, Be a u ch a m p GK. A n e w m e th o d fo r d e live r in g a ta ste with o u t flu id s to p r e te r m a n d te r m in fa n ts. De v Ps)ch0/ Ps) ch0/~0/ ~0/.. 1990 ;23:179 -191. Rosenstein D, Oster H. D iff ifferential erential facial responses to fou r basic tastes in n e w b o r n s. C h M D~w. 1 9 8 8 ;5 9 : 1555-1568. Gla sg o w AM , Bo e cl cl0 c RL , M ille r M K. Hyp e r o sm o la lity in sm a ll in fa n ts due to propylene glycol. Ped/utr/cs. 1983;72:353-355. Murch S , Coscel Cosceloe oe K. Hyperosmo lali lality ty related to propylene glycol in an infant. BMJ. 1990;301:389. Rigner CL, Jack FLTwiggs GA, R aisys VA. Hyp e r o sm o la lity in in d u ce d b y propylene g lycol. A complication o f silver sulfadiazine therapy. JAMA. 1985;253:1606-1609. Peleg O, B ar-Oz B, Arad I. Com a in a premature infant associated with the transdermal abs orption of propylene glycol. A cta P#ed~lr. 1998; 87:1195-1196. Gershanik J, Boecler B, Ensley H, e t

60. 68 rr-edeml edemlP.~st~r P .~st~r 2789-2790 (2003). 6 1 . 6 8 F ed e d er er l R ~ t e r 4 8 4 0 2 - 4 8 4 0 4 (2003). 6 2. 2 . 6 9 F , d e m l ~ 7 2 4 3 - 7 2 4 4 ( 2 00 0 0 4) 4) . 6 3. 3 . 7 0 F - e d e r # l ~ 3 9 3 7 - 3 9 4 0 ( 2 00 0 0 5) 5) . 64. Soler C, Figueras J, Roc a I, et al. Pulmonary peffusion scientigraphy in the evaluation o f the severi severity ty of

bronchop olmon ary dysp lasia. P~d/al P~d/alrr R~lid. 1997;27:32 35.

65. Marx MarxCM CM , Smith PG, LowrieLH, LowrieLH, et al. Opdmal selad on of mecha mechanic nicall allyyvendl ate l pediatric critical care patients. Cr/t CareMed. Care Med. 1994;22:163-170. 66. Po ets CF. Gascroesophageal reflux:A critical reviewof reviewof ts role in preEerm preEerm in04 ;1 ;1 1 3 :E :E 1 2 8 -E -E 1 3 2 . fants. ~ m ~ a . 2 0 04

67. Sifr im D, Castell D, Dent J, Kah rilas pJ. Gastro-oesoph ageal reflux monire p o r t toring: Re vie w a n d co n se n su s re on detection an d definiti definitions ons o f acid, non-acid, and gas reflug Gut. 2004;

53:1024-1031. 6 8 . Pe te r CS, Sp r o d o wsld N, Ah lb o m V, et al. Inter- and intraobserver agreem e n t for gasrroesophageal

reflux

detection in infants using multiple intraluminal intra luminal impedance. B/0/N e~te. 2004;85:11-14. 69. Braden B, Peterknecht A, Piepho T,

er al. M easuri easuring ng gastric gastric emp tying o f semisolids in children using 13Cacetate breath breath tes t A va lidat lidation ion study. D~gLi D~g Li wr Di s. 2 0 0 4 ; 3 6 : 2 6 0 - 2 6 4 . (continued on next page)

al. The gasping syndrome and benzyl alcohol poisoning. N E n ~ J M e / .

1982;307:1384-1388. 57. Lopez-Herce J, Bo ner C, M eana A, Albajara L. Benzyl Benzylalcohol alcohol poisoning following diazepam intravenous infusion. Ann Pl~rr~coCher. 1995;29: 632. 58. Brown W J, Buist NR, Gipson H T, et al. Fatal benzyl alcohol poisoning in a neonatal intensive care unit. Lan¢~t. 1982;1:1250 59. Anderson C W, N g KJ, KJ, Andresen B, Corder(>> L. Benzyl alcohol poisoning Corder( in a premature ne wborn infant. A m j Obstst Gpecd. 1984;148:344-346.

J u ne ne 2 0 0 5

Address correspondence to: George R Giacoia, MD, Obstetric and Pediatric Pharmacology Branch, Center for Research for Mothers and C h i l d re r e n , N a t i o n a l I n st s t it i t u te t e o f C h i l d H e a l t h a n d H u m a n D e v e l o p m e n t, t, N a t i o n a l In s t i t u t e s o f H e a l t h , 6 1 0 0 E x e c u t i v e B o u l e v a r d , M S C 7 5 1 0 , B e t h e s d a , M D 20 847. E-mail: gg65m@ nih.gov 807

 

C lili n ic ic al al T h e r a l x ~

Appendix

w

~

c h lr

EdaardoBanc~lari EdaardoBanc~l ari MD Professor o f Pe diatri diatrics cs Director, Division Division of Neonatology Universi Unive rsity ty o f Miami School of Medicine

planni pl anning ng Com mim ~ Debru L. Birenl Birenlxlum xlum MD FAAP Co-Chair FDA (until 2 /1/0 4) Program Progr am Leader (until 2/1 /04 ) Office o f Counter-Terrorism Counter-Terrorism and Pediatricc Dru g Development Pediatri US Food and D rug Administration Administration ShaAvhr~eBuckrnar~M ShaAvhr~eBuckrnar~ MD PhD Medical Officer Office o f Counter-Terrorism Counter-Terrorism and Pediatricc Dru g Development Pediatri Center for for Dru g Evaluation Evaluation and Research US Food and D rug Administration Administration

Lisa L. Ma this MD CDR USPHS Lisa Med ical Team Leader Office of Co unter-Terr unter-Terrorism orism and Pediatricc Dru g Development Pediatri Center for Dru g Evaluation Evaluation and

Hari Chenl Chen l Sat Saths hs MD FAAP Co-Chair FDA (from (from 2/1/04 to present) Medical O ffi fficer cer Office o f CounterCounter-Terr Terrori orism sm and

Research US Food and Drug Administration Administration

Pediatric Drug Development US Food and Drug Administration Administration Professor o f P ediatrics The G eorge W ashington Universi University ty School of Medici Medicine ne

Donald R. Madi son son MD

Acting Branch Chief Obs tetri tetrics cs and Pe diatri diatricc Pharmacology Branch Center for Research Research for Mo thers and C hil hildren dren National Institute of Child He alth and H uma n Development Development Susan K. Mc C une une MD

Medical Officer Office of Co unter-Terr unter-Terrorism orism and Pediatricc Dru g Development Pediatri Center for Dru g Evaluation Evaluation and Research US Food and Drug Administration Administration

GeorgeP. Giacoia GeorgeP. Giacoia M D Co-Chair NICHD New born D rug Development Initi Initiative ative Special Expert Cen ter for Resear Research ch for Mo thers and C hil hildren dren National Institute of Child Health and Hum an Development Development

GaY D. Pearson Pearson MD ScD

RosemaryH ~ i n s M D RosemaryH Program Scientist, Neo natal Resear Rese arch ch Ne twork Cen ter for D evelopmental Biology and Perinatal Med icine National Institute of Child Health and Hum an Development Development

Tonse TonseR R aju ajuScientist/Me MD D C H dical Officer Program Pregnancy Pregn ancy and Perinarology Branch Center for Development Developmental al Biology and Perinatal Medicine National Institute of Child He alth and H uma n Development Development

Jan Leah~

National Children s Study National Institute of Child Health and Hum an Development Development National Insti Institutes tutes of Health

Leader, Hea rt Development, Leader, Fun ction, and Failure Scientifi Scientificc Resear Rese arch ch G roup Division Divi sion o f H eart and Vascul Vascular ar Diseases National H eart, Lung, and Blood Institute

WilliamJ. Rodri WilliamJ. Rodriguez guez M D PhD Pediatricc Scie Pediatri Science nce D irector Office of Co unter-Terr unter-Terrorism orism and Pediatricc Dru g Development Pediatri Center for Dru g Evaluation Evaluation and Research US Food and Drug Administration Administration

Philip H. Sheridan Philip Sheridan M D Me dical R evi eviewer ewer Division of Neuropharmacological Drug P roducts Center for Drug E val valuati uation on and Research US Food and Drug Administration Administration L in in da da W r i t M D Deputy D irect irector or Cen ter for Research Research o r Mo thers and Ch ilildren dren National Instit Institute ute of Child Health and H uman Development ROUPS

Canfio/o~, Group Co-Chairs J e l ~ l L. Blu Blumer mer MD PhD Professor of Pediatrics and Pharmacology Case We stern Reser Reserve ve University Gerard R. Mar~n M D

Executive Executi ve D irector, C enter for He art, L ung, and Kidney Dis Disease ease Chief, Division o f Cardiology Children s National National Med ical Center Professor o f P ediatrics The G eorge W ashington Universi University ty School of Medici Medicine ne

(continued) 808

V o l um um e 2 7

Number 6

 

G .P . P . G im i m : ei eia a n d D . I ~ M ~ l m n

Appendix Continued)

Members lun Adutiu MBC hB FRCP C), MRCP UK) Associate Professor o f P ediatrics University o f Ca lilifornia, fornia, San Francisco Jacque~n Evans,M Jacque~nEvans, MD Medical Director Newborn/ Infant Center Professor o f Pe diatrics Children's Hospital of Philadelphia University of Pennsylvani Pennsylvaniaa Scho ol of Medi c ine ine je/frey Fineman,M Fineman,M D Professor o f Pe diatrics University Universi ty of Califomia, San Francisco D e an Follmann, P h D

Krisa Van Meurs, MD Krisa Professor o f Pediatrics Stanford University School of Medi c ine ine

Ha d CherylSachs, CherylSachs,MD MD , FA A P Medical Officer Office Offi ce o f Counter-Terroris Counter-Terrorism m and Pediatricc Drug Development Pediatri U S Food and D rug A dmi ni s tration tration

~ / R ~ v ~ RobertaA. Ball RobertaA. Ballard, ard, M D (Cardiovascular instability in preterm infants) Professor o f Pediatrics, Obs tetri tetrics, cs, and Gynecology University of Pennsylvani Pennsylvaniaa

Professor o f Pe diatri diatrics cs The George Washington Universi University ty School of Me dici dicine ne

Go/de Dude/I, Go/de Dude/I, M D (Cardiovascular instability in prererm infants) Attend ing Neonarologisr Division Divi sion o f Neonatology Department of P ediat ediatri rics cs Emoq~ University

Assistant Institute Institute Director for Biostarisrics Ch ief Biostadstics Research Branch National Instit Institute ute o f Allergy and Infectious Disea Diseases ses

Lynn Mahorg,M D Lynn (Postope rative cardiac dysfunction in the newbom) Professor o f Pediatrics University Universi ty o f Texas Southwestern Medical Center

Abraham A vi) M. Karkow ~, MD, PhD Abraham Team Leader Division Divis ion o f Cardio-Renal Drug Products Center for Drug Evaluati Evaluation on

Robe rt E. Shad@,M Shad@,M D (Postoperative cardiac dysfunction in the newborn) L George Veasy Prof Professor essor o f P ediatr ediatrics ics

Research USand Food and Drug Adm ini inistrat stration ion ..~epMn ..~ep Mn . Roth, M D, M PH Associate Professor o f P ediatrics Stanford University School of Medi c ine ine Billie Lou Short; M D

Ch ief Divi Division sion o f Neonarology Children's National Medical Center Professor o f Pe diatrics The G eorge Washington Universi University ty School of M edici edicine ne

une

2005

Division o f Pediatri Division Pediatricc C ardiol ardiology ogy Department of P ediat ediatri rics cs University Universi ty of Utah School of Medi c ine ine Co-Fdcal Fadlitamrs C_,ailD. D . Pearson,MD, Pearson,MD, ScD Leader, Heart Development, Fun ction, and Failure Scientifi Scientificc Researc Resea rchh G roup Division Divi sion of He art and Vascular Diseases National Heart, Lu ng, and Blood Institute

N w o/oB o/oB , Group Co-O~rs Robert R. Clangl Clangl,, M D Professor Profess or of Neurology Division Divis ion o f Neurology University o f Pennsylvania Scho ol of Medi c ine ine Children's Hospital of Philadelphia Jeffrey M . Pe r lm an MB ChB Jeffrey Professor of Pediatrics Weill Medical College of Weill Comell Univers University ity Members

S u sa sa n K . C u m m i n s M D M P H

Medical Team Leader Division Divi sion of Pediatric Drug Development Center for Drug Dr ug Evaluation and Research US Food an and d Drug dministration Deborah Hirt Hirtz, z, M D

Program Direct Director or Clinical Trials National Institut Institutee o f Neu rological Disorders and Stroke National Institutes of Health

Eli M. Mizrahi,M D Head, Peter Kellaway Kellaway Section Section of Neurophysiolo~ Professoro f N eurology and Pediatri Pediatrics cs Departments o f Neurology Neurology and Pediatrics Bay/or College College o f Medicine

(c onti nued)

809

 

Clinical

Appendi x Cont i nued)

MichaelJ. P ainter, ainter,M MD Professor Department of Neurol Neurology ogy University Universi ty of Pitt Pittsburgh sburgh John van van den Anker, MD , PhD Professor o f Pediatrics, Pharmaco logy, and Physiology George Washington Universi University ty School of Medicine and He alth Sciences B ~ / R . V ohr, ohr,M MD Director, Neona tal Follow-up C linic Professor o f Pediatrics Brown University Women and Infants Hospital of Rhode Island Island R e a c t o ~ / Hracho~j, R ~ e w e r sM D Richard,4. Professor Prof essor o f Neurology Peter Kellaway Kellaway Section o f Neurophysiology Raylor College of Medicine

Ma rk S. Scher,M Scher,M D Division Divis ion Chief, Pe diatri diatricc Neurology Director o f P ediatri ediatricc Sleep/ Epilepsy Epil epsy and Fetal/Neonatal Neurology Progr Programs ams Case Western Reser Reserve ve University Rainbow B abiesand Children s Hospital Fave Silverst~in,M FaveSilverst~in, MD Professor Depa rtment of Pediat Pediatri rics cs University Universi ty o f Michigan Co-F~eral Fa~ilitamors Philip H. Sheridan, Sheridan,M MD

Me dical R evi eviewer ewer Division Divis ion o f Ne uropharmacologi uropharmacological cal Drug Products Center for Drug E valuati valuation on and Research US Food and Drug Adm inist inistrati ration on

Linda W ri Linda right, ght, MD Deputy D irect irector or Center for Rese Resear arch ch or Mo thers and Chil Children dren National Institute Institute of Child He alth and Hum an Development Development National Insti Institutes tutes o f Health

Chris r~ Fan~ M D Chris Med ical Officer Division Divisi on of And-inflamm atory, Analgesic Analges ics, s, and Oph thalmic Drug Products

Pain ConJro/ Chair K.S.. Anand, D.Phil., MBBS K.S Professor Departments o f Pediat Pediatri rics, cs, Anesthesiology, Anesthesi ology, Neurob iology, and Pharmacology Critical Care Med ici icine ne University Universi ty of Arkansas or Me dical Sciences

Sharon Hertz, M D Sharon Deputy Director Divisi Divi sion on of And-inflamma tor/ tor/,, Analgesic Analges ics, s, and Oph thalmic Drug Products US Food and Drug Adm inist inistration ration

Members Jacob Jac ob V Aranda,MD , PhD, FRC°C

TomJaksi Tom Jaksic, c, M D, PhD Associate Professor o f Surgery Harvardd Med ical School Harvar Children Childr en s H ospital Boston

Professor o f Pediatrics, Pharmacology, and Pharma ceuticalSciences Network Children Childr en s Ho spital of Michi Michigan gan Ctmrles Berde, M D , PhD Ctmrles Chief, Division Division of Pain Medicine Professor Prof essor of Anesthes Anesthesia ia and Pediatrics Harvard M edical School RoseM. Boyle,M RoseM. Boyle, M N Neon atal Nurse Practitioner Practitioner Neon atal IntensiveCare U nit Montreal C hildren s Hospital McG ill University University Health Edmund C~l~relli, Pt~rmD EdmundC~l~relli, Associate Clin ical P rofessor of Pediat Pediatric ricss Co-Director, P ediatri ediatricc Pharm acology Research Research Unit University Universi ty of California, San Diego

Center for Drug Evaluation and Resear Research ch US Food and Drug Adm inist inistration ration

P at Hummel Hummel,, R N ~ MA , N N P , P N P Coo rdinator, Developmental Follow-up Program Loyola University Med ical Center

Celest~~ oh nston, RN , D E / Celest Professor School of Nursi Nursing ng McG ill University University Canada Vic~or~~ Tu ng Lehr, Pt~rm D Vic~or Associate Professor Depa rtment o f Pharmacy Pract Practice ice Eugene Eug eneApplebaum Scho ol o f Pharmacy and He alth Sciences Sciences Wayne State U niversi niversity ty Children Childr en s Hospital of Michigan Anne M. Lynn Lynn,, M D Professor o f Anesthesiology and Pediatrics Children s Hosp ital and Regional Med ical Center University Universi ty o f W ashington School o f Medicine Medicine

(continued) 810

V o lu lu m e 2 7 , N u m b e r 6

 

G.P.

iacoia and

D.R. Matdson

Appendi x Cont i nued) Dona ld R. MatZis MatZison on M D

Acting B ranch Chief Obstetrics Obstetri cs and Pediatri Pediatricc Pharmacology Branch Center for Research Research or Mo thers and Children National Institute Institute of C hild Health and Hum an Development Development L nne G. Maxwell Maxwell M D

Associate P rofessor Depa rtment of Anesthesi Anesthesiology ology University of Pennsyl Pennsylvani vaniaa Children s Hospital of Philadel Philadelphia phia 7~m O b e r l a n d e r

D

FRCPC

Associate Professor nd Ac ting D i v i si si o n H e a d D i v i s io i o n o f D e v e l o p m e n t a l P e di d i a t ri ri c s U n i v e r s it i t y f B r it it i s h o l u m b i a B C Children s Hospital V a n co u v er , C a n a d a

Les~r Schu Schultlthei heiss MD PhD

Medical Officer Division of Anesthetic, Critical C are, and Ad dicti diction on Drug Products Products Center for Drug Evaluati Evaluation on and Research US Food and Drug Adm inist inistrati ration on

Su~icioo G. Sonano M D Su~ici

Associate Professor o f A nesthesi nesthesiaa Harvard Me dical School Children Childr en s Hospital Boston

Anna Taddio Taddio PhD

Scientist, Popu lation Health Scientist, Sciences, Scienc es, Research n stitute an d Depa rtment o f Pharmacy Hosp ital for for Sick Children Ganj A. W alco PhD

Professor o f Pediatrics University Universi ty o f Med icine and Dentistq~ Dentis tq~ of New Jer Jersey sey Hackem ack University University Medical Center

June 2005

~ / R ~ v ~ (Summaryy of Pmce edinp of (Summar

Puk~aW

ro~

t h e N D D I N e o n a t a l P a in in Control Group) William Will iam O h M D

Nell Finer Finer M D

Professor o f Pediatri Pediatrics cs Brown Medical School Women and Infant s Hospital Hospital of Rhode Island Island

Depa rtment of Pediatr Pediatrics ics University of Califom ia San Diego University

Arne Ohls Ohlsson son M D MSc

Direc tor, Evidence-Based Evidence-Based Ne ona tal Care and Outcom es Resear Research ch Director, Canadian Cochrane Network and Centr Centree Depa rtment of Pediat Pediatric ricss Moun t Sinai Hospital Bonnie St Steve evens ns PhD RN

Professor o f Pediatrics Director, Division of Ne onatology

Michele Miche le Walsh MD MS

Professor o f Pediatrics Depa rtment of Pediatr Pediatrics ics Case Wes tern Reser Reserve veUniversity University

Members Marilee Maril ee C All Allen en M D

Professor Division Divisi on of Ne onatology Depa rtment of Pediatr Pediatrics ics Johns Hopkins School of Medici Medicine ne

Signy Hildur Eaton Chair in Signy Ped iatri iatricc Nu rsing Research Research Associatee Chief o f Associat Nu rsing Resear Research ch Hosp ital for Sick Children

Debra L. Bir Birenbaum enbaum MD FAA P

Dick Ti Tibboe bboell MD PhD

J onat ~ n M . D av is is M D

Professorand Pediatric Surgeon Professor Surgeon Erasmus Eras mus Med ical Center Sophia Children s Hospital Co-Rd~ral Fadlitm~rs ShaAvhr~e ShaAvh r~eBuclo~an MD PhD

MedicalofOfficer Office Counter-Terror CounterTerrorism ism and Pediatricc D rug Development Pediatri Center for Drug Evaluati Evaluation on and Resear Research ch US Food and Drug Administration Administration Tons To nsee Rap MD DCH

Program S cientist/ Program cientist/Med Med ical Officer Pregnanc Preg nancyy and Perinarology Branch Branch Center for Developmental Biology and Perinatal Medicine National Institute Institute of Child Hea lth and Hum an Development Development

Co-Chair FDA (until 2 /1/0 4) Program Prog ram Leader until 2/1 /04 ) Office o f Counter-Terrori Counter-Terrorism sm and Pediatricc D rug Development Pediatri US Food and Drug Administration Administration

Professor o f Pediatrics Depa rtment of Pediatr Pediatrics ics SUNYStony SUNY Stony BrookSchool Brook School o f Medic Medicine ine W inthrop Universit Universityy Hos pital

Alan H.. H..Iobe Iobe MD PhD

Professor o f Pediatrics Department of Neonarol Neonarology ogy Cincinnati Children s Hospital

John Katlwi Katlwinkel nkel M D

Chades Fuller P rof rofessor essoro f Neonarology Director, Division of N eonarology Depa rtment of Pediatr Pediatrics ics University Universi ty of Virginia H ealth System

(continued)

811

 

Clinical

Appendix Continued)

Gr~o nj L. Kear Kearns ns PharmD P hD Marion Merrell Dow/Missouri Chair in Pediatri Pediatricc Pharm acology Professor Profe ssor of Pediatr Pediatrics ics and Pharmacology University o f M issouri University issouri-Kansas -Kansas City Chief, Division of Pediatric Pharmacologyand Me dical Toxicology Director, Pediatric Pharmacology Research Un it Children s Me rcy Hospitals and Clini Clinics cs Jan Keltz PharmD MS Senior R esearch Pha rmacist Investigadon al Drug Service W inthrop Universi University ty Hospital Hospital Richard Richa rdJ. J. M a~ n M D Professor Departments of Pediat Pediatri rics, cs, Reproductive Biology, Physiology, an d Biophysics Rainbow Babies and Children s H ospital Case Me dical Schoo l Pe~r Sr~r Sr~rke ke M D Medical Team Leader Division Divis ion o f Pulmona ry and Allergy Drug Products Center for Drug Evaluati Evaluation on and Research US Food and Drug Adm ini inistrat stration ion Sr~nl~ Sze[le Sze[lerr M D Helen Woh lberg and Herman La mbert Chair in Pharmacokinedcs Hea d, Pediatric Clinical Pharmacology National Jewish Medical and Research Center Professor Profe ssor of Pediatr Pediatric ic and Pharmacology University Universi ty o f Colorado Health Science Center

~/R~ewers S ~ /en H . A bman M D (Bronchopulmonaty dysplasia) Professor/Director Pediatric Pediatr ic Heart Lun g Center University Universi ty o f Colorado School of Medi c ine ine

Keith Bam ~¢oK MB ChB Keith (Apnea o f premarurity) Associate Professor Department of P ediat ediatri rics cs McGill University Barbara Schmid~MD Schmid~ MD MS c (Apnea o f prematurity) prematurity) Professor Departments of Pediat Pediatri rics cs and Clini Clinical cal Epidem iol iology ogy and Biosrari Biosrariscics scics McM aster University University LindaJ . V an LindaJ an Ma n r MD MP H (Bronchopulmonary dysplasi dysplasia) a) Associatee Professor of Pediatr Associat Pediatrics ics Division Divi sion o f Newb om Medicine Department of P ediat ediatri rics cs Harvard M edical School Co-Federal Facilitators Roseman/H Roseman/ Hi~m MD Program Scientist, Neonatal Research Netw ork Center for D evelopmental Biology Biology and Perinat Perinatal al Medicine Medicine National Instit Institute ute o f Child Health and H um an D ev el opment Susan K. M cCune M Susan Medical Officer Office Offi ce of Cou nternter-Terrori Terrorism sm and Pediatric Pediatr ic Drug D evelopment Center for Drug Evaluati Evaluation on and Research US Foo d and Drug Administrati Administration on

D ru r u g P n o n ~ l i m G ro ro up up Co-Chairs Avroy Avr oy A. Far~ro~ M D (Chairman o f Pediatrics) Pediatrics) Eliza Eli za Henry Bam es Chair o f Neonatology Rainbow Babies and Childr Children en s Hospital Professor Profess or of Pediatr Pediatrics ics and Neonarology n Reproductive Biology R obert obertM. W ard M D Professor o f Pe diatri diatrics cs Director, Pediatric Pharmacology Program Department of Neonatology University Universi ty of Utah Members

W ililliliam am E. Benitz M D Associate Chief Division Divis ion o f Neona rology and Developmental M edici edicine ne Professor o f Pe diatri diatrics cs Stanford University Scho ol of Medi c ine ine Daniel Benj Benjamin amin MD PhD MP H Assistant Professor Department of Pediatrics Pediatrics Duke Universi University ty Duke Clinical Research Instit Institute ute Lillian R. Bladcmon Lillian Bladcmon M D Clinical Clini cal Associate Professor of Pediatrics University Universi ty of M ar/lan d School of Medi c ine ine J e ffff rf rf / H o ~ r M D Professor o f Pe diatri diatrics cs University Universi ty of V ermont Vermont Oxford Network

(c onti nued) 812

Volume 27 N u mb er 6

 

G P G im i m : ei ei a m ~ l D I ~ M ~ l m n

A ppendix ( C ont inued) Mark Hudak,M D Assistant Assist ant D ean and Professor Department of Pediatrics University of F lorida a t Jacksonville

W ill illiam iam J. Rodri Rodriguez, guez,M MD, PhD Pediatric Pediatr ic Science D irector Office Offi ce of Counter-Terrori Counter-Terrorism sm and Pediatric Pediatr ic Drug D evelopment Center for Drug Evaluati Evaluation on

John Lanros, Lanros,M MD Professor of Pediatr Pediatrics ics Associate Director, Director, Ma cLean Center Clinical Medical Ethics Co-Director, Co-Direct or, Ro bert W ood

Ror~ld L Pol Poland, and, M D Professor Profess or o f Pediatr Pediatrics ics Interim Inter im Ch ief of Neonatology Department o f Pediatrics/ Pediatrics/ Neonatolog) U niv ers ers ity ity o f N ew M ex ic o Children's Hospital

and Resear Research ch U S Food and D r ug A dm inis t r at ion ion

Johnson Clinical Scholars Program Departments o f Pediatrics Pediatrics and Medicine Universityy o f Chicago Universit

Arzu Sel Selen, en, PhD Deputy Division Director Division Divisi on of Pharmaceutical Evaluation III Office Offi ce o f Clini Clinical cal Pha rmacology and Biopharmaceutics Center for Drug Evaluati Evaluation on and Research U S Food and D r ug A dm inis t rat rat ion Co-F~eral F~ilim~ors George Geor ge P Giacoia,M D C o- C hair hair , N ew bor n D r ug Development Initiative Special Expert Center for Research Research for M othe rs and Children Na tional Institut Institutee o f Child H ealth and H um an D ev elopm ent

J u ne ne 2 0 0 5

~ s G r ou ou p Robert M . Skip Skip~' ~'Nelson, N elson, M D, PhD Associate P rofessor of A nesthes nesthesia ia and Pediatr Pediatrics ics Department of Anesthesiology Anesthesiology and Crit Critical ical C are Medicine University of Pennsylvania School of M edic ine ine Children's Hospital of Philadelphia M

0

Alan R. Flei Fleisckn~n, sckn~n, M D Senior Vice President N ew Y or k A c adem y o f M edic edicine ine

Benjamin Wilfond, M D Benjamin Head, Bioethi Bioethics cs and So cial Policy Social and Behavioral Research Branch N at ional H um an G enom e R es ear ear ch ch Institute National Institutes of Health Fedm 'al Facilit Facilita~m a~m Sara F. Goldkind, M D, M A Bioerhicist Office Offi ce o f Pediatric Pediatric Therapeutics Office of the Commissioner U S Food and D r ug A dm inis t r at ion ion

Da le E. Hamm erschmid~, erschmid~,M MD Associate Professor Department o f Medicine University Universi ty of Minnesota Medical School

813