`

ESSENC
CE - Interna
ational Jourrnal for Envvironmentaal Rehabilitaation and Conservation
n
Volume V: No. 2 2014 [5
50 – 64] [ISS
SN 0975 - 62722]
[ww
ww.essence-jouurnal.com]

Proceedings of
o National Coonference
“Environmental Conserrvation and Cllean India Proogramme” Deccember 2014, India
I

prehensivee study on
A comp n the regullation of pediatric in
n U.S., Eurrope and India
I

Neetika Rani, Vikaa

as Budhwaaar and Arun
n Nanda

2 2014 ⏐ Acccepted: Deccember 22, 20014 ⏐ Online:: December 31,

Received: November 25, 3 2014

Abstractt Keyywords: Reegulation | Pediatric Research

R
Metaboliism in a chilld is differennt from aduults. Equuity Act | Pediatric
P phharmacologyy | Best
Their ressponse to druugs is differrent in both the
t Phaarmaceuticals for Childdren Act | Pediatric
P
ways, pharmaco-kin
p netically annd pharmacco- Usee Marketing Authorizatioon
dynamicaally. Consid dering this fact, there are Intrroduction
specific regulations for pediatriics in US and a
50––90% of druugs used in children
c todday have
EU. In US, pediatrric exclusivvity provisioons
nevver been actuually studiedd in this poppulation,
were estaablished in 1997 as parrt of the Foood
andd the results of drug stuudies done in adults
and Druug Administration Modernization Act A
are often extrrapolated foor use in children
(FDAMA A), and in 20022 the Best B
(Yeewale and Dharampallan, 2012).. Some
Pharmaceuticals for Children Acct (BPCA) was w
seveere adverse drug reactioons in childrren with
introduceed followed by the Pediiatric Researrch
the drugs whicch were marrketed in thhe world
Equity Act
A (PREA) in 2003. In I Europe, thet
withhout any speecific studiees in childreen, made
Pediatricc Regulation (EC 1901/22006 Medicinnal
the practitionners and other heealthcare
Products for pediatriic use) came into forcee in
proffessionals reealize that chhildren and neonates
n
January 2007.
2 The arrticle compaares the current
are different froom adults annd thus the response
r
status off pediatric regulations
r i US and EU
in E
of any
a drug in their body would be different d
and empphasizes the need to deevelop speciific
fromm adults. Altthough the lawsl and reggulations
guidelinees for peediatrics inn developiing
govverning the marketing, production, clinical
countriess.
trialls, storage, stability etc.e of druugs and
For correespondence: exciipients for pediatrics
p haave been fraamed in
Departmennt of Pharmaceutical Scieences, Maharshi
the developed countries
c likke US and EU U, these
Dayanandd University, Rohtak,
R India reguulations aree relativelyy very new w. The
Email: prrajapatineetika9
90@gmail.comm
conndition is sttill worse in i India annd other
50
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

developinng countriess. Every yeaar an estimatted barrrier, liver, muscles,

m strratum corneeum and
26 millioon children are born in India (Whyy is diffferences in the
t constituution of boddy fluids
birth registration
r importantt? cited at andd plasma proteins, subcuutaneous fatss etc. are
http://wwww.unicef.orrg/india/resoources_1650..ht som
me of the major differennces contribbuting in
m) whichh suggests a huge dem mand for druugs diffferent Absorption,, Distrribution,
and vacccines throug ghout the coountry. Stilll a Mettabolism, Excretion
E (ADME) off many
little impportance is given
g to the regulations of druggs like sullphisoxazolee, chlorampphenicol,
drugs annd vaccines in these couuntries. Effoorts bennzyl alcohol and digoxinn etc. (Curleey et al.,
to harm monize thee pediatricc regulatioons 20001). The Discussion
D begins with
w the
throughoout the worrld, which wouldw lead to exam mples of thee some fatal consequencees of the
hassle free
fr export and imporrt of pediattric lackk of drug sttudies with children, esspecially
dosage forms
f withinn the countriies is also one
o the youngest children.
c Soome severe adverse
of the bigggest need of
o the hour. drugg reactions related with commonnly used
druggs in pediatrrics are:
Need foor the sep
parate Reggulations for
f
pediatriccs Sulp
phisoxazolee (Kernicturres)
Ignorancce or lack of knowledge of the t Thee major disaaster about drug
d use in children
differencces in pediaatric pharmaacotherapy has h happened in 19956, when newborns reeceiving
led to vaarious medicine-related tragedies
t in the
t sulpphisoxazole were foundd to be havinng more
past. Thhese tragic side effectss of drugs on kernnicterus (enntry of biliruubin into thhe brain,
children propelled much
m of the legislation
l thhat causing yellow w discoloratiion of brainn tissue,
led to the creation n of the Foood and Drrug seizzures, and death). It occcurs becausee infants
Administtration (FDA A) and Europpean Medicine havve diminishhed glucurronosyl traansferase
Agency (EMA) in its moderrn incarnatioon. actiivity, and therefore, less abiility to
Medicatiions that are generaally safe and a gluccuronidate bilirubin. Infants alsso have
effective for adullts may be b unsafe or immmature bloood-brain barrriers, whichh allow
ineffectivve or both fo
or some or all pediatric age
a morre of the frree bilirubinn to cross into
i and
groups or o may req quire changges in dosiing dammage the braain. It displlaces bilirubbin from
forms, caalculations, or
o scheduless to be safe and
a plassma proteinns, thus inncreasing thhe free
effective. Such disparities unnderscore the t fracction of bilirubin
b in the plasm ma and
necessityy for pediatriic drug studiies. enhhancing the movement
m o bilirubin into the
of
braiin (Casavantt et al., 20100).
Behaviorr of the d
drugs booth
pharmacoodynamicallly and pharm macokineticaally Chllorampheniicol (Gray baby
b syndroome)
is differeent in infantss and small children whhen Graay baby synddrome is a rare
r but serious side
comparedd to adultss. There arre some grooss effeect that occcurs in inffants (especcially in
differencces in childreen and infannt’s physioloogy premmature babiies) followiing the intrravenous
and anaatomy. Und derdevelopedd blood brain admministration of chllorampheniccol, a
51 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

becteriosstatic antibio
otic. Gray baby
b syndromme fromm antiasthm matic druggs (Committtee on
was firsst reported in 1959, in neonattes. Druugs, 1997), aspartame
a induced headaache and
Immaturee glucuronyll transferasee activity is one
o seizzures (Liptoon et al., 1989), saaccharin-
of the reasons off gray babby syndrom me; induuced cross-ssensitivity reeactions in children
inadequaate renal exccretion of chhloramphenicol withh sulphonam mide allerggy (Commiittee on
and its metabolitees is the other reasson Druugs, 1997)), propylenne glycol--induced
(Casavannt et al., 2010
0). hypperosmolalityy and lactic acidosis (Huuggon et
al., 1990) are some otherr adverse reactions
r
Benzyl alcohol
a
whiich occurreed due to irrational use of
In 1982, a common excipient, benzyl b alcohhol, exciipients in peediatric form
mulations.
was blammed for the neonatal
n gaspping syndrom me
This finally puurposed the regulatory agencies
a
and the deaths
d of prremature babbies. Used as a a
throoughout the world to serriously revieew these
bacteriosstatic preserrvative, it was given to
evennts and fromfr separaate guidelinnes for
children in a flush used to keeep intravenoous
peddiatrics. US and EU were amonngst the
lines pattent. The neeonatal gaspping syndrom me
pionneers with regard to step taken in this
consists of acidossis, respiraatory distreess,
conntext. The fraamework off separate guuidelines
circulatorry failure,, intracrannial bleedinng,
for pediatric sttarted with thet classificcation of
seizures, and death. Besides rem minding us thhat
peddiatric age caategories shoows the Tablle 1.
excipientts are nott inactive, the neonaatal
gasping syndrome ex xemplifies thet problem of Law
ws governin
ng the Pediaatrics in US
differentiial metaboliism of benzzyl alcohol in Thee US was ahhead of Eurrope in recoognizing
babies. Neonates
N prrobably metaabolize benzyl the need for legislationn to ensuure that
alcohol to benzoic acid, whichh accumulaates phaarmaceuticalss are develooped for, annd tested
and causees toxicity (FField et al., 2012).
2 in, the peddiatric poppulation. Pediatric P
Hepatotooxicity asso ociated withh the use of excllusivity provvisions weree establishedd in 1997
sodium Valproate (Jackson et e al., 19884), as part
p of the FoodF and Drug
D Adminnistration
increasedd risk of Rey
ye’s syndrom me with the useu Modernization ActA (FDAM MA), and in 20022 the
of salicyylates in chiildren with viral infectiion Besst Pharmaceuuticals for Children Act (BPCA)
(Busti et al., 2010), growth
g supppression/effeects wass introducedd followed by the PediatricP
on adrrenal function witth long-teerm Ressearch Equityy Act (PREA A) in 2003 (B Bhatti et
corticosteeroids (Dahhl, 2006), gastrointestin
g nal al., 2011).
bleeds with
w NSAIDss (Anyanwuu et al., 20113), In 1979, Produuct label innclude pediaatric use
risk of arrthropathy due
d to use of ciprofloxacin secttion rules were
w enactedd. Accordingg to this
in childreen (Adefurinn et al., 2011) are somee of rulee, if the druug is approved for a pediatric
p
the otherr adverse dru
ug reactions in the childrren indiication, thatt indication must be described
which leaad to the serious disasterrs. undder the indiccation and usage
u sectionn of the
Benzalkoonium chloriide-induced bronchospaasm labeeling, with dosing infformation provided
p
52 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

under usaage and adm ministration section.

s If there Peddiatric Reseaarch Equity Act
A (PREA) came in
t labeling must state thhat
is no peddiatric use, the forcce. PREA appplies only to those drrugs and
“safety and
a effectiveeness in the children
c below biollogical prodducts develloped for diseases
the age have not beeen establisshed” (Labsoon, andd/or conditioons that occuur in both thhe adult
2002). Inn 1994, Ped diatric labelling rule were andd pediatric populationns. Under PREA,
made, acccording to this rule, all a sponsors of sponnsors submitting a new w drug appllications
drug andd biologics product
p exam mine availabble (ND DA), Bioloogical License Appllications
data onn pediatricc use and submit a (BLLA), or suppplemental applicationss on or
supplemeental appliication for a pediattric afteer April 1, 19999 must incclude assessm
ments of
indicationn, if supportted by the exxisting data.. In safeety and effiicacy for alll relevant pediatric
p
cases whhere the spo onsors determ mined that thet poppulations forr claimed inndications (B Bhatti et
existing data did not n support pediatric use, u al., 2011). In 2007,
2 reauthhorization off BPCA
labeling could simp ply state, that “safety anda andd PREA toook place. The BPCA A 2007
effectivenness in ped diatric patieents below the t exteends the provvision offeriing additionaal patent
age of ( ) have not been establiished (Labsoon, excllusivity for on patent drrugs being teested for
2002). In I 1997, Section
S 111 of FDAM MA peddiatric use. In 2010, Biologicaal Price
established a new detailed statutoory program m to commpetition annd Innovattion Act (BPCIA) (
enhance the incentiv ves for the sponsors off a incoorporated thhe provision for the excclusivity
new druug applicattion (NDA)) to conduuct of pediatric
p bioologics. The BPCIA mayy extend
pediatric studies an nd collect pediatric use u by six months,, respectivelly, the geneeral four
informatiion at the FDA’s
F requeest on new anda yearr marketingg exclusivityy and twellve year
already approved
a dru
ugs. Compannies that satisfy dataa Protectionn periods. If applicabble, the
the requuirement off section 505A earn six BPC CIA will allso extend by six monnths the
months of o additionaal marketingg “exclusivitty” seveen-year periiod of orphan drug excclusivity
for a druug. This Act incorporates the provisiion for such bioloogic (Kogann, 2011). Inn 2012,
of writteen request (Labson,
( 20002). In 19998, PRE EA and BP PCA become permanennt. Food
Pediatricc rule requ uire that a new produuct andd Drug Administrattion Safetty and
applicatioon contain a pediatric usse section. This
T Innoovations Acct (FDASIA A) also creatted new
section briefly
b summmarizes the peediatric studdies provvisions goveerning deferrral extensionns under
conducteed (Labson, 2002).
2 the PREA. FDA ASIA establiishes that ann “initial
peddiatric study plan” musst be submitted not
In 2002, Best Pharmaaceuticals foor Children Act
A
later than 60 daays after thee date of thee end of
(BPCA), replaced thet FDAMA A. It is nott a
Phaase 2 meetiing with FDA or othher time
mandate for the manufactuurer. If the t
agreeed upon between
b FDAA and the sponsor
manufactturer also co
onducts a peddiatric studyy of
(Food and Drugg Administration, n.d.). Table 2
that drugg, he will then
t receivee a six-monnth
show ws the afforementioneed legislatiion for
extensionn to run after the iniitial Waxmaan-
chilldren in chrronological order and table 3
Hatch extension
e (L
Labson, 20002). In 20003,
53 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

shows thhe list of meedicine to which

w pediattric 19001/2006 and the amending Regulation (EC)
exclusiviity has been granted till date.
d No 1902/2006 (European Medicine Agency,
A
20007).
Pediatricc Regulation
n in Europeean Union
Thee Pediatric Regulation (Regulatioon (EC)
The Eurropean Meedicines Aggency enactted
19001/2006 as amended) establishes a new
Pediatricc Regulation
n in Januarry 2007. This T
scieentific commmittee of the European Medicine
M
legislatioon concernss the deveelopment and a
Ageency (EMA A), the Peediatric Committee
authorizaation of med
dicines for use
u in childrren
(PD
DCO) (Mediccine and Heealthcare Regulatory
aged up to 17 yearss and introduuced sweepiing
changes into the reegulatory ennvironment for Ageency, n.d.). The Pediatric
P
Com mmittee's (PDDCO's) maiin role is too assess
pediatric medicines (Mulberg
( et al., 2013).
the content of Pediatric Investiigational
In 19977, the Euro opean Com mmission (E EC) Plann (PIPs) annd adopt opinions
o onn them
organizedd at the Eu uropean Meddicine Agenncy (Roochhi et al., 2010).
2
(EMA) a round tab ble of expeerts to discuuss
EMMA, with the scientific suupport of thee PDCO,
pediatric medicines. In 1998, thhe Commissiion
devveloped a European
E neetwork of existing
supportedd the need for
f internatioonal discussiion
natiional and Euuropean netw works, invesstigators
on the peerformance ofo clinical trials in childrren
andd centres with
w specificc expertise in the
in the coontext of thee Internationnal Conferennce
perfformance of o studies in the paaediatric
on Harm monisation (ICH) ann organizatiion
poppulation. Thee Agency's Managemennt Board
working on th
he harmoonisation of
adopted an im mplementingg strategy for f the
pharmaceeutical reegulatory requirements
netwwork on 15 January
J 2008. Every yeaar, Enpr-
between the EU, Japan and a the US.
U
EMMA holds a workshopp at the European E
Subsequeently, the IC CH guidelinne became the t
Meddicines Agency in London.
L Enppr-EMA
Europeann guideline “Note forr guidance on
worrks with intternational partners
p speccializing
clinical investigation
i n of medicinnal productss in
in the
t regulatioon of medicines for children. It
the pediatric populaation” (ICH H Topic E11),
worrks with World Health Organization
O (WHO)
which has
h been in n force sinnce July 20002
andd United State Food F and Drug
(Europeaan Medicine Agency, 2007).
Adm ministration (European Medicine Agency,
A
On 29 September,
S 2004,
2 the ECC released the
t n.d..).
first propposal for a Regulationn on medicinnal
Thee Pediatric Regulation establishes a new
products for pediatric use. The Regulation
R w
was
agreed on typee of markeeting authorrization, callled the
o 1st Junee 2006 by the Europeean
Paediatric Usse Marketting Authoorization
Parliament. On 27 December 2006 the t
Regulatioon was pu (PU
UMA), inttended too stimulatte the
ublished inn the Officcial
devvelopment off off patent products foor use in
Journal ofo the Europ
pean Union. It entered innto
the pediatric poopulation. Itt has been designed
d
force on 26 January y 2007. The new pediattric
to promote
p peddiatric deveelopment of already
legislatioon comprisees Regulatiion (EC) No.
N
54 
 Rani et al. /Vol.
authorizeed productss which arre no longger
covered by a Supplementar
S ry Protectiion
Certificatte (SPC) (Co-ordinatio
( on Group for
Mutual Recognitio on and Decenteralissed
Procedurres-human (Co-ordinati
( on Group for
Mutual Recognition
R Decentralised procedurres-
Human, 2012).
2
The incenntives associated with thhe PUMA arre:
• PUMMA applicatiions have an ‘automaatic
accesss’ to thee centraliseed proceduure
(Articcle 31 of thee Pediatric Regulation).
R Dhaarampalan, 2012). Larrge proporttions of
• PUMMA benefits from the 8+ +2 year periiod
of daata and market protectionn (Article 388 of
the Pediatric Reg
gulation).
• PUM MA applicatiions submittted under the t
centralised proceedure benefitt from a parttial
exemmption from the payment of the fees fe
laid down in the t Regulattion (EC) No N
297/995. This parrtial exempttion applies to
the submission
s of
o the PUM MA applicatiion
and some of the post authorizatiion
activiities for 1 year as of the date of
grantting a PUMA A (Questionns and answ wers
on the Paed diatric Usee Marketiing
Authorization (PUMA) cited
http:///www.ema.eeuropa.eu/doocs/en_GB/ddo
cumeent).
So far, no orphan n medicinall product has h
benefitedd from pediiatric regulaation since the
t druggs used in children
entry intto force of the regulattion (Europeean
Medicinee Agency, 20014).
Table 4 shows the mediccinal produuct
authorizeed through central prrocedure sinnce
pediatric regulation
n came in force, which
include a pediatric indication.
i T
Table 5 shoows
/ V [2] 20114 /50 – 64 
the list of produucts authorizzed under PUUMA by
EMMA. Table 6 shows thhe differencces and
sim
milarities in pediatric
p leggislation of US and
EU..
Reggulations off Pediatrics in India and
d Other
Devveloping Coountries
Gloobally nearlyy nine milllion childrenn under
fivee years off age die every yeaar, with
pneumonia, diiarrhea, andd neonatal causes
beinng the majorm killeers (Yewalle and
thesse victims belong too India andd other
devveloping counntries. Manyy of these coonditions
couuld be treaated with safe s and effective
e
meddicines. Indiia, with 1.221 billion people is
the second mostt populous country
c in thhe world,
reprresenting almost
a 17%% of the world’s
poppulation. Evvery year, an estimaated 26
milllion childrenn are born in i India (Jaiin et al.,
2013). This stattistical data emphasizes
e t need
the
for strict andd mandatoory laws for f the
marrketing, maanufacturingg, packaginng and
labeeling of druggs in India. Unfortunatel
U ly this is
not the case.
at Peddiatric population by itseelf is a specctrum of
diffferent phyysiologies with siggnificant
variiation in pharmaacodynamicss and
phaarmacokinetiics. Unfortuunately, 50––90% of
c today have nevver been
actuually studiedd in this population,
p and the
resuults of drug studies donee in adults are
a often
extrrapolated for use in chhildren (Yew wale and
Dhaarampalan, 2012). Many medicines in
peddiatrics are off label or o unlicenseed. In a
reviiew in UK, over
o an eighht-year periood (1993
to 2000), there were 81 8 medicatiion-error
55 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

incidentss involving at least 1144

1 childrren. Orgganization (CDSCO) is the principal p
There weere at least 29 deaths, nine of which reguulatory boddy, which functions
fu unnder the
T most freequent type of
involved neonates. The Minnistry of Health
H andd Family Welfare,
W
medicatioon error involved an incorrect doose govvernment of India. It ennsures the approval,
a
(Cousins et al., 2002). prodduction, andd marketing of quality drugs
d in
Indiia. It is a matter of great concern and
Promotinng appropriiate and saafe drugs for
disaappointment that thhe Central Drug
children is a globaal concern. In Decembber
Stanndards and Control Orgganization does
d not
2007, WHO
W published its first ever
e model list
havve any guidellines/laws with
w regard too:-
of essenntial medicinne list for children withw
more thaan 200 mediccines, includding HIV/AID DS 1. Packaging and labelinng requirem
ments of
treatmentt, vaccines, anestheticcs, hormonnes, pediatrics inn India
vitamins,, and mineerals. This serves as a 2. Format for dossier
d requuired to be suubmitted
referencee for counttries to devvelop nationnal for approvval of peediatrics inncluding
essential medicines lists, according to thheir biologicals e.g.
e vacciness, in India
specific public
p health
h needs. Thee list is updatted
every tw
wo years and d has been reecognized as a a 3. List of excippients clameed to be safee for use
powerfull tool to promote healtth equity. The T in pediattric dosaage formss and
second edition
e was published in April 20010 laws/directivves governinng the same in India
(Yewale and Dharam mpalan, 20122). 4. Manufacture, sale, packkaging and labeling
In Indiaa, the esttablishment of essenttial of pediatric cosmetics inn India.
medicinees lists for children in i two stattes, Provvisions o
of manufaacturing, storage,
Orissa and
a Chhattissgarh, is cuurrently undder packkaging and labeling
l of drugs
d and coosmetics
way. Thee Indian Acaademy of Peediatrics is also
a for human usee were fram med in Indiia under
reviewing a list for f implementation at a Druugs and Cosmetics act in 1940.
national level. Thiis will alloow for bettter Unffortunately this
t act doees not conttain any
selectionn and procurrement of chhild medicinnes strinngent guideelines for peediatrics even after
based onn specific needs. Howevver there is still
s ameendments made
m in its provisions time to
a long journey to o be coverred. In Inddia, timee since thaan (Yewale and Dharaampalan,
pediatric drugs are developed
d baased on cliniical 2012).
trials andd protocols for
f a healthyy adult hum man.
Reccommendations
There area no speecific drug development
regulations for peediatrics. Inndian cliniical 1. There shoould be pediatric specific
practice relies
r heavilly upon safetty and efficaacy guidelines tot address thhe ethical isssues and
data publlished in oth
her developeed countries,, or clinical triaals design, efficacy andd safety
inferencee from adult dosing. compliance,, marketing and prescriibing of
drugs in Inddia
The Cenntral Drug Standards and Conttrol

56 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

2. Deveelopment off the way to calcullate pharmaceutical preparrations meant for

pediaatric dosing especially for
f drugs with
w adults, to small
s infantts after theiir doses
differrent ADME in children and
a adults. calculated superficially..
3. The financial grrants sanctiooned presenntly 4. Harmonizattion betweenn pediatric ruules and
for reesearch and development of pediattric regulations is required for their hasssle free
formuulations needs to be increassed export and import throuughout the world.
w It
worlddwide, whicch may ultim mately lead to would also contribute towards reectifying
the availability
a of more annd more fixxed the discrepaancies like drugs
d bannedd in one
dose combinatiions for pediatrics in country are being sold inn the other etc.
e
develloping coun ntries. This would prevent
the unethical
u prractice of prescribing
p t
the

ICH Guideeline E11 FD

DA
Terms A
Age Term
ms Age
Term
m newborn infants
i 0 to 27 days Neonatee Birtth to 1 montth
Infaants and todd
dlers 2 days to 233 months
28 Infant 1 month
m to 2 yeears

Chilldren 2 to 11 yearrs Childrenn 2 too 12 years

Adoolescents 1 to 16-18 years
12 y Adolescent 12 to
t <16 yearss

Table 1: Classificatioon of Pediatrric Age

Categories asa per ICH annd FDA
Guidelines (Z Zisowsky et al., 2010)

Year Legislaation
1979 Product laabel include pediatric use section
1994 Pediatric labeling
l rule
1997 FDA Mod
dernization Acct (FDAMA)
1998 Pediatric rule
r
2002 Best Pharm
maceuticals for
fo Children Act
A (BPCA)
2003 Pediatric Research
R Equuity Act (PRE
EA)
2007 Food and Drug Admiinistration Am
mendment Act
A (FDAMA); Reauthorizzation of BP
PCA and
PREA
2010 Pediatric Exclusivity
E foor Biologics (Biologics Priice Competition and Innovvation Act, 20010)
2012 Food and Drug
D Adminiistration Safetty and Innovaations Act (FD
DASIA)

Table 2: Hiistory of Pediaatric Regulationn in US

57 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

S. No. Drug Date of S

Sponsor Indicatioon(s)
Exclusiivity
1. Abacavir 14/12/98 GSK
K HIV
2. Albuterol 27/8/08 GSK
K Treatment annd prevention of o the bronchoospasm in
the children from
f < years of the age with
birth to <4
obstructive aiirway diseases
3. Alendronate 28/4/03 Mercck Osteogenesis imperfecta
4. Alfuzosin 7/9/10 Sanoofi Aventis Treatment off patients 2-16 years with elevated
detrusor leak point pressuree associated wiith known
nuerological disorder
d (e.g., spina bifida)
5. Almotriptan 13/1/09 Johnsson & Acute treatmeent of migrainee in the adolesccent, ages
Johnsson 12 to 17 yearss
6. Amlodipine 27/11/01 Pfizeer Hypertensionn
7. Amphetaminee 28/10/04 Shiree ADHD
mixed salt
8. Anagrelide 25/5/04 Shiree Thrombocytoopenia secondary to
myeloproliferrative disorder
9. Anastrozole 14/11/07 Astraazeneca Male puberttal patient with gynecosm matia and
female pediattric patients with
w McCune –Albright
–
Syndrome wiith progressive precocious puuberty
10. Aripiprazole 14/11/07 Otsukka Schizophreniaa; Bipolar deprression
11. Atomoxetine 18/12/01 Lilly Attention Defficite Hyperacttive Disorder
12. Atrovastatin 22/2/02 Pfizeer Hypercholeseerolemia
13. Atovaquone/P P 6/8/03 GSKK Prevention off malaria
roguanil
14. Azelastine 11/8/99 Asta Itching associiated with allerrgic conjunctivvitis
15. Balsalazide 23/8/06 Salixx Ulcerative colitis
16. Benazepril 2/703 Novaartis Hypertensionn
17. Bendamustinee 24/5/12 Cephhalon Relapsed or refractory
r acutee leukemia
18. Betaxolol 28/2/07 Falcoon Treatment of elevated intraoocular pressuree
19. Bicalutamide 19/9/08 Astraazeneca Treatment of gonadotropin independent prrecocious
puberty in boys with testotooxicosis
20. Capecetabinee 28/8/13 Hoffm
fman La Non dissemiinated intrinsiic diffuse brain stem
Rochhe gliomas
21. Dexmedetom
mi 12/3/13 Hosppira Loading and maintenance infusion
i for seedation in
dine intubated and mechanically ventilated pediatric
patients
22. Difluprednatee 21/3/13 Alconn Treatment of post opperative inflaammation
following cataract surgery
23. Efavirenz 29/1/13 BMSS Treatment of HIV-1
24. Entecavir 5/12/13 BMSS Chronic Hepaatitis B virus innfection
25. Palonosetronee 10/4/14 Helsiinn Prevention off post operativve nausea and vomiting
and chemotheerapy induced nausea
n and vom miting
26. Sapropterin 13/3/14 Biom
marine Treatment to reduce blood phenylalanine
p l
level
27. Vigabetrin 3/10/13 Lunddbeck Intractable complex
c partiial seizures and and
infantile spasm
m
28. Namenda 18/6/2014 Foresst moderate to severe
s confusioon (dementia) related to
(memantine Labooratories Alzheimer's disease.
d
hydrochloridee)
29. Namenda XR R 18/6/2014 Foresst moderate to severe
s confusioon (dementia) related to
Labooratories Alzheimer's disease
d
30. Rebeprazole 4/12/12 Eisaii Healing & maintenance
m of GERD & improvement
of GERD sym mptoms in childdren 1-11 yearrs of age
Table 3: List off medicine to which
w pediatriic exclusivity has
h been
grantedd till date in USA
U (Food andd Drug Adminnistration,
n.d. upddated 16 April, 2014)
58 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

Sr. Name of Medicinal

M Prod
duct Y
Year of Requirementt to fulfill ndication is pediatric-
In p
No autthorization Pediatric Reegulation o
only or ‘mixed
d’ (adult
at first authoorization and pediattric)
1. Altargo (Retapaamulin)
A 2007 No Mixedd
2. A
Atriance (Nelarrabine) 2007 No Mixedd
3. C
Cervarix (Hu
uman papillom mavirus 2007 No Mixedd
v
vaccine (types 16,1 18)
4. C
Cyanokit (Hydrroxocobalaminn) 2007 No Mixedd
5. E
Elaprase (Idursu ulfase) 2007 No Mixedd
6. O
Optimark (Gado oversetamide) 2007 No Mixedd
7. C
Cystadane (Bettaine anhydrous) 2007 No Mixedd
8. D
Diacomit (Stirippentol) 2007 No Pediatric only
o
9. Inncrelex (Mecasermin) 2007 No Pediatric only
o
10. A
Avamys (Fluticcasone furoate)) 2008 No Mixedd
11. P
Privigen (Human normal 2008 No Mixedd
immmunoglobuliin)
12. V
Vimpat (Lacosaamide) 2008 No Mixedd
13. M
Mycamine (My
ycamine) 2008 No Mixedd
14. K
Kuvan (Saproptterin) 2008 No Mixedd
15. M
Mepact (Mifam murtide) 2009 No Mixedd
16. V
Vedrop (Tocofersonal d-alpha 2009 No Pediatric only
o
toocopheryl polyethylene
p glycol
suuccinate
17. S
Synflorix (Pneum
moccocal 2009 No Pediatric only
o
p
polysaccharide conjugate vacccine)
18. P
Prevenar 13 (Pneum
moccocal 2009 Yes Pediatric only
o
p
polysaccharide conjugate vacccine)
19. M
Menveo (Meniingococcal grooup and 2010 Yes Mixedd
c
conjugate vacciine)
20. V
Vpriv (Velagluccerase alfa) 2010 Yes Mixedd
21. F
Fluenz (Influenza vaccinee (live 2011 Yes Pediatric only (Waiver)
P (
a
attenuated, nasaal)
22. B
Buccolam (Middazolam) 2011 Yes (PUMMA) Pediatric only
o
23. V
Votubia (Evero olimus) 2011 Yes Mixedd
24. C
Colobreathe (Colistimethate sodium)
s 2012 Yes Mixedd
25. X
Xaluprine (Merrcaptopurine) 2012 No Mixedd
26. N
NovoThirteen (Catridecacog)
( 2012 Yes Mixedd
27. E
Efavirenz Tevaa (Efavirenz) 2012 No Mixedd
28. K
Kalydeco (Ivacaftor) 2012 Yes Mixedd
29. D
Desloratadine Actavis 2012 No Mixedd
(DDesloratadine))
30. F
Fycompa (Peram mpanel) 2013 Yes Mixedd
Table 4: Meedicinal produccts authorized centrally
c since 2007, which innclude
a peediatric indicatiion (European Medicine Ageency, 2013)

Name of Drug Appproval Man nufacturer’s Indication Referen

nce
Date
D Name
Buccolam
m 11 August,
A VirooPharma Prolonged, acute,
a convulsivve seizures European
E M
Medicines
(Midazolam) 2009 in pediatric patients
p from thhe age of 3 A
Agency, 2011
months to 188 years
Hemangiol 21 Feebruary, Pierrre Fabre proliferative infantile haem
mangioma European
E M
Medicines
(Propranoolol 2014 Dermmatologie A
Agency, 2014
Table 5: EMA
A approved PU
UMA medicinaal product
.
59 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

US BPCA
B US PREA
A EU (PIP)
( (For EU PU UMA (exclusivvely for
patennted, SPC coveered off pattent and pediattric use
mediicines and new w medicinal product)
unauuthorized produuct)
Optional Mandatory
M Manndatory Optionnal
Written Request
R Peediatric Assesssment Pediaatric Investigattion Pediattric Investigatioon Plan
Plan
Waiver Provisionn of Yes Yes Yes
waiver iss absent
Deferral Provisionn of Yes Yes Yes
deferral is
i absent
Plan End of Ph hase 2 of Ennd of Phase 2 of mpletion of adullt PK
Com Completion of adult PK (End
discussionns clinical trrial to clinical trial to (Endd of Phase 1) of Phaase 1)
Begin post apprroval NDA/BLA apprroval
Final plann Variable W NDA/BLA
With A Priorr to MAA filing Prior to
t MAA filing
approval appproval
Reward Patent ex
xclusivity Paatent exclusivitty SPC or market 8+2 yeears data/ markketing
prrovision is abseent excluusivity (Orphann protecction, brand nam
me can
drugs) be retaained
Drugs Yes
Y Yes Yes Yes
Biologicss Yes (BP
PCI 2010) Yes Yes Yes
Biosimilaars Yes
Y Yes No No
Orphan Yes
Y No Yes No
drugs
Off patennt Yes
Y No No Yes
Generics No
N No No No
Homeopaath No
N No No No
ic
Decision Review Division
D Reeview Divisionn Pediaatric Committeee Pediattric Committeee
authority
T
Table 6: Commparison of BPCA, PREAA, PUMA
(Muulberg et al., 20013)

Abbreviations
ADME Absorptionn, Distributioon, Metaboliism, Excretioon
BLA Biological License Appplications
BPCA Best Pharmmaceuticals for
f Children Act
BPCIA Biological Price compeetition and Innnovation Act
A
CDSCO Central Druug Standardss and Controol Organization
EMA European Medicine
M Aggency
FDA Food and Drug
D Adminiistration
FDAMAA Food and Drug
D Adminiistration Moodernization Act
FDASIA
A Food and Drug
D Adminiistration Saffety and Innoovations Actt
ICH Internationnal Conferencce on Harmoonisation
NDA New Drug Applicationns
PREA Pediatric Research
R Equuity Act
SPC Supplemenntry Protectioon Certificatte
WHO World Heaalth Organizaation

60 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

Conclusiion NSAID ingestion inn children”. (2013):

Annals of
o Paediatriic Surgery. 9(2)
9 87–
Regulatioons of drug gs for pediaatrics are veery
89.
settle thrroughout thee world. Altthough US and a
EU are amongst
a thee pioneers inn initiating the
t Bussti, A.Z., Nuuzum, D.S., Stoll,
S J., Davves, B.J.
framework for regu ulating the approval,
a saale, and Mckkeever, G.C C. (2010): Hoow does
productioon, storage, clinicall trials and a the use of
o aspirin orr salicylates increase
packaginng/labeling of o pediatric dosage form ms, the risk of Reye’s syyndrome in children
yet a lonng journey iss yet to be covered
c in this
t with virral infectionn? Pharmaccological
directionn. History has witnessed many disastters weekly Pharmacottherapy New wsletter.
relating to the adveerse drugs and a excipieents 2(25) 999-103.
reactionss on mass scale in pediattric
Cassavant, J.M., & Griffithh, J. R. K. (2010):
populatioons. Many drugs
d which are considerred “Accesss Mediicine P
Pediatric
safe in addults are bannned for peddiatrics in somme Pharmaccotherapy Paart 1: The Hiistory of
countriess but still beeing used foor the same in Pediatricc Drug Therrapy: Learniing from
other couuntries. In faact most of the
t third woorld Errors, Not T
Trials”. M
Medscape
countriess consider children
c and neonates as Multispeeciality. Rettrieved 5 Deecember,
small aduults and theerefore the laws governiing 2013, from
the mediicines for adults
a are extrapolated
e in http://wwww.medscappe.com/view warticle/
children in major partp of the world.
w Furthher 726236__4.
there iss no harm monization between the t
countriess across thee globe. The enforcement Com
mmittee on the Drugs. (1997): “Inactive
“
departmeents in all thhe countries would havee to ingredieents in pharmmaceutical Products:
P
frame neew laws for pediatrics. ThisT would not n Update””. Americaan Academ my of
only enhance
e the
t exportt-imports of Pediatriccs. Pediatriccs. 99(2), 268-278.
pharmaceeuticals with hin the counttries but assuure Co--ordination Group
G for Mutual
M Recognition
better heealth care for
f pediatriccs at the sam me Decentralised proocedures- Human.
time. (2012): Recommenddation on pediatric
p
use marrketing authoorization. Retrieved
R
Referencces
15 October, 2013, from
Adefurinn, A., Sammmons, H., Aggrain, E.J. and
a ww.hma.eu//fileadmin/daateien/H
http://ww
C
Choonara, I. (2011): “Ciprofloxacin uman_M Medicines/CMMD_h_/Paeddiatric_
saafety in paediatrics:
p A systemmic
Regulatiion/Guidancce_Documennts/CM
reeview”. Archh Dis Child. 96 874-880. Dh_152_2009_Rev11_clean_20112_02.p
Anyanwuu, L.C., Mohammad, A.M. df.
“GGastrointestinal bleediing followiing

61 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

Cousins, D., Clarksson, A., Coonroy, S. and a 13Octobber, 2013, from

C
Choonara, I. (2002):
( “Meedication errors http://ww
ww.ema.eurropa.eu/ema//index.js
inn children - An
A eight yeaar review usiing p?curl=ppages/news__and_events//news/2
prress reports,” Paediatricc and Perinaatal 011/06/nnews_detail__001287.jsp&mid=
D
Drug Therapyy. 5(2) 52–58. WC0b01ac058004dd5c1.
Curley, MM.A.Q., and d Harmon, P.A.M.
P (20001): Eurropean Meddicine Agenncy. (2013): Better
C
Critical caree nursing of
o infants anda Medicinnes for Chilldren from Concept
chhildren. Reetrieved 17 April, 2014, to Reallity Progreess Report on the
frrom Pediatriic Regulaation (EC
C) no.
htttp://reposito
ory.upenn.eddu/miscellanneo 1901/20006. Retrievved 5 Deecember,
us_papers/4/. 2013, from
http://ecc.europa.eu/hhealth/files/ppaediatri
Dahl, R. (2006): “Systemic
“ side effects of
innhaled cortiicosteroids in patients in cs/2013__com443/paaediatric_repport-
com(20113)443_en.ppdf.
w
with asthma”. Respirattory Mediciine.
100 1307-131 17. Eurropean Mediicine Agencyy. (2014): Report
R to
the Eurropean Com mmission. Retrieved
R
Europeann Medicine Agency. (13 Septembber,
15 S
September, 2014, from
2011): Questtions and answers on the
http://ecc.europa.eu/hhealth/files/ppaediatri
P
Paediatric Use Marketiing
cs/2013__annual-repoort.pdf.
A n (PUMA). Retrieved 1
Authorization
D
December, 2013, froom Eurropean Meddicine Ageency. (20077): The
htttp://www.em
ma.europa.eeu/docs/en_G
GB Europeaan Pediatricc initiative: History
/ddocument_lib
brary/Other//2011/09/WCC5 of Pediaatric Regulaation. Retrieeved 12
00112071.pdff. Octoberr, 2
2013, from
http://ww
ww.ema.eurropa.eu/docs/en_GB
Europeann Medicine Agency. (22008): Ethical
/documeent_library/O
Other/2009/009/WC5
C
Consideration ns for Clinical Trials on
000036993.pdf.
M
Medicinal Prroducts Coonducted with w
thhe Pediatricc Populationn. Retrieved 19 Eurropean Mediicine Agenccy. (n.d.). European
E
Jaanuary, 2014, froom Networkk of Pediattric Researcch-EMA.
fttp://ftp.cordiis.europa.eu//pub/fp7/doccs/ (2013): from
etthical-consid derations- http://wwww.ema.eurropa.eu/ema//index.js
paediatrics_en n.pdf. p?curl=ppages/partneers_and_netw
works/g
eneral/ggeneral_conteent_000303..jsp.
Europeann Mediciine Agenncy. (2011):
“E European Medicines
M Agency givves Eurropean M
Medicines Agency. (2014):
fiirst positive opinion for paediatric use
u Europeaan Medicinnes Agencyy gives
m
marketing authorization
a n”. Retrievved second positive opinion for a
paediatrric-use markketing authorrization.
62 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

Retrieved 13 March, 2014, froom

R Jackkson, P.R.P.., Tredger, J.M.,
J and Williams,
W
htttp://www.em
ma.europa.eeu/ema/indexx.js R. (19885): “Hepatootoxicity to sodium
p?curl=pagess/news_and__events/newss/2 valproatte: A review
w”. Gut. 25((6) 673-
014/02/news_ _detail_0020030.jsp&midd= 681.
W
WC0b01ac05 58004d5c1 accessed.
a Jainn, A., Venkkatesh, T.MM., Kumar, P., and
Field, M
M.J., and Boaat, T.F. (2012): “Safe and
a Kumar, N. (2013)): “Regulattion for
E
Effective Usee of Medicinne in Children: Paediatrric Drug Development ini India:
pediatric studies condducted undder Need off the Hour”. Journal for Clinical
Pediatric Ressearch Equityy Act and Best
B Studies. 6(1) 14-16.
Pharmaceuticcals for Children Act”. The
T Koggan, L.A. (20011): “The U.S.
U Biologiics Price
N
National Aca
ademies Presss. ISBN: 9778- Competition and Innovation Act of
0-309-22549--6. 2009 Triggers Public Debates
Food aand Drug Administraation. (2014): Regulatoory/Policy Risks, and
P
Pediatric Exclusivityy Grantted. Internatiional Trade Concerns”.. Global
R
Retrieved 17
1 May, 2014, froom Trade annd Customs Journal. 6(111).
htttp://www.fd
da.gov/Druggs/Developm
men Labbson, M.S. (2002): “P Pediatric Prriorities:
tA
ApprovalProocess/DeveloopmentResouur
Legislattive and Reggulatory Initiative to
cees/ucm050005.htm. expand Research on the use of
Food andd Drug Adm
ministration. (n.d.).
( Officee of medicinne in the Pediatric
P Patients”.
P
Pediatric Th
herapeutics. Retrieved 15 Journal of Healthh Care Laaw and
M
March, 2014,
2 f
from 20014 Policy. 6(1).
6
htttp://www.fd
da.gov/AbouutFDA/Centeers Liptton, R.B., Newman,
N L.CC., Cohen, J.S.,
J and
O
Offices/Offic
ceofMedicalP ProductsanddTo Solomann, S. (1989)): “Aspartam me as a
bacco/OfficeoofScienceandHealthCooordi dietary trigger
t of heeadache”. Heeadache.
nation/ucm20 018186.htm. 29(2) 900–92.
Friedlandd, I. and Huntingtonn, J. (2011): Meddicine and Healthcare
H R
Regulatory A
Agency.
“PPediatric Drug Develoopment: Nott a (n.d.). Summary of Regulattion on
chhild’s Play”.
P J
Journal of Medicinnes for Pediaatric use. Retrieved
R
P
Pharmaceutic cal Servicess and Contrract 12 October, 2013, from
S
Services. http://ww
ww.mhra.goov.uk/home/ggroups/
Huggon, I., James, I.,
I and Macrrae, D. (19990): pla/docuuments/webssiteresourcess/con20
“HHyperosmollality relatedd to propyleene 25602.ppdf
glycol in an infant treated with w Mullberg, A.E., Murphy, D., Dunnee, J., &
ennoximone innfusion”. British
B Medical Mathis, L.L. (2013): Pediatriic Drug
Jo
Journal. 301((6742) 119–120.

63 
 Rani et al. /Vol.
/ V [2] 20114 /50 – 64 

Developmentt: Concept annd Applicatiion

D wale, N. and
Yew a Dharam
mpalan, D. (2012):
(22nd ed.). John
n Wiley & Sons
S Ltd., UK
K. “Promotting approprriate use of drugs in
childrenn”. Internattional Jourrnal of
Polgreenn, L. (2009): 84 childrenn are killed by
Pediatriics. 1-5.
m
medicine in Nigeria. The
T New Yoork
T
Times, p. A7. Zisoowsky, J., Krause,
K A., & Dingem manse, J.
(2010): “Drug developmennt for
Rochhi, F., Paoluccci, P., Ceci, A., Rossi, P.
Pediatricc Populationns: Regulatorry
(22010): “Th he European paediattric
Aspects”. Pharmacceutics. 2(44) 364-
leegislation: Benefits
B and perspectivees”.
388.
Ittalian journa
al of pediatrics, 36(56).
UNICEF
F. (n.d.). Why
W is birtth registratiion
im
mportant? Retrieved
R 26 August, 2014,
frrom
unicef.org/inddia/resources_
htttp://www.u
1650.htm.

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