ARCHIVES HISTORIQUES
DELACOMMISSION
COLLECTION RELIEE DES
DOCUMENTS "COM"
COM (80)789
V ol.1980/0248

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COMMISSION OFTHEEUROPEAN COMMUNITIES
\*
<7COM(80)789 final
Brussels-28November 1980
/•
REPORTONTHEAPPROXIMATION OFTHELAWS
RELATING TOPROPRIETARY MEDICINAL PRODUCTS
Proposalfora
COUNCILDIRECTIVE
amendingDirectives 65/65/EEC,75/318/EECand75/319/EECon
:theapproximation ofprovisionslaiddownbylaw,regulation
voradministrative actionrelatingtoproprietary medicinal
products
Proposalfora
COUNCIL RECOMMENDATION
concerningtestsrelatingtotheplacingonthemarketof
proprietary medicinalproducts
(submittedbytheCommissiontotheCouncil)
C0M(80)789final

-2-
REPORT ONTHE APPROXIMATION OFTHE LAWS ' ,
- ' • •.x
DELATING TOPROPRIETARY MEDICINAL PRODUCTS
/
1.Thepurpose ofthis report istopresent theOommiss ion'sproposals and
guidelines inthefield ofproprietary medicinal products inanoverall
framework .Thetwomain Lines ofaction oftheCommunity work areto
facilitate access tothemarket inorder tocreate aLarge open market and
toimprove itsoperation in*order tocreate atransparent andorderly market .
"I.'A-larfrfr -open market
, <• '.*. '
1.The results achieved
2.Four Council Directives andoneGouncil Decision ,with theaimof :
abolishing barriers tothefree movement ofmedicinal products ,have been
adopted .Inabolishing these barriers ,public health safeguards have been
developed ontwolevels :that oftheconception oftheproduct andthat
ofits manufacture .
3.Thefirst safeguard fortheproper conception ofamedicinal product
consists inthetests tobecarried outandtheprinciples tobefollowed
_during these trials . . . ,
Thesecond safeguard istheadoption ofasystem ofprior authorization ,
this being subject tothree fundamental conditions :,thequality ,harmless­
•ness andtherapeutic effect ofthemedicinal product .
4.Thesafeguards relating to^good manufacture arebased firstly ona
manufacturing authorization issued inthelight ofconditions concerning
premises ,plant andstaff ,then onthecompulsory presence ofaqualified
person incharge ofmanufacture andcontrol tests and ,lastly ,on ,
inspections carried outinmanufacturing establishments .
5.Nowthat these safeguards have been developed ,ithasbeen possible to
doawaywithsystematic checks uponimports frcrroneMember Stat^jto another ;
irrespective oftheplace ofproduction intheCommunity ,medicinal products
aremanufactured andtested inaccordance with the same rules and under the
supervision ofpersons with equivalent qualifications .

Nevertheless ,marketing authorizations have remained anational matter .
Inorder toobviate divergent decisions asfaraspossible ,cooperation
between competent authorites has taken place within aCommittee for
Proprietary Medicinal Products (hereinafter referred toastheCPMP ).
Lastly ,aPharmaceutical Gommittee hasbeen setupinorder toprovide
theCommission with appropriate advice inthefield ofproprietary
medicinal products .
2.The inadequacies noted
Generally speaking ,theimplementation oftheDirectives issatisfactory .
AlltheMember States have introduced thesystem ofprior authorization
into their laws andonly certain particular points ofcertain national
laws have toberectified .TheCommission isdealing with this ,as
provided for inArticle 169oftheTreaty ofRome ,inrelation toBelgium ,
Luxembourg and Italy .
Therequirements ofaunified market have notalways been fully taken into
account intheDirectives already adopted .Provisions which aresatisfactory
inanational market maybeunsuitable orinadequate inacommon market .
Since persons aswell asgoods circulate more andmore onCommunity
territory ,itisimportant forpublic health that thesame names should
cover thesame products ,except where there arelegitimate grounds tothe
contrary .
Similarly ,itisnotenough for acompetent authority tobeaware ofthe
marketing authorizations granted bytheother Member States .Itshould
also know what has been authorized and under what conditions .
Finally ,provisions which hamper trade between Member States must bekept
totheminimum necessary fortheprotection ofpublic health while provisions
designed toguarantee thehomogeneousness oftheexperimental work inthe
various Member States must bepromoted andthealignment ofdecisions by
thenational authorities improved .
There isathird cstecory ofinadequacy which results from thevery provisionsO
which have beer 1odepted orftle^st frotr .the Little usewhich hasbeen rr.sde
ofthen -,i.e. the CPMP procedure forthemarketing cfprcprietar )rec'icins I
products .Bythebe ,inning ofSeptenber 198G ,i.e. over aperiod ofnearly

four years ,only eight applications hadbeen filed under this procedure .
There hasbeen ,however ,atendency forthenumber ofapplications to
increase during recent months which nodoubt means that thecircles concerned
have been better informed .
Nevertheless ,thepharmaceutical industry hasreservations with regard to
this procedure .Fundamentally ,itconsiders that theexisting procedure is
notatallappropriate totheaimpursued andshould bereplaced byasystem
ofmutual recognition .During aninterim period ,-thepresent system could
bemodified inrespect oftwomain points :theconditions forinitiating the
procedure aretoorestrictive ;theapplicant does nothave anyopportunity
tobeheard during theprocedure .
» -
TheConsumers' Consultative Committee ,orrather oneofitsworking parties ,
also considers thepresent procedure tobeunsuitable ;initsopinion ,the
CPMP does nothave sufficient powers tobeable towork effectively .Itis
completely opposed totherecognition ofauthorizations andhopes forthe
gradual transformation oftheCPMP into aEuropean registration bureau .
3.The improvements andadditions proposed
10.Inview oftheproblems mentioned above andafter extensive consultations
with alltheparties concerned ,theCommission hasadopted thefollowing
positions :
-theprovisions ofDirectives 65/65/EECand 75/318/EECmust bebrought up
todate andsupplemented inorder tokeep pace with theprogress ofscience
andtotake better account oftherequirements ofasingle market ; "
-Chapter IIIofDirective 75/319/EECsetting uptheCommittee forProprietary
Medicinal Products -asprovided forbyArticle 15(2 )oftheaforementioned '
■Directive should beamended ;under present market conditions and .inthe
absence cfstrong reasons based onpublic health /thesetting upofa
European body for the issue endrevocation ofmarketing authorizations does ^
notappear tobeadvisable nordoes theextension ofthepresent system ,
which iswidely criticized andtherefore hastobe^abandoned ;recognition of
authorizations seems tobethesimplest andmost effective solution :
amedicine manufactured and marketed inone Member State or ,the basis of
harmonized provisions must ,inprinciple ,be..allowed onthemarket cfany
other Member State ,disputed cases being submitted totheCommittee for
Proprietary Medicinal Products foranopinion ;
\

-5-
,-theprinciples tobefollowed when implementing theprovisions of
Directive 75/318/EECrelating tothestandards andprotocols applicable
tothetesting ofproprietary medicinal products should bedetermined
inorder topromote the alignment ofnational -decisions ;aCouncil Re­
commendation appears tobethe most appropriate means ofkeeping upwith
developments inscience and technology and oftaking into account the
importance ofprotecting thepatient and ofpharmaceutical research .
II.Atransparent and orderly market
11.Owing tothe approximation ofnational laws and conceptions ,the
marketing ofmedicinal products nolonger constitutes thebarrier
itdid inthe past .Other barriers consequently take ongreater signi­
ficance with regard tothe proper functioning ofthe market .Itis
therefore ofcrucial importance that the Community use the powers of
-supervision conferred onitbythe Treaty and take the necessary har­
monization measures .
1«-Prices
12.The problems ofmedicine prices and reimbursement bythe social security
organizations are major barriers tofree movement .The fixing ofprices
that are too loworthe debarring ofamedicine from reimbursement
constitute just aseffective abarrier asthe refusal ofamarketing
authorization . *
With regard tosupervision ,thethinking ofthe Commission andthe
case law ofthe Court ofJustice ,having regard tothe implementation
ofArticles 30-36ofthe Treaty ,are clear .The Treaty basically
leaves completely intact the power ofMember States totake appropriate
measures with regard toprice formation ;atthe same time,however ,
Article 30isviolated when aprice system does not permit either a
producer oraCommunity importer tosell hisproduct onthe market of
that Member State ataremunerative price .Measures have already been
taken andothers are inpreparation .

-6-
■Butitisequally necessary toovercome the present dichotomy whereby
medicines and social security ,,consumer protection and growth in
consumption are brought into conflict byoutline measures andguidelines
intended toimprove competition byway ofprices .Greater competition
could only facilitate the reform ofthe social security systems .
Itshould beremembered inthis context that the proposal for aDirective
sent tothe Council on2June 1980 aims atestablishing aharmonized
system fortheregistration ofparallel importers ofproprietary medicinal
products .Inparticular ,itproposes the prohibition ofartificial
distinctions between products inthe various Member States brought about
either bytherapeutically unwarranted adjustments incomposition orby
changes inthe name ofthe product without legitimate reasons .
The Commission will continue itsefforts toestablish atransparent and
orderly market inwhich price could play the regulation role proper
toit.
2.Advertising
13.Advertising isanimportant means ofpenetrating markets aswell as
being aninstrument for the information ofdoctors and consumers .Ina
first approach the Commission attempted toharmonize thedifferences
between the relevant national taws .Ithas proved impossible tofind
acommon solution for the regulation ofadvertising :the preventive
system (prior authorization ),the repressive system (aporteriori
penalty cases ofinfringement )andthe system ofself-regulation (volun­
tary code ofconduct )seem tooperate tothe satisfaction ofthose
acquainted with them . '
Inasecond approach the Commission attempted tobring into line the
principles determining the content ofadvertising .Butitquickly emerged
that these common principles constituting /asitwere,base-level pro­
visions could not have any consequences from thepoint ofview ofthe
movement ofproducts orcompetition ,since each Member State would have'
remained free toaddtothese provisions .

-7-
.The advantage ofthese lengthy discussions inthefirst instance-was
tostimulate some hard thinking onthepart ofthe various circles
involved (authorities ,industry ,professional groupings etc.)and
subsequently toshow that aproposal for aDirective could not,inview
ofthis situation ,constitute real progress .
Inaddition ,itshould beremembered that there already isaproposal
for aDirective onmisleading andunfair advertising ,which lays down
the general basis for consumer protection . ,
Inthese circumstances ,the Commission does not think itadvisable to
make aspecific proposal onproprietary medicinal products .
3.The future
i .
14.The economic ,techmpal andfinancial problems ,important asthey are,
must not -beallowed tomonopolize our attention .Research isthe
driving force ofthe pharmaceuticals industry and,according toarecent
report ,"biology andgenetics arecertain toplay anincreasingly im­
portant role inthe manufacture ofcertain substances having athera­
peutic action ".^
With'regard toresearch ,theCommission senttotheCouncil on22January
1980 aproposal for afive-year programme ofindirect-action research in
thefield ofbiomolecular engineering .On4August 1980,itsent tothe
Council aproposal recommending tothe Member States theregistration of
work ondeoxyribonucleic acid (DNA)recombination .
\
Itistime tothink about the legal and regulatory consequences ofthe
transposition ofthis research totheindustrial stage ,inparticular
its use intherapy .
15.Finally weshould foster anawareness outside the Community ofthe
guarantee conferred bythis gradual andflexible process ofharmoni­
zation .Itconstitutes akind ofEuropean quality label which will
henceforth beattached toall our products ,and weshould ensure that
this has its effects atthe level ofinternational trade .

-8-
PROPOSAL FOR ACOUNCIL DIRECTIVE
amending Directives 65/65/EEC ,75/318/EECand 75/319/EEConthe
approximation ofprovisions laid down bylaw ,regulation or
administrative action relating toproprietary medicinal products
Summary .
, ■ • '
Thepurpose ofthis proposal istwofold :
-tobring up ,todate theDirectives adopted in1965 and1975 in
thefield ofproprietary medicinal products ;
-toamend theprocedure oftheCommittee forProprietary Medicinal
Products andintroduce theprinciple oftherecognition of
marketing authorizations .

-9-
Explanatory memorandum
I.General considerations
1.This proposal bytheCommission has atwofold aim :
-firstly ,toamend theprocedure oftheCommittee forProprietary
Medicinal Products (CPMP )with aview toattaining thefree movement of
these products ;
-secondly ,toamend andsupplement theDirectives already adopted onthe
approximation ofprovisions laid down bylaw ,regulation oradministrative
action relating toproprietary medicinal products with aview tobringing
them uptodate .
2.Asprovided forinArticle 15(2 )ofDirective 75/319/EEC ,"inthelight of
experience theCommission shall ,notlater than four years after theentry
into force ofthis Directive ,submit totheCouncil aproposal containing
appropriate measures leading towards theabolition ofanyremaining barriers
tothe free movement ofproprietary medicinal products ".
Experience has shown that thebarriers tofree movement connected with the
system ofnational marketing authorizations have notbeen substantially
overcome bytheCommittee forProprietary Medicinal Products (CPMP )
procedure setupunder Chapter IIIoftheabove-mentioned Directive .
3.The four years during which theCPMP procedure hasoperated adeguately
demonstrate theindustry 'sreservations towards it.
Theprocedure itself ,aslaid down inDirective 75/319/EEC ,iscertainly
under fire .Itshould therefore beimproved ,especially with regard totwo
main points ,according totheindustry itself :theconditions for
initiating theprocedure must bemade less restrictive andtheapplicants
must have theopportunity tobeheard during theprocedure .

-10-
4.However ,inaddition totheprocedure ,itseems that thesystem itself is
under fire . ' ^
Thepharmaceutical industry considers that thepresent procedures cannot be
deemed inanywayappropriate totheaimpursued .Mutual recognition ,
already adopted inmany fields ,istheonly system itcanaccept .
Cntheother hand ,theconsumers consider that recognition ,like thepresent
procedures ,cannot lead toacommon European policy forproprietary
medicinal products .Only asystem ofCommunity authorizations issued bya
European agency iscompatible with this aim .
Theauthorities oftheMember States ,which were consulted onvarious
occasions within thePharmaceutical Committee ,were unable toreach a
'common position -although themajority were infavour -ontherecognition
ofmarketing authorizations inthefairly near future .
5.Bearing inmind these differing attitudes andthework oftheCommittee
forProprietary Medicinal Products ,theCommission considers that merely
improving thepresent procedure would notfundamentally alter theproblems
andwould becontrary totheletter andthespirit ofArticle 15(2 )of ,
Directive 75/319/EEC . - ,
TheCommunity authorization solution is,ofcourse ,very tempting asfaras .
principles areconcerned ,butappears tobeextreme inthepresent situation .
Thesetting upofaEuropean body with very highly qualified scientific
experts ,alarge administrative staff andperhaps research laboratories
needed bythose experts would beprohibitive from thepoint ofview ofcost ,
allthemore sosince this European body would have tooperate concurrently
with thenational bodies foranindefinite period .
Even without considering thepolitical ,legal andmaterial problems which
would beinvolved inasolution ofthis kind ,thefinancial burden ofsuch
aventure seems tobeenormous compared with that ofthepresent situation
andtheresults which maybe ;expected ofit. '
6.TheCommission therefore proposes that recognition ofmarketing authorizations
ι
issued bythenational authorities onthebasis ofharmonized provisions be
introduced .Aproprietary product manufactured andmarketed inoneState in
accordance with theharmonized regulations must ,with certain exceptions ,
beallowed onthe markets ofthe other Member States . ,

11
Indisputed cases ,theCPMP shall becalled upon togive anopinion .
Such ,inbrief ,istheeconomic aspect oftheproposal forthegradual
achievement ofthefree movement ofproprietary medicinal products .
Theprovisions intended toupdate andsupplement theDirectives already
■adopted will bedealt with oneArticle atatime inthecommentary .

-12-
II.Commentary onthe Articles
Article 1
7.Thepurpose ofthis Article istoamend Council Directive 65/65/EEC .
Thechief amendment concerns theintroduction ofthedata sheet (paragraphs
2and 3)which isasort ofphotograph oftheauthorized proprietary '
medicinal product .Inother words ,this isadocument which provides a
syntheses oftheproduct 'squalities anddefects such asthey have been
recognized bythecompetent authorities .
This sheet should enable thecompetent authorities tokeep track ,ina
summarized form ,ofwhat hasbeen authorized .
Itshould enable manufacturers toknow exactly what information they can
impart intheir communications tothegeneral public andtheprofessional
circles concerned .
Owing totheir changing nature ,theeconomic particulars referred toin
paragraph 3.8have notbeen made compulsory .Nevertheless ,itwould appear
useful toconcentrate ,asfaraspossible inthesame place ,allparticulars
concerning proprietary medicinal products whether medical ,administrative
oreconomic .,
8.Theother amendments donot call foranyparticular comment except that
concerning Article 13.1 .Regular mention oftheinternational non-
proprietary name recommended bytheWorld Health Organization after the
special name seems tobeabsolutely necessary toensure atleast some
transparency inthemedicines' market *Fordoctors andpharmacists 'itis
theessential means ofrecognizing thereal -identity ofproducts which
appear tinder somany Special names .This is,there fore ,afundamental
provision from thepoint ofview ofhealth andcompetition .

-13-
Article 2
9.Thepurpose ofthis Article istoamend Directive 75/318/EEC .
Theessential aimoftheamendments relating toPart 1oftheAnnex tothe
Directive (physico-chemical ,biological ormicrobiological tests )isto
clarify anddefine certain points .
10.Ontheother hand ,theprinciple ofthebioavailability andmutagenesis
studies hasbeen introduced asaresult ofprogress inscientific knowledge .
Thebioavailability study provides information ontherate atwhich and in
what proportions amedicine 'sactive principle orfraction thereof reaches
the site where its action should occur when the medicine isadministered
inaparticular pharmaceutical form .
Mutagenesis concerns thechanges inthegenetic material ofindividuals or
cells which arespontaneous orcaused bychemical products orradiations
andwhich result inthe following generations differing abruptly from those
which preceded them inapermanent andhereditary way .Allpresent scientific
knowledge inthis field isbased onthehypothesis that many chemical
products possess much mutagenic properties and itistherefore necessary to
identify andlimit thediffusion ofthese products inthehuman environment .
Anynew therapeutic substance which contains newexcipients andnew active
principles andtowhich extensive exposure isforecast must betested for
mutagenicity .
The tests involved andthose forbioavailability will beconducted according
totheprinciples expounded inCommission Recommendations .
Article 3
11.This Article amends Chapter IIIofDirective 75/319/EECrelating tothe
Committee forProprietary Medicinal Products .
Theprevious system ,which made theCPMP ,towhich reference wasmade from
thevery beginning ,thehubofmarketing authorization ,isreplaced bythat
oftherecognition oftheinitial authorization which mainly concerns the
manufacturer andtheMember States towhich hesubmits hisapplication .
TheCPMP issimply informed anditsteps intogive anopinion only in
exceptional cases where recognition might bedisputed .

-14-
12.Theprevious Article 8.which defined therole oftheCPMP ,isamended in
respect oftwopoints ;theaimofthemutual recognition ofauthorizations
isintroduced andtheCPMP 'srole isexplained :itexamines anyquestion
concerning thequality ,safety andefficacy ofaspecific medicinal product
orof (agroup ofmedicinal products . *
13.Theprinciple ofrecognition andtheprocedures fortheapplication for
recognition arelaid down inArticle 9.Inorder tomake this application ,
theproprietary product inquestion needs only tohave obtained amarketing
'authorization inanother Member State .Under theprevious system ,notonly
wasthis initial authorization necessary tosettheCPMP inmotion but ,in
addition ,arequest hadtobemade fortheproduct tobemarketed inat
least five other Member States .
14.The cases ofreferral tothe Committee are laid down inthe new Articles
.10.11and 12.
-where anauthority does notrecognize theauthorization (Article 10);
-where national decisions clash (Article 11);
-where ,before taking adecision ,anauthority wishes tohave theopinion
oftheCPMP concerning aproblem ofCommunity interest (Article' 12)' .
15.Recognition isnormally obtained within afixed period of120days .This
period isrelatively long ,bearing inmind theconsiderable work onthe
re-examination ofoldproducts attheexpense oftheauthorities pursuant to
Article 39(2 )ofDirective 75/319/EECandbearing inmind thefresh .tasks
entrusted tothenational authorities pursuant tothenewArticle 13andthe
possibilities ofshortening this period provided forinArticle 15(2 ).
16.Thus ,assoon astheDirective (Article 4)enters into force ,theperiod of
120days will bereduced to60inthecase oftheproprietary medicinal
products referred toinArticle 13(1 ).These areproprietary products
containing anewactive substance ,i.e. onewhich isthesubject ofan
application formarketing authorization forthe first' time intheMember .
State concerned .This newprocedure isthus intended fornewproducts
rather than foroldones already sold onthevarious markets .

-15-
Compliance v.-ith this shorter period isfacilitated bytheexistence of
assessment reports ontheresults oftests drawn upbyatleast one
Member State ;these reports constitute ,sotospeak ,thestatement ofthe
reasons justifying thegrant oftheauthorization .Atfirst sight ,itmay
seem paradoxical toreserve this rapid procedure fornewproducts which ,
bydefinition ,areless well known than theoldproducts .Nevertheless ,
•thelatter are thesubject ofnational re-assessments (cf .Article 39(2 )
ofDirective 75/319/EEC )which take into consideration experimental data
andpublished particulars (cf.Article 4,item 8,2ndsubparagraph )that
are often difficult toassess .
Ontheother hand ,newproducts have been thesubject ofthorough
experimentation inaccordance with common principles which comply with the
state ofthe art inscience andwhich areexpounded inexplanatory notes
concerning the tests concerned with themarketing ofproprietary medicinal
products .This experimental workhasbeer ,carefully assessed bythe
competent authorities ofatleast one Member State which have provided
allthe justifications for their decision .Better knowledge ofthemedicine
inquestion will beobtained not somuch from afresh administrative
examination ofthe same data asfrom monitoring theproduct after ithas
been marketed .
Furthermore ,theassessment report shall besupplemented ,where necessary ,
byparticulars stemming from drug-monitoring systems ,forexample
(Article 13(3 )),i.e. byinformation ontheadverse reactions tomedicinal
products obtained after they have been marketed .
17.Article 14contains the -rules ofprocedure which apply when amatter is
referred totheCPMP .Gompared with theprevious rules ,there isachange
ofform ,insofarastherules which were previously dispersed over
several Articles aregathered together here ,andofsubstance .Theperson
responsible forplacing aproduct onthemarket mayexplain himself
verbally orinwriting before theCPMP ,aprodedure which wasstrongly
requested bytheindustry .

-16-
THECOUNCILOFTHEEUROPEAN COMMUNITIES ,
I
HavingregardtotheTreatyestablishing theEuropeanEconomicCommunity,
andinparticularArticle100thereof;
HavingregardtotheproposalfromtheCommission;
HavingregardtotheOpinionoftheEuropeanParliament;
HavingregardtotheOpinionoftheEconomicandSocialCommittee;
WhereastheDirectives ontheapproximation ofthelawsrelatingto
proprietary medicinalproductsmustbeadaptedtoscientific progressand
takeaccountoftheexperience obtainedsincetheirentryintoforce;
WhereasCounciI.Directive75/319/EEContheapproximation ofprovisions
laiddownbylaw,regulation oradministrative actionrelatingto
proprietary medicinalproducts (1)providesinArticle15(2)that"the
CommissionshallsubmittotheCouncilaproposalcontaining appropriate
measuresleadingtowardstheabolitionofanyremainingbarrierstothe
freemovementofproprietary medicinalproducts",notlaterthanfour'
yearsaftertheentryintoforceoftheabove-mentioned Directive;
Whereasitisnecessaryfromthepointofviewofpublichealthandthe
freemovementofproductsthatthecompetent ,authorities ,manufacturers and
consumers mayhavereadilyattheirdisposalallusefulinformation on
authorizedproprietary products,inparticular bymeansofdatasheetsand
appropriate labelling;
Whereasitisnecessarytospecifycertainprovisionsrelatingtophysico­
chemical,biologicalor_microbiologi caltestsonproprietary medicinal
productsandtointroducetheprincipleofbioavailability andmutagenesis
testsinordertosafeguardpublichealth;,
(1)0JL147,9.6.1975
/

-17-
Whereastheapproximation ofLawsbroughtaboutinthisconnection must
enableaproprietary product,manufactured andmarketedinoneMemberState
"onthebasisofharmonizedprovisions,tobeallowedonthemarketofany
otherMemberStatebyvirtueoftherecognition oftheinitialauthorization ,
saveinexceptional casessubjecttotheopinionoftheCommitteefor
Proprietary MedicinalProducts,
HASADOPTEDTHISDIRECTIVE :

ARTICLE 1
Council Directive 65/65/EEC .ontheapproximation ofprovisions laid down by
law,regulation oradministrative action relating toproprietary medicinal
products (1)shall beamended asfollows :
(1)Article 4shall beamended thus : *■
(a)Point 6:thewords "ifless than three years "shall bedeleted .
(b)Point 8(a)oftheEnglish version :thewords "published references "
shall bereplaced by"published data ".
(2)Thefollowing Article 4ashall beinserted after Article 4:
"Theapplication referred toinArticle 4shall also beaccompanied by
a data sheet which shall contain the following information :
1.Name oftheproprietary product ;. ,
2.International non-proprietary name recommended bytheWorld Health
1Organization ,where such name exists ,ofeach active principle ;
orfailing this ,thegeneric name orchemical description ;
3.Pharmaceutical form ; -
4.Pharmacological properties and ,insofar asthis information is
useful fortherapeutic purposes ,pharmacokinetic particulars ;
5.,Clinical particulars : , , • • -
5.1 therapeutic indications ;
5.2 contra-indications
5.3 undesirable effects (frequency andgravity )
5.4 special precautions foruse „ -
,5.5 useduring pregnancy andlactation ■,'■
5.6 interaction with other medicaments and other interactions
5.7 posology andmethod ofadministration •
5.8 overdose (symptoms ,emergency procedures ,antidotes )
'5.9 special warnings .
(1)0J22,9.2.1965

-19 -
6.Pharmaceutical particulars :
6.1 qualitative andquantitative composition inactive principles
6.2 constituents oftheexcipient which must beknown inorder to
permit correct administration ofthemedicinal product
6.3 major incompatibilities
6.4 shelf life
6.5 special precautions forstorage
6.6 contents ofcontainer
6.7 name orstyle andpermanent address orregistered place of
business ofmanufacturer ".
(3)Thefollowing Article 4bshall beinserted after Article 4a:
"Thecompetent authorities oftheMember States shall take allnecessary
measures toensure that thecontents ofthedata sheet are inconformity
with those accepted when the authorization isissued orsubsequently .
Inaddition ,the data sheet referred toinArticle 4ashall be
supplemented bythefollowing information :
7.Administrative particulars :
7.1 marketing authorization number
7.2 conditions ofsale tothepublic
7.3 date onwhich data sheet wasdrawn upanddate ofitslast revision .
Moreover ,the data sheet may besupplemented bythe "following information :
8.Economic particulars :
8.1 selling price tothepublic ofthevarious sizes ofpacks
8.2 cost ofdaily treatment
8.3 situation inrespect ofhealth insurance ."
(4)Article 5,paragraph 2,shall beamended thus :
"Authorization shall likewise berefused iftheparticulars anddocuments
submitted insupport oftheapplication donotcomply with Articles 4
and 4a."

-20-
(5)Thefollowing Article 9ashall beinserted after Article 9:
"After anauthorization hasbeen issued ,theperson responsible forplacing
theproduct onthemarket must ,inrespect ofthecontrol method provided
for inArticle 4,point 7,take account oftechnical andscientific progress
andintroduce anychanges that may berequired toenable theproprietary
medicinal product tobemore reliably checked ."
(6)Article 10shall beamended thus :
"Anauthorization shall bevalid forfive years andshall berenewed
"forfive-year periods onapplication bytheholder atleast three months
preceding expiry ."
(7)Article 11,paragraph 2,shall beamended thus :
"Anauthorization shall also besuspended orrevoked where theparticulars
supporting theapplication asprovided forinArticles 4and 4aarefound
tobeincorrect orhave notbeen amended inaccordance with Article 9a,
orwhen the controls referred toinArticle 8ofthis Directive orin
Article 27oftheSecond Council Directive 75/319/EECof20May1975 onthe
approximation ofprovisions laid down bylaw ,regulation oradministrative
action relating toproprietary medicinal products have notbeen carried out."
(8)Article 13,points 1,2 -and7,shall beamended thus :
"1.Name oftheproprietary product which maybeabrand ,name ,oracommon
name together with atrade mark orname ofthemanufacturer ,ora
scientific name together with atrade mark orname ofthemanufacturer .
Where thespecial name ofamedicinal product containing only one
active principle isabrand name ,this name must inallcases befollowed
bytheinternational non-proprietary name ,inlegible characters ,
recommended bytheWorld Health Organization where such name exists ."
"2.Astatement oftheactive principles expressed qualitatively and
quantitatively perdosage unit orasapercentage ,according tothe
pharmaceutical form ,using theinternational non-proprietary names
where such names exist ."
"7.Expiry date inplain language ."
» •
/ ■

-21-
ARTICLE 2
The Annex toCouncil Directive 75/318/EEC onthe approximation ofthe laws
ofMember States relating toanalytical ,pharma co-toxi cologicaIandclinical
standards andprotocols inrespect ofthetesting ofproprietary medicinal
1products shall beamended asfollows :
(1)InPart 1,C1,theseventh naraaraoh <?h^llbereplaced bythefollowing
text :
"Theroutine tests tobecarried outoneach batch ofstarting materials
must bestated intheapplication formarketing authorization ,with proof
that each batch ofstarting materials meets thequality requirements of
themonograph ofthepharmacopoeia concerned ."
Theeighth paragraph shall besupplemented thus :
"They shall inform theresponsible authorities which pharmacopoeia is
referred to."
(2)InPart 1,C,the following paragraph 3shall beinserted :
"3.Physico-chemical characteristics liable toaffect bio-availability
Thefollowing items ofinformation concerning active principles ,
whether ornot listed inthepharmacopoeias ,shall beprovided if
they relate tothebioavailability ofthemedicinal product :
-crystalline form andsolubility coefficients ^
-particle size ,where necessary after pulverization ,
-state ofhydration
-oil/water partition coefficient ,
therequirements ofthefirst three indents notbeing applicable
tosubstances used solely insolution ."
(3)InPart 1,E,thefollowing second paragraph shall beinserted :
"Abatch ofaproprietary medicinal product isalltheunits ofa
pharmaceutical form which aremade from thesame initial mass ofmaterial
andhave undergone asingle series ofmechanical operations orasingle
sterilization operation ."
OJL147 of9.6.1975

-22-
(4)Thefirst paragraph ofPart 1,E,shall besupplemented bythefollowing
4thsubparagraph : • ' .
"Furthermore ,solid pharmaceutical forms having tobeadministered by
oral rpute shall ,where necessary ,besubjected toinvitro studies onthe
liberation and dissolution rate oftheactive principle orprinciples .
Until standards arepublished bytheEuropean Pharmacopoeia ,theconditions
oftheexperiment andtheapparatus employed shall beprecisely described ."
(5)InPart 1,E2,the second subparagraph shall ,besupplemented thus :
"Except inthecase ofappropriate justification ,the .maximum acceptable
deviations maynotexceed 5%." *
(6)InPart 1,E3,thethird subparagraph shall bereplaced bythefollowing
text : ■ , - " "
"Anupper limit test shall beobligatory inrespect ofpreserving agents
andanyother excipient constituent liable toaffect physiological
functions ;anupper andlower limit test shall beobligatory inrespect
oftheexcipient ifitisliable toaffect thebioavailability ofan •
active substance ." •■ ' ' '
(7)InPart 1,E5,thefirst subparagraoh shall bereplaced bythefollowing
text : • '■ ,•
"Ifgeneral monographs onpharmaceutical forms appear intheEuropean
Pharmacopoeia orinthe -national pharmacopoeias oftheMember States ,
-finished products must meet therequirements contained therein .Ifnot ,
they shall bethesubject ofthe'determinations below ."
Inaddition ,thesubparagraphs referred toabove shall beamended as
foIlows : 1 ' /
"Injectable preparations :"TOml"shall bereplaced by"15ml"."
''Ointm ents ,creams ,etc.:colour andconsistency ;particle size ofthe
.active principles ;weight andacceptable margin ofvariation ;nature of
container ;microbiological control tests ,ifnecessary ."
"Suspensions :colour ;sedimentation rate ;where settlement occurs ,the
ease with which thesuspension can -beresumed ." ..
"Suppositories andpessaries :colour ;particle size oftheactive principles
weight andacceptable variations inunit weight ;melting temperature or
disintegration time ,with themethods used todetermine these ."

23"
(8)InPart 2,Chapter I,thefollowing title D'shall beinserted between
titles "D"and "E":
"D 1MUTAGENIC POTENTIAL
Thepurpose ofthestudy ofmutagenic potential istoreveal thechanges
which asubstance may cause inthegenetic material ofindividuals or
cells andwhich have theeffect ofmaking successors permanently and
hereditarily different from their predecessors .This study isobligatory
foranynewsubstance ."
(9)InPart 2,Chapter I,thetitle "E.CARCINOGENICITY "shall be
replaced by:"E.CARCINOGENIC POTENTIAL ".
Inaddition ,thefirst subparagraph shall beamended asfollows :
"Experiments intended toreveal carcinogenic effects shall normally be
required :". (The rest remains unchanged ).
Furthermore ,apoint 3shall beinserted :
"3.inrespect ofsubstances having given positive results inthemutagenic
potential tests orinother short term carcinogenicity tests ".
(10)InPart 2,Chapter I,G,the following new subparagraph shall beinserted
between the fourth and fifth subparagraphs :
"Formedicaments which must besubjected toabioavailability assessment ,
thedata must include changes intheresults asafunction oftime and ,more
generally ,indicate thebioavailability oftheproduct orofitsmetabolites ."
(11) InPart 3,Chapter II,thetitle "A.Pharmacological Particulars
(Clinical pharmacology )"shall bereplaced by"A.Pharmacological Particulars
(Clinical pharmacology andbioavailability )".
This same Chapter II,A,shall besupplemented byaparagraph 5,worded as
follows :
"5.Theassessment ofbioavailability must beundertaken inallcases where
itisessential intheinterests ofpatients ,e.g. where thetherapeutic
safety margin isnarrow orwhere theprevious tests have revealed
anomalies which mayberelated tovariable absorption ."

-24-
ARTICLE 3
I
Directive 75/319/EEContheapproximation ofprovisions Laid down byLaw,
reguLation oradministrative action reLating toproprietary medicinaL
products shaLL beamended asfoLLows : -
Theprovisions ofChapter IIIshaLL berepLaced bythefoLLowing provisions :
"Article 8 '
71.Inorder tofacilitate theadoption ofacommon position bytheMember 1
States regarding marketing authorizations andtopermit their mutual
recognition ,aCommittee forProprietary Medicinal Products ,hereinafter
referred toas"theCommittee ",ishereby setup.TheCommittee shall
consist ofrepresentatives oftheMember States andoftheCommission .
■- I . '
2.Theresponsibility oftheCommittee shall betoexamine ,attherequest of
oneofitsmembers ,anyquestion concerning thequality ,safety and
efficacy ofproprietary medicinal products and ,inparticular ,inaccordance
with Articles 9to14,questions concerning theapplication ofArticles 5
and 11ofDirective 65/65/EEC .
3.TheCommittee shall draw upitsownRules ofProcedure .
Article 9
1.Aholder ofamarketing authorization issued inaMember State inaccordance
with theprovisions oftheDirectives relating toproprietary medicinal
products mayrequest recognition ofsuch authorization when hefiLes an
appLication forauthorization inoneormore Member States , ,inaccordance
with ArticLe 4ofDirective 65/65/EEC .
2.Heshall inform theCommittee ofthis application ,mentioning theMember
States with which hehasfiled it,andalso forward totheCommittee a
copy ofthemarketing authorization orauthorizations already issued .
3.The Committee shall forward this information tothe Member States .
4.TheMember State(s )concerned shaLL grant recognition byissuing an
authorization vaLid ontheir market within 120days after thenotification
referred toabove orwithin 60days thereafter inthecase ofaproprietary
medicinaL product ofthe .kind referred toinArticLe 13(1),without
prejudice totheprovisions setoutbeLow .

-25-
Article 10
1.Where aMember State considers that itisunable torecognize amarketing
authorization ,itshall forward totheCommittee andtotheperson
responsible forplacing theproprietary medicinal product onthemarket
itsreasoned objection onthebasis ofArticle 5ofDirective 65/65/EEC ,
within the time Limits stipulated inArticle 9(4).
2.Upon theexpiry ofthis period ,thematter shall bereferred tothe
Committee andtheprocedure referred toinArticle 14shall beapplied .
3.Onreceipt ofthereasoned objection mentioned inparagraph 1,theperson
responsible forplacing theproprietary medicinal product onthe market
shall immediately submit totheCommittee one copy oftheparticulars and
documents enumerated inArticle 4(2 )ofDirective 65/65/EEC .
Article 11
Ifseveral applications submitted inaccordance with Article 4ofDirective
65/65/EEChave been made foraparticular proprietary medicinal product ,and
oneormore Member States have granted anauthorization while oneormore of
theother Member States have refused it,amember oftheCommittee mayrequest
theCommittee toapply theprocedure mentioned inArticle 14.
Thesame shall apply where oneormore Member States have suspended orrevoked
themarketing authorization while one ormore other Member States have not
done so .
Article 12
Thecompetent authorities ofMember States may ,inspecific cases where the
interests oftheCommunity areinvolved ,request theCommittee toapply the
procedure provided forinArticle 14,before they reach adecision onan
application foramarketing authorization ,itssuspension orrevocation and ,
inparticular ,when they intend toreject anapplication which concerns anew
proprietary product such asthat which isreferred toinArticle 13(1 )and
which hasalready been authorized inanother Member State .

-26-
Article 13
1.Inorder tofacilitate anydiscussions bytheGonmittee ,thecompetent
authorities shall draw upareport toassess theresults ofthe
analytical andtoxico-pharmacological tests andclinical trials ofany
proprietary product containing anewactive substance which isthe
subject ofanapplication foramarketing authorization intheMember
State concerned forthefirst time orofanyother proprietary product
they maychoose . i
2.Assoon asthenotification referred toinArticle 9(3 )isreceived ,
thecompetent authorities shall forthwith forward totheother Member
States andtotheCommittee anyassessment report relating tothesame
proprietary product orto'aproprietary product containing th6same
active substance .This shall also apply assoon asreference ismade
totheGonmittee pursuant toArticles 11and 12.
3.Ifnecessary ,theassessment report shall beupdated ,namely by
information -stemming from thedrug-monitoring systems .
s \
Article 14 ' ''
1.When reference ismade totheprocedure described inthis Article ,the
Committee shall consider thematter andexpress areasoned opinion ■
within 60days ofthedate onwhich thematter wasreferred toit.
Inthecases 'referred toinArticle 10,theperson responsible for
placing theproduct onthemarket may/athisrequest ,explain himself
verbally orinwriting before theCommittee expresses itsopinion .
Hemayalso obtain thesuspension oftheabovementioned time limit ..
)/
2.TheCommittee 's,opinion shall concern thecompliance oftheproprietary
medicinal product inquestion with theconditions laid down inArticle 5
orArticle 11ofDirective 65/65/EEC .
The Committee shall forthwith inform the Member Statefe )concerned and the
\ •
person responsible forplacing theproduct onthemarket ofitsopinion
■orofthose ofitsmembers "inthecase ofdifferences ofopinion .
3.TheMember States )concerned shall decide onthe action tobetaken
following theCommittee 'sopinion within 30days ofreceiving the
/ ' /
information referred toinparagraph 2.They shall forthwith inform the
Gommittee oftheir décision (s).

-27-
Article 15
1.TheCommission shall report totheCouncil biennially ontheoperation
oftheprocedure laid down inthis Chapter and itseffects onthe
development ofintra-Community trade .
onthebasis ofArticle 100oftheTreaty ,
2.Inthelight ofexperience ,theCommission shal]/ProP°seby1January 1988
atthelatest thereduction oftheperiods referred toinArticle 10
and ,where necessary ,anyadditional measure aimed atfacilitating the
mutual recognition ofmarketing authorizations .
3.TheCouncil shall decide ontheCommission 'sproposal by1January 1989
atthe latest ."
ARTICLE 4
Member States shall bring into force thelaws ,regulations andadministrative
provisions needed inorder tocomply with this Directive by1January 1983
atthe latest and shall forthwith inform the Commission thereof .
Member States shall communicate tothe Commission the text ofthe main
provisions ofnational lawwhich they adopt inthefield covered bythis
Directive .
ARTICLE 5
This Directive isaddressed tothe Member States .
Done atBrussels ,
For theCounc iI
The President

PROPOSAL FORACOUNCIL RECOMMENDATION
concerningtestsrelatingtotheplacingonthemarket
ofproprietary medicinalproducts

-29-
PROPOSAL FORACOUNCILRECOMMENDATION
concerningtestsrelatingtotheplacingonthemarket
ofproprietary medicinalproducts
SUMMARY
f
TheCommissionproposesthatMemberStatesshouldensurethattestsrelating
totheplacingonthemarketofproprietary medicinalproductsareconducted
andpresentedinaccordance withtheprinciples andmethodssetoutinthe
notesforguidancepursuanttoDirective 75/318/EEConstandards andproto­
colsinrespectofthetestingofproprietary medicinalproducts.
ί ■·
Thesenotesdealwiththefollowingaspectsofsafetyandefficacyofdrugs:
-singledosetoxicity,
-repeateddosetoxicity,
-reproduction studies,
_-carcinogenicity ,
-pharmacokinetics andmetabolisminanimals,safetystudies,
-fixedcombination products.

-30-
EXPLANATORY MEMORANDUM
1.ForfouryearstheMemberStateshavebeenauthorizing theplacingon
themarketofproprietary medicinal'productsbyapplyingatfirst .three,
it
andnowfour,CouncilDirectives . >
Directive 75/318/EECrelatesinparticulartotestsdesignedtoverifythe
,safety,efficacyandqualityofthedrugbeforeitisplacedonthemarket.
TheAnnextothisDirectivedescribesinverygeneral'termsthevarious
categoriesofteststobecarriedoutintheanalytical,pharmaco-toxi-
cologicalandclinicalfieldsandgivessomeindicationofhowdocuments
andresultsaretobepresented/
2.Experience hasshownthatdifferences ofopinionnotinfrequently arise
betweennationalauthorities asregardstheindications,contra-indications ,
etc.foragivendrugandevenastothedesirability ofgrantingor
refusingauthorization toplaceitonthemarket.
TheCommission hasfoundonthebasisofthisexperiencethatthedegree
ofharmonization achievedbytheexistingDirectiveswouldnotbe
sufficienttocreatetheconditions necessaryforthefreemovementof
proprietary medicinalproductsunlessitwerematchedbygreaterco­
operationbetweenthecompetentnationalbodies.
3.TheCommitteeforProprietary MedicinalProducts,whichwassetupin
ordertofacilitatetheadoptionofacommonapproachbytheMember
Statesonthequestionofmarketingauthorizations andiscomposedof
representatives ofthenationalauthorities andtheCommission,undertook ,
toreview ,thepresentnationalandinternational requirements andtoseek
jointsolutionsthattakeaccountofcurrintscientificandtechnical
knowledge.TheCommission hasfromtheoutsetsupportedthisscheme,
whichislikelytobringaboutasignificant alignmentofthepoints
ofviewofthenationalauthorities .TothisendtheCommittee hassetup,
-Directive 65/65/EECof26January1965
-Directive 75/318/EECof20May1975\
-Directive 75/319/EECof20May1975
-Directive 78/25/EECof12December1977
.**Directive 75/319/EEC,ChapterIII

-31-
under Article 13ofitsrules ofprocedure ,two groups ofscientific
experts designated bythe Member States todraw up,inaccordance with
certain priorities ,notes for guidance relating tothe free movement of
proprietary medicinal products within the Community .
4.Thedrafting and consultation procedure forthese notes for guidance is
designed toensure that they will bevalid and accepted both bythe
competent authorities and bythe manufacturers concerned .Thedrafts
ofthe two groups ofscientific experts on"safety "and "efficacy "have
been prepared inconjunction with specialists inthefield concerned .
/■
Thedrafts approved bythe Committee forProprietary Medicinal Products
were sent for consultation tothe national authorities and toassociations
representing the pharmaceutical industry .
Thedrafts were then re-examined bythe experts inthe light ofthe
comments received and afinal draft has been prepared which the Committee
has unanimously approved . -
5.Insubstance ,these notes are based largely oncurrent requirements oron
requirements which are inthe process ofbeing drawn upatboth national
and international level .Inthe wider context ofthetoxicity ofnew
chemical substances ,similar texts will berecommended bythe Commission
inthe sixth amendment tothe 1967 Directive ondangerous substances .
6.The main advantage ofthese notes forapplicants for marketing authoriza­
tions istoinform them inadvance ofthe requirements ofnational
authorities sothat they avoid additional delays inthe completion of *
their dossiers .Fortrade within the Community and,inthe long run,
with non-member countries aswell,these notes will spare applicants
thie need torepeat similar tests .Uptonow experimental models have been
defined differently indifferent countries .

-32-
These additional delays andduplications exist atthe moment and have
adetrimental effect onthe cost ofnew medicines .From anethical
point ofview,itisdesirable inparticular toavoid the repetition
ofclinical tests onman and the pointless proliferation ofanimal
experiments *
7.This first set ofnotes for guidance isconcerned more particularly
with allaspects ofthe safety ofmedicines ,other than mutagenicity .
The'Commission intends to ,propose the introduction ofthat discipline
into the categories oftests listed inDirective 75/318/EEC.The notes
for guidance concerned with safety will bereviewed from time totime
toensure that they are continually adapted toscientific andtechnical
progress .
8.This set ,also contains anote onthe efficacy ofproprietary medicinal
.products containing afixed combination ofactive principles .
More specific notes dealing with clinical tests onmedicinal products , '
belonging tocertain therapeutic categories are being elaborated .
9.These scientific texts ,which areguidelines rather than binding require­
ments ,must beinterpreted inaflexible manner andshall berevised
periodically .The Recommendation istherefore the most appropriate
instrument . -
Asthese guidelines are ofmajor importance for patient protection and
for pharmaceuti cal research ,the Commission proposes tothe Council to
adopt such aRecommendation ,after consultation ofthe European Parliament
and the Economic and Social Committee .

-33-
THE COUNCIL OFTHE EUROPEAN COMMUNITIES ,
Having regard totheTreaty establishing the European Economic Community ,
Having regard totheproposal from the Commission ,
Having regard tothe Opinion ofthe European Parliament ,
Having regard tothe Opinion ofthe Economic and Social Committee ,
1.Whereas Council Directive 65/65/EECof26January 1965*ledtotheapproxi
mation ofprovisions laid down bylaw,regulation oradministrative action
relating toproprietary medicinal products inthe Member States ;
whereas Direct ives 75/318/EEC and 75/319/EEC of20May 1975 continued
this approximation and developed theprinciples set out intheoriginal
■tDirective ;
2.Whereas inparticular Council Directive 75/318/EEC lays down ageneral
framework for thetesting ofproprietary medicinal products ,lists the
0
various types oftests tobeconducted and defines certain principles
tobefollowed inthe examination ofapplications forauthorization to
place aproprietary medicinal product onthe market ;
3.Whereas experience has shown that the conduct and content ofthese tests
should bedefined more precisely soastomake possible anidentical
interpretation ofthe Community Directives when such tests arecarried
out and when applications are examined bynational authorities ;
4.Whereas Notes for Guidance are therefore necessary inorder toprevent
differences ofinterpretation inthe implementation ofthe standards and (
procedures listed inDirective 75/318/EEC and will help topromote the
free movement ofproprietary medicinal 'products .;
_0J ECN°22,9.2.1965
XX0J ECN° L147,9.6.1975

5.Whereas tests designed toevaluate thequality ,safety andefficacy of
proprietary medicinal products must beconstantly adapted totake account
ofthe latest scientific andtechnical knowledge without ,however ,giving
rise either toawaste ofresources ortothe use oflaboratory animals
more than necessary ;
6.Whereas itistherefore highly desirable that the Notes for Guidance be
periodically revised totake account ofthe state ofthe art andthat new
Notes for Guidance bedrawn upasand when required ,inagreement with
the national authorities ;
7.Whereas such progress inharmonization ,essential atCommunity level ,
will also promote international recognition oftests onmedicinal products
conducted inaccordance with these Notes and will therefore tend to
render unnecessary the repetition oftests onproducts intended for export
tonon-Member States ;
8.Whereas the Pharmaceutical Committee and the Committee forProprietary
Medicinal Products have been consulted onthe measures contained inthis
recommendation ,
HEREBY RECOMMENDS THE MEMBER STATES TO: V
1.ensure that,inthe conduct oftests and inthepresentation ofresults ,
applicants forauthorization toplace proprietary medicinal products on
the market comply with theprinciples and adhere tothe methodology set
out inthe Notes for Guidance annexed hereto ;
2.examine andevaluate ,inaccordance with the Notes for Guidance ,all
applications for marketing authorization ;
3.apply these Notes for Guidance progressively and not later than three
years after notification ofthis recommendation . 1

-35-
ANNEX I:SINGLE DOSE TOXICITY
Note forGuidance concerning the application ofthe Annex ofDirective
75/318/EEC,2ndpart,Chapter I,B1,with aview tothegranting ofa
marketing authorization for anew drug .
1.INTRODUCTION
These guidelines deal with thequalitative andquantitative study oftoxic
phenomena andtheir occurrence related totime after asingle administration
ofthe substance (orcombination ofsubstances ).
ι· ,
These studies may give some indication ofthe likely effects ofacute
overdosage inman and may beuseful forthe design ofrepeated dose
toxicity studies and reproduction studies onthe relevant animal species .
The single dose toxicity tests should beconducted insuch awaythat
signs ofacute toxicity are revealed and the mode ofdeath determined .
Insuitable species aquantitative evaluation ofthe lethal dose can be
made but ahigh level ofprecision isnot required .
2.PRODUCT SPECIFICATION
2.1 Drug Substance
The active substance should have the same pattern ofimpurities asthe
product tobemarketed ,when possible .Should thefinal dosage form be
shown tohave impurities significantly different either inquantity or
quality from those inthetest batch then further steps should be
taken toascertain their possible toxicity .Consideration should be
given tothe physical characteristics ofthe drug substances inrelation
tothe route ofadministration ,e.g. theparticle size ofacompound
given orally .
2.2 Finished Product
When large' animals are used inthe acute toxicity study ,itmay be
possible toconduct astudy with the pharmaceutical formulation in­
tended tobemarketed ,andthis isdesirable .
2.3 Excipients
Where a-new excipient isused for thefirst time itshould beevaluated
as anew active substance .
2.4 Products containing aCombination ofActive Substances
Inthe case ofcombination ofactive substances itisnecessary to
make astudy ofeach active substance separately and ofthe combina­
tion ofactive substances inthe same proportions asinthe proposed
final product inorder that any change orpotential toxic effects are
revealed . . .
2.5 Degradation Products
Where degradation products occur under conditions ofstorage conside­
ration should begiven totheir possible toxicity andthis might be
best evaluated initially byanacute toxicity study .

-36-
3.ANIMALS
3.1Singledosetoxicitytestsmustbeconducted onatLeasttwomammalian
speciesofknownstrainusingequalnumbersofbothsexes.Rodentssuch
asthemouse,ratandhamsteraresuitableforthequalitative study
oftoxicsignsandthequantitative determination ofthelethaldose.
Inthecaseofothermammalstoxicsignsshouldbeobservedandre­
cordedindetailforeachanimalused.
3.2Whateverspeciesorstrainofanimalsareselecteditisessential
thatthefollowinginformation shouldbeprovided,age,sex,weight,
originandthetimespentinthelaboratorybeforetest,whetherornot
theanimalsareclassified asbeing.freeofspecificpathogens,whether
ornottheanimalshavebeenvaccinated orsubmittedtoanyother
procedure.Detailsofhousingandenvironmental conditions shouldbe
given.Accesstoandthenatureofthedietandtheavailability of
watershouldbestated.Alltheabovefactorsareknowntoaffectthe
acutetoxicityofsubstances .
4.ADMINISTRATION
4.1RouteofAdministration
Inthecaseofrodentsatleasttworoutesshouldnormallybeusedand
whenpossibleshouldincludethoseroutesproposedTormanandatleast
oneshouldensurefullaccessofunchangeddrugintothecirculation .
Iftheproposedrouteofadministration tomanisintravenous then
useofthisroutealoneinanimaltestingisacceptable .
4.2Conditions ofAdministration
Detailsofadministration oftheproductshouldbeprovidedandinclude
particulars ofthevehicleoradjuvants used,methodofpreparingthe-
suspensioninthecaseofinsolubleproducts,concentration ofthe
solutionusedandthevolumeadministered .Therouteandthemethod
ofadministration shouldbeclearlygiven.Iftheintravenous route
isusedtherateofinfusion (ml/min.)andthepHandtemperature of
thesolutionadministered shouldbeprovided.
Ifitisnecessarytousemorethanoneinjectionsiteforparenteral
administration thisshouldbestated.
\
4.3Doselevels
Inrodentsthenumberofdoselevelsusedshouldbesuchastoenable
thespectrumofacutetoxicitytoberevealedandtoenablethe
valuewithits95%fiduciallimitstobedetermined foreachroute
andbothsexes,ifpossible.
Inothermammalsthenumberofdoselevelsshouldbesuchthatthe
spectrumoftoxicityshouldberevealedandanestimateofthe
lethality •obtained.

-37-
5.OBSERVATIONS
Animalsshouldbeobservedatregularintervalsandallsignsoftoxicity
andthetimeoftheirfirstoccurrence andtheirseverityandduration
recorded.Thetimeandmodeofanydeathshouldbedocumented .Whenlarge
experimental animalsareusedanysignsoftoxicityshouldbepresented
separatelyforeachanimal.
Observation shouldusuallybefor14days,butshouldcontinuesolongas
signsoftoxicityareapparenteg.'progressive lossofweightorinhibition
ofgrowth.
6.AUTOPSY
Allanimalssurvivingtotheendofthestudyandallanimalsdyingduring
theperiodofobservation shouldbesubjectedtoautopsy.Ifinthelatter
casesautolysisisadvancedthisshouldbereported.
7.PRESENTATION OFDATA
Theresultsfromwhichanycalculations havebeenmadeshouldbegivenin
detail;themethodsofcalculation usedshouldbestated.
Thetoxiceffectsshouldbedescribedineachspeciesandforeachroute
ofadministration atalldoselevels.
Theinvestigator shoulddrawallrelevantconclusions fromthedata
obtainedinthesestudies.

-38-
ANNEX II:REPEATED DOSE TOXICITY
Note for G.uidance concerning theapplication ofthe Annex ofDirective
75/318/EEC,2ndpart,Chapter ,!/B2,with aview -tothegranting ofa
marketing authorization for anew drug .
1.INTRODUCTION
The purpose ofthese studies istoobtain information onthetoxicity of
aproduct when repeated exposure tothis medicinal product isanticipated
inorder that anassessment may bemade ofthe risk resulting from thera­
peutic administration ofthe product ,taking into account the products
ofbiotransformation . \
Theduration ofthese studies will bedetermined bythe proposed use in
manorbythe intended duration ofhuman exposure .The following periods
ofadministration are suggested asaguidance tocorrelate the duration
ofthe repeated dose toxicity studies with the proposed duration ofhuman
exposure tothe drug .
Proposed duration of Suggested duration of
human treatment repeated dose toxicity studies
One orseveral doses
within one day
Repeated doses for upto
7days
Repeated doses for upto
30days
Repeated doses beyond
30days2weeks
4weeks
3months
6months
When human exposure islikely tobelonger term ,for example when frequent
f i
discontinuous administration results inatotal period ofexposure ofone
month ormore inaperiod of 1year ,orwhen retention inthe body ofa
single dose ofthe drug isprolonged ,.then the duration ofthe repeated
dose toxicity studies will besix months .
- / 1
When itisnecessary toconduct toxicity studies ofthree orsix months
duration ,asubacute toxicity study of2or4weeks duration may be
designed and carried out insuch amanner that itacts asarange finding
study for the longer term investigation (see 2.5).
The reason isthat administration oftoo high adose would leave too few
animals alive atthe end ofthe study lasting three months ormore ;
administration oftoo low adose would prevent the development oftoxic
changes .

-39-
1.1 General specifications with regard tothe repeated dose toxicity
study
Theintroduction ofthe "Norms andProtocols EC75/318Part II,
Toxi cological and Pharmacological Experiments "states that these
experiments should indicate inter alia thetoxicity thresholds :
"Repeated dose toxicity tests are intended toreveal anyphysiological
and/orpathological changes induced byarepeated administration of
the active substance ,orcombination ofactive substances under exami­
nation andtodetermine how these changes arerelated todosage .
Generally itisdesirable that twotests beperformed :oneshort-term ,
lasting twotofour weeks ,theother long-term .Theduration ofthe
latter shall depend onthe conditions ofclinical use.Its purpose
shall betodetermine byexperiment the non-toxic dose range ofthe
product ".
Asthese thresholds can only bedetermined when they have been crossed
the repeated dose toxicity study must beconceived insuch away asto
demonstrate signs oftoxicity .This implies that :
1.1.1 Inthe selection ofspecies for long-term studies prior to
marketing ,itisdesirable that with regard tothe metabolism
andthe pharmacokinetics ofthe drug the species should beas
closely similar toman asispossible within the usual spectrum
oflaboratory animals used for repeated dose studies .Ifthere
aresignificant differences inmetabolism these should betaken
into account inevaluating the results .
1.1.2 Itisdesirable that the pharmacological target organs andthe
pharmacological effects oftheproduct inthespecies used should
bethe same asthose involved inthe therapeutic effect
envisaged for man where this isknown andispractical .
1.1.3 The dosage ,theroute andthe frequency ofadministration should
beplanned soastopromote aloading ofthe animal organism
with the product anditsmetabolites sufficient todemonstrate
thetarget organ(s )interms ofharmful secondary effects .In
designing theprotocol account will betaken ofthe pharma­
cokinetics ofthe drug .
Bycontinuous administration ofadrug insufficiently high
doses the following principal stages may bereached :

-40-
a.The Load ofthe drug inthe organism builds upuntil a
steady state isreached ..
-b.Adaptation ofthe organism tothe load with regard tothe
pharmacological target organs orthe biotransformation
enzymes orthe excretory mechanisms .
c.Insome cases asecond metabolic pathway may beactivated
due toanoverloading ofthe primary detoxication pathway ;
asaresult anew toxic metabolite may beformed .
d.Aphase ofmanifestation oftarget organ toxicity manifested
byfailure ofphysiological functions andultimately by
pathological changes .
Administration ofthe product inthe repeated dose toxicity studies
should besufficient with regard todosage and duration toreach this
final stage d.sothat the type oftoxicity produced byanexcessive
dose andthe multiple ofthe therapeutic dose producing toxicity may
beassessed .Notall drugs can bepractically administered indosages
that produce target organ toxicity .Under such circumstances evidence
should beproduced that the highest possible dose has been given and
that the drug has been systemically absorbed .
2.SPECIFICATIONS WITH REGARD TO THE DRUG AND ITS ADMINISTRATION
2.1 Drug quality
The active substance should present the same pattern ofimpurities
asthe product tobemarketed ,when possible .Should drug substance in
thefinal dosage form beshown tohave impurities significantly differ­
enteither inquantity orquality from those inthetest batch then
further steps should betaken toascertain their possible toxicity .
When the drug isgiven orally itsphysical characteristics such as
particle size may beimportant ;therefore the physical characteristics
andstability ofthe material used inthe repeated dose toxicity
studies should bestated ineach case .Whenever more than one batch of
active substance isused inrepeated dose toxicity studies this must
bestated and each batch identified .The batch orbatches used inthe
repeated dose toxicity studies should not beofahigher degree of
purity than those intended forthe final product .When the drug is
given inthediet orthe drinking water itshould beestablished
that itisstable inthat medium .
When anew excipient isused for thefirst time ,itshould betested
inaccordance with the same criteria asanew active substance .

-41-
2.2 Duration ofadministration
The duration ofthese studies should berelated tothe duration ofthe
proposed therapeutic use inman (see §1).
2.3 Route ofadministration
Whenever this istechnically feasible ,the product should bead­
ministered bythe route intended for use inman anditisdesirable
that the pharmacological effect isdemonstrable bythis route .When
this cannot beshown ,the use ofother routes should beconsidered .
(Administration byinhalation isdiscussed inthe Appendix ).
Thequantity ofdrug absorbed from the proposed site ofadministration
should beknown from pharmacokinetic studies .When the product is
administered inthe food orthedrinking water ,theapplicant must
,give assurance that areasonable and known amount ofthe drug ingested
isabsorbed .Dosing byincorporation ofthetest substance inthe
diet ordrinking water requires regular adjustment ofthe amount of
drug inthediet ordrinking water tocompensate for growth and
changing consumption . -
Inaddition tosystemic toxicity thepossibility oflocal toxicity
atthesite ofapplication should begiven dueattention ,for example
inthe case ofapplication tothe skin,intravaginal application ,
intravenous ,intramuscular ,rectal ,subcutaneous ,intra-arti cular ,
intrathecal ,conjunctival ,intranasal and aural application ,orwhen
the drug isgiven byinhalation .
2.4 Frequency ofadministration
The steady state ofthe loading ofthe organism with some products
isreached only when they are administered for seven days aweek .
Usually theadministration ofadrug toanimals should beconducted
onthis basis .Ifthis isnotpossible the reason should begiven .
When therate ofelimination isslow less frequent administration
may beacceptable .Arapid rate ofelimination orgastric intolerance
may make itnecessary toadminister theproducts more than once aday.
 /
2.5 Dose levels
The treatment should include :
a.Ahigh dose,selected forthe purpose ofcausing target organ
toxicity whenever possible orfailing this other non-specific
toxicity ,oruntil limited byvolume ofdose .

Foratoxicitystudyofthreeorsixmonthsdurationthisdose
shouldbederivedfromasubacutetoxicitytestof2or4weeks
duration,designed ,andcarriedoutasadoserangefindingstudy.
b.ALowdose,sufficienttoproduceapharmacodynamic effectorthe
desiredtherapeutic effect,ortoproducebloodlevelscomparable ■
tothoseexpectedtoproducetheseeffectsinman.
c.Anintermediate dose,suchasthegeometric meanbetweenthehigh
doseandthelowone.
d.Thestudyshouldincludeappropriate controlgroup(s);in special
casesapositivecontrolgroupmaybenecessary.
However,theaboveconsiderations donotapplywhenthepharmacodynamic
effectbyitselfwillcausetoxicity;hypoglycaemia byantidiabetic
agentsservesasanexample.
Theinvestigator shouldindicatetherationale onwhichthedose
levelswereselected.
2.6Pro-drugs
Whentheproductadministered isapro-drug,itsconversiontoan
activedrugshouldbedemonstrated inthespeciesunderstudy.
SPECIFICATIONS PERTAINING TOTHEEXPERIMENTAL ANIMAL
3.1Animalspecies:choiceandcharacterisations • 1'
;Asfaraspossiblethespeciesshouldbechosenonthebasisoftheir
similaritytomanwithregardtothepharmacokinetics includingthe
I
biotransformation oftheproduct(see§1.1.1).
Thepharmacodynamic effectofthedrugshouldifpossiblebedemonstra­
tedinatleastoneofthespecies,soastoprovideinformation
aboutthemarginbetweentherapeutic andtoxiceffects.
Theinvestigator shouldjustifythechoiceofthespeciesandstrain.
UseofSPFanimalsusuallyincreasesthevalueofthestudy.
3.2Sexes
Normallyequalnumbersofmaleandfemaleanimalsshouldbeused.

-43-
3.3 Size ofTreatment group s
When the size ofthe treatment groups isbeing considered ,attention
should begiven tothe following :
a.The size ofthe treatment groups should besuch that all toxi­
cologically important effects due totreatment will berevealed .
b.The size ofthe treatment groups should belarge enough topermit
the sacrifice ofanimals atintervals before the end ofthe study -
without interfering with the final statistical analysis .
c.The size ofthe treatment groups should belarge enough toallow
some animals toberetained atthe completion ofthe period of
dosing sothat the reversibility oftoxic changes atthe end of
the treatment may beevaluated .
d.Background knowledge concerning the ranges ofvariables tobe
stgdied inthe species and strains used isalso relevant to
consideration ofgroup size .
However ,the size ofcontrol and treatment groups will always be
limited for practical and financial reasons and for humane
considerations .
/
3.4 Number ofspecies
The purpose ofthe repeated dose toxicity studies istoprovide an
animal model for the repeated administration ofthe product toman .
The value ofthe model for extrapolation toman depends toalarge
extent onthequalitative similarity between the animal' model and
man;this isusually unknown .Toreduce the risk oferror inextra­
polation ,duetoeffects orlack ofeffects ,which arepeculiar to
one species ,atleast two species should beused ,one being anon
rodent .The choice ofspecies should bejustified (see &1.1.1 .).
4.ANIMAL HUSBANDRY
Ahigh level ofanimal husbandry isrequired andthe environmental
conditions should becontrolled and the diet should beofknown constant
composition throughout .Measures taken toobtain these conditions should
berecorded inthe report .

-44 _
5.OBSERV ATIONS
V
5.1 Pretreatment and Control Values
Control data from thecolony are necessary for small mammals forall
morphological ,biochemical andphysiological variables .Inthe case
oflarger animals pretreatment values should beobtained from the
animals used inthestudy . v \
5.2 Monitoring during the study
5.2.1 General monitoring'
\
General monitoring should becarried out during the study and
should include food intake ,body weight ,haematology ,clinical
chemistry ,urinanalysis ,ophthalmology ,ECG andgeneral behav­
ior.The selection oftechniques used and the choice ofother
tests should beappropriate tothe current state ofknowledge
and tothe animal species being used .Inrodents if ECG and
ophthalmologi cal orother specialised examinations are required
itisacceptable that these are'conducted inalimited number
ofanimals ateach dose level .
5.2.2 Frequency ofmonitoring
The frequency ofmonitoring inaddition topre-treatment studies
andfinal monitoring should beadapted tothe manifestations of
toxicity and also tothe pharmacokinetics ofthe drug .
Thetests performed (including the collection ofblood samples )
during the monitoring should also beperformed onthe controls ,
and should not affect the experimental animals inaway which
would influence the final interpretation ofthetoxicity test
results .
5.2.3 Food intake
When products are administered inthe food,particular attention
should begiven totheeffect ofthe product onfood consumption .
Allowance should bemade for consequent effects ondrug intake .
Λ
5.3 Terminal monitoring
Terminal observations should beascomplete aspossible .Autopsy must
beconducted onall animals .Histopathology should beperformed onall
organs andtissues ofthe high dose and the control groups listed in
thetable .Inrodents the examination ofthe lower dosed groups may be

45-
restricted tothose organs andtissues showing pathological changes
atautopsy .Inother species where small numbers ofanimals are used
histopathology onthose tissues listed should beconducted inall
animals atall doses .
Iforgans are not examined microscopically wax blocks orslides should
beprepared and conserved forfive years from thedate ofmarketing
for examination ifrequired .Peculiarities inthedistribution ofthe
drug maynecessitate further histopathologi cal studies .
6.IMMUNO-INTER FERENCE
The expansive growth ofimmunology and the recognition ofits importance
has made itnecessary topay attention tointerference with the immuno­
logic system bydrugs even when this does not belong totheir intended
activity .Such aninterference may cause undesired side effects
(interference with infection ;carcinoma ).Therefore itisparticularly
important toexamine the spleen ,the thymus and some lymph nodes macros­
copically andmicroscopically atthetermination ofthetoxicity study .
These should indicate anyeffect onthe immune system and thus the need
for further tests .
Since our present knowledge inthis field israpidly increasing ,any
test used toinvestigate the immunological effects ofadrug should rely
vonthestate ofthescientific knowledge atthat moment .
7.CONCLUSIONS
Conclusions should bedrawn from these studies bytheinvestigator .

-46-
APPENDIX A
Listoftissuestobestudiedhistologically inarepeateddosetoxicitystudy
i 1-grosslesions
-tissuemassesortumors(includingregionallymphnodes)
-bloodsmears(incaseofanaemia/enlargedthymus,lymphadenopathy )
-lymphnodes
-mammaryglands
-salivaryglands
-sternebrae,femurorvertebrae (includingbonemarrow)
-pituitary
-thymus
-trachea '.
-lungs
-heart
-thyroid
-oesophagus
-stomach
-smallintestine (Swissrollmethod)
-colon
-liver
-gallbladder
-pancreas
-spleen
-kidneys
-adrenals
^-bladder
-prostate ^
-testes
-ovaries
-uterus v
-brain(coronalsectionsatthreelevels)
-eyes
-spinalcord Y

-47-
APPENDIX B
Conduct oftoxicity studies byinhalation ]
1.INTRODUCTION
Medicinal products intended for administration tohumans byinhalation „
mayeither beaerosols containing the pharmacologically active substance
insolid orliquid state orthey may bevapors orgases .Thelatter
mentioned products are used asinhalation anaesthetics while aerosols in
general contain adrug material inthe form ofparticles delivered ina
propellant which inprinciple ought tobebiologically inactive .
Toxicological studies conducted byinhalation arenecessary where :
ι I
(a)Pharmacokinetics after administration byinhalation maydiffer
qualitatively orquantitatively from thepattern after other routes
ofadministration ;
or '
(b)Drug andpropellant may interact inthe body ;
or
(c)The inhaled product may have alocal effect inthe airways ,either
ashort term effect (effect onciliary function orother signs of
local irritation )oralong term effect (emphysema ,bronchitis ,
malignancy ).
Aerosols are used forthe administration ofdrugs either (i)toobtain a
local effect inthe respiratory system ,or (ii)for the purpose ofobtai­
ning systemic effects byusing the lining ofthe airways for absorption
ofthe active compound or (iii )for circumventing the alteration ofdrugs
inthegastrointestinal tract .
Insome circumstances toxicological studies onthe drug may have been
performed using other routes ofadministration ,therefore extensive
toxicological investigation byother routes ofadministration may already
have been performed when inhalational studies areplanned .Inother cases ,
for example ,locally acting compounds ,such asmucolytic agents ,toxi­
cological investigation byother routes ofadministration may benon-
existant oroflittle relevance .Planning ofthe toxicology studies by
inhalation should take into consideration any already existing toxicological
orpharmacological knowledge ofthe substance .
2.PHYSICO-CHEMICAL PROPERTIES
The information onthe active substance 'sphysico-chemical properties
should beprovided inthe same way asfor anyother toxicological study .
Additional information should beprovided onthe characteristics ofthe
aerosol ,which should include thedistribution oftheparticle ordroplet
size ofthe active substance andthe physico-chemical specification of
the substance orsubstances used asthe propellant .
Thepropellant system used inthese studies should bethat proposed for
thefinal product .Ifanovel propellant system isused,this should
'itself beinvestigated tothe same standard asanew active substance .

-43-
3.DOSING SCHEDULES
3.1 Administration
The method ofadministration depends onthe nature ofthe substance
and the intended use inman.Inacute studies itmay bereasonable
toadminister the substance directly into the airways via anaso-
tracheal tube orthrough atracheotomy .Inthis way the quantity
administered can bedetermined directly .
Inthe case ofLong term exposure studies itwill usually benecessary
touseeither "head only "or"nose only "exposure chambers ormasks
for inhalation .Ifwhole body exposure isused deposition ofthe drug
onthe skin ,inthepelt' ,inthe upper airways and the amount >
swallowed should betaken into account indetermining the dose of
substance administered .
Itshould bedemonstrated that the method ofadministration ensures
that the substance reaches the desired site .
3.2 Dose levels
Inthese studies normally three dose levels and one ormore control
groups asappropriate should beused inboth single dose and repeated
dose studies .Different levels ofdrug exposure can beachieved by
alteration ofconcentration ofsubstance inhaled orbyalteration of
the duration ofexposure .Inthe selection ofdose levels the same
principles should apply ,asfar asispossible tothose used for
toxicity studies byother routes .
The reasons for selecting particular dose levels should begiven .
3.3 Duration ofStudy
Theduration ofthe study should berelated ,atleast tosome extent ,
tothe proposed human exposure .
4.PHARMACOKINETICS AND METABOLISM
The metabolic pattern ofthe drug administered byinhalation maydiffer .
from thepattern observed following other routes ofadministration .
Theinvestigator should determine whether there are any pharmacokinetic
ormetabolic differences ofrelevance forthe interpretation ofthe
toxicologi cal studies conducted bythe inhalational route .
Adhen biotransformation occurs inthe lung itself thepossibility of
enzyme induction ofthis process should betaken into consideration /?"
5.ANIMALS
The experimental animals used inthese studies should befree ofpulmonary ,
infection and have alow incidence ofother pulmonary pathology .
The number ofexperimental animals tobeused ineach group should be
adequate forstatistical analysis and will bedetermined bytheduration
ofthe experiment and bythe number ofobservations ,measurements and
interim sacrifices tobemade during the exposure periods .Atleast one
rodent and one non-rodent species should beused forall repeated exposure
studies .

-49-
6.OBSERV ATIONS
Interim monitoring and terminal studies should beconducted asindicated
forother toxicity studies .Particular attention should bepaid toany
local effects .Ifthe drug istobeadministered repeatedly special
studies ofciliary function and onthe microflora may benecessary .
Blood level monitoring ofdrug and propel lant orother methods of
assessing absorption ofdrug and propel lant should beperformed at
intervals during repeated dose studies .
Terminal examination
Attheconclusion ofthe study allanimals should besubjected toautopsy
and examination oftissues should beconducted aswith other toxi cologi cal
studies .
Instudies conducted bythe inhalational route the lungs should be
weighed inall animals and histopathological examination conducted on
tissues taken from all exposed levels ofthe respiratory tract and from
associated lymphoid tissue .
7.PRESENTATION OF RESULTS AND CONCLUSIONS
These should bedrawn upinthe same manner asinother toxicity studies
andthe investigator should draw appropriate conclusions from the study .

-50-
ANNEX III :REPRODUCTION STUDIES
Note for Guidance concerning theapplication ofthe Annex ofDirective
75/318/CEE,2ndpart,Chapter 'I,Cand D,with aview tothegranting of
amarketing authorization for anew drug .
SENERAL STATEMENT
The study ofdrug effects onreproduction should beconducted onall new
drugs insuch amanner aswould reveal the presence ofanyeffect on
mating behaviour and ofanyeffect which might result infetal loss,fetal
1abnormality and damage totheoffspring inlater life,eg, ,
(i) changes infertility orinthe production ofabnormal young due
todamage tothe male and/orfemale gametes ,
(ii) interference with preimplantation and implantation stages in
the development ofthe conceptus , ■.
i
(iii)toxic effects onthe embryo ,
(iv) toxic effects onthe fetus ,
•• • • \t* •'
(v)/. changes inmaternal physiology producing secondary effects on
embryo orfetus ,
(vi) effects onuterine orplacental growth ordevelopment , .
(vii )interférence with parturition .
(viii )effects onpostnatal development and suckling ofthe progeny , N
•and onmaternal lactation ,
1(ix) late effects onthe progeny .
SPECIFIC GUIDELINES - ,
/ ' ' '•
Inthe interpretation ofthe following notes for guidance itmust be
appreciated that they are not rigid requirements and may not beuniversally
applicable .Interpretation should therefore beflexible andrelated to v
the proposed use ofthe drug ;justification for choice ofstudies must be
given . -
1.SELECTION 0FSPECIES
Embryotoxi city studies should normally beconducted ontwo mammalian
species one ofwhich should beother than arodent .Fertility and
perinatal studies should beconducted inatleast one species .
Where metabolism ofadrug inaparticular species isknown tobe
similar tothat inman,i'tisdesirable toinclude this species.'
Itisdesirable that one ofthe species isthe same asinthe long
term toxicity studies .Studies inathird species may behelpful if
conflicting results are obtained intheinitial two species .The
species andstrains used inthe studies should bespecified .
(4)
y

-51-
2.DOSAGE
Dosing should normally beconducted atthree dose levels .
The high dose usually should besuch that evidence ofsome maternal
toxicity isproduced ,for example decrease inbody weight gain .The
low dose should besufficient toproduce apharmacodynamic effect
similar tothedesired therapeutic effect ,ortoproduce blood levels
comparable tothose required toproduce theeffect (this does not apply
ifthe pharmacodynamic effect byitself will cause toxicity ).The
intermediate dose should bethe geometric mean ofthe high and lowdoses .
Dosing should beconducted bythe proposed route orroutes ofclinical
administration .
Dosing schedules for investigation ofdrug effects onreproduction should
normal lyinclude
(a)embryotoxi city studies ;dosing throughout the period ofembryogenesis
(organogenesis )intwo species one ofwhich should beother than a
rodent , ^
(b)afertility study should beconducted inatleast one species .
Dosing should commence inmale and female animals atasufficient
time before the proposed mating sothat anyeffects ofthe drug on
gametogenesi scould berevealed .Dosed animals may bemated with
dosed partners but inthe event ofpositive findings ofareproductive
defect then the study should berepeated using dosed animals mated
with undosed partners .After mating the dosed females should continue
tobedosed throughout pregnancy .
v
Half the females should bekilled during gestation ,preferably
some days before the expected date ofparturition ,and the fetuses
removed byCaesarean Section and examined .The remainder ofthe
females should beallowed tolitter normally andreartheir progeny .
(c)Perinatal studies should beconducted inatleast one species .Dosing
should cover the period ofgestation from the end oforganogenesis to
parturition and should extend throughout the period oflactation upto
weaning .
3.NUMBERS OF ANIMALS
Anadequate number ofanimals should beused ateach dose level toenable
valid assessments tobemade .With the exception ofprimates ,the
following minimum numbers per dose level are suggested :
(a)Embryotoxi city studies :20pregnant females inrodents ,
12pregnant females innon-rodents ;
(b)Fertility studies :24females and 24males ;
'(c)Perinatal studies :12pregnant females .

-52-
Where athird species isused itissuggested that adequate numbers
6fdosed animals should beused together with controls toallow aclear
conclusion tobedrawn from the study .
4.HOUSING AND DIET
»
Full details ofthe housing and caging conditions ofthe animals must
begiven .Thefull specification ofthediet (including additives )
must beprovided .
5.PHARMACOKINETICS
Intheconduct ofreproduction studies "account should betaken ofthe
pharmacokinetics ofthe drug inthe pregnant animal .The level of
exposure ofthe fetus tothe drug should have been determined asfar
asthis istechnically possible .
6.EV ALUATIONS
(a)Examinations should bemade ofthe fetuses "from the animals dosed
during the period ofembryogenesi s.Animals should bekilled andthe
fetuses removed byCaesarean Section .Inthese animals the numbers
ofcorpora lutea ,implantation sites (visible andthose determined
byspecial techniques e.g. bythe Salewsky method ),resorptions ,
the weight and sex oftheir individual fetuses should berecorded .
The individual fetuses should beexamined for external abnormalities
and adequate examination ofthe skeleton orviscera orboth made on
all fetuses .Where obvious abnormalities are found further appropriate
examination should beconducted .Special attention should bepaid to
abnormally high numbers ofresorptions asthis might indicate the
need forfurther studies for teratogenic effects inthe early stages
ofpregnancy .
(b)Inthefertility study females killed during the period ofgestation
should have their fetuses delivered byCaesarean Section and the
following information should berecorded :number ofcorpora lutea ,
implantation sites ,resorptions ,weight and sex ofindividual
fetuses .All individual fetuses should beexamined for either skeletal
and/orvisceral abnormalities .
From animals dosed during thefertility study and allowed tolitter
normally and rear their progeny tothe stage ofweaning ,alarge
enough number ofprogeny toallow for the subsequent investigations
should beallowed tolive and reach maturity .Late effects ofthe
drug onthe progeny interms ofauditory ,visual and behavioural
impairment should beassessed .Reproductive function should be
determined inthe progeny byallowing atleast one male and one
female from each litter ofdosed animals tobreed and produce onelitter
(brother /sister mating isnot envisaged ).
(c)The females dosed through the pre-andpost-natal period sho.uld be
allowed tolitter spontaneously andthe progeny examined atweaning .
All animals killed atthe end oflactation should besubjected to
athorough autopsy examination .Under certain circumstances

-53-
some ofthe progeny may beallowed tolive and reach maturity so
that their reproductive capacity could beassessed ,andother .
late effects ofthe drug onthe progeny interms ofbehavioural ,
visual and auditory impairment determined .
7.CONCLUSIONS
The investigator isrequired todraw overall conclusions from the results
ofthese studies indicating either
(a)there isnoevidence ofadverse effects ofthedrug onreproductive
function ,or
r
(b)there isevidence ofadverse effects onreproductive functionCs )
tobespecified ,
or
(c)the data are inadequate todraw conclusions .
Ifparticular studies have been omitted the investigator should justify
the omission .
APPENDIX
Duration ofgametogenesis .
Inrodent studies dosing ofthe male should befor aminimum of60days
andthe female for aminimum of14days prior tomating .Animals should
beabout 40days ofage atthe commencement ofdosing .Inthe present
stage ofknowledge these times would beregarded asacceptable .

ANNEX IV:CARCINOGENICITY
Note for Guidance concerning the application ofthe Annex ofDirective
75/318/EEC,2ndpart ,Chapter I,E,with aview tothegranting ofa
marketing authorization for anew drug . %
The strongest evidence that acompound isacarcinogenic hazard for manis
epidemiological although most known human carcinogens are found tobe
carcinogenic for experimental animals .There isnoevidence that all substan'
ces which are carcinogenic for animals are also carcinogenic for man,but
itisdifficult todeclare any compound asbeing non-carcinogenic for man
when ithas been shown tobecarcinogenic inanimal studies .
Extrapolation tomanisadifficult ,sometimes arbitrary ,procedure ,and the
ideal would betoanalyse the mechanisms involved inincreasing the incidenc
ofthe experimental tumours and todetermine whether such mechanisms invol­
ving specific biochemical pathways andthe formation ofthe proximate carci­
nogen would beapplicable toman.Thecriteria onwhich extrapolation is
based may vary with the agent under consideration ,itsprojected use,dosage
and mode ofadministration onthe one hand,and the species ,sites ,incidence
oftumours and required test dosage ,onthe other . . •
The likelihood ofcarcinogenic risk inman isincreased ifthere isahigh
yield ofmalignant tumours involving aspecific tissue when thetest animal
isgiven thetest substance bythe route tobeused inman and atadosage
equal toorlower than that which induces minimal toxicity .However ,since
there isnogood evidence ofathreshold •level ,anincrease inyield of
benign tumours ,ormalignant tumours athigher dosage ,orreduction of
latency should beinterpreted asconstituting apossible risk for man..In
such circumstances the agent isgenerally regarded asless potent and the
risk may more easily bereconciled with benefits associated with the thera­
peutic use ofthe compound .
1.REQUIREMENTS FOR CARCINOGENICITY STUDIES
. *Carcinogenicity studies will usually berequired inthe following
circumstances : ,
(a)When the medicine islikely tobeadministered regularly ,over a
substantial period oflife (continuously during aminimum period of
6months ,orfrequently inanintermittent manner sothat thetotal
exposure issimilar ). .-
.I .
or (b)Where asubstance has achemical structure that suggests acarcino­
genic potential
or (c)Where asubstance causes concern due to •
/ . '
(l) .Some specific aspects ofitsbiological action (ega >
therapeutic class ofwhich several members have produced
positive carcinogenic results ).
(ii)Itspattern oftoxicity orlong term retention (ofdrug or
metabolites )detected inprevious studies .
(iii)The findings inmutagenicity tests and/orshort term
carcinogenicity tests .

-55-
«τ
Carcinogenicity testing may not beregarded asnecessary where the
substance inquestion will beused only inpatients with aLife
expectancy shorter ,than that inwhich achemical might reveal any
carcinogenic hazard inman.Ifcircumstances alter and adrug of
the latter variety were used inless serious conditions then
carcinogenicity testing would become necessary .Insoluble substances
which are not absorbed may not require formal carcinogenicity studies .
2.5PECIES AND STRAIN SELECTION
Where carcinogenicity studies are required they should normally be
conducted ontwo species .The metabolic handling ofthe drug should be
known inthe species used and should preferably show similarities tothe
metabolism inman.Cognisance should betaken ofknown species andstrain
responses with similar chemicals .Species andstrains with ahigh inci­
dence of .spontaneous tumour formation should normally beavoided .Those
undertaking the study should select species andstrains known tobe
-sensitive toone ormore carcinogens .Positive controls will not be
required routinely but the spontaneous tumour incidence ofthe strains
used should berecorded .
3.DOSAGE
(a)Route and frequency ofdosing
Where possible ,dosing should beconducted bythe proposed clinical
route ofadministration .Where relevant ,evidence ofabsorption
should beprovided .The frequency ofdosing normally will bedaily .
(b)Dose levels .
Carcinogenicity testing should normally beconducted at3dose levels .
The top dose should produce aminimum toxic effect ,for example a
10 %weight loss orfailure ofgrowth ,orminimal target organ
\ toxicity .Target organ toxicity will bedemonstrated byfailure of
physiological functions andultimately bypathological changes .The
lowest dose should beofthe order of2-3 times the maximum human
therapeutic dose orthe dose that produces apharmacological effect
inanimals .The middle dose should bethe geometric mean ofthe high
and low dose .
Exceptions tothese principles may occur ,for example where thetoxic
dose ofthe drug isahigh multiple ofthetherapeutic dose ;inthese
circumstances itisacceptable ifthe top dose issetatapproximately
100times the human therapeutic dose,where technically feasible.'
4.PRACTICAL FEATURES - . * \
Animals should beingood general health initially andthis should be
maintained throughout the study .High standards ofanimal husbandry are
essential .Special precautions arenecessary when inhalational orvolatile
carcinogens are being tested .
Thepharmaceutical quality ofthebatchCes )used should beclearly
characterised .

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(a)Age ofanimals atcommencement ofstudy
Carcinogenicity studies should commence assoon aspossible after
.weaning i.e. assoon asthe animals are accustomed totheir diet
and surroundings . ,
(b)Duration ofstudies '
The currently recommended practice istoconduct studies for 24months
inrat and 18months inthe mouse and hamster .Where the survival
rate ishigh there may beadvantages inextending studies for 30
months intherat and 24months inthe mouse orforthe lifespan of
the animals i.e. to20 %survival inthe controls .
(c)Number ofanimals per group
For routine tests with mice ,rats and hamsters itissuggested that
for each sexthere should be50animals per treated group ,and two
control groups of50for each sex dosed with the vehicle bythe same
route (inmost cases the drug will beadministered inthe diet ).
(d)Composition ofdiet ' '
Commercial diets are variable and steps should betaken toprovide
asuniform adiet aspossible throughout the duration ofthe
carcinogenicity study .Full specification ofthediet should be
given .
5.ADDITIONAL M0NIT0RING
Carcinogenicity studies should bedesigned toobtain the maximum amount
ofinformation from the animals used but any investigations undertaken
toelicit additional toxi cologi cal data should not prejudice the prime
purpose ofevaluating adrug 'scarcinogenic potential .Information on
absorption ,distribution and metabolism ofthe drug and onwhether the
drug accumulated orwas anenzyme inducer should have been determined
during other toxicity studies . 1
6.STATISTICAL DESIGN OF STUDY '
Anappropriate experimental design should beselected and inparticular :
(i) The cages containing the animals inthe treatment and control
groups should bedistributed Within the animal house soasto
eliminate bias due totheeffects ofany local environmental
,factor . •
(ii)Animals should beallocated atrandom tothe various experimental
units (e.g. cages )and the method used toachieve this randomisation
should beclearly stated .
(iii)Ifforpractical reasons ofhandling such Large numbers ofanimals
itisdecided tostagger thestart ofthe study itisdesirable that
all groups should berepresented ateach start inequal numbers .
Ifthe study isconducted using astaggered start the times at
which the various batches ofanimals enter the study must bestated .

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7.TERMINAL INVESTIGATIONS
7.1 Autopsy
Afull autopsy should bemade onall animals dying during the study
orkilled because oftheir poor condition .
Atthe conclusion ofthe study all surviving animals should be
sacrificed and afull autopsy conducted oneach animal .Previously
demonstrated toxic effects may indicate particular topics for
investigation .Haematologi cal and biochemical investigations may be
helpful inthe interpretation ofany lesions found .
7.2 Histopathology
7.2.1 Carcinogenicity screening :
(i)Microscopical examination should becarried out onall
listed tissues and organs from all high dose animals and ,
from all controls , '
and
(ii)tissues from any animal inany group inwhich macroscopi cal
7lesions ofany kind are found atautopsy ;
Ifthe results from (i)indicate that tumours occur inone
ormore organs ortissues ,then
(iii )those tissues and organs should beexamined inthe mid-
and low-dose groups even when macroscopically normal .
All listed tissues should bemicroscopically examined from
all animals dying orkilled during the course ofthe
study .
7.2.2 Toxicity screening :
Previously demonstrated toxic effects may indicate parti­
cular aspects for investigation .
Haematologi cal and biochemical investigations may be
helpful intheinterpretation ofany lesion found .
Particular attention should bepaid tothesite of
application ifthe drug isadministered other than by
the oral route .,
8.PRINCIPLES OFREPORTING ONCARCINOGENICITY STUDIES
8.1 Definitions
Aneoplasm (tumour )isregarded asapopulation ofabnormal cells
with uncontrolled andusually increased proliferative activity and
other less well-defined morphological andfunctional features .
Amalignant neoplasm isone which invades surrounding tissues or
metastasises .Ingeneral terms ,the tumour isconsidered tobe
benign ormalignant onthebasis ofitshistopathologi calappearances
andthe correlation bythepathologist ofsuch changes with

-58-
biological behaviour known from previous experience tooccur in
tumours displaying comparable characteristics .
Tumours should bedescribed inconventional histopathological terms
according to.well-defined -classi.fi cations (e.g. W.H.O. ).
8.2 Présentation ofthe data
Inthefirst instance the findings should besummarised for each
treatment group and each control group .separately ,keeping the
sexes separate ,interms of: '
.1.Number ofanimals examined andtheir individual gross and
i microscopic examination ;
2.Numbers (andpercentages )ofanimals with tumours ofeach identi­
fied type inaspecified tissue ,distinguishing malignant from
benign tumours ,wherever possible ; '
3.For animals with one ormore tumours ofthe same ordifferent type,
afrequency distribution ofthetotal number oftumours found in.
the animal ;and another ofthetotal number ofmalignant tumours
found inthe animal .Ifthe tumours cannot beenumerated some
grading ofmultiplicity oftumours should beused instead ;
4.Time toeach interim death ;♦ '
t5.Time ofappearance ofany mass (starting from clinical palpation )
anditsprogress ,aswell asits eventual histopathology .
9-ANALYSIS OFTHE DATA
The form ofthe analysis and thetests ofstatistical significance used
should beappropriate tothe type ofdata andtothe basic experimental
design .Thestatistical procedures used should beclearly stated .
The responses should beassessed inthe following Ways :
(i) Thetotal incidence oftumour bearing animals .
(it) The total incidence oftumours .
; 1 . ' ix ,
(m)The incidence oftumours involving aspecific tissue .
(iv) The incidence oftumours judged tobemalignant .
(v) The latent period totumour appearance (using actuarial '
approaches ). : • v .
The analysis should bedirected towards :
(a) the assessment ofthe presence ofanyeffect ofthe substance
under study ,asshown bythe contrast between the response in
the 3treatment groups ,asaset,andthe response inthe 2
control groups ,asaset.

-59-
(b) the assessment ofwhether anyeffect isdose-related ,as
shown byatrend inthe responses inthe Low,middle and high
dose groups .This assessment isstatistically independent of
that in (a).
Professional statistical advice should beavailable inorder toassess
the influence ofother factors ,such asdeath oftest animals because
ofother diseases ,and premature killing ofanimals because ofclinical
detection oftumours .Theparticular tests ofstatistical significance
which should beused inassessing the presence ofaneffect oradose-
relationship areintentionally not specified .The data inone
experiment may require adifferent approach from the data inanother .
Thetest substance should beregarded ashaving thepotential toincrease
the risk ofneoplastic change ifany ofthe above responses ismaterially
increased (orthe latent period ismaterially decreased ).The compound may
beregarded aspossessing more powerful activity for the animal ifseveral
ofthe above responses are affected andifthere isevidence ofadose-
response aswell asthe presence oftheeffect .Araised incidence of
tumours intreated ascompared with control animals isofsignificance
whatever the mechanism postulated ordefined for the development ofsuch
tumours ,but anyparticular circumstances should beidentified orremarked .
Examples include known pathways which may bepeculiar toone species
(griseof ulvin and porphyrin metabolism inthe mouse ),severe stimulation
ofendocrine glands (especially inthe dog),orthe development of
physical features peculiar only tothetest spec/ies (vesical calculi in
the rat). r ■
Different circumstances may result in:
(i) anincreased incidence orreduced latency ofmalignant tumours
(ii) anincreased incidence ofbenign tumours
(iii ) local induction oftumours atthe site ofinjection .
10.USE OFSHORT-TERM CARCINOGENICITY STUDIES ,
Evaluation ofnew compounds inamutagenicity screen isdesirable .
However ,available techniques involving short-term testing ofchemicals
for mutageni city /carcinogeni city are not capable ofreplacing formal
carcinogenicity testing inanimals asameans ofevaluating adrug's
carcinogenic potential .Short-term studies giving positive results will
always indicate the need for formal carcinogenicity studies ifthe drug
istobedeveloped further ;those giving negative results donot preclude
the need for formal studies ,when these are advisable for the reasons given
inparagraph 1above .
11.CONCLUSIONS
Conclusions from these studies should bedrawn bythe investigator .

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APPENDIX
List oftissues tobestudied ,histologically inacarcinogenicity study
-gross lesions
-tissue masses ortumors (including regional lymph nodes )
-blood smears (incase ofanaemia ,enlarged thymus ,lymphadenopathy )
"lymph nodes '
-mammary glands
-salivary glands
-sternebrae ,femur orvertebrae (including bone marrow )
-pituitary -
-thymus
-trachea
-lungs
-heart
-thyroid
-oesophagus
-stomach
-small intestine (Swiss roll method )
-colon "• v
-liver
-gallbladder , ■
-pancreas
-spleen
-kidneys
..S-adrenals
-bladder
-prostate
-testes -
-ovaries
-uterus
-brain (coronal sections atthree levels )
-eyes
-spinal cord

-.61-
ANNEX V:.PHARMACOKINETICS AND METABOLIC STUDIES INTHE SAFETY EV ALUATION
======== OF NEW DRUGS INANIMAtS : ! : !
Note 'for Guidance concerning theapplication ofthe Annex ofDirective
75/318/EEC,2ndpart,Chapter I,Fand G,with aview tothegranting of
amarketing authorization for anew drug .
1. INTRODUCTION
<4
These notes areconcerned with thetime course oftheabsorption ,distribution and excretion ofnew drugs and with their metabolism in
relation totheir safety .For many steps inthe evaluation ofadrug
such data areessential ,for example :
(a) toassess the levels ofthe drug and ofits metabolites
andtheir kinetics inblood ,body fluids' and organs ;
1" ' -.ΐ"'
(b) toobtain information onthe relationship between target
organ toxicity and the blood ,body fluids and organ
concentrations ofthe drug;. '
,(c) toassess thepossibility ofenzyme induction and of ,
cumulation ofthe drug with repeated administration ;
*,
(d) .tochoose where possible the animal species tobeused in ''
toxi cologi cal studies onthe basis oftheir similarity to
man inhandling the drug ,and todetermine the relevance
ofthese toxicity studies toman.
2. DRUG SPECIFICATION
Specification ofthe physical and chemical properties ofthe drug
substance must begiven and thestability ofthe preparation should
beprovided . :
When alabelled drug isused theposition ofthe label inthe
molecule' and the specific activity ofthe material must bestated .
Consideration should begiven when selecting the position ofthe
label toits likely metabolic fate .
3.' METH0DS -,
Data onthe levels ofdrug andmetabolites inblood ,body fluids ,
organs and intheexcreta can beobtained byphysical ,chemical or
biological methods .Theinvestigator should justify thedetails of
the methods used,their validity andreproducibility ,including the
specificity ,precision and accuracy .(The study ofthe time course
ofits pharmacodynamic effects may provide useful additional
information ). '
When using labelled drugs attention must begiven tothefact that
the measured label inbody fluids may not correspond tothat ofthe
unmodified drug,but may include labelled metabolites and conjugates .
Attention should begiven tothepossibility ofisotope exchange
with endogenous compounds .

-62 "
4. SPECIES ,
The animal species inthese studies usually should bethose normally
used inthe laboratory for pharmacological and toxi cologi cal
investigations .The reasons for selection ofany other species
should begiven .
Apreliminary study ofkinetics and metabolism ofthe drug inafew
human subjects could provide useful information inchoosing the
animal species tobeused inrepeated dose toxicity studies .
5. DRUG ADMINISTRATION
Doses and routes ofdrug administration should berelated when
possible tothe proposed clinical use ofthe drug .One of -the routes
selected should ensure the absorption ofthe drug ifthis isrelevant
tohuman usage . „ ■' 1 i
6. PRESENTATION OF RESULTS
Information should bepresented onthe following items :
(i)absorption (fractional absorption ,kinetics );
(ii)distribution inthe principal organs andtissues and the
time course inbody fluids ;
(iii) blood ,plasma orsérum half life ;
(iv)plasma protein binding ;
(v) characterization ofthe pattern ofmetabolites inexcreta ,
and where practicable ,identification ofmajor metabolites ;
(vi) route and time course ofexcretion ofdrug and metabolites ;
(vii )ifbiliary excretion isamajor route ofelimination ,then
■thepossibility ofenterohepati crecycling should be .
investigated ; /
>(viii ) aquantitative account ofthe fate ofthe administered dose
should beattempted ; '
« - ,
(ix)possibilities ofenzyme induction should beinvestigated .
Ifenzyme induction isfound its relevance inthe context
^ oftheproposed useofthe drug should beexamined .
7. CONCLUSIONS
Appropriate conclusions should bedrawn from these studies inthe
context ofthe objectives indicated inparagraph 1. '(v)
(vi)

63
ANNEX VI:FIXED COMBINATION PRODUCTS
Note for Guidance concerning the application ofthe Annex ofDirective
75/318/EEC,3rdpart,Chapter II,C2,with aview tothegranting of
amarketing authorization for anew drug .
1.JUSTIFICATION .
Applicants will berequired tojustify theparticular combination of
active ingredients proposed .Fixed combination products will only be
considered acceptable ifthe proposed combination isrational and based
onvalid therapeutic principles .
For any individual combination itwill benecessary toassess thepotential
advantages intheclinical situation against possible disadvantages ,in
order todetermine whether the product meets the requirements ofthe Norms
and Protocols with respect toefficacy^and safety .
Potential advantages offixed combinations include :
1.animprovement inthe therapeutic /toxic ratio ,e.g. asaresult ofthe
potentiation ofthe therapeutic effect ;
2.simplification oftherapy ,resulting inimproved patient compliance .
Disadvantages offixed combinations include :
1.the fact that even acombination which meets the need ofthe average
patient isunlikely tobeideally formulated for the needs ofthe in­
dividual ;
2.accumulation ofadverse reactions .
Combinations may not beconsidered rational ifthehalf-life and/orthe
duration ofaction ofthe components differ significantly ,butthis may "
notnecessarily apply where itcan beshown that the combination is
clinically valid despite differences inthis respect e.g.,ifone compo -.
nent isintended toenhance absorption ofthe other orwhere the components
are intended toexert their effects successively .
The inclusion ofaningredient tocounteract anadverse effect ofone of
theother components may beconsidered justified but bnly ifthe adverse
reaction isacommonly occuring one.
The inclusion ofacomponent intended toproduce unpleasant side-effects
asameans ofpreventing abuse isundesirable .
Substances having acritical dosage range oranarrow therapeutic index
areunlikely tobesuitable for inclusion infixed combinations .
2.INDICATIONS .
The indications claimed for a"fixed combination product should besuch
that each component isneeded for each indication .The product should be
formulated sothat the dose andproportion ofeach component present is
appropriate toall the recommended uses .

• -64-
Clearly ,an"indication "must beawell-recognized disease state ,dysfunc­
tional state ,syndrome orpathological entity .The individual components
ofafixed combination may beintended torelieve simultaneously different
symptoms ofsuch adisease state ,butitwill not beproper toregard each
individual symptom asanindication for the fixed combination ,since itmay
also occur inother diseased and fortreating this symptom alone the other
constituents may beirrelevant .
3.SAFETY AND EFFICACY
Adistinction must bemade between those fixed combinations which correspond
closely tocombinations which are already inwidespread use provided these
are thoroughly and reliable documented ,and those combinations which are
essentially new (either because the drugs involved are hot usually combined
because the quantitative composition isunusual ,orbecause one ofthe
components isentirely new).
Safety studies inanimals with fixed combinations should asageneral rule
have been performed with the-active ingredients inthe proportions present
inthe product .Such studies will not berequired where all the components
have been extensively and safely used inhumans inidentical orvery simi-.
lar combinations for along period and the safety ofsuch combinations is
well-documented .
Both theefficacy andthesafety of,afixed combination product should have 4,
been investigated inman.For well-recognized combinations well-founded
bibliographical data will'be acceptable insome cases .Itwill beneces­
sary totest anew combination clinically against one ormore ofthe com­
ponents inorder todefine the role played byeach inthetotal .
4.INTERACTIONS
Thepossibility ofinteractions between the components should always be
considered .Where apharmaceutical ,pharmacokinetic orpharmacodynamic
interaction appears possible ,the applicant should submit data either to
establish that such interaction does not occur ,orthat itisclearly
recognized and defined .
5.ADVERSE EFFECTS'
Where there are grounds toexpect that afixed combination product may be
substantially more harmful .orgive rise tomuch more frequent adverse ef­
fects than any individual components given alone ,the applicant should
provide evidence that this does not occur intherapeutic use,orthat the
advantages ofthe combination ,e.g. increased efficacy ,outweigh such
disadvantages . . .
6.DOSAGE
The combination product must besafe andeffective throughout the whole
ofthe recommended dosage range . „
7.COMBINATION PACKS /
Theprinciples applicable tofixed combination products will also beapplied
inthe assessment ofpreparations consisting ofdifferent medicinal products
,incombination packs where the products are intended for simultaneous or
sequential administration . . : , ■'
8.CHEMICAL COMBINATIONS AND COMPLEXES -' •
Substances ofthis type which dissociate prior toabsorption into two or
more active components may beregarded for the application ofthe previous
provisions asfixed combinations ofthese substances ;rather than aschemi­
cal entities . '

-65-
9.LABELLING
Thepresentation andlabelling ofafixed combination product should be
such that itisclear tothe prescriber orpurchaser that the product
contains more than one active ingredient and the pharmacological nature
ofthe active ingredients should beclearly stated inappropriate terms .