regulatory guidance on bioavailability and bioequivalence studies

8/9/2019 Regulatory Guidance on Bioavailability and Bioequivalence Studies

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Regulatory Guidance onBioAvailability and

BioEquivalence Studies

FDA and EMA Guidances


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Outline

• Overview of BA and BE studies

• Methodology

–! studies

– "n#vitro studies

• BE $o%&arisons

• Additional considerations• General ! study design

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Bioavailability Studies

• 'o deter%ine the rate and &rocess by which the activeingredient in drug is absorbed and %oves to site of action

– Develo& a syste%ic e(&osure &ro)le by %easuringdrug*%etabolite concentration over ti%e

– +sually &art of ",Ds -investigational new drug. and ,DAs

– Assess &erfor%ance of for%ulations used with regards to safetyand e/cacy

– Serves as a bench%ar0 for subsequent BE studies

– rovide info on distribution1 eli%ination1 dose &ro&ortionality1linearity1 in2uence of en3y%es and trans&orters


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Bioequivalence Studies

• 'o establish the absence of a signi)cant di4erence in the rateand &rocess to which the active ingredient in drug equivalentsbeco%es available at the site of drug action

– $o%&are syste%ic e(&osure &ro)le of a test drug &roduct vs5reference drug &roduct -R6D.

– Active drug ingredient or active %oiety in test &roduct %uste(hibit sa%e rate and e(tent of absor&tion as R6D

– Serves to docu%ent &roduct quality

– More for%al co%&arison with &re#s&eci)ed criteria and li%its

– "f test &roduct levels are too high co%&ared to reference1 concern

is around safety of test &roduct – "f test &roduct levels are too low co%&ared to reference1 concern

is with thera&eutic e/cacy of test &roduct

– "f variability of test &roduct rises1 the concern is both safety ande/cacy

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Bioequivalence Studies

• ro&er %a&&ing of dose#res&onse or concentration#res&onsecurves are i%&ortant &articularly when the test drug &roducthas levels that are higher or lower than the R6D

– Studies with doses above the reco%%ended thera&eutic dosesai% to de%onstrate that the increase in &las%a levels are not

acco%&anied by additional ris0

– Studies with doses below the reco%%ended thera&eutic dosesai% to de%onstrate that the reduced levels of the test &roductco%&ared to the R6D are associated with adequate e/cacy

• +sually included in ,DA1 A,DA -generics.1 or &ost#a&&roval

sub%issions – BE studies are a critical co%&onent of A,DA sub%issions for

de%onstrating the BE between a &har%aceutically equivalentgeneric drug &roduct and the corres&onding R6D

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Methodology

• Methods to establish BA*BE -in orderof &reference.7 – !

– D

– $linical

– "n vitro

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– Most co%%only rely on ! %easures such as A+$ and $%a(

– 'y&ically cross#over design

• ,on#re&licate reco%%ended for i%%ediate#release and %odi)ed#release dosage for%s

• Re&licate 8 at least one treat%ent is re&eated in the sa%e sub9ect

• ,on#re&licate 8 no treat%ent is re&eated in the sa%e sub9ect

– Advantages of re&licate studies

• Allow co%&arisons of within sub9ect variances for test andreference

• rovide %ore info about intrinsic factors underlying for%ulation&erfor%ance

• Reduce the nu%ber of sub9ects in BE study

– +nder fasting conditions because fasting is considered %ostsensitive to detect for%ulation di4erences

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PK Studies


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! Studies -continued.

• Study &o&ulation – Si%ilar &ro&ortions of each se( in study

– "nclude as %any sub9ects :;< years in age for elderly studies

– Statistical analysis of subgrou&s not reco%%ended

– Restrictions on enroll%ent need be based on safetyconsiderations

– =ealthy sub9ects1 but %ay be a&&ro&riate to enroll &atientsde&ending on drug*dose

– -EMA. =ealthy volunteers is adequate and results can bee(tra&olated to &o&ulations for which &roduct is a&&roved in-elderly1 children1 etc.

– referably with BM" of >?5@#


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! Studies -continued.

• Single Dose studies are reco%%ended

– 'hey are %ore sensitive in assessing release of drug substancefro% drug &roduct into syste%ic circulation

• A+$ and $%a( are %ost co%%on %easures of BA*BE

–Early e(&osure7 &artial A+$ at '%a(

– ea0 e(&osure7 $%a(

– 'otal e(&osure7 A+$last1 A+$inf1 A+$tau -MD.

• Assu%e that variability arise %ainly fro% for%ulationfactors

• ilot studies are co%%only conducted before a full BE studyto validate analytical %ethods1 assess variability1 deter%ineti%e&oints of %easure%ent1 etc5

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"n#Citro Studies

• Dissolution test is used as a tool to identify for%ulationfactors that are in2uencing and %ay have a crucial e4ecton the BA of the drug

• +sed to assess batch#to#batch quality

• 'o establish an in vitro#in vivo correlation• $an be used to waive a BE study

– Such as highly soluble1 ra&idly dissolving orally ad%inistered&roducts

• S&eci)c info is required to be included in re&ort including

– &= solubility &ro)le – Dissolution &ro)les at di4erent agitation s&eeds

– Dissolution &ro)les in at least di4erent dissolution %edia-varying &=.

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BE $o%&arisons

• Reco%%ended a&&roach

– A criterion to allow co%&arison

– A con)dence interval for the criterion

– A BE li%it

• 6og#transfor%ation reco%%ended

• +se of an average BE criterion to co%&are BA %easures

• "n vivo study is reco%%ended for all solid oral for%s

• aiver for in vivo can be granted given

– 'he drug is in the sa%e dosage for%1 but di4erent strength

– 'he strength is proportionally similar to the strength of &roductwhich an in vivo study has already been conducted -ty&ically thehighest strength.

– 'he new strength %eets an a&&ro&riate in vitro dissolution test

– Oral solutions1 eli(irs1 syru&s1 etc5

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BE $o%&arisons

• ro&ortionally si%ilar is de)ned as

– All active*inactive ingredients are in e(actly the sa%e &ro&ortionbetween di4erent strengths

– "f not e(actly &ro&ortional btw strengths1 the ratios of inactiveingredients to total weight of dosage for% are within li%its

de)ned by S+A$#"R and S+A$#MR guidances – For high &otency drugs where the a%ount of active drug

substance is relatively low

• the total weight of the dosage for% re%ains nearly the sa%e for allstrengths -within *#>


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BE $o%&arisons

• Sus&ensions

– Both in vivo and in vitro studies are reco%%ended

• "%%ediate#release &roducts7 $a&sules and tablets

– A single#dose1 fasting study is reco%%ended

– "n vivo BE studies and in vitro dissolution &ro)les on all strengths

– S&eci)c guidance on &rea&&roval and &osta&&roval waivers of invivo BE studies

• Modi)ed#release &roducts -delayed or e(tended release.

– Delayed#release7 coatings are intended to delay release of%edication

• "n vitro dissolution tests should show they are stable under acidic conditions anddrug is released only in a neutral %ediu%

– E(tended release7 allow for reduction in dosing frequency

– Sub%it as ,DA for )rst %odi)ed#release drug &roduct followinga&&roved i%%ediate#release &roduct

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BE $o%&arisons•

-EMA. Strengths to evaluate de&ends on linearity of ! of activesubstance

• ! is considered to be linear if di4erence in dose#ad9usted %ean A+$sis no %ore than @ between di4erent strengths

• "f linearity is de%onstrated1 it %ay be su/cient to establish BE withonly one strength

•For drugs with linear !1 selection of a lower strength than the highestis also acce&table to &erfor% BE study5

– e5g5 if highest strength cannot be ad%inistered to healthy volunteers forsafety reasons

• For drugs with non#linear !

– "f %ore than &ro&ortional increase in A+$ with increasing dose1 BE studyshould be conducted at the highest strength

– "f less than &ro&ortional increase in A+$ with increasing dose1 BE studyshould be conducted at the highest and lowest strengths

• hen BE assess%ent at %ore than strengths is needed1 it isacce&table to conduct BE studies at the highest and lowest strengths

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Additional $onsiderations•

Food e4ect studies – A single#dose1 two#&eriod1 two#treat%ent1 two#sequence crossover

study is reco%%ended

• Measure%ent of %oieties

– For BA studies7 Both &arent drug and its %a9or %etabolites be%easured

• Measure%ent ta0es into account both concentration and activity – For BE studies7 Measure%ent of only &arent drug is generally needed

because concentration#ti%e &ro)le of &arent drug is %ore sensitiveto changes in for%ulation than a %etabolite

• 6ong half#life drugs

– For BE study7 A non#re&licate1 single#dose1 crossover study can be

conducted1 &rovided an adequate washout &eriod is used – "f crossover is &roble%atic1 a &arallel design can be used

– Sa%&le collection ti%e be adequate to ensure co%&letion of &assageand absor&tion of drug -# days.

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Additional $onsiderations

• 6ong half#life drug

– $%a( and truncated A+$ can be used to characteri3e &ea0 andtotal drug e(&osure

• For drugs with low intrasub9ect variability

A+$ H Ihrs can be used

• For drugs with high intrasub9ect variability

,eed to be cautious with A+$ truncation

• First &oint $%a(

– "nsu/cient early sa%&ling ti%es %ay lead to inaccurate%easure%ent of true $%a( if the )rst &oint is the highest &oint

in a concentration#ti%e curve – ilot study %ay hel& avoid &roble%

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General ! Study Design•

+nder fasting conditions1 unless food#e4ect study• -EMA. For &roducts with s&eci)c for%ulation characteristics1 BE

study should be &erfor%ed under both fed and fasted states – Either se&arate two#way crossover1 or a four#way crossover study

• =ighest %ar0eted strength be ad%inistered as a single unit

• Adequate washout &eriod -:@ half lives.

• Drug content of test &roduct cannot di4er fro% reference&roduct by %ore than @

• -EMA. At least > or %ore sub9ects in BE study

• $ollection of blood sa%&les is reco%%ended J seru% or &las%ain %ost cases

• -EMA. +rine is acce&table where it is not &ossible to reliably%easure &las%a concentration#ti%e &ro)le – should be collected over at least ti%es the half#life

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General ! Study Design

• Sa%&ling frequency and schedule

– >#>? sa%&les1 including &re#dose1 &er sub9ect &er dose isreco%%ended

– Sa%&ling should continue for at least or %ore half lives of drug

– At least #K sa%&les be obtained during ter%inal log#linear &hase

to obtain accurate esti%ate of eli%ination rate constant -L3. fro%linear regression

– Actual cloc0 ti%e when sa%&les are drawn as well as ela&sed ti%erelated to drug ad%inistration be recorded

– -EMA. Sa%&ling schedule should be long enough to ensure thatA+$


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• ! info reco%%ended for sub%ission

– las%a concentrations and ti%e&oints

– Sub9ect1 &eriod1 sequence1 treat%ent

– A+$


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• Statistical info to be &rovided for A+$


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• -EMA. For highly variable drug &roducts -=CD.1 theacce&tance criteria for $%a( can be widened to a%a(i%u% of ;N5?K#>K5>N – For $" to be widened1 %ust de%onstrate that the within sub9ect

variability for $%a( of the reference co%&ound is :


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• -EMA. 'wo#Stage Design

'wo#Stage a&&roach is acce&table for de%onstrating BE

– An initial grou& of sub9ects is treated and data analy3ed

– "f BE is not de%onstrated1 an additional grou& is recruited and

the results fro% both grou&s are co%bined in a )nal analysis• Overall ty&e " error %ust be &reserved

• Sto&&ing criteria needs to be clearly de)ned &rior to study

• lan to use two#stage a&&roach %ust be &re#s&eci)ed in&rotocol along with ad9usted al&has to be used for each

analysis• A ter% for stage should be included in the A,OCA %odel

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General ! Study Design• G6M or linear %i(ed e4ects %odel is reco%%ended

– Model should include factors such as sequence1 sub9ects nestedin sequences1 &eriod1 and treat%ent

• -EMA. Fi(ed e4ect A,OCA %odel only should be used

• For%ulation co%&arisons are &ri%arily based on &aired t test

– Only &atients who have data fro% both 'est and Reference

&eriod will be included

• "f there is no %issing data J the two %odels are equivalent

• "f there is %issing data J there can be di4erences

– 6ess data &oints will be included in the %ethod reco%%endedby EMA

• "nternally1 %i(ed e4ects %odel is reco%%ended as a defaulta&&roach5 it was found that the %i(ed e4ects %odel willhave %ore &ower

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References

• Guidance for "ndustry Bioavailability and Bioequivalence Studies for OrallyAd%inistered Drug roducts J General $onsiderations5 +S De&art%ent of =ealth and=u%an Services1 Food and Drug Ad%inistration $enter for Drug Evaluation andResearch -$DER.1 March

regulatory guidance on bioavailability and bioequivalence studies

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