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Regulatory framework on bioequivalence criteria for locally acting gastrointestinaldrugs: the case for oral modified release mesalamine formulationsGianluca Sferrazzaa, Paolo D Sivierob, Giuseppe Nicoteraa, Paola Turellac, Annalucia Serafinoa, Corrado Blandizzid

and Pasquale Pierimarchia

aInstitute of Translational Pharmacology, National Research Council, Rome, Italy; bPrincipia SGR s.p.a., Milan, Italy; cPharma Unit - pre-submissionAnalysis and Strategy, Intexo S.r.l., Rome, Italy; dDepartment of clinical and Experimental Medicine, Unit of Pharmacology and Pharmacovigilance,University of Pisa, Pisa, Italy

ABSTRACTIntroduction: Bioequivalence testing for locally acting gastrointestinal drugs is a challenging issue forboth regulatory authorities and pharmaceutical industries. The international regulatory framework hasbeen characterized by the lack of specific bioequivalence tests that has generated a negative impact onthe market competition and drug use in clinical practice.Areas covered: This review article provides an overview of the European Union and United Statesregulatory frameworks on bioequivalence criteria for locally acting gastrointestinal drugs, also discuss-ing the most prominent scientific issues and advances that has been made in this field. A focus on oralmodified release mesalamine formulations will be also provided, with practical examples of theregulatory pathways followed by pharmaceutical companies to determine bioequivalence.Expert commentary: The development of a scientific rationale to demonstrate bioequivalence in thisfield has been complex and often associated with uncertainties related to scientific and regulatoryaspects. Only in recent years, thanks to advanced knowledge in this field, the criteria for bioequivalenceassessment are undergoing substantial changes. This new scenario will likely result in a significantimpact on pharmaceutical companies, promoting more competition through a clearer regulatoryapproach, conceived for streamlining the demonstration of therapeutic equivalence for locally actinggastrointestinal drugs.

ARTICLE HISTORYReceived 16 May 2017Accepted 26 June 2017

KEYWORDSBioequivalence; EuropeanMedicines Agency; Food andDrug Administration;generic; guidelines; locallyacting gastrointestinal drug;mesalamine

1. Introduction

A generic medicine is a pharmaceutical product, which has thesame qualitative and quantitative composition in active com-pounds and the same pharmaceutical form as the referencemedicinal product, while the inactive ingredients can vary[1,2]. A generic product must be both pharmaceuticallyequivalent and bioequivalent to the reference medicinal pro-duct to allow bridging of preclinical testing with clinical trialsthat granted marketing authorization of the reference product[3,4]. Both in the European Union (EU) and United States (US),bioequivalence (BE) studies play a crucial role in the regulatoryapproval of systemically absorbed generic medicines. BE isdefined as

the absence of a significant difference in the rate and extent towhich the active ingredient or active moiety in pharmaceuticalequivalents or pharmaceutical alternatives becomes available atthe site of drug action, when administered at the same molardose under similar conditions in an appropriately designedstudy. [5]

On this basis, BE evaluations can be employed at regulatorylevel as surrogate of comparative clinical trials to demonstratethat two medicinal products are therapeutically equivalent interms of safety and efficacy profiles [5,6].

International regulatory agencies have issued recommen-dations to define the accepted methodologies for assessingcompliance to BE criteria during the development of a genericdrug. Different methodological approaches, suitable for theassessment of therapeutic equivalence, have been recom-mended by the US FDA: comparative clinical trials, pharmaco-kinetic (PK) BE, pharmacodynamic BE, and in vitro studies [7].In Europe, the accepted methods for assessing therapeuticequivalence are the same as the US ones; however, onlymedicinal products that demonstrate BE by PK studies canbe considered as generic products, while in other cases, themedicinal product can be authorized through hybrid applica-tions [4].

In general, for systemically absorbed drugs, the scientificand regulatory framework is well established and PK studiesstill represent the gold standard approach to demonstrate BEfor generic drugs [5,6]. However, when considering locallyacting drugs, with particular regard for oral gastrointestinal(GI) products, which are characterized by peculiar biopharma-ceutical properties, measuring concentrations of the activecompound at the site of action through conventional BEmethods is more difficult, or practically impossible [8–10].Therefore, pharmaceutical companies, who intend to developa generic product, must identify the most appropriate

CONTACT Gianluca Sferrazza [email protected] Institute of Translational Pharmacology, National Research Council, Via Fosso del Cavaliere 100,Rome 00133, Italy

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equivalence methods to ensure a sensitive and accuratedetection of putative in-vivo differences between the testand originator product. In this context, the development of aregulatory strategy has been more complex than for systemicabsorbed drugs, and it has been often associated with uncer-tainties related to scientific and regulatory aspects. Theseissues have strongly affected the availability of GI genericproducts in the pharmaceutical market, thus reducing compe-tition and economic savings for both patients and NationalHealth Services [11].

Based on the above background, the aim of this reviewarticle is to appraise the state of the art of the regulatorybases underlying the assessment of BE for medicinal productsacting locally in the GI tract, highlighting the advances made inEU and US. However, as drugs belonging to this class arecharacterized by peculiar pharmaceutical and clinical features,we will focus on products that have been frequently associatedwith challenges related to BE testing, such as oral modifiedrelease mesalamine (5-aminosalicylic acid [5-ASA]) and steroidsformulations. Indeed, 5-ASA displays a complex biopharmaceu-tical profile that reflects the majority of issues associated withthe demonstration of BE for locally acting GI products. Thesuitability of clinical efficacy or PK studies for assessing BE oforal 5-ASA formulations has been matter of debate, with muchdiscussion revolving around their potential correlation withlocal concentrations achieved by 5-ASA at the site of action,or even its release behavior from oral formulations throughoutthe GI tract [8–12]. Only in recent years, thanks to the scientificand regulatory advances made in this field, the criteria for BEassessment of locally acting GI products are undergoing sub-stantial changes, mainly in EU. Novel BE criteria have beenrecommended by regulatory agencies and several researchactivities have been promoted to develop alternative methods,suitable for detecting putative differences in the in-vivo beha-vior of locally acting GI drugs. The BE issues that will bediscussed for oral modified release 5-ASA formulations arealso valid for locally active oral steroids, such as budesonidethat is used for the treatment of inflammatory bowel disease[13]. Budesonide is a glucocorticoid with topical anti-inflamma-tory action that has a high first-pass elimination resulting in alow systemic bioavailability and less systemic activity than con-ventional corticosteroids. One of the main aspects that supportthe rationale behind the clinical use of budesonide in inflam-matory bowel disease is based on the local delivery of theactive compound in the inflamed GI mucosa, preventing asmuch as possible the systemic absorption of the drug [14,15].Similarly to 5-ASA, various modified release formulations havebeen developed with the last innovation represented by theMulti Matrix System technology that allows the release of thedrug at a controlled rate throughout the colon. As will bereported for 5-ASA, the PK profile of budesonide is complex.After administration, a fraction of the active ingredient exerts alocal action in the GI tract and a fraction becomes detectable inthe systemic circulation leading to uncertainties during thedevelopment of a strategy for BE purpose [14,15]. For thesereasons, the regulatory framework and the recommendationsprovided for oral 5-ASA dosage forms may also be applied forthe development of generic version of modified release bude-sonide formulations [13].

2. BE of locally acting GI drugs

The demonstration of BE for locally acting GI drugs has gen-erated hard challenges since many years. In this setting, thedefinition of standardized BE criteria has been more difficultthan for systemically absorbed products. In general, locallyacting GI drugs are conceived for delivering the active ingre-dient within the gut lumen and are formulated to prevent asmuch as possible its systemic absorption. Consequently, forthese products, the performance of their pharmaceuticalforms is crucial, since dissolution is the primary determinantof the rate and extent to which the active ingredient is deliv-ered to the site of action and exerts its therapeutic effect [9].In this context, the assay of drug concentration in the systemiccirculation might not be relevant for BE purposes. Even if alocally acting GI drug generates a measurable systemic PKprofile, it is necessary to evaluate if and how these plasmaconcentrations correlate with the availability of the activeingredient at the site of action. These aspects are crucial todefine whether systemic PK end points are relevant for BEpurpose, and whether the scientific rationale of BE appliedfor systemically absorbed drugs can be considered as validalso for locally acting drugs [8,16–18]. In order to betteraddress the above issues, we provide here some examples oflocally acting GI drugs widely employed in clinical practice,with the purpose of discussing how their biopharmaceuticaland PK features can impact on the process of BE demonstra-tion. In general, three different scenarios for locally acting GIdrugs can be hypothesized: (1) no systemic exposure; (2)minimal systemic exposure; (3) measurable PK profiles, butthe gut region of absorption may or not overlap with thesite of action in the human GI tract [19]. Among locally actingGI drugs, each medicinal product differs from others in termsof mechanism of action, system of drug delivery, and physico-chemical properties (Table 1) [8]. Therefore, a BE methodshould be selected in accordance with the specific featuresof the test medicinal product, and the application of generalBE criteria, as for systemically absorbed products, may not berecommendable [8]. Over the past, clinical studies have beenrequested to compare different drug products for purposes ofBE demonstration. However, increasing advances in the knowl-edge of pharmaceutical and pharmacological features oflocally acting drugs have led to improvements in the pro-cesses of BE evaluation, thereby fostering the developmentof alternative BE methods, able to document with high accu-racy similarity profiles and in-vivo differences between differ-ent medicinal products.

Medicinal products that generate minimal or not measur-able systemic concentrations, such as Lanthanum carbonate,require a BE approach based on other methods than PKstudies. In this case, the FDA recommended that in vitro dis-solution tests and phosphate binding studies or pharmacody-namic end points in human subjects should be employedwhen developing a generic product [29,30]. Indeed, the imple-mentation of comparative dissolution studies allows to revealpotential differences in the manufacturing process that canaffect the deliver and availability of the active ingredient atthe site of action. Conversely, phosphate binding studies arecarried out to assess comparatively whether the generic and

2 G. SFERRAZZA ET AL.

reference product display the ability of binding phosphate inan equivalent manner [29,30].

When considering the case of more complex drugs, such as5-ASA or budesonide, for which a fraction of the active ingre-dient exerts a local action in the GI tract and a fractionbecomes detectable in the systemic circulation, selecting themost accurate BE method is more challenging. Clinical trialsbased on efficacy endpoints have been employed in the pastto compare oral 5-ASA products, even though they are gen-erally characterized by low sensitivity and are rather expensive[11]. Conversely, clinical PK studies have been used for safetyevaluations, but whether the estimated 5-ASA plasma concen-trations correlate with its bioavailability at the local site ofaction, and whether systemic PK data could be taken assurrogate end points for the assessment of BE, remains amatter of debate [8]. Several additional factors, such as intra-subject variability of 5-ASA plasma concentrations and theinfluence of physiological GI parameters, amplify further thedegree of complexity and increase the risk of failing BEdemonstration [31]. Moreover, the paucity of studies compar-ing the local GI concentrations of 5-ASA released by differentoral formulations adds more uncertainty on their potentialdifferences in clinical efficacy and interchangeability [31,32].All the above issues have been discussed for long time both inthe scientific literature and at regulatory level, highlighting theneed for generating further evidence about the BE testing oforal 5-ASA formulations [12,31,32].

3. 5-ASA case study

5-ASA is a derivative of salicylic acid employed since manyyears for the therapeutic management of inflammatory boweldiseases, with particular regard for mild-to-moderate ulcera-tive colitis [33]. After oral or rectal administration, 5-ASA actslocally in the colon and its effectiveness is related with con-centrations achieved in the bowel mucosa [33]. The exactmechanism of action of 5-ASA is currently unclear [8].However, several putative therapeutic targets have been pro-posed. These include, among the others, the peroxisome

proliferator-activated receptor gamma [34,35], the inhibitionof cyclo-oxygenase and lipoxygenase with consequent block-ade of prostanoid end leukotriene production [35–37]. Recentdata suggest also that 5-ASA can interfere with other inflam-matory pathways, such as nuclear factor-kappa B activation,thus inhibiting the release of tumor necrosis factor and inter-leukin-1 [38–41]. Other possible mechanisms comprise thealteration of GI bacterial flora and antioxidant/scavenger activ-ity [42,43]. As 5-ASA is believed to exert a direct effect oncolonic mucosa through a variety of anti-inflammatorymechanisms, direct application of this agent to the mucosaof this gut region is required [44,45]. Free 5-ASA, if adminis-tered orally, is completely adsorbed from the proximal smallintestine, followed by extensive metabolism to N-acetyl-5ASAby the N-acetyl-transferase 1 in intestinal epithelial cells andthe liver, and then excreted in the urine as a mixture of free 5-ASA and N-acetyl-5ASA [46].

Therefore, to carry out its topical activity, 5-ASA must bedelivered to ensure its direct contact with the mucosal layeraffected by the inflammatory process, in the distal ileum andcolon, while avoiding its early systemic absorption in the upperGI tract. This goal has been pursued with the development ofdifferent types of drug delivery technologies: delayed-releaseproducts, extended release products, prodrugs, and topicalproducts [47]. Oral modified release products are the mostwidely prescribed dosage forms of 5-ASA and have capturedthe main market share [48,49]. The implementation of thesetechnologies allows the delivery of 5-ASA in close proximity ofthe site where its pharmacological action is required, with aconsequent low systemic bioavailability, about 20–30% of 5-ASA detectable in plasma [8,25], and a better safety and efficacyprofile. The last innovation was introduced some years ago withthe development of Multi Matrix System technology. The latterproduct is a high-strength formulation of 5-ASA (1.2 g of 5-ASAper tablet), designed for once-daily administration to enhancepatient’s compliance and simplify the treatment schedule [50].This technology allows to release 5-ASA to the full length of thecolon by delayed and controlled release mechanisms. This goalis achieved through a delivery system based on gastroresistant

Table 1. Examples of locally acting gastrointestinal medicinal products.

Drug and dosageform Product category Therapeutic indication Rate of systemic absorption References

ColesevalamTablet or oral

suspension

Binding agents Reduces elevated low-density lipoproteincholesterol in adults with primaryhyperlipidemia as well as boys andpostmenarchal girls with heterozygousfamilial hypercholesterolemia

Improves glycemic control in adults with type2 diabetes mellitus

Minimal or trace tissueconcentrations

[8,20]

Lanthanumcarbonate

Chewable tablet

Binding agents Treatment of hyperphosphatemia in patientswith end stage renal disease

0.002% [8,21,22]

VancomycinCapsule

High soluble immediate release dosageforms

C. difficile-associated diarrheaEnterocolitis caused by Staphylococcus aureus

No measurable concentrations inblood

[8]

OrlistatCapsule

Low soluble immediate release dosageforms

Obesity management <2% [8,23,24]

MesalamineCapsule and tablet

Modified release products Treatment of ulcerative colitis 20–30% [8,25]

BudesonideCapsule and tablet

Modified release products Treatment of ulcerative colitis and Crohn’sdisease

10–20% [26–28]

EXPERT REVIEW OF CLINICAL PHARMACOLOGY 3

coating and a tablet core containing hydrophilic and lipophilicexcipients. When the outer layer of the tablet begins to dissolveat pH 7 or higher, the lipophilic excipients reduce the aqueouspenetration and the dissolution of the active ingredient. Thecore matrix, in contact with intestinal fluids, causes the forma-tion of a viscous gel mass, thus providing a controlled release of5-ASA throughout the colon [51].

All these 5-ASA products have been formulated to targetthe inflamed bowel area, beyond the proximal intestine.Accordingly, the release profile of 5-ASA from enteric-coatedtablets is the dominant factor for achieving an adequate localbioavailability [44,46] that is strictly correlated with the clinicalefficacy [25,52–54]. Clinical evidence demonstrated that theconcentration of 5-ASA at the site of action is inversely corre-lated with the severity of endoscopic and histological activityscores in patients with ulcerative colitis. Patients with highermucosal concentration of 5-ASA had lower or none colonicinflammation than those with severe activity of ulcerativecolitis [52–54]. While these products have displayed goodsafety and efficacy profiles, differences among the technolo-gies employed for the development of pharmaceutical forms,in conjunction with intra-subject variability, could lead todifferences in drug-release profiles, systemic PK profiles, anddrug concentration at the site of action [8,44,55–57]. Takentogether, all these sources of variability increase further thecomplexity of assessing BE for modified release 5-ASAproducts.

3.1. Available BE methods for oral modified release 5-ASA products

Local concentrations of 5-ASA at the site of action are crucialfor ensuring its therapeutic action in the inflamed bowel area.Therefore, several methods have been developed to charac-terize the biopharmaceutical properties of 5-ASA products.Since several techniques have been discussed extensively inliterature, only their most relevant features will be summarizedin this section [12,25]. An ideal method should allow a carefulevaluation of the behavior of oral modified release 5-ASAformulations and the delivery of the active ingredient intothe colon to unravel putative differences between different5-ASA dosage forms.

3.1.1. In vitro dissolution testsThe dissolution test is a key tool routinely employed by thepharmaceutical industry for evaluating the performance char-acteristics of solid oral dosage forms. It is successfully usedboth for quality control purpose and as relevant part of the BEstudies performed for the development of generic medicine.

The dissolution test assesses the amount of drug dissolvedin a known volume of liquid medium at a predetermined time,using a specified apparatus designed to control the para-meters of dissolution testing [6]. It provides useful data forthe optimization of drug delivery and formulation design dur-ing the early phase of drug development or for supportingchanges made to the manufacturing process [6]. It is also usedas a surrogate test to predict the in-vivo performance of drugproducts, when applicable, and to get information on the testbatches used in BE and pivotal clinical studies. From a

regulatory point of view, it plays a major role in genericmedicine development since it is used to waive BE studies orto assess pharmaceutical equivalence between test and refer-ence product [6]. Therefore, in vitro dissolution studies repre-sent the primary scientific and regulatory step that allows toobtain relevant information about the potential GI behavior ofa drug product. The experimental condition is a key factor tosimulate the physiological conditions of the GI tract andobtain a good chance of predicting the in-vivo performanceof pharmaceutical forms. During the early stage of genericdrug development process, comparative dissolution tests arecrucial for an early detection of potential differences in the in-vivo GI behavior among different 5-ASA products [8,12,25].However, it is generally acknowledged that compendial dis-solution methods cannot adequately predict the in-vivorelease behavior of locally acting GI drugs, since they cannotmimic all variables affecting GI functions, such as the physico-chemical properties, composition and volume of luminal fluidsin different gut regions, the residence time of the dosage unitin each GI segment, the mechanical forces resulting from GImotility, and many other factors [8,16,25,56,57].

3.1.2. PK studiesThe systemic PK profile of modified release 5-ASA products iswell known and has been extensively discussed in previousarticles [25,46]. Briefly, it is acknowledged that about 20–30%of the total 5-ASA dose administrated trough oral modifiedrelease formulations is absorbed and can be detected inplasma [8,25,46]. Therefore, PK parameters are helpful for theevaluation of the safety profile of 5-ASA products. Conversely,the role of systemic bioavailability as surrogate end point fordemonstrating BE of different 5-ASA products has been matterof much debate. However, in general, traditional PK BE studiesare not sufficient to support the demonstration of similarity ofthese products, since 5-ASA plasma concentrations reflect theabsorption throughout the GI system, and not specifically atthe site of action [8,11,16,25]. Nevertheless, as discussed in thefollowing sections, the implementation of partial AUC in theexperimental design of BE studies is useful to correlate 5-ASAplasma profiles with its concentration at the site of action inthe colon and to define the therapeutic equivalence betweengeneric and reference products.

3.1.3. Clinical studies of therapeutic equivalenceFor many years, comparative trials based on clinical end-points have represented the main methodological approachto the determination of BE among 5-ASA products.However, more recently, there has been a paradigm shiftconcerning the scientific and regulatory value of these stu-dies in the assessment of BE. Indeed, the majority of reg-ulatory agencies have judged clinical trials as the leastsensitive method to detect differences in the pharmaceuti-cal performance of locally acting drugs, such as 5-ASA[8,11]. These studies are also very expensive and requirelarge numbers of patients to obtain clinically and statisti-cally significant results. Based on these drawbacks, alterna-tive BE methods that could be able to unravel in-vivo GIdifferences among 5-ASA formulations have been devel-oped and validated [8,11].


3.1.4. Pharmacoscintigraphic studiesScintigraphic techniques can provide useful information onthe in-vivo performance of oral formulations, such as thetransit rate and the site where the erosion of the dosageforms and the release of the active ingredient start, withoutthe limitations that affect in vitro dissolution tests. This meth-odology has been employed, alone or in combination withconventional PK studies, as a part of clinical data produced forthe authorization of new medicinal products as well as tocompare the in-vivo release profiles of different 5-ASA formu-lations [58–63]. However, even if scintigraphy allows a directvisualization of drug release within the gut lumen, the imagesmay not be useful to estimate the amount of released 5-ASAor to document whether the release of the active ingredientoccurs at different rates than that of radiolabeling. Therefore,scintigraphy cannot provide accurate data on the distributionof 5-ASA after its release from the formulation. Accordingly,scintigraphy alone is not regarded as a suitable tool to docu-ment all the aspects relevant to BE determination [25].

4. The regulatory framework

BE testing for locally acting GI medicines is a challenging issuefor both pharmaceutical industries and global regulatoryauthorities. In general, the regulatory approval process forgeneric locally acting GI products has been more complicatedthan systemically acting ones. The FDA and EMA have releasedguidances dedicated specifically to locally acting drugs in anattempt of providing recommendations for pharmaceuticalcompanies. However, the activities implemented by FDA andEMA in this context differ in several respects. Improvementshave been introduced, both from a scientific and regulatorystandpoint, by the FDA, with the development of specificguidances and the promotion of new research activities. Bycontrast, for long time, only general recommendations havebeen issued by the EMA and other European NationalAgencies. Only in April 2017, the EMA has published a draftguideline that introduces the possibility of alternativeapproaches to traditional comparative clinical studies [64].This regulatory scenario has lead to quite different therapeuticequivalence and authorization pathways for oral modifiedrelease 5-ASA formulations in EU and US, as shown inTable 2. Only few relevant regulatory cases are available forthe purposes of this review. In US, oral modified release 5-ASAproducts are still covered by patents [67]. In EU, only oneassessment report for an oral modified 5-ASA product, rele-vant for the scope of this review, is available [68].

4.1. FDA regulatory view

The US regulation 21 CFR 320.24, addressing the methodolo-gies eligible for BE evaluation, includes in-vivo PK studies, in-vivo pharmacodynamic studies, clinical endpoint studies, invitro studies, and any other approach deemed adequate [7].The general background recommendation is to employ themost accurate, sensitive, and reproducible method accordingto the specific features of the drug product. However, forlocally acting GI drugs, clinical studies have been recom-mended for BE demonstration, even if the FDA regards thisapproach as ‘the least accurate, sensitive, and reproducible ofthe general approaches for measuring bioavailability ordemonstrating bioequivalence’ [7,8]. Over the years, this reg-ulatory paradigm has been largely modified, and considerableadvances have been made in the research activities promotedby the FDA for the development of alternative BE approaches[10]. In 2010, the FDA has issued product-specific recommen-dations for BE studies [69]. The definition of product-specificrecommendation has delineated a clear regulatory frameworkthat helps pharmaceutical companies in the development ofscientific evidence in line with the expectations of regulatoryagencies [70]. To date, 1554 guidances, covering any type ofmedicinal products, have been released. In this context, sev-eral recommendations for locally acting GI products havebeen issued [70]. These guidances (although not mandatory)represent an important aid to pharmaceutical companies forthe development of generic drugs, with particular regard forthose exerting a topical action. It is evident how the FDAapproach is structured and oriented to provide specific recom-mendations that reflect actually the features of the medicinesunder investigation, thus allowing to simplify and shorten thedevelopment of generic medicines.

4.1.1. BE recommendations for oral modified 5-ASAproducts in USThe paradigm change implemented by the FDA about the BEassessment for oral modified release 5-ASA products could berelated to two different citizen petitions submitted to the USagency [71]. One of the main issue raised by these petitionsfocused on the role of PK studies for BE assessment of thegeneric versions of modified release 5-ASA formulations. TheFDA stated that standard PK parameters, such as AUC andCmax (maximum concentration), are not sufficient to discrimi-nate between two 5-ASA products. Conversely, however, theagency recommended the use of partial AUC in addition toconventional parameters, arguing that, if plasma 5-ASA con-centrations are monitored over specified time intervals, it is

Table 2. Bioequivalence criteria adopted in US and EU for the development and authorization of 5-ASA delayed release formulations.

Drug product Bioequivalence approach adoptedYear ofapproval Approving countries References

5-ASA delayed releasecapsules

In vitro comparative dissolution testPK study based on the evaluation of conventional PK parameters

(Cmax and AUC) in addition to partial AUC8–48

2013 United States [65]

5-ASA delayed release tablets First step: in vitro comparative dissolution test and PK studiesSecond step: combined pharmacoscintigraphic and PK analysis,

single-dose PK study, and phase III comparative clinical efficacystudy

2010 United Kingdom andGermany

[66]

5-ASA: 5-aminosalicylic acid; PK: pharmacokinetic; AUC: area under the curve; Cmax: maximum concentration.


possible to evaluate the absorption rate at the site of action.Accordingly, the FDA assumes that the combination of com-parative in vitro dissolution tests and properly designed PKstudies, under fast and fed condition, are suitable for detect-ing any difference in the drug release, and estimating if two 5-ASA products are absorbed at the same rate and extent at thesite of action [71]. Overall, both citizen petitions have lead tothe release of specific recommendations for the BE demonstra-tion of modified release 5-ASA products. Table 3 provides asummary of BE criteria recommended by the FDA in the draftguidance for oral modified release 5-ASA products. Furtherinformation about the design of PK studies or the experimen-tal conditions required for other kinds of locally acting GIdrugs, such as rectal 5-ASA products, cholestyramine, lantha-num carbonate, and acarbose, are available in the FDA web-site section dedicated to Product-Specific Recommendationsfor Generic Drug Development [70].

4.2. EMA regulatory view

The first guidance released by the EMA in 1995 was the ‘Notefor guidance on the clinical requirements for locally applied,locally acting products containing known constituents’ [78].This guideline covers all type of locally acting medicinal pro-ducts without making specific reference to locally acting GIdrugs. In principle, the regulatory strategy suggested by theEMA for the demonstration of equivalence for ‘generic’ locallyacting products relies on the conduction of comparative effi-cacy clinical trials. However, depending on the type of medic-inal product, the EMA allows other BE approaches, providedthey are validated adequately. Indeed, the application for theapproval of a generic product should be supported by adocumentation consisting of

pharmacodynamic studies or local bioavailability studies; possiblyin vitro studies or augmentation in case of minor differences.Otherwise clinical studies. Any safety issue has to be addressedappropriately. The choice of the most appropriate method and theomission of such data should be justified by the pharmaceuticalcompany. [78]

If we consider the heterogeneity of medicinal productsbelonging to the GI class, these recommendations sound as

very general and may lead to different interpretations,depending on the type of product. These difficulties havebeen pointed out by the EMA in 2013 in the ‘Concept paperon the development of a guideline on the demonstration oftherapeutic equivalence for locally applied and locally actingproducts in the gastrointestinal tract’ [79]. In this paper, theEMA acknowledged that clinical or pharmacodynamics endpoints may not be able to predict and detect differencesbetween locally acting products. At the same time, theyagreed that the in vitro pharmaceutical properties of thesemedicinal products are relevant for the purpose of BE demon-stration. On these bases, the Agency underscored the need forestablishing alternative in-vivo and in vitro methods for BEevaluation [79]. It is surprising that this scenario was themain regulatory reference for over 20 years. Unfortunately,the lack of univoque interpretation of this guideline has hada negative impact on the regulatory strategy for generic/hybrid drug development. A similar trend has occurred forthe definition of product specific recommendations for BEpurposes. In 2013, the EMA released the ‘Concept paper onthe development of product-specific guidance on demonstra-tion of bioequivalence’, which was then converted into anapproved guidance [80]. In this guidance, the first approachfocused specifically on oral immediate release formulations. Todate, 42 guidelines have been released. However, no product-specific guidance for locally acting GI drugs has been issuedby the EMA [81].

4.2.1. The new EMA draft guidance on the demonstrationof therapeutic equivalence for locally acting GI drugsIn April 2017, a ‘Draft guideline on equivalence studies for thedemonstration of therapeutic equivalence for products thatare locally applied, locally acting in the gastrointestinal tract asaddendum to the guideline on the clinical requirements forlocally applied, locally acting products containing known con-stituents’ has been issued by the EMA [64]. This draft guidanceupdates the guideline published in 1995. At present, it is openfor consulation, and the dead line for this phase falls on 30September 2017. This new draft guidance reflects the begin-ning of a substantial change in the regulatory paradigm driv-ing this area, introducing the possibility of demonstratingtherapeutic equivalence of locally acting GI drugs through

Table 3. Bioequivalence criteria for oral modified 5-ASA formulations recommended by the FDA.

Pharmaceutical form and strength In vitro dissolution studies PK endpoints References

Delayed release tablet 400 mg Stage 1: acid pHStage 2: 6 different pH values from 4.5 to 7.5

AUC8–48, AUC0–t, Cmax

Other partial AUCs may be evaluated[72]

Delayed release tablet 800 mg Stage 1: acid pHStage 2: 6 different pH values from 4.5 to 7.5



Delayed release tablet 1200 mg Pretreatment stage 1: acid pHPretreatment stage 2: basic pHEvaluation stage: 4 different pH values from 6.5 to 7.5.



Delayed release capsule 400 mg Stage 1: acid pHStage 2: 6 different pH values from 4.5 to 7.5



Extended release capsule 375 mg Stage 1: acid pHStage 2: 6 different pH values from 4.5 to 7.5

Fasting: AUC0–3, AUC3–t, AUC0–t, Cmax

Fed: AUC0–t, Cmax

[76]

Extended release capsule 500 mg Stage 1: acid pHStage 2: 6 different pH values from 4.5 to 7.5

Fasting: AUC0–3, AUC3–t, AUC0–t, Cmax

Fed: AUC0–t, Cmax

[77]

AUC: area under the curve; Cmax: maximum concentration.The BE package comprises three studies: in vitro comparative dissolution test and in-vivo fast and fed PK studies for each type of formulation. A reference-scaledaverage BE approach is recommended for each type of dosage form.


alternative models than comparative clinical or PD end points.A more specific scientific and regulatory approach is proposed,with several additional clear recommendations, based on thecharacteristics of drug products, such as the site and mechan-ism of action, their biopharmaceutical and PK properties, thepharmaceutical form, and the state of the active ingredientwithin the dosage form. For each class of GI drugs, the EMAproposes a decision tree that indicates clear and useful reg-ulatory and experimental strategies that should be takenproperly into account. The approach proposed by the EMAallows to follow several regulatory pathways requiring differ-ent levels of scientific evidence to demonstrate therapeuticequivalence. These strategies include ‘pharmaceutical qualitydata alone; pharmaceutical quality data + in vitro model;pharmaceutical quality data plus in vivo PK data; pharmaceu-tical quality data plus in vitro model + in vivo PK data’. Theselected strategy should be adequately justified according tothe drug product characteristics.

The EMA recognizes that, in some instances, in vitro and in-vivomethods may display better sensitivity than clinical or PD endpoints to reveal potential differences betweenmedicinal productscontaining the same active substance. It is acknowledged thatthesemethods could be employed towaive clinical trials, providedthe applicant justifies adequately that they are able to reflect thein-vivo drug release and availability at the site of action. Theregulatory strategies and methods accepted for demonstrationof therapeutic equivalence, as described by the EMA in its draftguidance, are numerous and should be selected depending on thespecific features of each GI drug class. Therefore, to remain within

the primary purpose of the present article, we have paid attentiononly to the recommendations concerning products acting locallyin the intestine (Figure 1). In this regard, the EMA proposes that, inthe case ofmodified release productswith systemic bioavailability,such as 5-ASA, BE studies could be based on the assessment ofdrug plasma concentrations along with the estimation of partialAUC parameters, in order to discriminate the absorption resultingfrom an early drug release from that ascribable to drug release atthe site of action. For these drugs, BE studies could be designed assingle-dose PK tests under fasted and fed conditions, or as multi-ple-dose tests in the case of prolonged release formulations [64].Partial AUC should be taken as the primary PK end point in eachtype of BE study. Of note, these approaches can be considered assurrogates for the equivalence of efficacy and safety profiles only ifthe systemic absorption of the active ingredient occurs at the siteof action [64]. The implementation of a new regulatory frameworkfor locally acting GI products has been waited for a long time. Inthis respect, the release of this new draft guideline represents arelevant regulatory advance in this area. It is likely that this newscenario will have a significant impact on pharmaceutical compa-nies, promoting more generic competition through a clearer reg-ulatory approach, conceived for streamlining the demonstration oftherapeutic equivalence for locally acting GI drugs.

5. New evidence about the in-vivo GI behavior of 5-ASA medicinal products

Understanding the implications that the pharmaceutical fea-tures of locally acting drugs have for their in-vivo and clinical

Figure 1. Therapeutic equivalence decision tree for solid dosage forms acting locally in the intestine.Based on European Medicines Agency locally acting gastrointestinal drug guideline [64]. In red a potential regulatory pathway for the demonstration of therapeuticequivalence for oral modified release 5-ASA products. BCS: biopharmaceutics classification system; PD: pharmacodynamics; SD: single dose; MD: multiple dose. Fullcolor available online


performance is crucial for a correct definition of the BE criteriafor such products. Several research and regulatory projects areongoing in this field, as reported by the FDA [82]. With regardfor 5-ASA, FDA started a collaboration with the University ofMichigan focused on the BE challenges related to GI behaviorof 5-ASA medicinal products [31,83]. To address this importantissue, a clinical trial is ongoing [83]. The aim of the study wasto measure directly the dissolution and release of oral 5-ASAformulations in the stomach, duodenum, jejunum, and ileum;to quantify 5-ASA content in the colon (through a measure-ment of its excretion in the feces); and to investigate andprovide data to FDA about the relationship between the con-centration–time profiles of 5-ASA in the plasma and GI tract[31,83].

The collection of GI fluid samples was accomplished by anew device consisting of a multi-port luminal catheter withfluoroscopic positioning of four gastric and small bowelaspiration ports, to quantify the regional drug concentrationsthroughout the digestive tract. The study was performed inaccordance with a randomized, open-label, crossover PKdesign (modified release formulations), followed by a sin-gle-arm treatment (oral 5-ASA solution). Healthy volunteerswere enrolled to receive one of the three modified release 5-ASA formulations: 2 × 500 mg of 5-ASA controlled releasecapsules, 3 × 375 mg of 5-ASA extended release capsules,and 1 × 1200 mg of 5-ASA delayed release tablets [31,83].After the crossover phase, subjects received an oral solutioncontaining 100 mg of 5-ASA. Such an immediate release 5-ASA arm was included to obtain baseline individual PK para-meters to be employed for the deconvolution process anddeveloping a new index designated as composite appear-ance rate (CAR) [31]. CAR was defined as the net appearanceof 5-ASA into the systemic circulation and was conceivedspecifically to capture disintegration, dissolution, transit,and absorption of modified release 5-ASA formulations.Deconvolution is a predictive model that was used to dis-sociate the absorption phase from the clearance and volumeof distribution that are involved in the systemic bioavailabil-ity of 5-ASA. In particular, the authors chose to isolate theabsorption process for reducing putative bias due to inter-subject variability of the clearance and volume of distribu-tion as well as to predict the physiological process involvedin the appearance of the observed drug profile. According tothis model, the baseline plasma profile, obtained uponadministration of the 5-ASA solution, was used to calculatethe CAR of 5-ASA versus the time of the three tested for-mulations. Based on these results, CAR was validated as areliable composite index able to predict the absorption rateof 5-ASA from the GI tract [31,84,85].

The above clinical study documented for the first time anin-vivo sampling and comparison of GI 5-ASA concentrationsreleased by three different formulations. The analysis of datahighlighted a variable release of 5-ASA and its metabolite(acetyl-mesalamine) in the GI tract, in line with the technologyinvolved in the development of the formulations administeredin this study. By contrast, comparable fecal levels of acetyl-mesalamine were detected, suggesting similar profiles of dis-solution and release at the site of action. Furthermore, rele-vant information were obtained about the in-vivo relationship

between the modified release forms of 5-ASA and severalparameters related to the GI system, such as solubility pH, GItransit, and motility that have been often regarded as unpre-dictable variables [31].

The results obtained from the application of CAR are also ofgreat interest. Indeed, this index was able to reflect the dis-solution and release of each formulation, generating finalscore values that were in line with plasma 5-ASA concentra-tion and its in-vivo GI release. Each modified release formula-tion showed a specific CAR profile; therefore, this index wasable to detect differences among the in-vivo GI behavior of thethree formulations employed in the clinical study. Due to CARperformance, the authors have proposed this index as apotential new tool to improve the demonstration of BE forlocally acting GI and modified-release products [31]. Of note,the above results will likely provide also a scientific basis forthe development of more accurate methods suitable for BEtesting of locally acting drugs, or to reevaluate the relevanceof traditional BE methods, and to review and develop BEguidances concerning other medicinal products. In US, accord-ing to data published by the FDA, the outcomes of this studyhave been taken as a basis for the development and review ofBE guidances specifically dedicated to oral modified release 5-ASA products, oral modified release budesonide products, andbinding agents [13].

6. New perspectives on generic drug developmentand authorization

In recent years, the significant advances made in biopharma-ceutical sciences, along with the BE issues associated withcomplex drug products, have fostered the introduction ofnew tools into the process of drug development. These newmethodologies, such as modeling and simulation tools, willlikely play a considerable role in the future perspectives ofpharmaceutical and regulatory sciences, simplifying and redu-cing the failure rates of research and development procedures.

In this context, the physiologically based pharmacokinetic(PBPK) is one of the most widely used in the development ofboth generic and new drug products. PBPK is a mathematicalmodel that integrates the physicochemical properties of drugsubstances, formulation properties of drug products and phy-siological parameters in order to predict in-vivo absorption,distribution, metabolism, and excretion [86–89]. Several appli-cations of this model have been defined in the area of phar-maceutical sciences, and several research and regulatoryactivities are ongoing in this field [90]. For instance, theOrbito Project (Oral BIopharmaceuticals Tools) has beenfunded by the European Commission with the aim of expand-ing our knowledge about the interaction between orally admi-nistered drugs and the digestive system, and therebydeveloping new experimental approaches and simulationmodels that should allow of better predicting the in-vivoperformance of drug products [91].

Pharmaceutical companies are increasingly employing theabovementioned tools to address BE issues related with drugproducts [91–95]. The application of the PBPK model is lesscomplex in the context of generic drug development, due tothe availability of PK and pharmaceutical data of the originator


that could be used as input parameters or to calibarate andvalidate the tool [90]. According to FDA data, absorptionmodeling has been used by pharmaceutical companies in 34medicinal products reviewed by the agency from 2010 to 2016both for immediate and modified release formulations [96].More interestingly, from 2009 to 2015, some label informationfor 26 approved medicinal products were extrapolated bymeans of the PBPK model [96]. According to the increasinguse of this tool by pharmaceutical companies, both the EMAand FDA have released guidances on the use and validation ofPBKP during the development of new drug products [97,98].

In the context of regulatory activities, since 2004, the FDAOffice of Generic Drugs has adopted the above tools for bettercharacterizing several equivalence issues in about 22 projectsthat included the development of BE guidance, revision of theabbreviated new drug application, regulatory research studies,and post-approval issues [90]. With specific regard to BE fororal 5-ASA products, the FDA applied the simulation andprediction models in order to support the use of AUC3–t as aPK parameter that is able to better correlate, than other partialAUC parameters, with the colonic exposure to the activeingredient when two 5-ASA extended release capsules werecompared [99].

7. Conclusions

The advances made in understanding the scientific features oflocally acting GI drugs has led to considerable progress in theBE area. Regulatory agencies have released guidances dedi-cated specifically to locally acting drugs to provide advicesand simplify the development of generic medicinal products.However, a remarkable difference can be noted when compar-ing the EU and US regulatory activities in this field. The FDAhas delineated a specific regulatory framework with the devel-opment of product-specific guidances that define a clear strat-egy for each product belonging to this pharmacological class.In the case of oral modified release 5-ASA products, partialAUC was identified as a new PK parameter that allows tocorrelate drug plasma profile with its local concentrations atthe site of action. Furthermore, the FDA has started a numberof additional research initiatives to provide a strong scientificbasis for locally acting GI drugs and promote further thescientific and regulatory advances for such products. InEurope, the regulatory framework has been characterized for20 years by a general paradigm that was difficult to apply toall types of drug products belonging to the class of locallyacting GI medicines. However, very recently, with the publica-tion of the draft guidance that revises the guideline issued in1995, the EMA is trying to change the European regulatoryframework pertaining to the demonstration of therapeuticequivalence for locally acting GI drugs, moving toward anew regulatory framework that reflects closely the oneadopted by the FDA. This shift denotes a great advance inthis field, as it opens to a simplification of the scientific andregulatory process that pharmaceutical companies should fol-low to achieve marketing authorization. The possibility ofdemonstrating therapeutic equivalence through in vitro and/or PK BE studies, rather than comparative clinical and PDendpoints, will likely result in a significant impact on

pharmaceutical companies, which are implementing researchand development programs to foster competition in this field.In this light, it is desirable that the new EMA draft guidancewill be quickly approved and made available in its definitive.

8. Expert commentary

BE studies play a key role in the development of generic drugsand new drugs. For most systemically absorbed drugs, thescientific and regulatory framework is well established andconventional PK studies still represent the gold standardapproach to demonstrate BE. However, for more complicateddrug products, there are still many open questions. For locallyacting GI products, the development of a regulatory strategyhas been complex and it has been often associated withuncertainties related to scientific and regulatory aspects. Thelack of specific BE regulatory recommendation has generateda negative impact on the market competition reducing eco-nomic savings for both patients and National Health Servicesdue to the high cost and risk of failure associated with theclinical development process [11,82]. The case of oral modified5-ASA drug products summarizes the challenges when con-sidering the development of a BE strategy for locally acting GIdrugs. The suitability of clinical efficacy studies or PK studiesfor assessing BE of oral 5-ASA formulations has been matter ofdebate, with much discussion revolving around their potentialcorrelation with local concentrations achieved by 5-ASA at thesite of action, or even its release behavior from oral formula-tions throughout the GI tract [8–12]. Several additional factors,such as intra-subject variability of 5-ASA plasma concentra-tions and the influence of physiolological GI parameters,amplify further the degree of complexity and increase therisk of failing BE demonstration [31]. However, thanks toadvance that has been made in this area, the BE recommen-dations for locally acting GI drugs have substantially changedover the last 10 years, as seen by the evolution from clinicalend point BE studies to tailored experimental approaches ableto ensure a sensitive and accurate detection of putative in-vivodifferences between the test and originator product. Theintroduction of partial AUC as PK parameter that allows tocorrelate 5-ASA plasma profile with its local concentrations atthe site of action is one of the interesting advance that hasbeen made in this field. However, the activities implementedby EU and US agencies in this context differ in severalrespects. Improvements have been introduced, both from ascientific and regulatory standpoint, by the FDA, with thedevelopment of specific guidances and the promotion ofnew research activities. By contrast, for long time, only generalrecommendations have been issued by the EMA and otherEuropean National Agencies. Only in April 2017, with thepublication of the draft guidance that revises the guidelineissued in 1995, the EMA is trying to change the Europeanregulatory framework pertaining to the demonstration of ther-apeutic equivalence for locally acting GI drugs, moving towarda new regulatory framework that reflects closely the oneadopted by the FDA. This shift denotes a great advance inthis field, as it opens to a simplification of the scientific andregulatory process that pharmaceutical companies should


follow to achieve marketing authorization. This new scenariowill likely result in a significant impact on pharmaceuticalcompanies, promoting more competition through a clearerregulatory approach, conceived for streamlining the demon-stration of therapeutic equivalence for locally acting GI drugs.

9. Five-year view

In recent years, the increasing advances in the knowledge ofpharmaceutical and pharmacological features of locally actingdrugs have led to improvements in the processes of BE eva-luation, thereby fostering the development of alternative BEmethods, able to document with high accuracy similarity pro-files and in-vivo differences between different medicinal pro-ducts. The regulatory paradigm has been largely modified, andconsiderable improvements have been made both from ascientific and regulatory standpoint. This new scenario willsimplify the scientific and regulatory process that pharmaceu-tical companies should follow to achieve marketing authoriza-tion. However, since BE is a continuously evolving science, wecan speculate that simulation and prediction tools will likelyplay a considerable role in all phases of the research anddevelopment of generic drugs. The full implementation ofthese models in the future perspectives of pharmaceuticaland regulatory sciences will help to demonstrate the thera-peutical equivalence for complex drugs as well as to assesspotential failure modes and risks to product equivalence, sim-plifying the research and development procedures.

Key issues

● Bioequivalence testing for locally acting gastrointestinaldrugs is a challenging issue for both regulatory authoritiesand pharmaceutical industries. The international regulatoryframework has been characterized by the lack of specificbioequivalence tests that has generated a negative impacton the market competition due also to the high cost andrisk of failure associated with the clinical developmentprocess.

● Thanks to advances made in this field, novel bioequivalencecriteria have been recommended by regulatory agenciesand several research activities have been promoted todevelop alternative methods suitable for detecting putativedifferences in the in vivo behaviour of locally acting gastro-intesinal drugs.

● In April 2017, the European Medicines Agency has pub-lished a draft guideline, which proposes a new scientificand regulatory paradigm that simplifies the demonstrationof bioequivalence for locally acting gastrointestinal drugs.

● Partial area under the curve, that allows to correlate sys-temic bioavailability and drug concentration at the site ofaction, is a key pharmacokinetic parameter for the BEassessment of oral modified release mesalamineformulations.

● Combination of comparative in vitro dissolution tests andproperly designed PK studies, under fast and fed condition,are suitable for detecting any difference in the drug release,and estimating if two 5-ASA products are absorbed at thesame rate and extent at the site of action.

● Modeling and simulation tools will likely play a consider-able role in the future perspectives of pharmaceutical andregulatory sciences, simplifying and reducing the failurerates of research and development procedures.

Acknowledgments

The authors thank Dr. Matilde Paggiolu, Institute of TranslationalPharmacology, National Research Council, Rome, Italy, for scientific secre-tariat support. The authors also thank Dr. Pamela Papa, Institute ofTranslational Pharmacology, National Research Council, Rome, Italy, foradministrative support.

Funding

This work was supported by the Institute of Translational Pharmacology,National Research Council of Italy (CNR), Projects DSB.AD007086 toPasquale Pierimarchi and by Italian Ministry of Education, University andResearch (CNR Research Project on Aging, Grant N. B81J12001510001) toPasquale Pierimarchi.

Declaration of interest

G Sferrazza has no conflict of interest to report. PD Siviero has served as aspeaker for Roche, a consultant for Roche, Biomarin and BoehringerIngelheim, an advisor board member of Janssen Cilag. G Nicotera has noconflict of interest to report. P Turella has served as a consultant for Sofar.A Serafino has no conflict of interest to report. C Blandizzi has served as aspeaker and consultant for Alfa-Wassermann and Sofar. P Pierimarchi hasno conflict of interest to report. The authors have no other relevantaffiliations or financial involvement with any organization or entity witha financial interest in or financial conflict with the subject matter ormaterials discussed in the manuscript apart from those disclosed.

References

Papers of special note have been highlighted as either of interest (•) or ofconsiderable interest (••) to readers.

1. European medicines Agency. Generic medicine definition. 2012[cited 2017, May 15]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000335.jsp&mid=WC0b01ac0580514d5c

2. Food and Drug Administration. Generic drugs: question andanswer. 2017 [cited 2017, May 15]. Available from: https://www.fda.gov/drugs/resourcesforyou/consumers/questionsanswers/ucm100100.htm

3. Food and Drug Administration. Guidance for Industry. ANDASubmissions - Content and format of abbreviated new drugApplications. 2014 [cited 2017, May 15]. Available from: https://www.fda.gov/downloads/drugs/guidances/ucm400630.pdf

4. European Parliament. Directive 2001/83/EC relating to medicinalproducts for human use. 2001 [cited 2017, May 15]. Available from:http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf

5. Food and Drug Administration. Guidance for Industry.Bioavailability and Bioequivalence. Studies for Orally AdminsiteredDrug Products - General Considerations. 2003 [cited 2017, May 15].Available from: https://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B1_07_GFI-BioAvail-BioEquiv.pdf

6. European Medicines Agency. Guideline on the Investigation ofBioequivalence. 2010 [cited 2017, May 15]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf

7. Food and Drug Administration. Title 21, Volume 5 Code of Federalregulations (CFR) Part 320, Section 320.24 2016 [cited 2017, May15]. Available from:https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=320.24


http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000335.jsp%26mid=WC0b01ac0580514d5c



https://www.fda.gov/drugs/resourcesforyou/consumers/questionsanswers/ucm100100.htm



https://www.fda.gov/downloads/drugs/guidances/ucm400630.pdf

https://www.fda.gov/downloads/drugs/guidances/ucm400630.pdf

http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf

http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf

https://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B1_07_GFI-BioAvail-BioEquiv.pdf

https://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B1_07_GFI-BioAvail-BioEquiv.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf



https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=320.24

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=320.24

8. Xiaojian J, Yongsheng Y, Ethan S. FDA Bioequivalence Standards.New York Heidelberg Dordrecht London. Springer. 2014. Chapter12, Bioequivalence for drug products acting locally within gastro-intestinal tract. 297–334.

•• This book chapter provided an excellent overview of the bioe-quivalence and clinical aspects related to locally acting gastro-intestinal drugs.

9. Yu A, Sun D, Li BV, et al. FDA Bioequivalence Standards. New YorkHeidelberg Dordrecht London: Springer; 2014. Chapter 1,Bioequivalence History. 1–27.

10. Zhang X, Zheng N, Lionberger RA, et al. Innovative approaches fordemonstration of bioequivalence: the US FDA perspective. TherDeliv. 2013;4:725–740.

11. Lionberger RA. FDA critical path initiatives: opportunities for gen-eric drug development. Aaps J. 2008;10:103–109.

• This paper showed the challenges involved in the develop-ment of generic drugs focusing on scientific and regulatoryaspects that could accelerate the approval of new drug.

12. Forbes A, Cartwright A, Marchant S, et al. Review article: oralmodifed release mesalazine formulations-proprietery versus gen-eric. Aliment Pharmacol Ther. 2003;17:1207–1214.

13. Food and Drug Administration. Locally-Acting GastrointestinalDrugs. 2017 [cited 2017, May 15]. Available from: http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm512493.htm

14. Gionchetti P, Praticò C, Rizzello F, et al. The role of Budesonide-MMX in active ulcerative colitis. Expert Rev Gastroenterol Hepatol.2014;18:215–222.

15. Lichtenstein GR. Budesonide multi-matrix for the treatment ofpatients with ulcerative colitis. Dig Dis Sci. 2016;61:358–370.

16. Chen ML, Shah V, Patnaik R, et al. Bioavailability and bioequiva-lence: an FDA regulatory overview. Pharm Res. 2001;18:1645–1650.

17. Zou P, Yu LX. FDA Bioequivalence Standards. New York HeidelbergDordrecht London: Springer; 2014. Chapter 9, PharmacodynamicEndpoint Bioequivalence Studies. 217–241.

18. Food and Drug Administration. Bioequivalence testing for locallyacting gastrointestinal drugs. 2004 [cited 2017, May 15]. Availablefrom: https://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4078B1_07_Bioequivalence-Testing.pdf

19. Wen H, Zang X The science of therapeutic equivalence. 2016 [cited2017, May 15]. Available from: https://pharm.ucsf.edu/sites/pharm.ucsf.edu/files/cersi/media-browser/OGD_Slides.pdf

20. Heller DP, Burke SK, Davidson DM, et al. Absorption of colesevelamhydrochloride in healthy volunteers. Ann Pharmacother.2002;36:398–403.

21. Damment SJ, Pennick M. Clinical pharmacokinetics of the phos-phate binder lanthanum carbonate. Clin Pharmacokinet.2008;47:553–563.

22. Pennick M, Dennis K, Damment SJ. Absoulte bioavailability anddisposition oh lanthanum in healthy human subjects adimnisteredlanthanum carbonate. J Clin Pharmacol. 2006;46:738–746.

23. Zhi J, Melia AT, Guerciolini R, et al. Retrospective population-basedanalysis of the dose–response (fecal fat excretion) relationship oforlistat in normal and obese volunteers. Clin Pharmacol Ther.1994;56:82–85.

24. Zhi J, Melia AT, Eggers H, et al. Review of limited systemic absorp-tion of orlistat, a lipase inhibitor, in healthy human volunteers. JClin Pharmacol. 1995;35:1103–1108.

25. Lichtenstein GR, Kamm MA. Review article: 5-aminosalicylate for-mulation for the treatment of ulcerative colitis-methods of compar-ing release rates and delivery of 5-aminosalicylate to the colonicmucosa. Aliment Pharmacol Ther. 2008;28:663–673.

26. O’Donnel S, O’Morain CA. Therapeutic benefits of budesonide ingastroenterology. Ther Adv Chronic Dis. 2010;1:177–186.

27. Italian Medicines Agency. Cortiment® (budesonide) Summary ofproduct characteristics. 2016 [cited 2017, May 15]. Available from:h t t p s : / / f a rma c i . a gen z i a f a rmaco . go v . i t / a i f a / s e r v l e t /PdfDownloadServlet?pdfFileName=footer_007051_043461_RCP.pdf&retry=0&sys=m0b1l3

28. Food and Drug Administration. Entocort EC® (budesonide)Highlights for prescribing information. 2011 [cited 2017, May 15].

Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021324s012s013lbl.pdf

29. Food and Drug Administration. Draft guidance on Lanthanum chew-able tablets. 2013 [cited 2017, May 15]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM270541.pdf

30. Yang Y, Shah RB, Yu LX, et al. In vitro bioequivalence approach fora locally acting gastrointestinal drug: lanthanum carbonate. MolPharm. 2012;10:544–550.

31. Yu A, Baker JR, Fioritto AF, et al. Measurement in vivo gastrointest-inal release and dissolution of three locally acting mesalamineformulations in regions of the human gastrointestinal tract. MolPharm. 2017;14:345–358.

32. Haidar SH, Davit B, Chen ML, et al. Bioequivalence approaches forhighly variable drugs and drug products. Pharm Res. 2008;25:237–241.

33. Bergman R, Parkes M. Systematic review: the use of mesalazine ininflammatory bowel disease. Aliment Pharmacol Ther.2006;23:841–855.

• Review on mesalamine use in ulcerative colitis.34. Lewis JD, Lichtenstein GR, Deren JJ, et al. Rosiglitazione for

Ulverative Colitis Study Group. Rosiglitazone for active ulcerativecolitis: a randomized placebo-controlled trial. Gastroenterology.2008;134:688–695.

35. Rousseaux C, Lefebvre B, Dubuquoy L, et al. Intestinal antiinflam-matory effect of 5-aminosalicylic acid is dependent on peroxisomeproliferator-activated receptor-gamma. J Exp Med. 2005;201:1205–1215.

36. Stenson WF, Lobos E. Sulfasalazine inhibits the synthesis of che-motactic lipids by neutrophils. J Clin Invest. 1982;69:494–497.

37. Mahida YR, Lamming CE, Gallagher A, et al. 5-Aminosalicylic acid isa potent inhibitor of interleukin 1 beta production in organ cultureof colonic biopsy specimens from patients with inflammatorybowel disease. Gut. 1991;32:50–54.

38. Rachmilewitz D, Karmeli F, Schwartz LW, et al. Effect of aminophe-nols (5-ASA and 4-ASA) on colonic interleukin-1 generation. Gut.1992;33:929–932.

39. Kaiser GC, Yan F, Polk DB. Mesalamine blocks tumor necrosis factorgrowth inhibition and nuclear factor kappaB activation in mousecolonocytes. Gastroenterology. 1999;116:602–609.

40. Horvath K, Varga C, Berko A, et al. The involvement of hemeoxygenase-1 activity in the therapeutic actions of 5-aminosalicylicacid in rat colitis. Eur J Pharmacol. 2008;581:315–323.

41. Egan LJ, Mays DC, Huntoon CJ, et al. Inhibition of interleukin-1-stimulated NF-kappaB RelA ⁄p65 phosphorylation by mesalamine isaccompanied by decreased transcriptional activity. J Biol Chem.1999;274:26448–26453.

42. Ahnfelt-Ronne I, Nielsen OH, Christensen A, et al. Clinical evidencesupporting the radical scavenger mechanism of 5-aminosalicylicacid. Gastroenterology. 1990;98:1162–1169.

43. Campregher C, Gasche C. Aminosalicylates. Best Pract Res ClinGastroenterol. 2011;25:535–546.

44. Qureshi AI, Cohen RD. Mesalamine delivery systems: do they reallymake much difference? Adv Drug Deliv Rev. 2005;57:281–302.

45. Haagen Nielsen O, Bondesen S. Kinetics of 5-amino-salicylic acidafter jejunal instillation in man. Br J Clin Pharmacol. 1983;16:738–740.

46. Sandborn WJ, Hanauer SB. Systematic review: the pharmacokineticprofiles of oral mesalazine formulations and mesalazine pro-drugsused in the management of ulcerative colitis. Aliment PharmacolTher. 2003;17:29–42.

47. Ham M, Moss AC. Mesalamine in the treatment and maintenance ofremission of ulcerative colitis. Expert Rev Clin Pharmacol.2012;5:113–123.

48. Bohm SK, Kruis W. Long-term efficacy and safety of once-dailymesalazine granules for the treatment of active ulcerative colitis.Clin Exp Gastroenterol. 2014;7:369–383.

49. Harris MS, Lichtenstein GR. Review article: delivery and efficacy oftopical 5-aminosalicylic acid (mesalazine) therapy in the treatmentof ulcerative colitis. Aliment Pharmacol Ther. 2011;33:996–1009.


http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm512493.htm

http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm512493.htm

https://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4078B1_07_Bioequivalence-Testing.pdf

https://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4078B1_07_Bioequivalence-Testing.pdf

https://pharm.ucsf.edu/sites/pharm.ucsf.edu/files/cersi/media-browser/OGD_Slides.pdf

https://pharm.ucsf.edu/sites/pharm.ucsf.edu/files/cersi/media-browser/OGD_Slides.pdf

https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_007051_043461_RCP.pdf%26retry=0%26sys=m0b1l3



https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021324s012s013lbl.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021324s012s013lbl.pdf

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM270541.pdf



50. Kamm MA, Sandborn WJ, Gassull M, et al. Once-daily, high-con-centration MMX mesalamine in active ulcerative colitis.Gastroenterology. 2007;132:66–75.

51. Sandborn W, Kamm MA, Lichtenstein GR, et al. MMX Multi MatrixSystem mesalazine for the induction of remission in patients withmild-to-moderate ulcerative colitis: a combined analysis of tworandomized, double-blind, placebo-controlled trials. AlimentPharmacol Ther. 2007;26:205–215.

52. Frieri G, Giacomelli R, Pimpo M, et al. Mucosal 5-aminosalicylic acidconcentration inversely correlates with severity of colonic inflam-mation in patients with ulcerative colitis. Gut. 2000;47:410–414.

53. Naganuma M, Iwao Y, Ogata H, et al. Measurement of colonicmucosal concentrations of 5-aminosalicylic acid is useful for esti-mating its therapeutic efficacy in distal ulcerative colitis: compar-ison of orally administered mesalamine and sulfasalazine. InflammBowel Dis. 2001;7:221–225.

54. Sonu I, Lin MV, Blonsky W, et al. Clinical Pharmacology of 5-ASAcompounds in inflammatory bowel disease. Gastroenterol ClinNorth Am. 2010;39:559–599.

55. Nugent SG, Kumar D, Rampton DS, et al. Intestinal luminal pH ininflammatory bowel disease: possible determinants and implica-tions for therapy with aminosalicylates and other drugs. Gut.2001;48:571–577.

56. Garbacz G, Klein S. Dissolution test of oral modifed release dosagforms. J Pharm Pharmacol. 2012;64:944–968.

57. Garbazc G, Rappen GM, Koziolek M, et al. Dissolution of mesalazinemodified release tablets under standard and bio-relevant test con-ditions. J Pharm Pharmacol. 2015;67:199–208.

58. Wilding I. Bioequivalence testing for locally acting gastrointestinalproducts: what role for gamma scintigraphy? J Clin Pharmacol.2002;42:1200–1210.

59. Wilding IR, Kenyon CJ, Hooper G. Gastrointestinal spread of oralprolonged-release mesalazine microgranules (Pentasa) dosed aseither tablets or sachet. Aliment Pharmacol Ther. 2000;14:163–169.

60. Wilding IR, Behrens C, Tardif SJ, et al. Combined scintigraphic andpharmacokinetic investigation of enteric-coated mesalazine micropel-lets in healthy subjects. Aliment Pharmacol Ther. 2003;17:1153–1162.

61. Wray H, Joseph R, Palmen M, et al. Combined pharmacokinetic andscintigraphic analyses for the comparison of 5-ASA release profilesfrom MMX mesalamine and another delayed-release mesalamineformulation: P0030. Inflamm Bowel Dis. 2008;14:S19–S20.

62. Brunner M, Greinwald R, Kletter K, et al. Gastrointestinal transit andrelease of 5-aminosalicylic acid from 153Sm-labelled mesalazinepellets vs. tablets in male healthy volunteers. Aliment PharmacolTher. 2003;17:1163–1169.

63. Brunner M, Lackner E, Exler PS, et al. 5-aminosalicylic acid releasefrom a new controlled-release mesalazine formulation during gas-trointestinal transit in healthy volunteers. Aliment Pharmacol Ther.2006;23:137–144.

64. European Medicines Agency. Guideline on equivalence studies forthe demonstration of therapeutic equivalence for products that arelocally applied, locally acting in the gastrointestinal tract as adden-dum to the guideline on the clinical requirements for locallyapplied, locally acting products containing known constituents.2017 [cited 2017, May 15]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/04/WC500225230.pdf

•• The draft guidance that introduced a new regulatory paradigmfor the evaluation of bioequivalence for locally acting gastro-intestinal drugs in Europe.

65. Food and Drug Administration. Delzicol® (mesalazine) ClinicalPharmacology and Biopharmaceutic review(s). 2013 [cited 2017,May 15]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204412Orig1s000ClinPharmR.pdf

66. Medicine and Healthcare products Regulatory Agency. Norasa®(mesalazine) Public assessment report. 2010 [cited 2017, May 15].Available from: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con096943.pdf

67. Food and Drug administration. Orange book: approved mesalazineproducts with therapeutic equivalence Evaluations. 2017 [cited

2017, May 15]. Available from: https://www.accessdata.fda.gov/scripts/cder/ob/search_product.cfm

68. Heads of Medicines Agency. Public Assessment report forMesalazine in European Union. [cited 2017, May 15]. Availablefrom: http://mri.cts-mrp.eu/Human/Product/AdvancedSearch

69. Food and Drug Administration. Guidance for Industry.Bioequivalence Recommendations for Specific Products; 2010[cited 2017, May 15]. Available from: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072872.pdf

70. Food andDrug Administration. Product-specific guidances for genericdrug development. 2017 [cited 2017, May 15]. Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm

71. Food and Drug Administration. Response to Dockets No. FDA-2010-P-0111 and FDA-2008-P-0-507. 2010 [cited 2017, May 15].Available from: https://www.regulations.gov/document?D=FDA-2010-P-0111-0011

•• In these citizen petitions, the FDA introduced the partial AUCas pharmacokinetic parameter able to correlate mesalamineplasma profile with its local concentrations at the site ofaction.

72. Food and Drug Administration. Draft guidance on mesalamine.Delayed release tablet 400 mg; 2016 [cited 2017, May 15].Avai lable f rom: http ://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320002.pdf

73. Food and Drug Administration. Draft guidance on mesalamine.Delayed release tablet 800 mg; 2016 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320003.pdf Accessed 24 Apr 2017.

74. Food and Drug Administration. Draft guidance on mesalamine.Delayed release tablet 1200 mg; 2016 [cited 2017, May 15].Avai lable f rom: http ://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320004.pdf

75. Food and Drug Administration. Draft guidance on mesalamine.Delayed release capsule 400 mg; 2016 [cited 2017, May 15].Avai lable f rom: http ://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM384149.pdf

76. Food and Drug Administration. Draft guidance on mesalamine.Extended release capsule 375 mg; 2014 [cited 2017, May 15].Avai lable f rom: http ://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320000.pdf

77. Food and Drug Administration. Draft guidance on mesalamine.Extended release capsule 500 mg; 2014 [cited 2017, May 15].Avai lable f rom: http ://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM319999.pdf

78. European Medicines Agency. Note for Guidance on the clinicalrequirements for locally applied, locally acting products containingknown constituents. 1995 [cited 2017, May 15]. Available from:http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003687.pdf

• The first guideline issued by EMA focusing on authorizationpathway that should be followed for the development of dif-ferent type of local acting drug products.

79. European Medicines Agency. Concept paper on the developmentof a guideline on the demonstration of therapeutic equivalence forlocally applied and locally acting products in the gastrointestinaltract. 2013 [cited 2017, May 15]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/10/WC500150770.pdf

80. European Medicines Agency. Concept paper on the developmentof product-specific guidance on demonstration of bioequivalence.2013 [cited 2017, May 15]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/07/WC500147001.pdf





https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204412Orig1s000ClinPharmR.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204412Orig1s000ClinPharmR.pdf

http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con096943.pdf

http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con096943.pdf

https://www.accessdata.fda.gov/scripts/cder/ob/search_product.cfm

https://www.accessdata.fda.gov/scripts/cder/ob/search_product.cfm

http://mri.cts-mrp.eu/Human/Product/AdvancedSearch

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072872.pdf



http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm



https://www.regulations.gov/document?D=FDA-2010-P-0111-0011


http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320002.pdf


























81. European Medicines Agency. List of product-specific bioequiva-lence guidance. [cited 2017, May 15]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000625.jsp&mid=WC0b01ac0580848f74

82. Food and Drug Administration. Regulatory science priorities forfiscal year 2017. 2017 [cited 2017, May 15]. Available from:https :/ /www.fda .gov/downloads/For Industry/UserFees/GenericDrugUserFees/UCM526900.pdf

83. NCT01999400. Correlation of Mesalamine Pharmacokinetics WithLocal Availability. [cited 2017, May 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT01999400

84. Sun D, Amidon GL Potential New Method to ImproveBioequivalence (BE) of Modified Release (MR) Drug Products by invivo Dissolution Studies In Human GI tract. [cited 2017, May 15].Available from: http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM506184.pdf

85. Sun D In Vivo Drug Dissolution in GI tract, Computational Model,and Wireless Pharmaceutical Analysis Device to Ensure BE andProduct Quality of Generic Drugs. [cited 2017, May 15]. Availablefrom: http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM450800.pdf

86. Jones HM, Gardner IB, Watson KJ. Modelling and PBPK simulationin drug discovery. Aaps J. 2009;11:155–166.

87. Benjamin B, Barman TK, Chaira T, et al. Integration of physicochem-ical and pharmacokinetic parameters in lead optimization: a phy-siological pharmacokinetic model based approach. Curr DrugDiscov Technol. 2010;7:143–153.

88. Jiang W, Kim S, Zhang X, et al. The role of predictive biopharma-ceutical modeling and simulation in drug development and regu-latory evaluation. Int J Pharm. 2011;18:151–160.

89. Jones HM, Chen Y, Heimbach T, et al. Physiologically based pharmaco-kineticmodeling in drug discovery and development: a pharmaceuticalindustry perspective. Clin Pharmacol Ther. 2015;97:247–262.

90. Zhang X, Lionberger RA. Modeling and simulation of biopharma-ceutical performance. Clin Pharmacol Ther. 2014;95:480–482.

91. Innovative Medicines Initiatives. Orbito Project [cited 2017, May15]. Available from: https://www.imi.europa.eu/content/orbito

92. Zhao L The utility of modeling and simulation in understandinglocally acting drug delivery. 2016 [cited 2017, May 15]. Availablefrom: https://zerista.s3.amazonaws.com/item_files/4037/attachments/264334/original/425.pdf

93. Food and Drug Administration. Mechanistic Oral AbsorptionModeling and Simulation for Formulation Development andBioequivalence Evaluation. 2016 [cited 2017, May 15]. Availablefrom: https://www.fda.gov/Drugs/NewsEvents/ucm488178.htm

94. Liongberger R Application of PBPK models in assessment of bioe-quivalence. 2014 [cited 2017, May 15]. Available from: https://zerista.s3.amazonaws.com/item_files/0df5/attachments/31736/original/248.pdf

95. Food and drug Administration. Physiologically-Based Absorptionand Pharmacokinetic Models models. 2017 [cited 2017, May 15].Available from: https://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm503044.htm

96. Food and Drug Administration. Oral absorption and simulation forformulation development and bioequivalence evaluation. 2016[cited 2017, May 15]. Available from: http://www.fda.gov/downloads/Drugs/NewsEvents/UCM505000.pdf

97. Food and Drug Administration. Physiologically BasedPharmacokinetic Analyses - Format and Content. 2016 [cited2017, May 15]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM531207.pdf

98. European Medicines Agency. Draft Guideline on the qualificationand reporting of physiologically based pharmacokinetic (PBPK)modelling and simulation. 2016 [cited 2017, May 15]. Availablefrom: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500211315.pdf

99. Food and Drug Administration. Response to Docket No. FDA-2013-P-0470. 2013 [cited 2017, May 15]. Available from: https://www.regulations.gov/document?D=FDA-2013-P-0470-0003


http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000625.jsp%26mid=WC0b01ac0580848f74



https://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM526900.pdf

https://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM526900.pdf

https://clinicaltrials.gov/ct2/show/NCT01999400

https://clinicaltrials.gov/ct2/show/NCT01999400

http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM506184.pdf




https://www.imi.europa.eu/content/orbito

https://zerista.s3.amazonaws.com/item_files/4037/attachments/264334/original/425.pdf

https://zerista.s3.amazonaws.com/item_files/4037/attachments/264334/original/425.pdf

https://www.fda.gov/Drugs/NewsEvents/ucm488178.htm

https://zerista.s3.amazonaws.com/item_files/0df5/attachments/31736/original/248.pdf



https://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm503044.htm

https://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm503044.htm

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM505000.pdf

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM505000.pdf








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