European Medicines Agency
Pre-Authorisation Evaluation of Medicines for Human U
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E-mail: mail@emea.europa.eu a.europa.eu
London, 24 July 2008 Doc. Ref. CPMP/EWP/QWP/1401/98 Rev. 1
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE
(CHMP)
DRAFT GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE
DRAFT AGREED BY THE EFFICACY WORKING PARTY
July 2008 ADOPTION BY CHMP FOR RELEASE FOR CONSULTATION
24 July 2008 END OF CONSULTATION (DEADLINE FOR COMMENTS) 31 January 2009
This guideline will replace the “Note for guidance on the investigation of bioavailability and bioequivalence" CPMP/EWP/QWP/1401/98 and the related questions in the Q&A document (EMEA/CHMP/EWP/40326/2006). This guideline includes recommendations on BCS-bad biowaivers.
Comments should be provided to EWPSecretariat@emea.europa.eu using this template
KEYWORDS Bioequivalence, pharmacokinetics, biowaiver, in vitro dissolution, generics
GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE
TABLE OF CONTENTS
EXECUTIVE SUMMARY (3)
1
1.INTRODUCTION (BACKGROUND) (3)
2
3
2.SCOPE (4)
4
3.LEGAL BASIS (4)
5
4.MAIN GUIDELINE TEXT (5)
4.1D ESIGN, CONDUCT AND EVALUATION OF BIOEQUIVALENCE STUDIES (5)
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7
4.1.1Study design (5)
8
4.1.2Reference and test product (6)
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9
4.1.3Subjects (7)
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4.1.4Study conduct (7)
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4.1.5Characteristics to be investigated (9)
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4.1.6Strength and do to be investigated (10)
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4.1.7Chemical analysis (12)
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4.1.8Evaluation (12)
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4.1.9Narrow therapeutic index drugs (15)
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4.1.10Highly variable drugs or drug products (16)
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4.2I N-VITRO DISSOLUTION TESTS (16)
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4.2.1In-vitro dissolution tests complementary to bioequivalence studies (16)
4.2.2In-vitro dissolution tests in support of biowaiver of strengths (16)
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4.3V ARIATIONS (16)
4.4S TUDY REPORT (17)
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DEFINITIONS (17)
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APPENDIX I (19)
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D ISSOLUTION TESTING (19)
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APPENDIX II (21)
B IOEQUIVALENCE STUDY REQUIREMENTS FOR DIFFERENT DOSAGE FORMS (21)
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APPENDIX III (24)
BCS-BASED B IOWAIVER (24)
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APPENDIX IV (28)
D ECISION TREE ON MEASUREMENT OF PARENT COMPOUND OR METABOLITE (28)
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APPENDIX V (29)
D ECISION TREE ON SELECTION OF DOSE AND STRENGTH IN BIOEQUIVALENCE STUDIES (29)
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EXECUTIVE SUMMARY
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34
This guideline defines when bioequivalence studies are necessary and formulates requirements for 35
their design, conduct, and evaluation. The guideline focus primarily on bioequivalence for
immediate relea dosage forms with systemic action.
36
(background)
37
1. INTRODUCTION
38
Two medicinal products containing the same active substance are considered bioequivalent if their 39
bioavailabilities (rate and extent) after administration in the same molar do lie within acceptable 40
predefined limits. The limits are t to ensure comparable in vivo performance, i.e. similarity in
terms of safety and efficacy.
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42
In bioequivalence studies, the plasma concentration time curve is ud to asss the rate and extent of
43
absorption. Meaningful pharmacokinetic parameters and pret acceptance limits allow the final 44
decision on bioequivalence of the tested products. AUC, the area under the concentration time curve, 45
reflects the extent of exposure. C max, the maximum plasma concentration or peak exposure, and th
e
46
time to maximum plasma concentration, t max, are parameters that are influenced by absorption rate.
It is the objective of this guideline to define when bioequivalence studies are necessary and to
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formulate requirements for their design, conduct, and evaluation. The possibility of using in vitro 49
instead of in vivo studies is also addresd.
The concept of bioequivalence forms the basis for approval of generic application, but it may also be
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51
applicable to hybrid application, extensions and variations applications, and to different formulations 52
ud during the development of a new medicinal product containing a new chemical entity.
For generic applications, the purpo of establishing bioequivalence is to demonstrate equivalence in
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biopharmaceutic quality between the generic product and a reference medicinal product in order to 55
allow bridging of clinical data associated with the reference medicinal product. The current definition
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for generic products is found in Directive 2001/83/EC, Article 10(2)(b). In general, a generic product 57
is a product which has the same qualitative and quantitative composition in active substances as the
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reference medicinal product, the same pharmaceutical form as the reference medicinal product, and who bioequivalence with the reference medicinal product has been demonstrated by appropriate 59
60
bioavailability studies. By definition it is considered that different salts, esters, ethers, isomers, 61
mixtures of isomers, complexes or derivatives of an active substance are considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy.
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63
Furthermore, various immediate-relea oral pharmaceutical forms are considered to be one and the 64
same pharmaceutical form. It is also stated in the Directive that bioavailability studies need not be
65
required if it can be demonstrated that the generic medicinal product meets the relevant criteria for a 66
biowaiver.
67
Hybrid applications rely on the results of preclinical tests and clinical trials of an approved reference
medicinal product and include new data. The new data may include bioequivalence or comparative
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bioavailability data.
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Also applications for extensions such as additional dosage forms, new strengths, new routes of 71
administration often need support of bioequivalence in order to bridge data from the authorid 72
reference medicinal product.
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Variations for a change in composition or for significant manufacturing changes which may affect drug bioavailability may also require support of bioequivalence studies.
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During development of a new chemical entity, the principles of bioequivalence may be applied in 76
梦见怀孕了order to bridge data between different between a formulation ud in the pivotal clinical studies and the to-be-marketed formulation. In such situations however, wider acceptance 77
78
limits may be acceptable if the are justified bad on data provided with a complete application,
adequately addressing the clinical relevance of the widening from both a safety and efficacy 79
perspective. 80
2. SCOPE 81
This guideline focus on recommendations for bioequivalence studies for immediate relea 82
formulations with systemic action. 83
Specific recommendations regarding bioequivalence studies for modified relea products, 84
transdermal products and orally inhaled products are given in other guidelines (e ction 3). 85
Recommendation for the comparison of biologicals to reference medicinal products can be found in 86
guidelines on biosimilar products. Recommendations for pharmacokinetics of therapeutic proteins are 87
also described in a specific guideline (CPMP/EWP/89249/04). 88
In ca bioequivalence cannot be demonstrated using drug plasma concentrations, in exceptional 89
circumstances pharmacodynamic or clinical endpoints may be needed. This situation is outside the 90
scope of this guideline and the reader is referred to therapeutic area specific guidelines. 91
Furthermore, this guideline does not cover aspects related to generic substitution as this is subject to 92
national legislation. 93
3. LEGAL BASIS 94
This guideline applies to Marketing Authorisation Applications for human medicinal products 95
submitted in accordance with the Directive 2001/83/EC as amended, under Art. 8(3) (full 96
applications), Art 10b (fixed combination), Art. 10 (1) (generic applications), Art 10(3) (hybrid 97
applications), and also for line extension and variation applications in accordance with Commission 98
经邦济世Regulations (EC) No 1084/2003 and 1085/2003. 99
This guideline should be read in conjunction with the Annex I of Directive 2001/83/EC as amended, 100
as well as European and ICH guidelines for conducting clinical trials, including tho on: 101
广州财经学院− General Considerations for Clinical Trials (ICH topic E8, CPMP/ICH/291/95) 102 − Guideline for Good Clinical Practice (ICH E6 (R1), CPMP/ICH/135/95) 103 − Structure and Content of Clinical Study Reports (ICH E3, CPMP/ICH/137/95) 104 − CHMP guidance for urs of the centralid procedure for generics/hybrid applications 105 (EMEA/CHMP/225411/2006) 106
− Modified Relea Oral and Transdermal Dosage Forms: Section II (CPMP/EWP/280/96) 107 − Re
quirements for clinical documentation for orally inhaled products (OIP) including the 108 requirements for demonstration of therapeutic equivalence between two inhaled products for 109
u in the treatment of Asthma and Chronic Obstructive Pulmonary Dia (COPD) 110
(CPMP/EWP/4151/00 rev 1). 111
− Fixed Combination Medicinal Products (CPMP/EWP/240/95) 112 − Clinical Requirements for Locally Applied, Locally Acting Products containing Known 113 Constituents (CPMP/EWP/239/95) 114
− Good manufacturing practice (Eudralex volume 4). 115
The guideline should also be read in conjunction with relevant guidelines on pharmaceutical quality. 116
The test products ud in the bioequivalence study must be prepared in accordance with GMP-117
regulations. 118
Bioequivalence trials should be conducted in accordance to Directive 2001/20/EC of the European 119
parliament and of the Council. 120
Companies may also apply for CHMP Scientific Advice, via the EMEA, for specific queries not 121
covered by existing guidelines.
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4. MAIN GUIDELINE TEXT
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4.1 Design, conduct and evaluation of bioequivalence studies
125
In the following ctions, requirements for the design, conduct and evaluation of bioequivalence
studies investigating immediate relea formulations with systemic action are described.
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127
The formulation and the characteristics of the active substance can affect the requirements for
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bioequivalence studies. When the test product contains a different salt, ester, ether, isomer, mixture of 129
isomers, complex or derivative of an active substance than the reference product, bioequivalence 130
should be demonstrated in appropriate bioavailability studies. However, when the active substance in
131
test and reference products are identical or contain comparable salts, in vivo bioequivalence studies may, in some situations, not be required as described in APPENDIX II (bioequivalence study 132
133
requirements) and III (biowaiver).
134
The pharmacokinetic and physico-chemical properties of the substance affect the number of studies needed and the design of the studies. The choice of number of studies and study design should be 135
136
thoroughly justified bad on the physico-chemical characteristics of the substance and its 137
pharmacokinetic properties, discussing especially linearity in pharmacokinetics, activity of
138
metabolites, contribution of metabolites to the effect, the need for enantiolective analysis, and 139
solubility of the active substance. In the context of this guideline, high solubility and low solubility is 140
defined according to the Biopharmaceutics Classification System (BCS) definition of high and low
solubility, as defined in APPENDIX III.
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The clinical overview of an application for marketing authorisation should list all studies carried out
143
with the product applied for. All bioequivalence studies comparing the product applied for with the reference product of interest must be submitted.
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design
4.1.1 Study
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The study should be designed in such a way that the formulation effect can be distinguished from 147
other effects.
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Standard design
149
If two formulations are going to be compared, a two-period, two-quence single do crossover
150
design is the design of choice. The treatment periods should be parated by an adequate wash out 151
period.
152
页脚横线怎么添加Alternative designs
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In general, single do studies will suffice. However, in ca of do or time-dependent pharmacokinetics, resulting in markedly higher concentrations at steady state than expected from 154
155
single do data, a potential difference in AUC between formulations may be larger at steady state 156
than after single do. Hence, a multiple do study may be required in addition to the single do 157
study to ensure that the products are bioequivalent regarding AUC also at steady state. However, if the
158
single do study indicates very similar PK profile for test and reference (the 90% confidence interval 159
for AUC is within 90-111), the requirement for steady-state data may be waived.
In certain cas when a single do study cannot be conducted in healthy volunteers due to tolerability 160
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张莹莹reasons, and a single do study is not feasible in patients, conduct of a multiple do study in patients 162
may be acceptable (e also ction 4.1.6 Strength and Do).
A multiple do study as an alternative to a single do study may also be acceptable if problems of 163
164
nsitivity of the analytical method preclude sufficiently preci plasma concentration measurements
165
after single do administration. As C max at steady state may be less nsitive to differences in the absorption rate than C max after single do, bioequivalence should, if possible, be determined for C max 166
167
after the single do administration (i.e. after the first do of the multiple do study) as a measure of
