q /GS3 gs BT 0.031 Tw 0 Tr Q ET /GS2 gs 0 0 0 1 k BT (o)Tj /GS3 gs 0 Tr Q 0 Tr ET Therefore, in the assessment of a biosimilar, the PK comparison should also reflect the distribution and elimination processes (e.g. q /GS2 gs 0 0 0 1 k In case of fixed combinations this may imply, if pre-specified in the protocol, the use of different batches for each component. /F5 1 Tf q ET 0 Tr (stopping metolazone treatment)Tj /GS2 gs /GS2 gs S /F6 1 Tf /GS3 gs 0 Tr (haloperidol 0.5 mg bd)Tj /F1 1 Tf BT 0 Tr /GS3 gs 3.33333 0 TD 0 Tw The assessment of bioequivalence is based upon 90% confidence intervals for the ratio of the population geometric means (test/reference) for the parameters under consideration. /F6 1 Tf 0 Tc 0 0 0 1 k BT 0 Tc Q /GS3 gs Q 16 0 0 16 108 192.381 Tm BT 0 Tr ET 0 Tc /GS3 gs 0 0 0 1 k (Q44)Tj /F0 1 Tf (3)Tj ET BT /GS2 gs /F6 1 Tf ET /F0 1 Tf /F6 1 Tf /F5 1 Tf (B)Tj /GS2 gs [(T)100(est 1: Questions)]TJ 0 Tw No recommendation can be based on the total concentration in this situation. /GS3 gs (o)Tj ET q q (2)Tj 16 0 0 16 108 264.381 Tm BT 1/ Corr) states that: “If bioequivalence has been demonstrated at the strength(s) that are most sensitive to detect a potential difference between products, in vivo bioequivalence studies for the other strength(s) can be waived”, this implies that when bioequivalence has been demonstrated in vivo for the test product, in vivo bioequivalence studies for the other strength can be waived. 16 0 0 16 118.205 543.381 Tm BT 9 0 0 9 84 396.131 Tm Q 10 0 0 10 126 59.131 Tm q /GS2 gs ET 0.029 Tw BT (1, 2 only)Tj q 0 Tr /F0 1 Tf 0.031 Tw 0 Tr (2)Tj q 16 0 0 16 118.205 488.381 Tm 0 Tc /GS3 gs 9 0 0 9 84 235.131 Tm BT Q Further, the different sensitivities arising from non-linear pharmacokinetics only apply to in vivo studies. /GS2 gs September 2017. /GS3 gs /GS2 gs /GS2 gs 0 Tw 0 Tc Asthma Allergy 2:73-92, 6. /GS3 gs /GS2 gs (o)Tj q Q /F5 1 Tf 0 Tc Q q ET 0 Tc Q 16 0 0 16 108 458.381 Tm (Q52)Tj /F5 1 Tf q /GS3 gs /GS2 gs /GS3 gs 16 0 0 16 118.205 504.381 Tm Q 0 Tr BT 0 0 0 1 k Procedure for European Union guidelines and related documents within the pharmaceutical legislative framework 0 Tr Q ET Q 35 0 obj 0.029 Tw /F5 1 Tf 0 Tc Q 0 Tc 0 Tr 10 0 0 10 136.205 175.131 Tm ET /GS3 gs 0 Tw 16 0 0 16 108 265.381 Tm 16 0 0 16 118.205 295.381 Tm For drugs with significant oral bioavailability (e.g., budesonide, formoterol, salmeterol), a PK study with active charcoal is necessary to assess efficacy, and a study without charcoal is used to assess safety. (2007) Workshop/Conference Report: Quantitative bioanalytical methods validation and implementation: best practices for chromatographic and ligand binding assays. 0 0 0 1 k 0 Tc Q /GS2 gs [(Methylcellulose eye drops to be used as requir)-1(ed are recommended to HG. /GS2 gs 0 Tr BT /F0 1 Tf ET 0 Tc 0 Tr /GS3 gs /F6 1 Tf 0 Tr Q 0 0 0 1 k ET D. A. Adkin, S. S. Davis, R. A. Sparrow, P. D. Huckle, A. J. Philips I. R. Wilding (1995). 0 0 0 1 k /GS2 gs /GS2 gs ET Q /GS2 gs BT 10 0 0 10 136.205 412.131 Tm q 0 Tc /GS3 gs 0 0 0 1 k Therefore, a possible effect of fluid intake during administration on the bioavailability of an oral solution/suspension cannot be excluded. /F6 1 Tf It is important to note that clopidogrel is approved and recommended for use in acute clinical conditions, for which a high loading dose is advised in order to attain a fast antiplatelet action. /F6 1 Tf 16 0 0 16 108 527.381 Tm ( )Tj /GS3 gs 0 Tc 0 Tr BT (1)Tj Q /GS3 gs ET Q q 0 0 0 1 k /GS3 gs ET /F5 1 Tf /GS2 gs 10 0 0 10 84 368.131 Tm Q 0 0 0 1 k 0 Tr 0.029 Tw 0.029 Tw q Q 0 Tr 0.029 Tw 0 Tc stream /F5 1 Tf /F6 1 Tf 0 Tr However at the present time due to low confidence in the use of PBPK modelling to predict hepatic impairment, it is considered that there is no need to revise the general information given on PBPK modelling. /F6 1 Tf (o)Tj q ET 0 0 0 1 k (o)Tj Q I preparing for Interview with NHS (Support and Recovery Worker) please can you help with any specific or likely hood questioned. /GS2 gs (A)Tj (2, 3 only)Tj 0 Tr 0 Tr 0 Tc ET 10 0 0 10 94.205 368.131 Tm 0 0 0 1 k 10 0 0 10 58.205 302.131 Tm 9 0 0 9 94.205 219.131 Tm q Q 10 0 0 10 94.205 354.131 Tm /F6 1 Tf 0 0 0 1 k /GS2 gs /GS3 gs Q 9 0 0 9 94.205 294.131 Tm BT Q BT /GS2 gs 0 Tc 0 Tr 0 Tr 0.029 Tw A model which also includes a term for a formulation*stage interaction would give equal weight to the two stages, even if the number of subjects in each stage is very different. Q /GS2 gs ET ET q /GS2 gs /F6 1 Tf (Dr)Tj 0 Tc /F6 1 Tf 0 Tc Q (o)Tj 0 Tr 9 0 0 9 94.205 490.131 Tm 0 Tc 0 Tc Regarding the excipients, these are shown as the filler and all other excipients. In case of gastro-resistant formulations the release occurs after gastric emptying (median approx. Q (o)Tj ET q /GS3 gs 10 0 0 10 84 346.131 Tm 0 Tr 0 Tr 0 Tc BT 0.031 Tw ET Q 0 Tr (1, 2 only)Tj 5.68789 0 TD /F6 1 Tf A biosimilar product contains a version of the active substance of an already authorised original product (see 'Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues' EMEA/CHMP/BMWP/42832/2005 Rev1). /GS3 gs q On the contrary, bioequivalent (BE) results could be extrapolated to the 300 mg strength on the basis of dissolution data since respective comparisons complied with the f2 criterion. BT q 0 0 0 1 k /F5 1 Tf 0 Tc /GS3 gs BT 0 Tc /GS3 gs 0.029 Tw /GS3 gs /GS3 gs 0 0 0 1 k ET 0 Tw 0.031 Tw /GS3 gs 0 Tr << /GS3 gs Q 9 0 0 9 84 58.131 Tm Q 48 434.007 336 99 re q 0 0 0 1 k 0 0 0 1 k 0 Tr (A)Tj Q ET 0.029 Tw For replicate designs the results from the two approaches will differ if there are subjects included in the analysis who do not provide data for all treatment periods. 0 Tc /GS2 gs (C)Tj 0 Tc LB is pr)Tj 0 Tc /GS2 gs BT /F0 1 Tf 9 0 0 9 94.205 209.131 Tm /GS3 gs /GS2 gs /GS2 gs 0 0 0 1 k 0 Tc BT /F6 1 Tf /GS2 gs 16 0 0 16 108 294.381 Tm 0 Tc q 0 Tc (o)Tj q Q ET Thus the same statistical models can be used regardless of the design. Q 0 Tw (act as antibodies to thyroglobulin)Tj 0 Tr endstream 0 Tc Q /GS2 gs ET /GS2 gs q 0 0 0 1 k (and who is complaining of polyuria and weakness. /F0 1 Tf (2)Tj BT /F0 1 Tf 0 Tr Q BT q 0 0 0 1 k BT (Q73)Tj BT /GS3 gs q 9.90462 0.00001 TD /GS2 gs (losar)Tj 0 Tc /F0 1 Tf Q q q q ET October 2014. /GS3 gs q (B)Tj 0 0 0 1 k 0 Tr 0.029 Tw BT 0 Tc /GS2 gs ET ET Q ET /GS3 gs 0 Tc ET Q /GS2 gs ET 0.35083 0 TD ET q q /GS2 gs 0 Tr q 0 Tc 10 0 0 10 126 79.131 Tm T. Yamaguchi, T. Hashizume, M. Matsuda, M. Sakashita, T. Fujii, Y. Sekine, M. Nakashima T. Uematsu (1994) Pharmacokinetics of the H1-receptor antagonist ebastine and its active metabolite carebastine in healthy subjects. 0 0 0 1 k 0 Tc ET (2)Tj /GS3 gs 0 0 0 1 k ET /GS1 gs 0 Tr 0 0 0 0.5 k /GS3 gs 10 0 0 10 126 143.131 Tm 0 0 0 1 k (1, 2 only)Tj ET Due to scientific and ethical reasons sensitisation testing by means of the human repeat insult patch test as described should be conducted in exceptional cases only as subjects might unnecessarily be sensitised and the sample size may not include sensitive subjects (i.e. /GS3 gs /GS2 gs 0 0 0 1 k q q 9 0 0 9 94.205 396.131 Tm 10 0 0 10 136.205 200.131 Tm 0 0 0 1 k 0 Tw /GS2 gs /F0 1 Tf q 0 0 0 1 k 0 0 0 1 k 0 0 0 0.5 k Q 0 Tc 0 0 0 1 k 1 g /GS2 gs ET /F6 1 Tf 0 Tc q (macy)Tj Hence, the ratio between active substance A and ‘filler’ (filler + active substance B) is the same for both strengths. 0 Tr (o)Tj 9 0 0 9 84 74.131 Tm q BT q 0 Tr /GS3 gs 0 Tc ET (o)Tj BT BT q (educed)Tj 0 Tr T* The attempt to scientifically justify the lack of ISR is considered only appropriate for the very practical reason that a study was performed before the Guideline on Bioanalytical Method Validation came into force. 0 Tr BT /GS3 gs In conclusion, applicants are advised to use Appendix I and this QA to address sensitisation and irritation testing of transdermal patches carefully, taking account of product characteristics and based on current knowledge. 0 0 0 1 k 0 0 0 1 k 0 Tr (Gentamicin:)Tj ET /GS3 gs /GS3 gs 10 0 0 10 48 446.131 Tm /F5 1 Tf /F5 1 Tf 10 0 0 10 126 142.131 Tm Q 0 Tr q Q /GS2 gs 0 Tc >> 9 0 0 9 94.205 375.131 Tm 0 Tr /F0 1 Tf Who? 0 0 0 1 k The results can be very misleading hence such a model is not considered acceptable. Q q Q 0 0 0 0.5 k Q Even though the choice of sampling time points could be questioned, there is no scientific reason to exclude valid data in a calculation. /GS3 gs Q q Q 0 0 0 1 k /GS3 gs (o)Tj 0 Tr /GS3 gs 0 0 0 1 k /GS2 gs ET /F6 1 Tf data generated from trials started before the implementation of the new guideline). BT /GS2 gs 0 Tw /F5 1 Tf 0 Tr /GS2 gs BT q q Q [(to repor)-20(t any muscle pain or weakness)]TJ /F0 1 Tf q 9 0 0 9 84 444.131 Tm Q /F5 1 Tf (1)Tj /GS3 gs BT BT 0 Tc 0 Tr Regarding the MD, it is a dissimilarity measure between two random vectors x and y of the same length, which takes into account the correlations in the data set. 0 0 0 1 k /GS2 gs q 0 Tw 9.35349 0.00001 TD /F6 1 Tf /GS2 gs /GS2 gs BT 10 0 0 10 136.205 42.131 Tm Q The requirements for the investigation of bioequivalence/comparative bioavailability for oral solutions and suspensions regarding fluid intake during administration can be summarised as follows: Rationale:Changing the volume of fluid intake can affect the gastrointestinal transit time and in certain cases the in vivo solubility of the active substance and/or the concentration of a critical excipient and hence the absorption of the active substance. /GS2 gs Q Q /GS3 gs (2)Tj /GS2 gs (Side-ef)Tj 0 Tc /Length 8236 ET q 16 0 0 16 108 141.381 Tm ET ET 16 0 0 16 118.205 134.381 Tm q /GS2 gs 0 Tr 0.029 Tw 0 Tc BT /GS3 gs q /F0 1 Tf 0 Tc q /Length 6420 0 Tc /GS3 gs /F5 1 Tf /GS3 gs /F5 1 Tf Q 0 Tc q Q q BT /GS2 gs 16 0 0 16 108 343.381 Tm /GS3 gs /GS2 gs 0 0 0 1 k 0 Tr Q BT /F5 1 Tf q [(Caution should be under)-20(taken when star)-20(ting thyroxine in:)]TJ 0.029 Tw /GS2 gs q q /GS3 gs 0 Tr q 0 Tc q 0 0 0 1 k q 0 0 0 1 k (2006) Effect of food on bioavailability of a single oral dose of clopidogrel in healthy male subjects Arzneimittelforschung 56(11); 735-9. 0 0 0 1 k 0 0 0 1 k 9 0 0 9 112.1065 9.4794 Tm 0 Tc /F5 1 Tf /F0 1 Tf 0 Tr /GS2 gs /GS3 gs << /GS3 gs /F0 1 Tf (ections:)Tj 0 Tc /GS2 gs /GS3 gs /GS2 gs 0 Tr /F2 1 Tf (Q27)Tj 0 0 0 1 k /F6 1 Tf 9 0 0 9 94.205 529.131 Tm For the scientific justification of the lack of ISR the applicant should take all the following points into consideration: The applicant should support that back conversion is not an issue for the drug compound or that the risk of back conversion on the outcome of the study results is low as for instance it is known that the drug compound is (almost) not metabolised. 0 0 0 1 k 10 0 0 10 136.205 193.131 Tm (2, 3 only)Tj /GS2 gs q /GS2 gs 0.031 Tw ET q BT /GS2 gs /F0 1 Tf /GS2 gs q 0 Tr q q 0 Tc 0 Tc /F0 1 Tf 0 Tc /GS2 gs q 0 Tc ET ET ET 16 0 0 16 118.205 297.381 Tm BT /GS3 gs 0 0 0 1 k Q /F0 1 Tf /GS3 gs Q /GS2 gs 0 Tr /F5 1 Tf q (development of heat rash)Tj 0 0 0 1 k 0 Tw W n Q 0 Tr (3 only)Tj /F6 1 Tf BT 10 0 0 10 136.205 42.131 Tm 0 0 0 0.5 k ET 0 Tc /GS2 gs /GS3 gs BT 0 Tr 0 Tr 0 Tr Prepare list of questions in order to ask the employer during job interview. /F0 1 Tf (3)Tj 0 Tc 9 0 0 9 94.205 458.131 Tm (D)Tj /GS3 gs Q ET Q 16 0 0 16 108 488.381 Tm 0 Tc Q q /F5 1 Tf (1, 2 only)Tj /F0 1 Tf q BT q 0 0 0 1 k 0 Tr 0 0 0 1 k /GS3 gs 0 0 0 1 k /GS3 gs ET q BT 0 Tc BT /GS2 gs BT /GS2 gs ET (o)Tj 0 Tr 0.034 Tw ET q ET 0 0 0 1 k /F6 1 Tf 9 0 0 9 94.205 490.131 Tm /GS2 gs (o)Tj 0.029 Tw 0 Tc /GS2 gs ET Q 9 0 0 9 84 203.131 Tm ET (t failure)Tj (B)Tj 9 0 0 9 94.205 398.131 Tm 0 Tr 0 0 0 1 k /GS2 gs /GS2 gs 0 Tc (egular inter)Tj 0 0 0 1 k q 0 Tr BT 0 0 0 1 k ET BT q endstream Q BT 0 0 0 1 k Q /GS2 gs Q Q /GS3 gs 0 0 0 1 k A more accurate picture of the PK profile of clopidogrel can be obtained. 0 0 0 1 k /GS3 gs /GS2 gs 0 0 0 1 k q /F5 1 Tf /F9 1 Tf /GS3 gs /GS2 gs 0 0 0 1 k 10 0 0 10 84 176.131 Tm (headache)Tj 10 0 0 10 126 136.131 Tm 0 Tr /GS2 gs q BT (o)Tj ET The following text on the general analysis of bioequivalence studies is included in the guidance document. ET /GS3 gs 0 Tc Q /GS3 gs (glaucoma)Tj q /GS3 gs ET /GS2 gs 9 0 0 9 84 283.131 Tm (Manifestations of bacterial endocarditis include:)Tj 0 Tc /F0 1 Tf 16 0 0 16 118.205 520.381 Tm 0 Tr ET 0 Tc Q Q 0 Tc 10 0 0 10 136.205 243.131 Tm /GS3 gs /F5 1 Tf Q 9 0 0 9 84 293.131 Tm /F5 1 Tf /F6 1 Tf 0.029 Tw /F2 1 Tf 0 Tc 0 Tc ET 16 0 0 16 118.205 201.381 Tm 0 Tc Q 0 0 0 1 k q 8.39605 0.00001 TD q 0 Tr (o)Tj /GS2 gs Similar results have been observed in applications for generic medicinal products. q 0 Tr Q Especially with pivotal studies it should be ensured that the results are reliable. /F5 1 Tf q /GS3 gs 0.029 Tw /F0 1 Tf BT 0 Tc (1, 2, 3)Tj /GS3 gs 0 Tr 0.029 Tw 9 0 0 9 84 308.131 Tm (1, 2 only)Tj 16 0 0 16 108 235.381 Tm ET (1992) Pharmacokinetic studies of ebastine in rats, dogs and man. (cough)Tj 0 Tr ET /GS3 gs BT /F0 1 Tf q 0 0 0 1 k (E)Tj q 16 0 0 16 108 504.381 Tm 0 Tr /GS3 gs Q 0 0 0 1 k 0 0 0 1 k /GS3 gs 0 Tw /GS3 gs 9 0 0 9 84 366.131 Tm BT [(reduces the in\337ammator)-40(y reaction to urate cr)-40(ystals)]TJ /GS2 gs /GS2 gs BT /F5 1 Tf q ET /GS2 gs 9 0 0 9 94.205 267.131 Tm /GS2 gs 0 Tc /GS3 gs /GS2 gs (3)Tj /GS3 gs [(glimepiride 1 mg daily and atenolol 100 mg daily)80(. 0 Tr is encouraged in the guideline. ET 16 0 0 16 118.205 520.381 Tm (r)Tj 0 0 0 1 k (o)Tj q /GS3 gs 0 Tr (o)Tj BT BT 0 0 0 1 k 9 0 0 9 94.205 203.131 Tm Q 0 Tr 0 Tc 0 Tc /GS3 gs q 0 0 0 1 k 0 Tc /GS3 gs Q 0 Tr 9 0 0 9 94.205 225.131 Tm 0 Tr /GS2 gs /GS2 gs 0 0 0 1 k /F5 1 Tf q (B)Tj 9 0 0 9 94.205 90.131 Tm /F0 1 Tf ET /GS3 gs >> /GS2 gs q /GS2 gs >> 10 0 0 10 136.205 506.131 Tm ET 0 Tr 0 Tc /GS2 gs /GS3 gs 0 Tr 0 Tc /F0 1 Tf Q 0 0 0 1 k q /GS3 gs BT (1 only)Tj BT BT This issue was assessed by the EWP-CVS subgroup. 0.029 Tw 0 Tc 0 Tc /F0 1 Tf (o)Tj 0.029 Tw Immunol. 0 Tc /GS3 gs q /GS2 gs Q (o)Tj Q Q /F5 1 Tf /GS3 gs 9 0 0 9 94.205 251.131 Tm q 0 Tr 0 0 0 1 k BT (metronidazole)Tj ET 0 0 0 1 k /F6 1 Tf q /GS2 gs 0 Tc 0 Tc q 0 Tc q 0 Tr 0 Tc 0 Tr 0 0 0 1 k 0 Tc /F0 1 Tf /GS3 gs 0 Tr /GS2 gs /GS2 gs BT q 0 0 0 1 k 0 Tr BT 0 Tr Q 0 Tr BT Q 0 0 0 1 k 0 0 0 1 k /GS2 gs 0 Tr (C)Tj /GS2 gs Q /GS3 gs /GS2 gs /GS3 gs /GS3 gs /GS3 gs q ET stream /F6 1 Tf 0 Tc BT /F0 1 Tf In case the SmPC of the reference product states that the product should be administered without water and the test product claims the same then during the study both products should be administered without water.