DOCSLIB.ORG

Buchanan Ingersoll 1.\\ Rooney PC

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Buchanan Ingersoll 1.\\ Rooney PC Buchanan Ingersoll 1.\\ Rooney PC 1700 K Street, N.W., Suite 300 Washington, DC 20006-3807 Edward John Allera T 202 452 7900 202 452 7985 F 202 452 7989 [email protected] www.bipc.com Barbara A. Binzak Blumenfeld 202 452 7906 [email protected] -V1 December 1, 2015 VIA HAND DELIVERY RETURN RECEIPT REQUESTED - Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services 5630 Fishers Lane, Rm. 1061 Rockville, MD 20852 CITIZEN PETITION On behalf of Concordia Pharmaceuticals ("Concordia" or "the Company"), sponsor of the 1 Lanoxin ® (digoxin tablets) new drug application ("NDA"), the undersigned submit this Citizen Petition ("Petition") and accompanying Expert Statement2 in five parts (one original plus four copies) pursuant to § 505Gi of the Federal Food, Drug, and Cosmetic Act ("FFDCA" or "the Act") and 21 C.P.R. § 10.20, § 10.30, and Part 320. Concordia requests that the Acting Commissioner of Food and Drugs take two specific actions. First, the U.S. Food and Drug Administration ("FDA" or "the Agency") should amend the May 2008 digoxin tablets bioequivalence guidance to reflect digoxin's narrow therapeutic index ("NTI") drug status and recommend more appropriate bioequivalence tests and specifications. Second, FDA should change the therapeutic equivalence rating for the approved generic digoxin tablet products in the "Approved Drug Products with Therapeutic Equivalence Evaluations" ("Orange Book") from AB to BX because they do not meet appropriate bioequivalence and other requirements to be considered therapeutically equivalent and therefore substitutable. FDA has long recognized that digoxin is an NTI drug product due to the narrow window between efficacious and toxic doses, as well as the need for therapeutic monitoring and dose adjustments. Digoxin was first marketed before 1938 and, in the 1970s, existing digoxin products were subject to FDA's batch certification program to ensure appropriate dissolution, potency, and bioavailability. Lanoxin was the first historical digoxin tablet product to receive NDA approval in 1997, and it is the reference listed drug ("RLD"). 1 NDA 20-405 (approved September 30, 1997). 2 Expert Statement ofManju Beier. 3 Codified at 21 U.S. C. § 355G). Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 20 15 Page2 The Agency's views on NTI drug bioequivalence have evolved in recent years in conjunction with the recommendations of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology ("AC"). These recommendations impact the design and acceptable pharmacokinetic ("PK") parameters for NTI drug bioequivalence studies. FDA agreed with these recommendations, and stated that its product-specific bioequivalence guidance documents for NTI drugs would incorporate appropriate study design and testing parameters. A number of these product-specific guidance documents, including warfarin, incorporate some of the AC's recommendations. However, the digoxin guidance was never updated to include them. FDA should therefore amend the May 2008 digoxin guidance to reflect, at a minimum, the same bioequivalence criteria that the Agency has already recommended for other NTI drugs, including: (1) 4-way, fully-replicated crossover in vivo fasting and fed studies; and (2) a reference-scaled average bioequivalence ("RSABE") approach. Concordia also urges FDA to include the AC's other NTI drug bioequivalence recommendations in the digoxin guidance as well- specifically: (3) a 90% confidence interval ("CI") for area under the curve ("AUC'') and maximum concentration ("Cmax") of 90-111.11%; and (4) a drug substance potency range of 95.0-105.0%. These requirements are imposed on NTI drugs such as oncology drugs. Four of the five abbreviated new drug applications ("ANDAs") for digoxin tablets were approved prior to issuance of the existing May 2008 digoxin guidance, and all five were approved before the AC's NTI drug bioequivalence recommendations from 2010 and 2011. Pursuant to the Agency's contemporary NTI standards, at least some of these drugs would not be bioequivalent to Lanoxin. Furthermore, ongoing concerns about digoxin bioavailability, content uniformity, dissolution, and potency- as well as recalls due to poor current good manufacturing practices ("cGMPs") and splitting digoxin tablets that may not be bioequivalent to Lanoxin - also raise bioequivalence questions. As a result, these generic digoxin products cannot be therapeutically equivalent to Lanoxin. Their AB ratings should be changed to BX. Substituting a generic drug that is not therapeutically equivalent to Lanoxin may result in sub- or supra-therapeutic doses causing severe adverse events or worse. As the RLD NDA holder, Concordia is responsible for maintaining its labeling, and inappropriate drug substitution raises significant questions of product liability for the Company. Because the safety and effectiveness of digoxin is called into question by inappropriate bioequivalence standards, specification concerns, and inadequate cGMPs, FDA should adopt the AC's recommendations for NTI drug bioequivalence studies before any generic is considered therapeutically equivalent to Lanoxin. A. Action Requested As addressed further herein, Concordia respectfully requests that FDA take the following actions: Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 3 1. Amend the May 2008 digoxin tablets bioequivalence guidance to reflect digoxin's NTI status and to recommend that generic drug sponsors meet the bioequivalence criteria recommended in other NTI drug guidance documents, including: a. Conducting a 4-way, fully-replicated crossover design for both in vivo fasting and fed studies; and b. Using an RSABE approach. Amend the digoxin guidance to reflect the AC's additional NTI drug bioequivalence recommendations, including: c. Meeting a bioequivalence range of 90-111.11% for the 90% CI for both AUC and Cmax, and require that the data "cross the one" (i.e., cross the 100% point); and d. Meeting a drug substance potency range of95.0-105.0%. 2. Determine that approved generic digoxin oral drug products are not therapeutically equivalent to Lanoxin and should therefore be rated BX. The bases for our requests are discussed in detail below. B. Statement of Grounds I. INTEREST OF CONCORDIA A. Concordia is the Lanoxin NDA Holder and Therefore Responsible for Maintaining Product Labeling Concordia acquired NDA 20-405 for Lanoxin oral tablets from Covis Pharma Sarl ("Covis") on April 21, 2015. As the current NDA holder, Concordia remains responsible for monitoring, collecting, and reporting adverse events associated with the drug product to FDA. The Company also remains responsible for updating its labeling based upon new safety and pharmacovigilance signals, which generic digoxin drug sponsors rely upon for their own product labeling. Concordia has a vested interest in ensuring that any generic digoxin drugs are, in fact, bioequivalent and therefore therapeutically equivalent to Lanoxin. Approving a generic digoxin product that does not meet appropriate NTI drug bioequivalence criteria will introduce drug variability making therapeutic substitution potentially dangerous for patients. It also creates marketplace liability risks for Concordia. These labeling responsibilities and potential liability issues are discussed in greater detail in Section V.G. herein. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page4 B. The Current Petition is an Extension of Two Earlier Petitions This current Petition is an extension of the issues raised in two prior petitions that Co vis filed in 2013. The first petition,4 filed on October 21, 2013, requested that FDA require all ANDA sponsors of digoxin 0.0625 mg and 0.1875 mg dosage strengths to conduct and pass all validation testing that FDA required Covis to perform, namely dissolution and blend uniformity. That Bioequivalence Petition also requested that FDA not grant testing waivers for these two dosage strengths. Covis filed a second petition5 on October 21, 2013 asking FDA to confirm that the Agency had not fully approved the 0.0625 mg and 0.1875 mg Lanoxin tablets in 1997, and that the awarded three-year exclusivity for these two strengths only began running in October 2013 when FDA approved Covis' prior approval supplement ("PAS") containing the validation testing refe1Ted to above. FDA has not yet responded to this Exclusivity Petition or to the Bioequivalence Petition. Neither petition requested amendment of the digoxin bioequivalence guidance to reflect digoxin's NTI status, and neither raised the issue of therapeutic equivalence. As a result, this current Petition is intended to complement and not duplicate those previous 2013 submissions. Because the issues are inteiTelated, Concordia requests that FDA render decisions on all of the petitions at the same time. II. DIGOXIN BACKGROUND A. Digoxin is an NTI Drug Digoxin is a cardiac glycoside used to treat a number of cardiovascular conditions. Lanoxin tablets are indicated for (1) treatment of mild to moderate heart failure in adults; (2) increasing myocardial contractility in pediatric patients with heart failure; and (3) control of resting ventricular rate in patients with chronic atrial fibrillation in adults. 6 Digoxin is an NTI drug because therapeutic levels are only slightly lower than toxic
Load more

Recommended publications
  • Bioequivalence Study Protocol
    Study Code: Date: NOV2020/01917 NCT04406194 28.04.2020 Version: Clinical Study Protocol 1.0 OPEN-LABEL, RANDOMISED, SINGLE ORAL DOSE, TWO-PERIOD, CROSS-OVER TRIAL TO ASSESS THE FAVICOVIR 200 MG FILM BIOEQUIVALENCE OF TABLET (TEST DRUG) IN COMPARISON WITH AVIGAN 200 MG FILM TABLET (REFERENCE DRUG) IN HEALTHY MALE SUBJECTS UNDER FASTING CONDITIONS CLINICAL STUDY PROTOCOL “CONFIDENTIAL” Principal Investigator: Prof. Dr. Muradiye Nacak Clinical Center: Gaziantep Üniversitesi FARMAGEN GCP Center, Gaziantep –Turkey Sponsor: Atabay Kimya San. ve Tic. A.Ş. İstanbul-Turkey Contract Research Organisation (CRO) : ALPAN Farma Ltd.Şti. Kayseri- Turkey Contracted Analytical Laboratory: Novagenix Bioanalytical Drug R&D Centre, Ankara - Turkey NOTE: No part of this document may be reproduced. The document should be treated as the confidential property of Atabay Kimya San. ve Tic. A.Ş., Alpan Farma and Novagenix. Not divulged to unauthorised persons in any form, including publications and presentations, without written consent of Atabay Kimya San. ve Tic. A.Ş., Alpan Farma and Novagenix. Page 1 of 67 Study Code: Date: NOV2020/01917 28.04.2020 Version: Clinical Study Protocol 1.0 STUDY SYNOPSIS Study Title: Open-label, randomised, single oral dose, two-period, cross-over trial Favicovir 200 mg Film Tablet(Test to assess to bioequivalence of Drug) Avigan 200 mg Film Tablet (Reference in comparison with Drug) in healthy male subjects under fasting conditions Study Code: NOV2020/01917 Drugs: Test Drug* Favicovir 200 mg Film Tablet : “ ” containing 200 mg (Atabay-Turkey). favipiravir *: This drug is manufactured by Atabay Kimya San. ve Tic. A.Ş., Turkey. Reference Drug** Avigan 200 mg Film Tablet : “ ” containing 200 mg (Toyama Chemical Industry Co.Ltd./Japan).
    [Show full text]
  • Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development
    Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development Gerlie Gieser, Ph.D. Office of Clinical Pharmacology, Div. IV Objectives • Outline the Phase 1 studies conducted to characterize the Clinical Pharmacology of a drug; describe important design elements of and the information gained from these studies. • List the Clinical Pharmacology characteristics of an Ideal Drug • Describe how the Clinical Pharmacology information from Phase 1 can help design Phase 2/3 trials • Discuss the timing of Clinical Pharmacology studies during drug development, and provide examples of how the information generated could impact the overall clinical development plan and product labeling. Phase 1 of Drug Development CLINICAL DEVELOPMENT RESEARCH PRE POST AND CLINICAL APPROVAL 1 DISCOVERY DEVELOPMENT 2 3 PHASE e e e s s s a a a h h h P P P Clinical Pharmacology Studies Initial IND (first in human) NDA/BLA SUBMISSION Phase 1 – studies designed mainly to investigate the safety/tolerability (if possible, identify MTD), pharmacokinetics and pharmacodynamics of an investigational drug in humans Clinical Pharmacology • Study of the Pharmacokinetics (PK) and Pharmacodynamics (PD) of the drug in humans – PK: what the body does to the drug (Absorption, Distribution, Metabolism, Excretion) – PD: what the drug does to the body • PK and PD profiles of the drug are influenced by physicochemical properties of the drug, product/formulation, administration route, patient’s intrinsic and extrinsic factors (e.g., organ dysfunction, diseases, concomitant medications,
    [Show full text]
  • Narrow Therapeutic Index Drugs
    Quality and Bioequivalence Standards for Narrow Therapeutic Index Drugs Lawrence X. Yu, Ph.D. Deputy Director for Science and Chemistry Office of Generic Drugs Center for Drug Evaluation and Research Food and Drug Administration GPhA 2011 Fall Technical Workshop 1 Bioequivalence • The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administrated at the same molar dose under similar conditions in an appropriately designed study…” (21 CFR §320.1) 2 Plasma Concentration Profile Cmax 10000 AUC ln Concentration 1000 Concentration Time Tmax - time of maximum concentration 100 Time 3 0 5 10 15 20 25 Possible Outcome of BE Studies Demonstrate BE Fail to Demonstrate BIE Fail to Demonstrate BE Demonstrate BIE Demonstrate BIE 80% T/R (%) 125% 4 5 FDA 12 Year BE Data Distribution of AUCt Ratios Average difference = 3.56% 10 N = 2069 8 6 Percent of Total(%) of Percent 4 2 0 0.84 0.86 0.88 0.90 0.92 0.94 0.96 0.98 1.00 1.02 1.04 1.06 1.08 1.10 1.12 1.14 1.16 1.18 1.20 6 AUC Point Estimate (T/R) Effect of Variability on BE Studies High variability 80% T/R (%) 125% 7 Development of BE Standard for Highly Variable Drugs 4/2004 First presentation to the FDA Advisory Committee 10/2006 Second presentation to the FDA Advisory Committee 3/2007 Received the first ANDA which used the new FDA BE approach 5/2007 Critical Path Opportunities for Generic Drugs BE of HVD 1/2008 FDA OGD’s first publication on BE of HVD (Pharm.
    [Show full text]
  • Bioavailability and Bioequivalence Studies Submitted in Ndas Or Inds — General Considerations
    Guidance for Industry Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact the CDER Office of Clinical Pharmacology at 301-796-5008 or [email protected]. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) March 2014 Biopharmaceutics Guidance for Industry Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs— General Considerations Additional copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue, Silver Spring, MD 20993 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm Phone: 301-796-3400; Fax: 301-847-8714 [email protected] U.S. Department of Health and Human Services Food
    [Show full text]
  • Guideline for Bioequivalence Studies of Generic Products
    English translation of Attachment 1 of Division-Notification 0229 No. 10 of the Pharmaceutical and Food Safety Bureau, dated February 29, 2012 Guideline for Bioequivalence Studies of Generic Products Index Section 1: Introduction Section 2: Terminology Section 3: Tests A. Oral immediate release products and enteric-coated products I. Reference and test products II. Bioequivalence studies 1. Test methods 1) Design 2) Number of subjects 3) Selection of subjects 4) Drug administration a. Dose b. Single vs. multiple dose studies i. Single dose studies ii. Multiple dose studies 5) Measurement of biological samples a. Biological fluids to be sampled b. Sampling schedule 1 c. Substances to be measured d. Analytical method 6) Washout period 2. Assessment of bioequivalence 1) Parameters to be assessed 2) Bioequivalent range 3) Statistical analysis 4) Acceptance criteria III. Pharmacodynamic studies IV. Clinical studies V. Dissolution tests 1. Number of vessels 2. Testing time 3. Testing conditions 1) Products containing acidic drugs 2) Products containing neutral or basic drugs, and coated products 3) Products containing poorly soluble drugs 4) Enteric-coated products 4. Acceptance criteria for similarity of dissolution profiles VI. Reporting of test results 1. Samples 2. Results 1) Summary 2) Dissolution tests 3) Bioequivalence studies 4) Pharmacodynamic studies 5) Clinical studies 2 B. Oral extended release products I. Reference and test products II. Bioequivalence studies 1. Test method 2. Assessment of bioequivalence 1) Bioequivalence range, parameters, data transformation and statistical analysis 2) Acceptance criteria III. Pharmacodynamic and clinical studies IV. Dissolution tests 1. Number of units 2. Testing time 3. Test conditions 4. Acceptance criteria for similarity and equivalence of dissolution profiles V.
    [Show full text]
  • Impact of Gastrointestinal Tract Variability Onłoral Drug Absorption and Pharmacokinetics
    European Journal of Pharmaceutical Sciences 162 (2021) 105812 Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review Zahari Vinarov a,b, Mohammad Abdallah c, Jos´e A.G. Agundez d, Karel Allegaert e,f, Abdul W. Basit g, Marlies Braeckmans a, Jens Ceulemans h, Maura Corsetti i,j, Brendan T. Griffin k, Michael Grimm l, Daniel Keszthelyi m, Mirko Koziolek n, Christine M. Madla g, Christophe Matthys o,p, Laura E. McCoubrey g, Amitava Mitra q, Christos Reppas r, Jef Stappaerts h, Nele Steenackers o, Natalie L. Trevaskis c, Tim Vanuytsel s, Maria Vertzoni r, Werner Weitschies l, Clive Wilson t, Patrick Augustijns a,u,1,* a Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium b Department of Chemical and Pharmaceutical Engineering, Sofia University, Sofia, Bulgaria c Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia d University Institute of Molecular Pathology Biomarkers, UEx. ARADyAL, Instituto de Salud Carlos III, Caceres,´ Spain e Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands f Department of Development and Regeneration and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium g UCL School of Pharmacy, University College London,
    [Show full text]
  • Current Challenges and Future Perspectives in Oral Absorption Research: an Opinion of the UNGAP Network
    Advanced Drug Delivery Reviews 171 (2021) 289–331 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network Zahari Vinarov a,b,BertilAbrahamssonc,PerArturssond,HannahBatchelore,PhilippeBerbenf, Andreas Bernkop-Schnürch g, James Butler h,JensCeulemansi, Nigel Davies j,DidierDupontk, Gøril Eide Flaten l,NikolettaFotakim, Brendan T. Griffin n, Vincent Jannin o, Janneke Keemink i,1, Filippos Kesisoglou p,MirkoKoziolekq, Martin Kuentz r, Alan Mackie s, Antonio J. Meléndez-Martínez t, Mark McAllister u, Anette Müllertz v, Caitriona M. O'Driscoll n,NeilParrottw, Jadwiga Paszkowska x, Petr Pavek y, Christopher J.H. Porter z, Christos Reppas aa,CordulaStillhartw, Kiyohiko Sugano ab, Elena Toader ac,Kateřina Valentová ad, Maria Vertzoni aa, Saskia N. De Wildt ae, Clive G. Wilson e, Patrick Augustijns a,2,⁎ a Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium b Department of Chemical and Pharmaceutical Engineering, Sofia University, Sofia, Bulgaria c Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg, Sweden d Department of Pharmacy, Uppsala University, Uppsala, Sweden e Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom f Pharmaceutical Development, UCB Pharma SA, Braine- l'Alleud, Belgium g Department of Pharmaceutical Technology, Institute
    [Show full text]
  • Generic-Reference and Generic-Generic Bioequivalence of Forty-Two, Randomly-Selected, On-Market Generic Products of Fourteen
    Hammami et al. BMC Pharmacology and Toxicology (2017) 18:78 DOI 10.1186/s40360-017-0182-1 RESEARCH ARTICLE Open Access Generic-reference and generic-generic bioequivalence of forty-two, randomly- selected, on-market generic products of fourteen immediate-release oral drugs Muhammad M. Hammami1,2* , Sophia J. S. De Padua1, Rajaa Hussein1, Eman Al Gaai1, Nesrine A. Khodr1, Reem Al-Swayeh1, Syed N. Alvi1 and Nada Binhashim1 Abstract Background: The extents of generic-reference and generic-generic average bioequivalence and intra-subject variation of on-market drug products have not been prospectively studied on a large scale. Methods: We assessed bioequivalence of 42 generic products of 14 immediate-release oral drugs with the highest number of generic products on the Saudi market. We conducted 14 four-sequence, randomized, crossover studies on the reference and three randomly-selected generic products of amlodipine, amoxicillin, atenolol, cephalexin, ciprofloxacin, clarithromycin, diclofenac, ibuprofen, fluconazole, metformin, metronidazole, paracetamol, omeprazole, and ranitidine. Geometric mean ratios of maximum concentration (Cmax) and area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or truncated to Cmax time of reference product (AUCReftmax)were calculated using non-compartmental method and their 90% confidence intervals (CI) were compared to the 80.00%–125. 00% bioequivalence range. Percentages of individual ratios falling outside the ±25% range were also determined. Results: Mean (SD) age and body-mass-index of 700 healthy volunteers (28–80/study) were 32.2 (6.2) years and 24.4 (3.2) 2 kg/m , respectively. In 42 generic-reference comparisons, 100% of AUCT and AUCI CIs showed bioequivalence, 9.5% of Cmax CIs barely failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence.
    [Show full text]
  • Branded Vs. Generic of Antibiotics: Evidence-Based Approach
    Branded vs. generic of antibiotics: Evidence-based approach Paul M. Tulkens, MD, PhD Cellular and Molecular Pharmacology & Center for Clinical Pharmacy Louvain Drug Research Institute Université catholique de Louvain Brussels, Belgium Middle East Anti-Infectives Forum Yas Island, Abu Dhabi, U.A.E 10-11 November 2017 With approval of the Belgian Common Ethical Health Platform – visa no. 17/V1/10411/093945 11 Nov 2017 Middle East Anti-Infectives Forum 1 Disclosures and slides availability • Research grants – Theravance, Astellas, Targanta, Cerexa/Forest, AstraZeneca, Bayer, GSK, Trius, Rib-X, Eumedica, Debiopharm – Belgian Science Foundation (F.R.S.-FNRS), Ministry of Health (SPF), Walloon and Brussels Regions, European Union (FP7 programme) • Speaking fees – Bayer, GSK, Sanofi, Johnson & Johnson, OM-Pharma • Decision-making and consultation bodies – European Committee for Antimicrobial Susceptibility Testing [EUCAST] (General Assembly and steering committee (2010-2012)) – European Medicines Agency (external ad-hoc expert) – US National Institutes of Health (grant reviewing) – Drive-AB [Driving reinvestment in R&D and responsible use for antibiotics] (governance) Slides: http://www.facm.ucl.ac.be Lectures 11 Nov 2017 Middle East Anti-Infectives Forum 2 Abu Dhabi opens an new Museum… http://static.gulfnews.com/polopoly_fs/1.2085814!/image/3964771986.jpg_gen/derivatives/box_620347/3964771986.jpg Last visited: 8 Nov 2017 11 Nov 2017 Middle East Anti-Infectives Forum 3 Would you prefer to see there originals or copies ? http://static.gulfnews.com/polopoly_fs/1.2085814!/image/3964771986.jpg_gen/derivatives/box_620347/3964771986.jpg Last visited: 8 Nov 2017 https://www.npr.org/2015/06/23/412244490/could-the-masterpiece-be-a-fake-profit-revenge-and-the-art-of-forgery Last visited: 8 Nov 2017 11 Nov 2017 Middle East Anti-Infectives Forum 4 Why choosing a "generic" antibiotic ? 1.
    [Show full text]
  • Narrow Therapeutic Index Drugs: a Clinical Pharmacological Consideration to Flecainide
    Eur J Clin Pharmacol (2015) 71:549–567 DOI 10.1007/s00228-015-1832-0 REVIEW ARTICLE Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide Juan Tamargo & Jean-Yves Le Heuzey & Phillipe Mabo Received: 5 December 2014 /Accepted: 4 March 2015 /Published online: 15 April 2015 # The Author(s) 2015. This article is published with open access at Springerlink.com Abstract specify flecainide as an NTID. The literature review demon- Purpose The therapeutic index (TI) is the range of doses at strated that flecainide displays NTID characteristics including which a medication is effective without unacceptable adverse a steep drug dose–response relationship for safety and effica- events. Drugs with a narrow TI (NTIDs) have a narrow win- cy, a need for therapeutic drug monitoring of pharmacokinetic dow between their effective doses and those at which they (PK) or pharmacodynamics measures and intra-subject vari- produce adverse toxic effects. Generic drugs may be substitut- ability in its PK properties. ed for brand-name drugs provided that they meet the recom- Conclusions There is much evidence for flecainide to be con- mended bioequivalence (BE) limits. However, an appropriate sidered an NTID based on both preclinical and clinical data. A range of BE for NTIDs is essential to define due to the poten- clear understanding of the potential of proarrhythmic effects tial for ineffectiveness or adverse events. Flecainide is an an- or lack of efficacy, careful patient selection and regular mon- tiarrhythmic agent that has the potential to be considered an itoring are essential for the safe and rational administration of NTID.
    [Show full text]
  • Of Bioequivalence Studies with Pharmacokinetic Endpoints For
    Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document, contact (CDER) David Coppersmith at 301-796- 9193. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) August 2021 Generics Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA Guidance for Industry Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: [email protected] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) August 2021 Generics Contains Nonbinding Recommendations Draft — Not for Implementation TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND ............................................................................................................... 2 III. ESTABLISHING BIOEQUIVALENCE ........................................................................ 2 A.
    [Show full text]
  • What Is Bioavailability and Bioequivalence?
    What is Bioavailability and Bioequivalence? All generic medicines in New Zealand are approved from the GI tract, but also other factors including pre- by Medsafe and have been shown to be bioequivalent systemic metabolism, distribution and elimination. to innovator medicines, according to internationally accepted criteria and standards.1 This means that any Bioavailability is assessed using three main differences in bioavailability between generic and pharmacokinetic variables (see Figure 1); innovator medicines are not clinically significant. ▪ the area under the blood drug concentration versus time curve (AUC) Bioavailability ▪ the maximum blood concentration (Cmax) Bioavailability is a measurement of the extent of a ▪ the time to reach maximum concentration (Tmax) therapeutically active medicine that reaches the systemic circulation and is therefore available at the site of action. Bioavailability example For most medicines that are taken orally, the active A hypothetical drug given orally has a bioavailability of 50% ingredients are released in the gastrointestinal (GI) tract (or 0.5), this is due to: and arrive at their site of action via the systemic circulation. 1. incomplete absorption in the GI tract so that only Blood concentrations of the active ingredients and/or 70% of the initial dose is absorbed. their active metabolites thereby provide a marker for the concentration at the site of action and a valid measure of 2. subsequent metabolism of a further 20% before bioavailability. it reaches the systemic circulation (e.g. first pass through the liver). A blood concentration – time curve (achieved by serial measurements over time) reflects not just the release of Therefore only 50% of the original oral dose reaches the the active ingredient from the medicine and its absorption systemic circulation.
    [Show full text]