RAPS Webcast. BRAZIL Regulatory Challenges with Drug Submissions. By Adriana Serrão Marcela Saad

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1 RAPS Webcast BRAZIL Regulatory Challenges with Drug Submissions By Adriana Serrão Marcela Saad February 10, 2012

2 Speakers: Adriana Serrão Regulatory Affairs & Marcela Saad President & Senior Consultant MarcM Consulting Canada

3 BRAZIL Regulatory Challenges with Drug Submissions

4 BRAZIL Regulatory Challenges with Drug Submissions ANVISA Structure

5 BRAZIL Regulatory Challenges with Drug Submissions 1976: General Health Law 6360/76 Regulation Timeline 1977: General Health Decree 79094/ : Registration requirements resolution IN 01/ : GMP RDC 16/ : National Health Council Resolution RDC 196/96 Ethics in CT 1997: Leaflet Ordinance 110/ : ANVISA creation Law 9782/99; Generic Law 9787/ : Generic registration RDC 391/ : Vitamins RDC 4/00; Herb Drug register RDC 17/00; Advertisement RDC 102/00

6 BRAZIL Regulatory Challenges with Drug Submissions Regulation Timeline 2001: Patent Review Law 10196; Generic Registration RDC 10/01 update; GMP update RDC 134/ : Biologic Registration RDC 80/02; Generic Registration update RDC 84/ : Price Control CMED Law : Innovative; Specific; Similar; Generic update; Homeopathic Drugs registration RDCs 136/03, 132/03, 133/03, 135/03, RDC 139/ : Guide for OTC (therapeutic indication) RDC 138/03 (under review) 2003: Registration update RDC 134/ : Leaflet update RDC 140/03; Labeling RDC 333/03; Pregnancy Risk RDC 1548/ : Herb Drug registration update RDC 48/03; Clinical Trial RDC 219/03

7 BRAZIL Regulatory Challenges with Drug Submissions Regulation Timeline 2005: Biologic Drugs registration update RDC 315/ : Generics RDC 16/07 update; Similar Drug registration update RDC 17/ : Registration Review Linkage IN 06/ : Priority RDC 28/08 (under review) 2008: Clinical Trial update - RDC 39/ : Patent Review RDC 45/ : Clinical Trial update RDC 41/ : Leaflet update RDC 47/ : Labeling update RD 71/ : API registration RDC 57/09

8 BRAZIL Regulatory Challenges with Drug Submissions 2010: GMP update RDC 17/10 Regulation Timeline 2010: Herb Drugs registration update RDC 14/ : API GMP RDC 29/ : Biologic Drug registration update RDC 55 (+ 4 guidelines) 2011: QC Imported Drug update RDC 10/ : Specific Drug registration update RDC 24/ : Bio exemption guideline update RDC 37/ : Biologic Drug variation RDC 49/ : Biologic Drug stability RDC 50/11

9 BRAZIL Regulatory Challenges with Drug Submissions Applicable Guidelines (in force) RE 482/02: In Vitro-In Vivo Study Correlation RE 894/03: Bioequivalence Protocol and Report RE 898/03: Bioequivalence Study Design and Statistic Detailing RE 899/03: Method Validation (under review) RE 01/05: Stability Study (under review) RE 1170/06: Bioequivalence Study IN 02/09: RE 48/09: IN 11/09: RE 31/10: Pivotal Batch Variation implementation after approval (under review) Variation automatic implementation after 60 days Pharmaceutical Equivalence and Dissolution Profile Note: Reference Drugs and Biologic Drugs guidelines being re-written

10 BRAZIL Regulatory Challenges with Drug Submissions Definitions Reference product: registered and marketed innovative drug with demonstrated quality, safety and efficacy Generic product: similar drug to a reference or innovative drug, interchangeable, usually produced after patent expiration, with demonstrated quality, efficacy and safety, named by its DCB or DCI Similar product: contain same API, strength, dosage form, administration form, posology and indication; equivalent to registered reference drug; may be different only regarding shape and size, shelf life, packaging, labeling, excipients; always named by brand or trade mark

11 Drug Registration Rationale Pre Registration Registration Post Market RDC 136/03: Innovative Product Registration RDC 55/10: Biologic Product Registration Clinical Trial requirement RDC 16/07: Generic Product Registration RDC 17/07: Similar Product Registration Equivalence Test requirement RDC 24/11: RDC 14/10: RDC 135/03: Specific Drug Registration Herb Drug Registration Homeopathic Drug Registration 11

12 Registration Flow - Pre Submission 1) Brazilian Reference Drug or CT protocol approval - website list or request to ANVISA similar/generic only - clinical trial protocol approval innovative/biologic only 2) Samples and Manufacturing Dossier - pivotal batch or imported samples + technical documents - reference drugs: acquired in Brazil by authorized labs or CROs 3) Testing prior to Registration Submission - equivalence: QC specifications + DP (solids) similar/generic only - accelerated stability study - long term stability study: zone IV b - bioequivalence study: absorbed drugs similar/generic only - QC test (waiver for biologic drugs/transportation validation) + R&D - clinical trial results innovative/biologic only

13 Stability Study Applicable Regulation: RE 01/05 (Stability Study) similar to ICH zone IVb In vitro test: specification must be maintained during shelf life under normal storage conditions. Performed only to test drug and prior to bioequivalence test; Samples under controlled temperature and RH conditions, periodic test: accelerated: 0, 3, 6 months; long term: 0, 3, 6, 9, 12, 18, 24 months (+ every 12 months); post market: every 12 months; Specification: aspect, assay, related substances, ph (if applicable), dissolution (if applicable). Other specifications on 0 and end point; 3 batches required for registration: > 10% industrial size; Performed for higher and lower strength (proportional formulation); Performed for all primary package materials and all storage conditions; Protocol and report must be attached to the registration dossier.

14 Stability Study Study Temperature/RH Period Analysis period accelerated room temp 40 ± 2 C / 75 ± 5% 6 months 0, 3, 6 months 40 ± 2 C / 25 ± 5%* long term room temp 30 ± 2 C / 75 ± 5% 30 ± 2 C / 35 ± 5%* 6 months 0, 3, 6, 9,12, 18, 24 (+ every 12) months accelerated cold chain 25 ± 2 C / 60 ± 5% 6 months 0, 3, 6 months long term cold chain 5 ± 3 C 6 months 0, 3, 6, 9,12, 18, 24 (+ every 12) months long term freezing - 20 ± 5 C 12 months 0, 3, 6, 9,12, 18, 24 (+ every 12) months Notes: 1) Stability test is allowed at 25 C only for hospital drugs that cannot bear zone IVb conditions + chain validation 2) Impermeable packages such as glass can adopt room humidity * Semi-permeable packages

15 Registration Flow - Submission 4) Registration dossier assembly: legal, technical, testing 5) Submission to ANVISA: dossier (hard copy and CD) + fee 6) Dossier evaluation by ANVISA: 12 to 24 months (questions) 7) Registration grant: Official Gazette 8) Price Submission: innovative, biologic, generic and similar 9) Price Approval: innovative, biologic and similar only 10) Product Launch 11) Registration variation: if applicable 12) Registration renewal: every 5 years

16 Registration Flow Innovative/ biologic similar/ generic submission Protocol Approval Reference election Stability study Register Dossier Review Clinical Trial Pivotal Batch Notification CQ Test registration certificate Price Equivalence /Biostudy Register Dossier price approval 16

17 Registration Dossier for Innovative Drugs Forms, fees and legal documents: site license (QC laboratory + warehouse at least) QP certificate power of attorney third part contracts (pre-approved by ANVISA) GMP certificate issued by ANVISA & origin country HA (legalized) CPP or register evidence issued by origin country HA (legalized) Labeling lay out and leaflet model BSE data DMF: API characteristics and manufacturer information methods, specification, validation, stability synthesis route, intermediary products, contaminants, solvents polymorphic and stereoisomer data, if applicable 17

18 Registration Dossier for Innovative Drugs Product information Formula, dosage form, strengths, presentations pharmacokinetics: pka, ½ life, absorption, distribution, biotransformation, clearance indication, use, administration, posology warnings, precautions, contra indications, AE action mechanism, overdose, interactions marketing category & restrictions, batch SOP Technical information R&D report QC methods & specification + reference (API, excipient, product, packaging) CofA API and product (local and imported) stability, shelf life, storage & transport condition manufacturing process, in process control, equipment list, batch size method validation if non-pharmacopoeial 18

19 Registration Dossier for Innovative Drugs Clinical information: Pre-clinical report: toxicity (acute, sub acute, chronic, reproductive), mutagenesis, oncogenesis Clinical trial report: phase I, II and III Bioavailability report for association PSUR, pharmacovigilance plan Price Report Clinical Trial: approved by ANVISA prior to execution (if in Brazil) Patents: approved by ANVISA prior to INPI Price: approved by CMED prior to launch 19

20 QC Test: local CofA Applicable Regulations: RDC 10/11 (Imported products) RDC 16/07 (Generic Drug Registration) RDC 17/07 (Similar Drug Registration) In vitro QC test: product under registration complies with its specification; Performed at company s local QC laboratory (Brazil); All specified tests must be performed and comply with specification; Methods: according to manufacturer or justification; 20

21 QC Test: local CoA QA must release each batch after document review (including QC tests); Third party analysis: - allowed only for complex equipment or method, - allowed only for some tests, not all for the same product, - third part contract must be submitted for ANVISA's approval; CoA must be attached to registration dossier. 21

22 Generic x Similar: What s different? Generic (Res. RDC 16/07) - equivalent to a reference (API, strength, dosage form, administration, posology, indication of use) - interchangeable - no brand (DCB or DCI) - image ID on box - price 65% below reference - restriction for OTC registration Similar (Res. RDC 17/07) - equivalent to a reference (API, strength, dosage form, administration, posology, indication of use) - not interchangeable - brand - no image ID on box - price approved by ANVISA - no restriction for OTC registration With bioequivalence since 1999 No bioequivalence until

23 Similar product: Distortion x Adaptation 2013 Similar Similar Generic Innovative w/ BE RDC 133/03 w/ BE w/ BE w/ CT RDC 134/ no BE Adapting from 2004 to

24 Registration Dossier Similar/Generic Products Forms, fees and legal documents: site license (QC laboratory + warehouse at least) QP certificate power of attorney third part contracts (pre-approved by ANVISA) GMP certificate issued by ANVISA & country of origin HA (legalized) CPP or register evidence issued by country of origin HA (legalized) Labeling lay out and leaflet model BSE data DMF: API characteristics and manufacturer information methods, specification, validation route of synthesis, intermediary products, contaminants, solvents polymorphic and stereoisomer data, if applicable 24

25 Registration Dossier Similar/Generic Products Product information Formula, dosage form, strengths, presentations indication, use, administration, posology warnings, precautions, contra indications, AE action mechanism, overdose, interactions marketing category & restrictions, batch SOP Technical information R&D report QC methods & specification + reference (API, excipient, product, packaging) CofA API and product (local and imported) stability, shelf life, storage & transport condition manufacturing process, in process control, equipment list, batch size 3 batch records: < 3 years, higher & lower strength, used on equivalence test method validation if non-pharmacopoeial 25

26 Registration Dossier Similar/Generic Products Clinical information: pharmaceutical equivalence certificate bioequivalence study, if applicable Price also regulated, submitted after registration approval Pricing rules are not the same for generic, similar and innovative 26

27 Products Not Allowed as Generic Exempted from registration Parenteral drugs Biologic drugs Biotech products Vitamins and minerals Herb drugs Hospital antiseptics Radiologic contrasts and diagnostic products OTC, except: - antacids and carminatives; - non-narcotic analgesics; - non-steroidal topical anti-inflammatory, naproxen, ibuprofen, ketoprofen; - expectorants, balsamic and mucolytic agents, anti-cough; - topical antifungal; - miorelaxant products; - oral and topic anthelmintic mebendazole and levamizole; - anti-histaminic; - anti-spasmodic; - topical anti-bacterial neomycin and bacitracin; - topical hemorroidal; - topical nasal decongestant; 27

28 Pharmaceutical Equivalence Test RE 31/10 (Pharmaceutical Equivalence and Dissolution Profile Test) In vitro test: both reference and test drug contains same API, dosage, form, dissolution profile and same specifications; Performed by ANVISA s certified labs (REBLAS): acquires reference; Test drug is provided by company: pivotal batch or license to import (acquired by certified labs if product is already on the market); Prior to bioequivalence test, same batch; Pharmacopoeia methods or in-company method (full validation); All strengths must be tested; Reference and test drug results must be comparable; Pharmaceutical equivalence certificate on registration dossier. 28

29 Bioequivalence Study: Exemption Applicable Regulation: RE 37/11 (Exemption for Bioequivalence Study) Target: excludes non-absorbed products from biostudy and provides alternatives for special situations Which ones are exempted from biostudy? aqueous IM/EV drugs; aqueous solution oral drugs; powder for reconstitution; gaseous products; otological and ophthalmic solution; topical non systemic absorption products; aqueous inhalation products; non-absorbed oral products. Note: Excipients may affect absorption same as reference Ex: sorbitol When does equivalence/dissolution profile replace biostudy? Other strengths, proportional formulation (dissolution profile). Highly soluble immediate release oral forms (dissolution profile + fast dissolution results + candidate list IN 04/11). Note: Ibuprofen (biostudy) and other registered OTC (according to RE 37/11): first renewal after 30/06/12 When does pharmacodynamic study replace biostudy? otological and ophthalmic suspension inhalation products on suspension or powder (if < LOQ on plasma) 29

30 Bio exemption IN 04/2011 I - acetyl salicylic acid; II - propranolol, HCl; III - doxycycline, HCl; IV - dypirone; V - stavudine; VI - fluconazole; VII - isoniazide; VIII - levofloxacin; IX - metoprolol; X - metronidazole; XI - acetaminophen; XII - sotalol.

31 Bioequivalence Study Applicable Regulation: RE 1170/06 (Bioequivalence Study) In vivo test: both reference and test drug are equal for bioavailability on human body, considering drug amount and speed of absorption; Performed at CRO certified by ANVISA: annual inspection, acquires reference drug; Drug is provided by company: pivotal batch or license to import (acquired by certified labs if product already on market); After pharmaceutical equivalence test (same batch), stability test and Ethics Committee approval for protocol. Test and reference drug assay variation < 5%, meet all specifications; Usually higher strength of absorbed product requires biostudy (linear pharmacokinetic and non-linear pharmacokinetic when higher dose causes disproportional higher increase of pharmacokinetic parameters); lower strength (higher dose causes disproportional lower increase of pharmacokinetic parameters); Clinical, analytical and statistical phases; Biostudy protocol and report on registration dossier. 31

32 Registration Variation Applicable Regulation: RDC 48/09 + IN 11/09 Immediate Marketing: - packaging site: change or inclusion (primary/secondary) - manufacturing process: minor change - equipment: change or inclusion (packaging/mfg same design) - batch size: inclusion up to 10 times registered one - excipient: minor change - methods/specifications: authorized pharmacopoeia/ < limit - manufacturing /packaging site exclusion - shelf life reduction: same storage conditions Marketing after 60 days: - manufacturing site: change or inclusion (mfg process, none or minor changes and/or equipment having same design) Note: Annual review must include those changes (submission) 32

33 Registration Variation Marketing After Approval: manufacturing process: minor or major change equipment: change/inclusion mfg equipment different design batch size: inclusion above 10 times registered one new presentation: flavor addition excipient: minor or major change methods & specifications update: other pharmacopoeias, change/exclusion shelf life and/or storage condition change presentation inclusion packaging inclusion route of synthesis change or inclusion API manufacturer change or inclusion posology change target population inclusion administration via inclusion: innovative or non-innovative indication of use inclusion: innovative or non-innovative new strength inclusion: innovative or non-innovative new dosage form inclusion: innovative or non-innovative labeling change: not related to other changes trade mark change manufacturing interruption/ reactivation registration cancellation: full or partial 33

34 Registration Renewal Submission: - Every 5 years - Filed 6 months before registration expiration date - Automatic renewal by law Note: ANVISA may monitor quality of batches on market. long term stability study final report Legal documents, forms and fees Commercialization evidence Leaflet Modification list CofA for 3 batches (imported only) GMP PSUR Phase IV report (not mandatory) 34

35 Biologic Drugs This extensive topic will be the subject of another webcast. Applicable Regulation: RDC 55/10 Biologic drugs - biological origin or biotechnology for mfg: Vaccine Serum Blood compounds Bio drugs: from biologic fluids or animal tissue from biotechnology Monoclonal antibody Drug with microorganisms (alive, dead or attenuated) Does not include antibiotics, estrogens (contraceptives), allergenic, probiotic There is no definition for biosimilar, only for biologic drugs (innovative and non innovative). Possibilities: comparability or development 35

36 OTC Applicable Regulation: RDC 138/03 (GITE Specific Therapeutic Groups and Indications) New molecule must be registered as innovative even if indication/therapeutic group is listed on GITE GITE lists all indications/therapeutic groups that are prescription free Any product registered more than 5 years in FDA or EMEA as OTC plus PSUR (safety) may receive approval as OTC in Brazil 36

37 Timelines Step Legal Actual Inspection 120 days 1 year Registration Innovative 90 days 2 years Registration Similar 120 days 19 months Registration Priority 60 days 1 year Price Approval 60 days 60 days ANVISA Questions: days to answer at most; OR archive up to 360 days. 37

38 Q & A Thank You! Adriana Serrão & Marcela Saad Regulatory Affairs President & Senior Consultant serraoguilherme@uol.com.br MarcM Consulting Canada saadma@marcmconsulting.ca

1. Checklist for Grant of permission to manufacture/import of Bulk Drug already approved in the country

1. Checklist for Grant of permission to manufacture/import of Bulk Drug already approved in the country S no 1. Name of Applicant with address 2. Name of Drug 3. Therapeutic Class 4. Date of Approval Documents