1 International Drug Regulatory Affairs 2 Regulatory structure

1 International Drug Regulatory Affairs

2 Regulatory structure • The pharmaceutical industry is one of the highly regulated industries with various structures of drug regulation ▫ Drug laws ▫ Drug regulatory agencies ▫ Drug evaluation boards ▫ Quality control laboratories ▫ Drug information centers

3 What is the need? • Drug laws provide the basis for drug regulation • Regulatory tools such as standards and guidelines equip authorities with the practical means of implementing those laws • Regulatory Agencies monitor the implementation of these laws

4 Regulatory Scenario Regulated Markets Emerging Markets • US • Latin America • Canada • Eastern Europe • EU-27 states • CIS • Japan • Africa • Australia • Asia Pacific • New Zealand • Gulf countries

5 Regulatory Agencies USA Europe Japan Australia Brazil Nigeria China India Uganda International Food & Drug Administration (FDA) The European Agency for the Evaluation of Medicinal Products (EMEA) Ministry of Health, Labour & Welfare(MHLW) Therapeutic Goods Administration (TGA) National Health Surveillance Agency (ANVISA) National Agency for Food and Drug Administration and Control (NAFDAC) State Food and Drug Administration (SFDA) Central Drugs Standard Control Organization (CDSCO) Uganda National Council for Science and Technology (UNCST) International Conference on Harmonization (ICH) World Health Organization (WHO)

9 Obstacles • Pharmaceutical, Non-clinical and Clinical issues emerge in all stages of development • Regulatory guidelines don’t always address problems encountered • Language barrier • Bureaucracy • Political environment

10 Registration Procedure of Drugs for International Marketing

11 Drug Approval Process • A regulatory process by which a person/organization/sponsor/innovator gets authorization to launch a drug in the market

12 Various Stages • Application to conduct clinical trials • Conducting clinical trials • Application to marketing authorization of drug • Post-marketing studies

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14 API Plant Inspection Vendor Selection Approved API Excipients Packing Material Test, Import & Manufacturing License BE studies approved CRO Finished Product Development Patent/ development Strategy BE Strategy Dossier Writing Regulatory Filing to Authorities Dossier Evaluation Product Approval Plant inspection

16 Common Technical Document (CTD) • Consists of documents like Application form, legal documents (GMP, Licences etc. ), labelling etc. Required for generics and New Drug • Required for generics and New Drug. • For generics summary on Quality part only required • Summarizes Module 3, 4 and 5 • Provides abstract of documents provided in the whole application • Required for generics and New Drug • Documents related to Chemistry, manufacturing and Control of both Drug Substance and Drug Product • Critical assessment of the clinical data and related reports • Generics require only BE study • Data on pharmacologic, pharmacokinetic, and toxicological evaluation of the pharmaceutical product • Not required for generics

17 ICH Stability Zones Zone III Zone IVb Type of Climate Temperate zone Mediterranean/subtropical zone Hot dry zone Hot humid/tropical zone ASEAN testing conditions hot/higher humidity Long Term Testing Conditions Climatic Zone III Zone IVb Refrigerated Frozen Temperature 21ºC ± 2ºC 25ºC ± 2ºC 30ºC ± 2ºC 5ºC ± 3ºC -15ºC ± 5ºC Humidity 45% r. H ± 5% r. H 60% r. H ± 5% r. H 35% r. H ± 5% r. H 65% r. H ± 5% r. H 75% r. H ± 5% r. H No Humidity Minimum Duration 12 Months 12 Months Accelerated and Intermediate Testing Conditions Climatic Zone Accelerated Ambient Accelerated Refrigerated Accelerated Frozen Intermediate Temperature 40ºC ± 2ºC 25ºC ± 2ºC 5ºC ± 3ºC 30ºC ± 2ºC Humidity 75% r. H ± 5% r. H 60% r. H ± 5% r. H No Humidity 65% r. H ± 5% r. H Minimum Duration 6 Months

18 COUNTRY SPECIFIC GUIDELINES

19 Regulatory Agency • Food & Drug Administration • Main consumer watchdog in this system is FDA's Center for Drug Evaluation and Research (CDER)

20 Laws, Regulations, Policies & Procedures • The Federal Food, Drug, and Cosmetic Act (1938) ▫ With numerous amendments it is the most extensive law of its kind in the world • Code Of Federal Regulations (CFR) ▫ Section 21 of the CFR contains most regulations pertaining to food and drugs • Manual of Policies and Procedures (Ma. PPs) ▫ Approved instructions for internal practices and procedures followed by CDER staff to help standardize the new drug review process and other activities

21 Types of Applications under Sec 505 • New Drug Application (NDA) • Abbreviated New Drug Application (ANDA)

22 New Drug Application (NDA) 505 (b) (1) MA for New Chemical Entities (NCE) 505 (b) (2) MA for changes to an approved drug (Change in dosage form, strength, indication etc. )

23 NDA • Since 1938, every new drug has been the subject of an approved NDA before commercialization. • The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U. S. • The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA. • Generally approval of an NDA is granted within two years (on an average), however, this process can be completed from two months to several years.

24 Applicable Regulations, Policies & Procedures (NDA) • 21 CFR Part 314 - Applications for FDA Approval to Market a New Drug or an Antibiotic Drug. • Ma. PPs ▫ 5015 -6: Review of the Same Supplemental Change to More than One NDA or ANDA in More Than One Review Division ▫ 6010. 5: NDAs: Filing Review Issues ▫ 6020. 8: Action Packages for NDAs and Efficacy Supplements ▫ 6050. 1: Refusal to Accept Application for Filing From Applicants in Arrears ▫ 7211. 1: Drug Application Approval 501(b) Policy ▫ 7600. 6: Requesting and Accepting Non-Archivable Electronic Records for New Drug Applications.

25 Abbreviated New Drug Application (ANDA) Paragraph I For the products for which no patent information is available in the orange book Paragraph II Used for the products for which all the applicable patents are expired 505 (j) MA of generics Paragraph III Used for the patent products where the applicant confirms that the product will not be placed in the market till such patents are expired Paragraph IV Used for patented products where applicant files the product which does not infringe the patent. Successful applicant enjoys 6 month exclusivity

26 ANDA • Applications are termed "abbreviated" as preclinical and clinical data is not required • Reviewers focus on bioequivalence data, chemistry and microbiology data, requests for plant inspection, and drug labelling information. • A generic drug must be comparable to an innovator drug in dosage form, strength, route of administration, quality, performance characteristics and intended use • Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public

27 Applicable Regulations, Policies & Procedures (ANDA) • 21 CFR ▫ Part 314 : Applications for FDA Approval to Market a New Drug or an Antibiotic Drug ▫ Part 320 : Bioavailability and Bioequivalence Requirements ▫ Part 310 : New Drugs • Ma. PPs: ▫ Chapter 5200 - Generic Drugs

28 Data requirements Site Registration Yes Plant GMP approval US FDA Audit of both API and FP manufacture Stability Zone I & II Stability Requirements 25 ± 2 C; 60% ± 5% RH No. of submission batches One pilot scale or minimum 100, 000 units whichever is higher Stability guidelines reference ICH Stability data 3 months BE study for generics Against US reference listed drug (RLD) in any country by USFDA app CRO Major Holdup Patent non-infringement, FDA audit, competition Dossier format CTD Registration time 12 -24 months

29 Drug Registration Process in US Pre NDA Meeting 9 -12 months prior to NDA submission Filing of NDA to FDA Application sent to CDER Not OK Checking Application Inform Applicant OK Notify the applicant about deficiency Sent to Reviewer Within 180 days Submission of amended application -ve Submit review report to CDER +ve Issue Marketing Authorization +ve Review of amended application -ve Rejection of Application

30 COUNTRY SPECIFIC GUIDELINES

31 Regulatory Agencies • EMEA • Committee for Human Medicinal Products (CHMP)

32 Types of Procedures • Centralized Procedure • Decentralised Procedure • Mutual Recognition Procedure • National Procedure

33 Centralized Procedure • When used ▫ Used for biologic products or other products using hightechnology procedures ▫ Products for HIV/AIDS, cancer, diabetes, neurodegenerative disease, auto-immune or other dysfunctions, and viral diseases ▫ Products for orphan conditions ▫ Other new active substances at the request of the applicant • Pros ▫ One application applies to all countries in the EU. ▫ Relatively quick procedure. ▫ A positive outcome is very beneficial to the sponsor. • Cons ▫ A negative outcome will affect access to the entire EU

34 Centralized Procedure Guidelines Pre-Application -120 Days EMA notified Rapporteur/ Co-rapporteur appointed Validation 14 Days Application - validation CHMP scientific assessment and opinion 210 Days CHMP scientific assessment CHMP opinion Unfavourable Possible appeal 120 Days Applicant Appeal Favourable European Commission Draft Commission Decision-making process +90110 Days Decision approving Community authorization Standing Committee

35 Decentralised Procedure • When used ▫ Used for products that fall outside the scope of the EMA centralized procedure. • Pros ▫ Simultaneous authorization in numerous countries in the EU. ▫ May be more efficient than national authorization since a positive outcome results in numerous country approvals. ▫ Sponsor can select which countries to apply to; does not have to be all EU countries. • Cons ▫ A negative decision on an application may affect numerous countries.

36 Decentralized Procedure Guidelines Report sent to Applicant Objection Application filed to CMS & RMS chosen Member state having objection refuse to grant MA Validation of Application by CMS (14 days) Objection not solved EMEA/CHMP assess application (60 days) Objection solved No Objection not solved RMS assesses the application (120 Days) Report to coordination working group (60 days) Objection solved Communicate to RMS, CMS & Applicant Report sent to CMS & applicant Objection CMS assess application (90 Days) No Objection National MA Granted

37 Mutual Recognition Procedure • When used ▫ Individual application to one country within the EU for products that fall outside the scope of the EMA centralized procedure. • Pros ▫ Review by one country and other countries accept the decision. ▫ Only one application needs to be submitted. • Cons ▫ Individual national approvals can add significant time to the process. ▫ A negative outcome can affect numerous countries

38 Procedure Guidelines • Similar to the de-centralized procedure with some differences. • MRP is applicable to medicinal products which have received a marketing authorization in any member state whereas the decentralized procedure is applicable to those products which were never approved in any member states of the European Union. • The evaluation of application by RMS can be taken within 90 days instead of 120 days (in decentralized procedure). • After the grant of marketing authorization, the product can be marketed, which may be called as Phase IV trials, wherein new uses or new populations, long-term effects etc. can be explored.

39 National Procedure • When used ▫ Individual applications to each country within the EU. ▫ Used for products that fall outside the scope of the EMA centralized procedure. • Pros ▫ If application rejected in one country, can still access other EU countries. • Cons ▫ Separate applications required for each country. ▫ Unique requirements and formats may be required.

40 Procedure Guidelines • This type of authorization is granted on countryby-country basis by the competent authorities, in each member state. • Each country within the EU has its own procedures for authorizing a marketing application for a new drug. • A sponsor can consult the website of the regulatory agency in each country in which it is interested in obtaining marketing approval to obtain details of the approval process.

41 Data requirements Plant GMP approval Audit by any member states of EU Stability Zone I & II Stability Requirements 25 ± 2 C; 60% ± 5% RH No. of submission batches 2 pilot scale + 1 lab batch Stability guidelines reference ICH Stability data 6 months BE study for generics Against European Reference Product (ERP) in any country. Fed, Fast and Steady state required. Major Holdup Patent non-infringement, GMP audit, high cost of registration, maintenance of registration, Administrative procedures for each member states. Dossier format CTD Registration time As per the procedure (DCP, MRP) schedule, Usually 12 -18 months

42 COUNTRY SPECIFIC GUIDELINES

43 Regulatory Agency • MHLW • Pharmaceutical (PMDA) and Medical Devices Agency ▫ NDA/ANDA Application ▫ Review of GCP/GMP on-site inspection • P’ceutical (PAFSC) affairs & food ▫ Consultation on Review Data sanitization council

44 Data requirements Site Registration Yes Plant GMP approval Audit by PMDA of both FP and API sites Stability Zone II Stability Requirements 25 ± 2 C; 60% ± 5% RH No. of submission batches 3 pilot scale Stability guidelines reference ICH Stability data 12 months BE study for generics Against Japan reference drug in any country Major Holdup Stand alone development, Quality by Design in practice, translations, generic acceptance Dossier format CTD Registration time 18 -24 months

45 Drug Registration Process in Japan New Drug Approval Application PMDA PAFSC Nomination Experts Evaluation Committees P’ceutical Affairs Section Consultation Advice Inquiry Response Approval Review Compliance Review GMP review Notice of Review Results MHLW (Evaluation & Licensing Div, PFSB) Approval & entry in NHI Price List PFSB: P’ceutical and Food Safety Bureau Minister of MHLW (Final Evaluation)

46 COUNTRY SPECIFIC GUIDELINES

47 Regulatory Agency • The TGA regulates therapeutic goods through: ▫ Pre-market assessment ▫ Post-market monitoring and enforcement of standards ▫ Licensing of Australian manufacturers and verifying overseas manufacturers' compliance with the same standards as their Australian counterparts • Australian Drug Evaluation Committee (ADEC) ▫ Gives advice for new medicines • Drug Safety and Evaluation Branch (DSEB) ▫ NDA/ANDA Application

48 Guidelines • An application is submitted to TGA to register the drug in Australian Register of Therapeutic Goods (ARTG) after the completion of clinical trials. • The application consists of data to support the quality, safety and efficacy of the product for its intended use. • The application is assessed (on an administrative level) to make sure for compliance with basic guidelines and further evaluated by different sections and advice can also be sought on key issues to take final decision. • A company can make comments on the evaluation report, if necessary.

49 Drug Registration Process in Australia Preparation & submission of Application to DSEB of TGA Application reviewed by entry review team Accepted -ve Sent back to Applicant Evaluation of Application Within 225 days Report sent to TGA delegates Delegates seek advice of ADEC Delegates make final decision noting any recommendation from ADEC Approval of Drug Sent to Applicant comments on the report and submits supplementary data Applicant has an opportunity to comment on delegates report

50 COUNTRY SPECIFIC GUIDELINES

51 Regulatory Agency • State Food and Drug Administration (SFDA) • Provincial Drug Administration Authorities (PDAAs) ▫ Organize the works of the formal review of submitted materials • Centre for Drug Evaluation (CDE) ▫ Evaluate the submitted information

52 Drug Approval Process • After formal review, the PDAAs send the qualified applications to the SFDA for further review. • The import drug registration application should be directly submitted to SFDA by the applicant. • SFDA’s Department of Drug Registration carefully reviews the completeness of the submitted materials, files the qualified applications and transmits all the materials of qualified applications to the directly attached to SFDA. • CDE determine whether the safety and effectiveness information submitted for a new drug are adequate for manufacturing and marketing approval and send the report of review to SFDA. • SFDA carefully considers the recommendations of CDE and makes a decision whether or not the drug registration application can be approved and issues the certificate of drug approval and drug approval number to the qualified applicant.

53 New Drug Registration Process of China Filing drug registration application to PDAA After formal review Application sent to SFDA for reviewing the completeness Within 30 working days Dossier transferred from SFDA to CDE for technical review If complete within 120 days If not complete Notify applicant for deficiency Dossier transferred from CDE to SFDA for administrative approval Within 4 months Resubmission of amended application by applicant Within 30 days Within 40 days Technical review report of amended application by CDE Regulatory approval granted +ve Opinion of CDE on technical review -ve Refusal to Proceed

54 COUNTRY SPECIFIC GUIDELINES

55 Markets • Brazil, Mexico, Venezuela , Ecuador and Colombia are some of the major pharmaceutical markets • Brazil and Mexico considered Regulated Markets • ANVISA : Stringent norms comparable to USFDA • Brazil : As per ANVISAs norms, CROs used for BE studies have to be approved and certified by the Brazilian authority. • For BE studies, innovator product manufactured in Brazil has to be used for comparison • ANVISA has implemented generic law to facilitate generic market entry into the country • Mexico: Extensive analytical raw data of 3 stability batches. • Venezuela : Copies of source data

56 Drug Regulatory Requirements Technical • Manufacturing Formula and Justification • Manufacturing Process • Process Validation • Batch Numbering • Batch Records • Stability Studies (Source Data) ▫ Accelerated ▫ Long Term

57 Drug Regulatory Requirements - Legal • Free Sale Certificate / Product Permission • GMP Certificate • Manufacturing License • Power of Attorney / Contract • Trademark Registration • Contract with local quality control facility

58 Critical Success Factors • US FDA / UK MCA / TGA approved facilities • Strong Regulatory Support • Good Distribution Set up • Price Competitiveness • Good Marketing Support • Strong group for registering products in place • Expansion in new markets and new products under feasibility studies

59 Stability Issues • Common Technical Document (CTD) norms are taken as guidance for regulatory aspects during drug development • Major discrepancies in requirements of storage conditions for various countries • Stability studies on three batches - as per ICH guidelines / individual country norms ▫ Brazil: 30 ± 2 C; 75% ± 5% RH ▫ Colombia, Peru, Ecuador: 30 ± 2 C / 65% ± 5% RH ▫ Others: 25 ± 2 C; 60% ± 5% RH

60 Data requirements Site Registration Yes Plant GMP approval Major countries do audit. (Brazil, Mexico, Colombia) Stability Zone II & Zone IVb Stability guidelines reference ANVISA and ICH Stability data 6– 12 months BE study for generics Brazil: Against Brazil reference drug in any CRO approved by ANVISA. PE to be done in Brazil Mexico: Against Mexican reference, in Mexico Only. Others: The BE for Brazil /Mexico is normally accepted. Major Holdup Certificate of P’ceutical Pdt. , Legalizations, Translations, GMP audits, local requirements, time delay Dossier format Country specific

61 Time and cost for registering a drug Country Number of months Cost in US dollars (2003) Argentina 3 -4 $1, 000 for original; $333 for generic/similar Bolivia 1 $50 Brazil Original = 12 -14 similar = 8 -12 generic = 6 -8 $2, 700 -27, 000 for original (the price depends on the size of the manufacturer); $7, 000 for a similar; $2, 000 for a generic Colombia New = 6 Similar/generic = 3 $1, 200 new; $1, 000 re-validation Chile 8 -12 $1, 300 for original ; $800 for generics/similars Ecuador 1 $1, 339 foreign; $535 national; $344 essential Nicaragua 3 $485 foreign; $166 national Peru 7 days $89 Uruguay 46 $500

62 COUNTRY SPECIFIC GUIDELINES

63 Guidelines • Russia has its own, unique regulatory system which does not correspond to U. S. or EU practices. • Cultural and language barriers often become a challenge to foreign companies attempting to register pharmaceuticals by themselves • Registration procedure is also quite complicated and the documents tend to be modified due to constant changes in the regulatory requirements. • Before exporting a pharmaceutical product to Russia it has to be registered at the Ministry of Health of the Russian Federation; Department for registration of pharmaceuticals of the Federal Service for Health Control

64 Registration Procedure • The best way to accomplish registration of a pharmaceutical product in Russia is trough one of the following types of companies: ▫ Company incorporated in Russia and belonging to the Indian parent company ▫ Russian distributor/authorized agent ▫ Consulting company

65 Documentation • For the registration procedure a company has to submit the following: ▫ General documents ▫ Certificates ▫ Information and test reports ▫ Samples and package

66 General documents • Application for the State registration of a pharmaceutical which includes the name of the pharmaceutical preparation, the name and the contact information of the manufacturer • Name of the pharmaceutical preparation, including international non-proprietary name, scientific name in Latin, trade name and main synonyms • List of active ingredients and components • Recommended dosage, instruction for use • Description of the drug and its packaging, shelf life and storage conditions • Power of Attorney issued by the manufacturer to the authorized company for carrying out registration procedure (notarized original with apostil)

67 Certificates • Copy of Free Sales Certificate (must be notarized and apostilled) • Copy of the license of pharmaceutical manufacture (must be notarized and apostilled) • Copy of GMP certificate (must be notarized and apostilled) • Copy of Certificate of manufacturer registration in their own country (must be notarized and apostilled) • Original of Certificate of analysis of the drug and its active substance (must be signed and stamped by manufacturer) • Copy of Certificate of trade mark (must be signed and stamped by the manufacturer) • Information of registration of the drug in the country of the manufacture and in other countries • A certificate of analysis of the drug in the country of origin of the manufacturer, GMP certificate and information on registration of the drug in the foreign country.

68 Information and test reports • Summary of the method of the drug manufacturing (must be signed and stamped by manufacturer) • Complete description of the quantitative and qualitative control methods with references to the pharmacopoeia and specification (must be signed and stamped by manufacturer) • Stability data of three drug series – by date • Patterns of the spectrums and chromatograms of the drug • Report of the pharmacological (specific) activity study substantiated the indications for use which are formed and described in the instruction • Test report of the drug toxicity (acute, sub chronic, chronic toxicity)

69 Information and test reports • Test report of the specific influences (cancerogenity, mutagenic and teratogenic effects, embryotoxicity, allergic and local-irritative effects) • Clinical trial report of the medicine usage in clinic (the information which concerns only the drug that is produced by this manufacturer) • Copies of publications of the medicine usage in clinics after its registration in the country of origin (the information which concerns only the drug that is produced by this manufacturer) • Report of pharmacokinetics of the pharmaceutical study and its bioequivalence to the original drug • Summary information of the side effects, in comparison with other analogous medicines, used at the same indications • Instruction for use (must be signed and stamped by the manufacturer)

70 Samples and package • Information of the material used for package: Certificates of the packaging materials (must be signed and stamped by the manufacturer) • Colour design of internal and external packages (Original and Russian version) • Standard samples of the active substance for quality control • Standard and referenced samples of the drug for the binding examination of quality (should be in the standard package)

71 Approval Procedure • The Ministry of Health determines whether these approvals are sufficient for an exemption of the drug from clinical and other testing in Russia before issuing a registration certificate. • Officially Russia does not recognize FDA and EU certificates. • According to the Law on Medicines, a fee in form of a state duty is to be paid for state registration and the registration should take no longer than six month.