US FDA Regulatory Submissions

Basic information for beginners...

1. US Submissions By, CHANDRA MOHAN

2. INTRODUCTION (Regulated Countries and Regulatory Bodies) USFDA FILING ( Types of Applications) Drug Master File (DMF) Investigational New Drug Application (IND) New Drug Application (NDA) Abbreviated New Drug Application (ANDA)

3. REGULATED COUNTRIES Regulated market comprises of the following: U.S.A. Europe ( 28 EU nations) Canada Australia New Zealand Singapore Japan South Africa

4. SEMI REGULATED COUNTRIES The semi regulated markets comprises of the Rest of the World namely: Asia ( Srilanka , Myanmar, Bangladesh, Thailand, Malaysia, Philippines,Vietnam ) Africa (Kenya, Uganda, Nigeria, Algeria, Zambia) Middle East (Gulf Co-operation Council countries i.e. Bahrain, Kuwait, Oman, Qatar , Saudi Arabia, UAE ) Latin America (Mexico, Brazil, Panama, Peru, Guatemala, Argentina, Chile, Dominican Republic) Russia CIS (common wealth of independent states)

5. REGULATORY BODIES (REGULATED MARKETS) 1) U.S.A. – United States Food Department & Administration (FDA) Europe: 2) U.K.– MHRA (Medicines & Healthcare Products Regulatory Agencies) 3) Germany – Bfarm 4) Sweden – Medical Product Agency 5) Ireland – HSE (Health Safety Executive) 6) Netherlands – MEB (Medicines evaluation Board) 7) France – HAS (Haute Authorite de Sante)

6. COUNTRY FOOD / DRUG REGULATORY AUTHORITIES / AGENCIES WEBPAGE/LINK EUROPE  European Medicine Agency   http://www.emea.eu.int   CANADA   Health Canada   http://www.hc-sc.gc.ca   AUSTRALIA   Therapeutic Goods Administration   http://www.tga.gov.au   NEW ZEALAND  Australia New Zealand Joint Therapeutic Products Agency Health and Ageing   http://www.tgamedsafe.org   Medsafe   http://www.medsafe.govt.nz   SINGAPORE (ASEAN MEMBER)  Ministry of Health   http://www.hsa.gov.sg   JAPAN  National Institute of Health Sciences (NIHS)   http://www.nihs.go.jp   SOUTH AFRICA   Medicines Control Council  http://www.mccza.com/   INDIA  Central Drugs Standard Control Organization   http://www.cdsco.nic.in   CHINA   State Food and Drug Administration   http://www.sfda.gov.cn   HONG KONG  Department of Health: Pharmaceutical Services   http://www.psdh.gov.hk   ISRAEL  Ministry of Health   http://www.health.gov.il  

7. COUNTRY FOOD / DRUG REGULATORY AUTHORITIES / AGENCIES WEBPAGE/LINK PHILIPPINES (ASEAN MEMBER) Bureau of Food and Drugs http://www.bfad.gov.ph MALAYSIA (ASEAN MEMBER) Ministry of Health http://dph.gov.my MYANMAR (ASEAN MEMBER) Ministry of Health http://www.dph.gov.my POLAND Narodowy Instytut Zdrowia Publiccznego http://www.il.waw.pl SINGAPORE (ASEAN MEMBER) Ministry of Health http://www.hsa.gov.sg TAIWAN Bureau of Food and Drug Analysis http://www.nlfd.gov.tw THAILAND (ASEAN MEMBER) Food and Drug Administration http://www.fda.moph.go.th/ UNITED ARAB EMIRATES Ministry of Health http://www.moh.gov.ae VIETNAM (ASEAN MEMBER) Boy te Ministry of Health http://www.moh.gov.vn

8. USFDA

9. TYPES OF APPLICATIONS DRUG MASTER FILE (DMF) INVESTIGATIONAL NEW DRUG APPLICATION (IND) NEW DRUG APPLICATION (NDA) ABBREVIATED NEW DRUG APPLICATION (ANDA)

10. DRUG MASTER FILE (DMF ) DMF is a submission to the FDA Usually concerning the CMC of a component of a drug product There is no legal or regulatory requirement to file a DMF Normally the CMC for a compendial excipient is not reviewed The DMF will be reviewed ONLY when it is referenced in an Application or another DMF The holder MUST submit an LOA (2 copies) to the DMF THEN send a copy to the APPLICANT The applicant submits copy of LOA in their Application. This is the ONLY mechanism to trigger review of the DMF

11. Types of DMFs Originally Five Types I - Manufacturing plant information (No longer acceptable by FDA) II - Drug substance, drug substance intermediates and material used in their manufacture III - Packaging material IV - Excipients, colorant, flavor V - FDA accepted reference information (FDA discourages its use)

12. Who is Who? The person or company who submits a DMF is the HOLDER The person or company who represents a DMF HOLDER is the AGENT The person or company who references the DMF is the APPLICANT or the CUSTOMER or the AUTHORIZED PARTY (AP) Reason for DMF To Maintain confidentiality of proprietary information (e.g., Manufacturing procedure) for the holder Permit review of information by reviewers in the CDER to support applications submitted by one or more applicants

13. INVESTIGATIONAL NEW DRUG APPLICATION ( IND) Means through which the sponsor technically obtains exemption from the FDA to distribute or transport the new drug under evaluation Application must contain the following information: Manufacturing information Animal Pharmacology & Toxicology Studies Clinical protocols and Investigator information Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials

14. NEW DRUG APPLICATION (NDA) Means through which the drug sponsor seek approval from the FDA to sale & market a new pharmaceutical in US Factors considered by FDA reviewer to reach the following key decisions: Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks. Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain. Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity. Human Clinical Trials data becomes part of NDA

15. ABBREVIATED NEW DRUG APPLICATION (ANDA) Means through which the applicant seek approval from the FDA to manufacture and market a safe, effective, low cost alternative (the generic drug ) in US Termed as abbreviated because the preclinical (animal) and clinical (human) data to establish safety and effectiveness is not needed

16. WHAT IS A GENERIC DRUG? Generic products rely on the findings of safety and efficacy of the innovator drug after expiration of certain patents and exclusivities Generic drugs are copy versions of brand drugs.   Generic drugs are safe and effective alternatives to branded drugs. “Equal quality” at “Low cost ” Therapeutically equivalent = Phamraceutical equivalent + Bio equivalent

17. GENERIC DRUG REVIEW Pharmaceutical Equivalence: The generic drug must have same active ingredient(s) same labeled strength same dosage form same administration The drug company must show the generic drug is “Bioequivalent” to the brand-name drug active ingredient works in the same way active ingredient works in the same amount of time

18. GENERIC DRUG REVIEW The generic drug’s labeling must be basically the same as that of the approved brand-name drug (RLD) The drug company must: fully document the generic drug’s chemistry, manufacturing steps, and quality control measures detail each step of the process The raw materials and the finished product must meet USP specifications, if applicable

19. GENERIC DRUG REVIEW The drug company must: show that its generic drug maintains stability as labeled before it can be sold continue to monitor drug’s stability The drug company must: comply with federal regulations for cGMPs give a full description of the facilities it uses to manufacture, process, test, package, label, and control the drug Inspection at the proposed manufacturing site ensures that the firm: is capable of meeting commitments of the application can manufacture the product consistently USFDA visits every two years

20. FDA REQUIREMENTS Brand Name Drug NDA Requirements Chemistry Manufacturing Controls Labeling Testing Animal Studies Clinical Studies Generic Drug ANDA Requirements Chemistry Manufacturing Controls Labeling Testing Bioequivalence

21. ANDA Y N N Y Y Y Y Generic Drug Review Process Bioequivalence Review Labeling Review Chemistry & Micro Review Request for Plant Inspection APPLICANT Acceptable & Complete Application Review N Chem/Micro OK? Labeling OK? Bioequivalence OK? PreApproval Inspection Results OK? Not Approvable Letter Approval Withheld until Results Satisfactory Bio Deficiency Letter APPROVED ANDA N N Refuse to Receive Letter

22. ORANGE BOOK All FDA approved drug products listed (NDA’s, OTC’s & ANDA’s) Therapeutic equivalence codes “A” = Substitutable “B” = Inequivalent, NOT Substitutable Expiration dates: patent and exclusivity Reference Listed Drugs/brand drugs identified by FDA for generic companies to compare with their proposed products

23. PATENT CERTIFICATION A certification on patent situation referred in Orange book This certification must state one of the following: PARA I : No patent information on the drug product PARA II : The listed patents have expired PARA III : The patent will expire on a stated date and generics will be launched upon expiration PARA IV : The listed patents are invalid, not infringed or not enforceable by the manufacture , use or sale of the generic drug .

24. PATENT CERTIFICATION

25. REWARD TO 1 ST ANDA FILER First ANDA filer with Paragraph IV - 180 day exclusivity period No other ANDA approval for subsequent generics for 180 days Measured from the earlier date of marketing or court decision

26. POST-APPROVAL CHANGES Level I (Minor) change Level II (Moderate) change Level III (Major) change Chemistry (A/C test, Stability) In Vitro dissolution/release In Vivo bioequivalence test / IVIVC Annual report Change being effected supplement Prior approval supplement Level of Change Tests Filing

27. THANK YOU! Questions ?