New Drug Application [NDA]

The NDA application is the vehicle through which drug sponsors, such as biotech and pharmaceutical companies, formally propose that the FDA approve a new pharmaceutical for sale and marketing

1. 1 New Drug Application[NDA] Mr. Sagar Kishor Savale [Department of Pharmaceutics] [email protected] 2015-2016 Department of Pharmacy (Pharmaceutics) | Sagar Savale 6/18/2016 Sagar Kishor Savale

2. Introduction Definition : The NDA application is the vehicle through which drug sponsors, such as biotech and pharmaceutical companies, formally propose that the FDA approve a new pharmaceutical for sale and marketing. For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). 2 6/18/2016 Sagar Kishor Savale

3. Since 1938, every new drug or therapy has been the subject of an approved NDA before US commercialization. The documentation required in an NDA is supposed to tell the drug's whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged. 3 6/18/2016 Sagar Kishor Savale

4. Definitions Drug : Drug are the substance intended to be used for or in the diagnosis, treatment, mitigation, or prevention of any disease or disorder in human being or animal. New drug: Drug that has not been declared safe and effective by qualified expert under the condition prescribed, recommended, or suggested in the and that may be new chemical formula or an established drug prescribed for use in new way. 4 6/18/2016 Sagar Kishor Savale

5. 5 Drug All medicines for internal or external use of human beings or animals or All substances intended to be used for or in the diagnosis, treatment mitigation or prevention of any disease or disorder in human and animal. Such substances (other than food) intended to affect the structure or any function of human body. All substances intended for use as components of a drug including empty gelatin capsules. Such devices intended for internal or external use in the diagnosis, treatment, mitigation or prevention of disease or disorder. 6/18/2016 Sagar Kishor Savale

6. 6 New drug A new substance of chemical, biological, or biotechnological origin in bulk or prepared dosage form used for diagnosis, treatment, mitigation or prevention of any disease or disorder in human or animal which except during local clinical trial has not been used in the country to any significant extent and during local clinical trials has not been recognized in the country as effective and safe for the proposed claims. 6/18/2016 Sagar Kishor Savale

7. 7 New Drug Application (NDA) An application submitted by the manufacturer of a drug to the FDA - after clinical trials have been completed - for a license to market the drug for a specified. New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new. Abbreviated New Drug Application (ANDA) An application for a license to market a generic (or a duplicate) version of a drug that has already been granted an approval under a full NDA (i.e. the drug has already met the statutory standards for safety and effectiveness. 6/18/2016 Sagar Kishor Savale

8. OBJECTIVE OF NDA Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain. Whether the drug is safe and effective in its propose use, and whether the benefits of the drug outweigh the risks . 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. 8 6/18/2016 Sagar Kishor Savale

9. NDA FORM Form FDA-356h. Application to market a new drug, biological or an antibiotic drug for human use. Form FDA 3397. User fee cover sheet. Form FDA 3331. New drug application field report. Impurity in drug substances. Required specification for FDAs IND, and ANDA drug master file binders. Refusal to file. 9 6/18/2016 Sagar Kishor Savale

10. 10 FORM NO 356 TH 6/18/2016 Sagar Kishor Savale

11. 11 Approval time TOTAL APPROVAL YEAR NO AVG APPROVAL TIME (MONTHS) DECEMBER APPROVAL 1980 12 35 2 1981 27 31 7 1982 28 29 6 1983 14 29 2 1984 22 39 8 1985 30 32 16 1986 20 34 10 1987 21 32 15 1988 20 31 13 1989 23 33 10 1990 23 27.7 - 6/18/2016 Sagar Kishor Savale

12. 12 Introduction of NDA and ANDA NDA and ANDA is application is send to FDA for approval of new drug and abbreviated ( generic) new drug. When new drug application is submitted to food and drug administration it must be carefully prepared , comprehensive , readable and well indexed. The guideline issued by FDA has to follow Should follow D & C Act. Code of federal regulation title 21 section 314 ( 21 CFR 314) is provided a brief description for NDA and ANDA Experience : It is generally planned 3 years ago. 6/18/2016 Sagar Kishor Savale

13. 13 Requirement Requirement for NDA Format requirement A) No of copies - Before 1985- 3 copies & now only 2 copies. Archival copy Review copy 1) Archival copy - Reference copy for FDA ( i.e. retained by FDA ) - Locate information not contained in review copy 2) Review copy - Divided in to five or six section containing technical and scientific information separately bound - It contains copy of cover letter, application form, overall summary, index, specific review section 6/18/2016 Sagar Kishor Savale

14. 14 B) Assembling the application 1) Folder - Color folder Eg. archival copy - blue chemistry section – red - Name of applicant and name of drug product - NDA no. if known 2) Paper size and binding - Page 8.5 – 11 inches - Bound at left side - Use both side - Accurately no. 3) Pagination – page no of both copy should have same 6/18/2016 Sagar Kishor Savale

15. 15 4) Volume size and identification - Not more than 2 inches thick - Should have name of applicant, drug and - NDA no. 5) Packing carton - Box size 14 -12- 9.5 inches 6/18/2016 Sagar Kishor Savale

16. 16 Basic requirements Archival copy contains - Application form (FDA 356 th ) It contains - basic identification information - as per form items no. 1 and 2 should bound together - 3 to 12 submitted separately - 13 and 14 separately - Index - 6/18/2016 Sagar Kishor Savale

17. 17 Summary requirement 1) Labeling : -Proposed label - It is also called mini summary 2) Pharmacological class Intended use Potential clinical benefit 3) Foreign marketing history - List of country who approved same drug - List of country who withdrawn same drug 6/18/2016 Sagar Kishor Savale

18. 18 4) Chemistry, mfg., control A) Drug substance Names :- name, synonym, code designation, brand name, identification no. and chemical name. Physical and chemical properties: MP, BP, mol wt., solubility, mol. Formula structural formula, PH, isomer, polymorphs. Stability Manufacture- Name and method. 6/18/2016 Sagar Kishor Savale

19. 19 B) Drug product a) Composition b) Dosage form c) Manufacture d) Specification e) Analytical method f) Container g) Closure h) Stability i) Investigational formulation 6/18/2016 Sagar Kishor Savale

20. 20 5) Nonclinical pharmacology and toxicology summary A) Pharmacological studies B) Acute toxicity studies C) Multi dose toxicity studies D) Mutagenicity studies E) Reproduction studies F) ADME studies 6) Human pharmacokinetic summary 7) Microbial summary - Microbial spectra - Mechanism of action 6/18/2016 Sagar Kishor Savale

21. 21 8 ) Clinical data summary and result A) Clinical pharmacology B) Overview of clinical studies C) Controlled clinical studies D) Uncontrolled clinical studies E) Other studies and information F) Safety summary a) Extent of exposure b) Adverse event c) Clinical laboratory data e) Over dose f) drug abuse 6/18/2016 Sagar Kishor Savale

22. Guidance Documents for NDA Submitting documentation for the stability of human drugs and biologics. Format and content of human pharmacokinetics and bioavailability section of an application. Providing clinical evidence of effectiveness for human drug and biological product. 22 6/18/2016 Sagar Kishor Savale

23. 23 9) Discussion of benefit to risk relationship and proposed post marketing studies. 10) Bioavailability summary NDA technical section requirement 1) Chemistry, manufacturing, and control A) Drug substance B) Product 2) Non clinical pharmacology and toxicology 3) Human pharmacokinetics 4) Bioavailability section 6/18/2016 Sagar Kishor Savale

24. 24 5) Microbiology A ) Mechanism of action B) Pharmacokinetics C) Antimicrobial activity D) Enzyme hydrolysis rate E) Assessment of resistance F) In vivo animal studies G) In vitro studies during clinical trial H) Published literature I) Miscellaneous studies 6/18/2016 Sagar Kishor Savale

25. 25 6) Clinical data section - adverse dose- response information - drug -drug interaction - drug disease interaction Other NDA requirement A) Safety updates B) Sample : 4 samples C) Method validation D) Label : Draft labeling -4 copies Final print labeling -12 copies E) Case report 6/18/2016 Sagar Kishor Savale

26. 26 NDA and ANDA Requirements Brand Name Drug Generic Drug NDA Requirements ANDA Requirements 1. Chemistry 1. Chemistry 2. Manufacturing 2. Manufacturing 3. Controls 3. Controls 4. Labeling 4. Labeling 5. Testing 5. Testing 6. Animal Studies 7. Clinical Studies 6. Bioequivalence 8. Bioavailability 6/18/2016 Sagar Kishor Savale

27. 27 NDA Classifications New Molecular Entity New Salt of Previously Approved Drug (not a new molecular entity) New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity) New Combination of Two or More Drugs Already Marketed Drug Product - Duplication (i.e., new manufacturer) New Indication (claim) for Already Marketed Drug (includes switching marketing status from prescription to OTC) Already Marketed Drug Product - No Previously Approved NDA 6/18/2016 Sagar Kishor Savale

28. Specification for FDAs DMF binders Polyethylene binder : Front- 248× 292 mm Back- 248× 305 mm Ink Colour must be BLACK 28 6/18/2016 Sagar Kishor Savale

29. Paper binder Front 267×292mm Back 267× 305mm Ink must be BLACK , Marron Colour binder ink must be WHITE 29 6/18/2016 Sagar Kishor Savale

30. FORM COLOUR DOCUMENT FDA form 2226 Blue NDA archival binder FDA form 2675 Red IND archival binder FDA form 3316 Red Drug master file binder FDA form 3316a Blue Drug master file binder archival binder 30 6/18/2016 Sagar Kishor Savale

31. FORM COLOUR DOCUMENT FDA Form 2626a Red NDA chemistry binder FDA Form 2626b Yellow NDA pharmacology binder FDA Form 2626c Orange NDA pharmacokinetic binder FDA Form 2626d White NDA microbiology binder FDA Form 2626e Tan NDA clinical data binder FDA Form 2626f Green NDA statistics binder FDA Form 2626h Marron NDA field submission chemistry binder FDA Form 2675a Green IND chemistry binder 31 6/18/2016 Sagar Kishor Savale

32. Assembling application for submission 32 FDA Archival copy Review copy 6/18/2016 Sagar Kishor Savale

33. Archival copy Reference copy for FDA ( i.e. retained by FDA ) . Locate information not contained in review copy. It must bound in blue cover Review copy Divided in to five or six section containing technical and scientific information separately bound. It contains copy of cover letter, application form, overall summary, index, specific review section. 33 6/18/2016 Sagar Kishor Savale

34. NDA Contents The NDA have as many as 15 different section in addition to the Form FDA 356h itself. The specific content of NDA will depend on the nature of the drug product and the information available at the time of submission the application. 34 6/18/2016 Sagar Kishor Savale

35. NDA content 35 section 1 Section 2 Section 3 Section 4 Chemistry , manufacturing and control Section 5 Nonclinical pharmacology and toxicology Index summary Sample and labeling 6/18/2016 Sagar Kishor Savale

36. NDA Contents 36 Section 6 Section 7 Section 8 Section 9 Section 10 Human pharmacokinetics and bioavailability Clinical microbiology Clinical data Safety update report statistics 6/18/2016 Sagar Kishor Savale

37. NDA Contents 37 Section 11 Section 13 Section 12 Section 14 Case report tabulation Case report form Patent information Patent certification Section 15 other 6/18/2016 Sagar Kishor Savale

38. 38 THE TWO TRANSLATIONAL BLOCKS Basic Biomedical Research Clinical Science and Knowledge Goal: Improved Health Block 1 Block 2 Translation from basic science to human studies Translation of new knowledge into clinical practice 6/18/2016 Sagar Kishor Savale

39. 39 DRUG DEVELOPMENT PROCESS 6/18/2016 Sagar Kishor Savale

40. 40 NDA review Usually six different teams responsible for reviewing NDA includes Chemistry Clinical Pharmacology/ toxicology Statistics Biopharmaceutical Microbiology 6/18/2016 Sagar Kishor Savale

41. 41 New Drug Development and Review Process Steps from Test Tube to New Drug Application Review 41 6/18/2016 Sagar Kishor Savale

42. 42 Phases of clinical testing Phase Number of patients Length Purpose Percent successfully completing Phase 1 20-100 Several months Mainly safety 67 Phase 2 Up to several hundred Several months to two years Some short-term safety but mainly effectiveness 45 Phase 3 Several hundred to several thousand 1-4 years Safety, effectiveness, dosage 5-10 6/18/2016 Sagar Kishor Savale

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44. 44 NDA Review Process 44 6/18/2016 Sagar Kishor Savale

45. FDA –Approval process 45 6/18/2016 Sagar Kishor Savale

46. Fast track approval Drug for Serious disease. Fill an unmet need. Must be requested by the drug company . FDA 60 days review decision. 46 6/18/2016 Sagar Kishor Savale

47. Accelerated approval In 1992 FDA instituted the accelerated approval regulation. Based on surrogate endpoint, not on clinical outcome. A surrogate endpoint is a marker- a laboratory measurement, or physical sign that is used in clinical trial as an indirect or substitute measurement that represent a clinically meaningful outcome, such as survival or symptom improvement. 47 6/18/2016 Sagar Kishor Savale

48. Priority review A priority review designation is given to drug that offer major advances in treatment. The goal for completing a priority review is 6 month. It can given for drug used in serious/non serious disease. 48 6/18/2016 Sagar Kishor Savale

49. 49 Common Technical Documents MODULE-1 : Administrative Information MODULE- 2: Quality Overall Summary MODULE-3: Quality MODULE-4: Non- Clinical Studies MODULE-5: Clinical Studies 6/18/2016 Sagar Kishor Savale

50. 6/18/2016 Sagar Kishor Savale 50 MODULE 1 MODULE 3 MODULE 4 MODULE 5 MODULE 2 Regional Admin. Information Quality Overall summary Non Clinical overview Non Clinical Summary Clinical Overview Clinical Summary Quality Non Clinical Report Clinical Report Not part of CTD CTD The CTD Triangle 50

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52. 52 The NDA in CTD Format Module 1 is not part of the CTD because it is not harmonized CTD NDA: 314.50 Module 1 Application form c)2.1 Annotated text of proposed labeling e)Samples and Labeling h)Patent information Patent certification j)Claimed exclusivity Module 2 c)Summaries d)5.7 Abuse potential Module 3 d)1 CMC Module 4 d)2 Nonclinical pharm/ tox Module d)3 Human PK d)4 Microbiology d)5 Clinical data d)6 Statistical section f) CRF and CRT 52 6/18/2016 Sagar Kishor Savale

53. Difference between NDA & ANDA NDA ANDA Applicable for new drug Applicable for generic drug Money requirement is high Less money compare to NDA 12 to 15 year required 1 to 2 year required Cost of drug is high Cost of drug is less Non clinical and clinical study are essential. Bioavailability and bioequivalence study essential 53 6/18/2016 Sagar Kishor Savale

54. REFERENCE www.hhs.gov www.fda.com www.usfda.com www.slideshere.com www.mpssociety.org www.jpsr.pharmainfo.in Richard A. Guarino , (1993) New drug Approval process, Marcel Dekker, 2 nd edition, p.no 256-319 Ram .I. Mahato pharmaceutical dosage form and drug delivery CRC press pharmacy edu . series p.no 7 54 6/18/2016 Sagar Kishor Savale

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