IND,NDA..............................pptx

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1. IND

2. Various steps involved in drug approval process at FDA 1.Priclinical testing 2.sponser/FDA meetings(Pre-IND) 3.Submission of IND to DCGI 4. Phase I 5. Phase II 6.sponsor/ DCGI meetings 7. Phase III 8.Sponsor/ DCGI Meetings 9.New drug application( NDA)Submission to DCGI (For marketing approval) 10.FDA reviewers will either approve it or not 11.Permission for marketing 12.Post marketing review

3. For new drugs and even for most follow-on products (besides generics), the results of certain nonclinical studies, known as IND-enabling studies, must be submitted with the IND application to support the investigational drug use in humans. IND-enabling studies are beneficial because they: Predict potential safety concerns Allow estimation of safe starting doses and dose ranges for clinical trials Identify key parameters for monitoring

4. What are IND-Enabling Studies? IND-enabling studies include  in vitro  and  in vivo  assessments that help define the pharmacological and toxicological properties of a drug. This includes dose and exposure dependencies and the reversibility of toxic effects. IND-enabling studies allow drug developers to assess: Pharmacodynamics and safety pharmacology Pharmacokinetics, including absorption, distribution, metabolism, and excretion (ADME) and  radiolabeled mass balance studies Toxicology, including single-dose, repeated-dose, reproductive and developmental toxicity, and genotoxicity studies

5. Additional studies, such as immunotoxicity and local tolerance studies, may also be required to enable initial human trials, depending on the drug, route of administration, and indication . While IND-enabling studies support initial human studies, this is not the end of nonclinical development. On the contrary, most development programs require additional, often long-term, nonclinical studies to characterize the potential for long-term toxicity (including carcinogenicity). In addition, juvenile animal studies may also be required before the drug can be administered to pediatric patients.

6. What Key IND-Enabling Studies Are Required? IND-enabling studies are conducted to evaluate the potential toxicity risks prior to human studies and to estimate starting doses for clinical trials. A complete IND-enabling program is dependent on the class of drug, route of administration, planned indication, and planned duration of treatment. The key IND-enabling studies typically required include pharmacology, pharmacokinetics, and toxicology assessments.

7. Pharmacology IND-enabling safety pharmacology studies assess the effects of a drug on the cardiovascular, central nervous, and respiratory systems in animals. Primary pharmacodynamic studies are generally also included to define the therapeutic effects of the drug, including relationships to dose and/or exposure.

8. Pharmacokinetics (PK) IND-enabling PK assessments typically include  in vitro  metabolism and plasma protein binding studies, as well as systemic exposure studies in the same species as repeated-dose toxicity evaluations. While these studies are generally sufficient for supporting initial human trials, additional studies to characterize ADME, drug-drug interactions (DDI), and metabolite profiling are often required prior to conducting later phase clinical studies. The amount of information needed depends in part on the phase of development and design of the proposed clinical study.

9. Toxicology The IND-enabling toxicology assessment may include both acute (single-dose) and repeated-dose toxicity studies. Acute toxicity studies are generally conducted in two mammalian species (one non-rodent) using the clinical route of administration and a parenteral route (e.g., intravenous or subcutaneous). Dose levels should be chosen for these studies that will allow the determination of a maximum tolerated dose (MTD) and a no-observed-adverse-effect level (NOAEL). These parameters are important for predicting human safety and for clinical dose selection.

10. Acute toxicity studies can be the primary IND-enabling toxicology studies, but they are often combined with repeated-dose toxicology studies. Repeated-dose studies are designed with a similar duration and route of administration as the proposed clinical trial. These studies should match or exceed the duration of treatment of the proposed human clinical trial . Dose levels and dose regimens should be selected so that observed exposures ( Cmax and AUC) in nonclinical species will adequately cover expected clinical exposures.

11. To determine the mutagenic potential of an investigational drug, a gene mutation assay (e.g., Ames assay) is conducted to support single dose clinical trials . Additional chromosomal damage assessments are conducted to support repeated-dose clinical studies. Complete genotoxicity testing should be completed prior to Phase 2. Depending on the drug, mechanism of action, indication, and other considerations, other toxicity studies may be conducted and submitted with the initial IND application. These may include reproductive toxicity (e.g., embryo-fetal toxicity), immunotoxicity , phototoxicity , and abuse liability testing. Long-term carcinogenicity studies are typically carried out after the initial IND submission.

12. Need of IND IND needed IND not needed For New chemical entity For a drug not approved for the indication under investigation . For a new dosage form. For a new combination to be approved For a drug not intended for human use but only for in-vitro testing For non-clinical studies (on laboratory animal or microbes) For the study of an approved drug for approved indication.

13. IND is submitted to respective government. Authority to requesting permission to respective government authority. If IND is approved then it is evidence of safety and efficacy for proposed human studies. IND allows the company to legally ship/transport an unapproved drug or import a new drug from another counrty .

14. Investigational New Drug (IND) Application It is a re quest submitted to resp. Govt. authority (FDA in US, DCGI in Mumbai ) to allow / clinical study of a new drug product /human exposure to the experimental drug. • IND is an ongoing file at FDA containing data on drug as it passes through the development process to test the drug in human. The IND program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines (usually to clinical investigators) before a marketing application for the drug has been approved. The FDA reviews the IND application for safety to assure that research subjects will not be subjected to unreasonable risk. If the application is approved, the candidate drug usually enters a Phase 1 clinical trial .

15. Types of IND An Investigator IND : is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed.  A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population. Emergency Use IND : allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with  21CFR , Sec. 312.23 or Sec. 312.34. It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist. Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

16. IND application: information in three broad areas Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.  Also included are any previous experience with the drug in humans (often foreign use). Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product.  This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug. Clinical Protocols and Investigator Information - Detailed protocols to assess whether the initial-phase trials will expose subjects to unnecessary risks.  Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties.  Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.  

17. A clinical study is required for an IND--- If it is intended to support a New indication . Change in the approved  route of administration or dosage level. Change in the approved patient population  ( e.g. pediatric ) or a population at greater or increase of risk ( elderly, HIV positive, immunocompromised ). Significant change in the promotion of an approved drug . The IND is also the vehicle through which a sponsor go for clinical trials Drug Clinical trials may proceed 30 days after filing the IND application.

18. Importance of IND Discloses Knowledge about the manufacturing, Pharmacology and toxicology of the drug to support its use in human testing Requires that the clinical investigation be performed in accordance with GCP Provide an additional level of protection through FDA oversight

19. IND Content/components Cover Sheet (Form FDA 1571) Table of Contents Introductory Statement Basic investigational plan Investigator’s Brochure Actual and proposed chemistry Pharmacological and toxicological information of compound Previous Human Experience with the Investigational Information Additional Information of Drug asked by FDA

20. Cover Sheet (form FDA 1571) The form is provided for basic information like----- name of drug submission date sponsor identification phase of proposed clinical investigation signed commitments by investigator. Identification of clinical monitor and safety evaluator Signed commitment by the investigator. Name of sub investigator. information regarding transfer of responsibilities to a contract research organization

21. Commitment of sponsor in form 1571 The sponser should not initiate clinical trial untill 30 days after the FDA receive the IND Not start till notify by FDA, or when placed on hold Sponsorer should ensure IRB grant the initial approval, and periodic review Should conduct investigation in accordance with other applicable regulatory requirments . Note –deviation on inclusion of false statement is criminal offence.

22. Review OF IND by FDA Once it is received, it is sent to different branches like-chemistry, Pharmacology, Toxicology, Biopharamceutics in order to ensure safety. Further approval is given

23. Table of Contents 1. Detailed cover sheet- 2IND table of contents Item title volume/page Introductory statement & general investigational plan… 3. Introductory statement…. 4General Investigational Plan….. 5 Investigator’s Brochure……. 6 Protocol…….. 7 Chemistry, Manufacturing & Control Information… (a) Drug substance………… (b) Drug Product……………. (c) Placebo (if applicable)… (d) Labeling……………………. (e) Environmental Analysis …. 8 Pharmacology & Toxicology Information…….

24. 1st subsection: (introductory statement) Introductory Statement & General Investigational Plan: Name of drug, indications, P’cological Class Structural formula Route of administration Broad objectives additionaly –rationale , Planned duration of the proposed clinical, typical clinical studies to be conducted, no of patients . CONTENT OF IND- It consists of four subsections:

25. Investigator’s Brochure (IB)- key document That present summary from clinical, non-clinical, CMC( Chemisrty , Manufacturing and control Information) data that support the clinical study. Sponsor must provide to all clinical investigators, not required for sponsor investigators (21 CFR 312.55). It must include: Brief product description –Physical, chemical AND pharmaceutical properties of drugs. Stoarge , supply, handling Info Chemical name , structure  Pharm / tox summaries-Preclinical pharmacology  Previous human experience-Safety and efficacy profile if studied earlier  Description of anticipated risk and any special monitoring needs

26. Protocol Should include – Objectives Trial design Selection of subject Critical elements-monitoring of vital sigs

27. Name ,Add, qualification of each investigator and co investigator, Name and Add of clinical site Name and Add of IRB Introduction and rationale Case report form copy-With the form 1572 in case of phase I,II Inclusion and exclusion criteria of subject. Estimated No of subjects . Overall study design, method employed to minimize bias on part of subject and investigator. Max dose and duration of exposure . Method for Measurement and observation clinical procedure and lab test planned to monitor the effects of drug in the subject. Data analysis and statistics. Ethical considerations. Protocol –content

28. Pharmacology and Toxicology information A review on data obtained from Non clinical study Data must give good level of confidence regarding safety of drug for human use. Useful to decide initial starting dose Insufficient data result in clinical hold

29. Common nonclinical safety studies Safety pharmacology Single and repeated dose toxicity study Genotoxicity -evaluate mutation and chromosomal damage Reproduction toxicity study Other supplementary studies All should include MOA, Pcological effects, Pkinetic profile Also submit integrated summary. Description of design of trial, Any deviation, systemic presentation of findings , name of Investigator, facility centre, and declaration regarding GLP.

30. content of integrated summary. Brief description of the design of the trial Details of deviation from design in contuct of the study A systemic presentation of finding Organ or system wise presentation of data Name and qualification of evaluators along with their report and animal safety data. Name and Add of place where studies conducted and reports are stored A declaration regarding performance of studies are conducted according to GLP.

31. The final summary report should include Full data tabulation includind indivisual data report Brief technical report Abstract of each study and ammendments Details of human experiences if used earlier on humani ) i ) Summary of Previous Human Experience…. (ii) If the drug is a combination of drug previously investigated/marketed……. (iii) If the drug has been marketed outside the contry . The IND must include P’kinetics , P’dynamics and observed ADE Published information regarding that drug List of countries where marketed /withdrawn due to safety issue Specific info- drug dependence, Drug abuse potential, radioactive sub Safety and effectiveness in padiatric population etc.

32. Other document to be submitted with IND Financial disclosure from Investigator or SubInvestigator Revised Financial disclosure Copy of ICF List of references previously submmited to FDA Drug Master File

33. IND Safety Reports:  If a sponsor notify any unexpected fatal / life threatening experience associated with the use of the drug requires to notify the FDA by telephone no later than 3 working days after receipt of the information, followed by a written report within 10 days

34. IND Protocol Amendments  21 CFR 312.30 A new protocol  Safety or design related changes to an existing protocol New investigator (notification is required within 30 days of being added) These should be submitted to the FDA prior to implementation IRB approval is needed prior to implementation IND Information Amendments 21 CFR 312.31 Information amendments advise the FDA of: New tox , CMC or other technical information Notice of discontinuance of a clinical study

35. Annual Reports  21 CFR 312.33 To be submitted within 60 days of the Include enrollment, demographic and conduct status information for each study Adverse event summaries (safety reports,deaths , dropouts) Drug action information Preclinical study status information. CMC ( chemistry,Mfg . &control) change information Revised/updated investigator brochure with revisions described general investigatin plan for next year Withdrawal of an IND - It is option of a sponsor to withdraw an IND at any time without prejudice. On withdrawn, sponsor must notify the FDA. Significant marketing development like approval, withdrawal, or suspension in other counrty

36. Sponsor Investigation Site Team IRB/IEC Monitor / Auditor Regulatory authority Subject/Participant Study documents Regulatory bodies Management Proposed protocol Investigators Brochure Case record form Institutional review board Independent ethics committee Sponsor Investigator Monitor Auditor Informed consent form  

37. The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects Its purpose is to provide the investigators with the information of many key features of the protocol, such as the Dose Dose frequency/interval Methods of administration Safety monitoring procedures   SUBPART-A GENERAL PROVISIONS SUBPART-B Applications SUBPART-C Abbreviated Applications SUBPART-D FDA Action on Applications and Abbreviated Applications SUBPART-E Hearing Procedures for New Drugs SUBPART-F Reserved SUBPART-G Miscellaneous Provisions SUBPART-H Accelerated Approval of New Drugs for Serious or Life-Threatening Ilnesses SUBPART-I Approval of New Drugs when Human efficacy Studies are not Ethical or Feasible  

38. Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials.  During this time, FDA  has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk. The following resources have been gathered to provide you with the legal requirements of an IND application, assistance from CDER to help you meet those requirements, and internal IND review principles, policies and procedures:- Pre-IND Consultation Program Guidance Documents for INDs. CDER offers a Pre-Investigational New Drug Application (IND) Consultation Program to foster early communications between sponsors and new drug review divisions in order to provide guidance on the data necessary to warrant IND submission. The review divisions are organized generally along therapeutic class and can each be contacted using the designated Pre-IND Consultation List .

39. Most INDs are paper submissions. While only 12% of INDs are submitted electronically, 28% of IND amendments are submitted electronically as result of maintaining a growing number of INDs submitted electronically to date. Though the percentage of INDs submitted in eCTD format remained stable from 2008 to 2009, the number of IND amendments in eCTD format nearly doubled, indicating that companies are beginning to understand the benefits of electronic submissions.   Experimental drugs under an IND must be labeled :- “ Caution : New Drug--Limited by Federal (or United States) law to investigational use ”.    

40. 09/07/2007 Dept. of Pharmaceutics 40 IND Review Process

41. NEW DRUG APPLICATION Introduction : For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938 , every new drug has been the subject of an approved NDA before U.S. commercialization. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) becomes part of the NDA. 2/50

42. New Drug Application (NDA) An NDA is an application submitted to USFDA for permission to market a new drug product in the US. To obtain the permission, drug mfg. or sponsor Submits all pre-clinical and clinical trial data, drug information and descriptions of mfg. procedures If approved, drug may be marketed with labeling specifically approved by FDA and only for conditions in which the drug has been shown to be effective . Once a drug is approved, you may prescribe it for a non-approved use - this is ‘ off label ’ prescribing. Labeling may be altered later, based on wider experience .

43. NDA Content and Format Requirements NDA must provide all relevant data and information that a sponsor has collected during the product's research and development. The FDA has numerous guidelines that relate to NDA content and format issues. These guidelines can be obtained from CDER's Drug Information Branch (DIB) or on its website. 7/50

44. NDA Classifications CDER/FDA classifies new drug applications with a code that reflects both the type of drug being submitted and its intended uses. The numbers 1 through 7 are used to describe the type of drug 8/50

45. 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 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

46. The following letter codes describe the review priority of the drug : S - Standard review : For drugs similar to currently available drugs. P - Priority review : For drugs that represent significant advances over existing treatments . 10/50

47. GENERAL REQUIREMENTS The new (present) NDA regulations require that an application be submitted in multiple copies : (a) an archival copy that serves as a permanent record of the submission, and (b) a review copy. (c) Field copy- req. by FDA inspectors during pre-approval facilities inspections. The review copy is made up of a no. of separate technical volumes, each tailored to the needs of the disciplines involved in the review. Both the archival and review copies are submitted in hard copy , the regulations permit an application to submit the archival copy as microfiche (flat rectangular piece of film bearing microphotographs of documents.) 11/50

48. The archival copy of the application should include a comprehensive index by volume and page number . It is recommended that additional copies of the index be prepared and included with any material submitted to FDA for the NDA . This will easily access locating important parts of the submission that may be needed for meetings / view by individual technical reviewers. 16/50

49. Fundamentals of NDA Submission As outlined in Form FDA-356h, Application to Market a New Drug for Human Use Or As An Antibiotic Drug For Human Use , NDAs can consist of as many as 15 different sections : Index Summary Chemistry, Manufacturing and Control; Samples, Method Validation Package and Labeling Nonclinical Pharmacology and Toxicology Human Pharmacokinetics and Bioavailability

50. SUMMARY It has been suggested that the summary consists of 50 - 200 pages. It should discuss all aspects of the application and needs to be written at approximately level of detail required for publication and meet the editorial std. applied by referred scientific and medical journals. It is advantageous to provide data in the summary in tabular and graphic form with clear explanation of any terminology used in the tabulations or graphics.

51. Microbiology (for anti-microbial drugs only); Clinical Data; Safety Update Report (typically submitted 120 days after the NDA's submission); Statistical; Case Report Tabulations; Case Report Forms; Patent Information; Patent Certification; and Other Information. (e.g. the marketing history of the drug (if any) outside the U.S., a concluding discussion of benefit/risk considerations and of proposed additional studies or postmarketing surveillance plans etc.) 6/50

52. CHEMISTRY, MANUFACTURING AND CONTROLS Imp. is the specific citation needed for the solid state forms of the drug substance and their relationship to bioavailability. Chemistry, mfg. and controls summary must provide a general overview or abbreviated version of the drug substance and drug product. Drug substance: Description including physical and chemical characteristics and stability Drug product: Composition and type of dosage form, mfg., specifications and analytical methods, container/closure system, stability, investigational formulations. Details are provided in 21CFR 25.1

53. The chemistry section , because of its length, and highly detailed sections dealing with the manufacturing and control processes, is required to be submitted 90-120 days prior to the submission of the application for facilitating the identification of deficiencies in the filed NDA.

54. NONCLINICAL PHARMACOLOGY AND TOXICOLOGY Nonclinical lab studies include any invivo / invitro expt. to determine its safety, activity or disposition. This section includes Toxicological effects of drugs on reproduction and the developing fetus, ADME animal expt. of the drugs It provide a description, tabulation and graphics from Nonclinical lab studies of drug.

55. HUMAN PHARMACOKINETICS AND BIOAVAILIBILITY I st section: : overall tabulated summary of all in-vivo Biopharmaceutics studies carried out on the drug grouped by type of study. II nd section : The summary of bioavailability or pharmacokinetic data and overall conclusions ( Cmax , Tmax , Kel , AUC etc.) 23/50

56. III rd section : List of all formulations used in clinical trials and invivo bioavailability or pharmacokinetic studies together with each formulation used in studies. IV th section : Analytical methods used to measure the levels of drug and major metabolite. V th section : Dissolution data on each strength and dosage form for which approval is being sought . A comparative dissolution study with the lots used. In vivo biopharmaceutics studies should also be included.

57. MICROBIOLOGY Applicable to anti-infective and antiviral drugs. It should include description of : Biochemical basis of the drug’s action / microbial physiology. Antimicrobial spectra of the drug, including results of invitro preclinical studies that demonstrate effectiveness. Any known mechanisms of resistance to the drug, including results of epidemiological studies to demonstrate privilege of resistance factors. Clinical microbiological lab methods needed for effective use of the drug.

58. CLINICAL DATA To understand overall safety and effectiveness: Sections: List of investigators, List of IND’s and NDA’s Background or overview of clinical investigations. Other studies and information Integrated summary of effectiveness of data Integrated summary of safety information Drug abuse & overdose

59. CLINICAL DATA This section includes descriptions, summaries and analysis of : Clinical pharmacology studies including animal study and toxicology. Controlled clinical studies including the protocol and description of the statistical analyses used to evaluate the studies . Uncontrolled clinical studies , including all necessary details of the studies. Any other data/information relevant to an evaluation of safety and effectiveness obtained from any source, foreign or domestic (U.S.). 26/50

60. THE SAFETY UPDATE REPORTS The required safety data must be submitted in same format as integrated summary of safety described under clinical data section of the NDA content and format (21 CFR 314.50). Additionally the NDA format is req. to include case report forms for each patient who died during a clinical study or who did not complete the study due to an adverse event. Safety update reports must be submitted at 4 months after the initial submission of an application, following receipt of an approvable letter and other times as requested by the FDA.

61. STATISTICS section should include: A statistical evaluation of the clinical data A copy of the data given in the description and analysis of each controlled clinical study, along with the statistical analysis. A copy of the data included in the integrated summary of all available information about the safety of the drug.

62. NDA REGULATIONS Review Time Frames (21 CFR 314.100) This time frames includes : Within 180 days of receipt of an application, the FDA will review and issue an approval, approvable, or not approvable letter. This 180-day period is called the ‘review-clock ” During the review period an applicant may withdraw an application (21 CFR 314-65) and later resubmit it. The time period may be extended by mutual agreement between the FDA and the applicant or as the result of submission of a major amendment (21 CFR 314.60) 28/50

63. Filing Time Frames (21 CFR 314.101 ): Within 60 days after the FDA receives an application, a determination will be made whether the application may be filed. This will determine whether sufficient information is provided to proceed with an in-depth review of application. If FDA files the application, the applicant will be notified in written. The date of filing will be the date 60 days after the FDA received the application. The date of filing begins the 180-days period of the review. If FDA refuses to file the application, the sponsor will be given the opportunity to meet with FDA to discuss the reasons why the application is not fileable .

64. APPROVAL OF NDAs BASED SOLELY ON FOREIGN DATA (21 CFR 314.106) Clinical data will be considered on merit regardless of country of origin. Foreign Clinical data meeting U.S. criteria for approval may be approved if : The foreign data are applicable to the U.S. Population and U.S. Medical practice The studies have been performed by clinical investigators of recognized competence. If an inspection is necessary, FDA is able to validate the data through an on-site inspection or other appropriate means or the data may be considered valid without the need for an on-site inspection by FDA. 30/50

65. FDA will apply this policy according to the nature of the drug and the data being considered. The FDA is willing to explore all areas to remove the need to conduct repetitive clinical testing in U.S. When adequate foreign data have been generated a pre-NDA submission meeting is encouraged when approval being solely on foreign data is sought. 31/50

66. FDA DIALOGUE ON SCIENTIFIC & MEDICAL ISSUES (21 CFR 314.102) Approximately 90 days after the NDA is received, the FDA will provide applicants with an opportunity to meet with reviewers to discuss the general progress and status of the application Particularly for new chemical entities and major new indications of marketed drugs, this meeting will generally be held at the applicant’s option and may be held by telephone . With the issuance of an approvable/not approvable letter, an opportunity will be provided to applicants to meet with the FDA and discuss what further steps need to be taken before the applications can be approved. Priority for these meetings will be given to applications for new chemical entities and major new indications for marketed drugs. 32/50

67. NDA PRE-APPROVAL AND POST- APPROVAL SAFETY REPORTS In 21 CFR 314.50 (d) (5) (vi) (b), the FDA details the necessity to periodically update a pending application with new safety information which affects the statements of contraindications, warnings, precautions and adverse reactions in the draft labeling . The safety update reports are required to include the same kinds of information from clinical or animal studies as well as other sources, and must be submitted in the same format as the previously described integrated summary of safety. 33/50

68. In case of any adverse drug experience, the surveillance system requires the reporting of such experience as soon as possible within 15 working days of initial receipt of the information. These ‘alert reports’ are required to be submitted on Form FDA 1639 (Drug Experience Report) All reactions subject to 15 day alert report require follow-up reports within 15 working days of receipt of new information Even if no such reports are reported, the follow up reports has to be submitted in separate cover and as a summary / tabular form to be presented in periodic report 35/50

69. NDA holders must review periodically (quarterly for the first three years and yearly thereafter) the frequency of adverse drug experience reports that are serious and unexpected and report any significant increase in frequency (e.g. a doubling) within 15 working days to determine whether a significant increase in frequency exists or not. 36/50

70. Applicants must adhere to a reporting schedule that calls for submission of each quarterly and each annual report within 60 days of the anniversary date of approval of the application . 37/50

71. A 15-day alert report based on information from the scientific literature must be accompanied by a copy of the published article. These literature reports should be either case reports or the reporting of a formal clinical trial 38/50

72. NDA REVIEW TIMES Following deficiencies are typically encountered in drug development: Sponsors do not pursue advice from the FDA regarding their drug development plan Sponsors routinely more ahead to the next clinical trial without completely analyzing results of the most recent trial Sponsors sometimes provide a minimal amount of data in an effort to get drug approvals 39/50

73. COMPUTER ASSISTED NEW DRUG APPLICATON (CANDA) Concept: it is designed to shorten FDA review time by submitting data to FDA in a form ready for manipulation by a computer. Importance is given on the clinical sections of the NDA, as they require the maximum time to review and often require manipulation of the data by FDA. 40/50

74. On September 15, 1988 Federal Register Notice, FDA stated to increase the use of computers in field of improving efficiency of the drug review process. FDA had not provided exact blue print on how to best organize / submit a CANDA, but two basis computer systems have been developed so far: Involves keeping the data on a mainframe computer that is operated either by the sponsor / by the computer company assisting it with FDA able to access the information via a telephone connection. Putting the data on a floppy disk, laser disc , etc. for use by FDA via desktop computers that are provided by the sponsor. 41/50

75. One possible concern of CANDAs is the possibility of ‘data dredging’ by FDA reviewers, that is pursuing tangential rather than Central issues because the computer makes it easy to do so, but this has not been observed routinely . 42/50

76. HOW TO IMPROVE NDA HANDLING Be sure to supply additional (desk copy) submissions of the clinical data section and integrated summaries of safety and efficacy for the medical reviewer; the pharmacokinetic and bioavailability summary for the biopharmaceutics reviewer; the chemistry, manufacturing, and control process summary for the statistician reviewer; and extra copies of draft labeling for the medical reviewer. The submission should be placed in a proper jacket binders: use the proper numbering system 43/50

77. If requested, be prepared to submit for review draft copies for advertising and promotional material to be used in the initial or launch campaign to the Division of Drug Advertising and Labeling (HFN-240). Place the IND, NDA, or petition number on every letter or submission: include supplement numbers where applicable. 44/50

78. Submit new information in reviewable bundles or marketed with references suitable to all the material FDA reviewers need to consider in making a decision – this will help avoid lengthy file searches. FDA files are chronological: submissions stating “this replaces, corrects, or up-dates section or page so-and-so,” do not fit well in the FDA document-tracking or review system. 45/50

79. APPLICABLE NDA REGULATIONS It is noteworthy to be familiar with the regulations applicable to the NDA. The general NDA requirements are coded in Title 21, Code of Federal Regulations, Part 314. Subpart A contains the general provisions, section 314.1 to 314.3 Subpart B details the sections for applications as follows: 46/50

80. 1. Application 2. Index 3. Summary 4. Technical Sections 1. Chemistry, manufacturing and controls 2. Nonclinical pharmacology and toxicology 3. Human pharmacokinetics and bioavailability 4. Microbiology 5. Clinical data 6. Statistical 5. Samples and labeling 6. Case report forms and tabulations 7. Other 8. Format of an original application 47/50 Subpart B:

81. REFERENCES Remington: The Science And Practice Of Pharmacy, 20th edition, Lippincott,Williams & Wilkins, page no: 930-943 New Drug Approval Process: second edition, revised and expanded, edited by Richard A. Guarino page no: 39-64, 243-263 48/50

82. Continued…… www.fda.gov/cder/handbook/ndabox.htm www.fda.gov www.phrma.org 49/50

83. 09/07/2007 Dept. of Pharmaceutics 85 NDA Review Process

84. 09/07/2007 Dept. of Pharmaceutics 86 Generic Drug (ANDA) Review Process

85. 09/07/2007 Dept. of Pharmaceutics 87 OTC Drug Monograph Review Process

86. 1. Introduction ANDA contains data submitted to FDA's Center for Drug evaluation and Research, Office of Generic Drugs, for review and ultimate approval of a generic drug product. Once ANDA is approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public. A generic drug product is the one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use. ANDA

87. All approved products, both innovator and generic, are listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations ( Orange Book ). Generic drug applications are termed "abbreviated" Use of bioequivalence as the base for approving generic drug products was established by the " Drug Price Competition and Patent Term Restoration Act of 1984 ," also known as the WAXMAN-HATCH ACT . ANDA

88. 1. Pharmaceutical Equivalence: Same active ingredient Same conditions of use, route of administration, dosage form, strength, labeling 2. Bioequivalence 3. Patent certification (I to IV) PE + BE = Therapeutic Equivalence =>Safety & Effectiveness presumed Requirements for an ANDA: 90

89. Paper based filing of ANDA: Application copies and general format: Submit Archival (reference, retained and official approved copy) and filed copy (duplicate, used by FDA investigators) in english Translation copy with original reference copy Review copy (duplicate, FDA viewer, destroyed) in 2 sets of binders (jackets) In first binder CMC In another BE data Remaining data (table of contents, labeling) in both Consistency in color coding binders, volume size and specifications, size and quality of paper ANDA

90. Difference between submission of NDA and ANDA: NDA requirements ANDA requirements Well-controlled clinical studies to demonstrate effectiveness Detailed descriptions of the components Preclinical and clinical data to show safety Manufacturing, controls, packaging, and labeling data sufficient to assure the bioavailability or bioequivalence of the drug to be marketed. Detailed descriptions of manufacturing and packaging procedures Proposed annotated labeling referencing all studies from which statement s contained in the package insert has been derived.

91. -Drug product requirements:- Validation studies - to verify the accuracy, precision, specificity, recovery and sensitivity of the method (s) conducted by the sponsor’s product with those obtained with the original brand name product using the same methodology. - ANDA expiration dates:- Tentative approval of two year expiration date for a product if satisfactory data reflecting at least three months storage under accelerated conditions Final approval for the expiration date is obtained when acceptable shelf life data for two years on more than one production lot is made available ANDA

92. 6. 180-Day Generic Drug Exclusivity under the Hatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act ANDA

93. The first three paragraphs (I, II, III) results in no generic drug being sold during the term of the innovator’s patent protection. In case paragraph IV certification generic drugs can be sold during the term of the innovator’s patent protection. with rule of 45days suit and 30 months ban.

94. 7. Concept of paragraph I to IV: For filing ANDA, generic company must include a patent certification as per section 505(j) (2) (A) (vii) of the Hatch Waxman Act. The certificate has to make one of the following statements: No patent information on the drug product that is the subject of the ANDA has been submitted to FDA That such patent has expired The date on which such patent expires That such patent is invalid or will not be infringed by the manufacture, use, or sale of the drug product which the ANDA is submitted. ANDA

95. 8. SUBSTANTIALLY COMPLETE ANDA: “Substantially complete” means application with all required information like bioequivalence, etc. If a new bioequivalence study required for ANDA approval- not substantially complete and the applicant would not be eligible for exclusivity. Withdrawal of paragraph IV certification – voluntarily/ settlement/ defeat in patent litigation by first applicant-looses exclusitivity. Again first applicant submit paragraph IV certificate for 180 days exclusivity and there are no subsequent applicants then first applicant would be eligible for exclusivity. ANDA

96. 13. 505(b)(2) APPLICATION:- Section 505 of the FD&C Act describes 3 types of new drug application : An application that contains full reports of investigations of safety and effectiveness (Section 505 (b)(1)) An application that contains full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference (Section 505(b)(2)) An application that contains information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics, and intended use, among other things, to a previously approved product (Section 505(j)) ANDA

97. What kind of information can be used for 505(b) (2) application? Published literature The FDA’s findings of safety and efficacy for a previously approved drug product without requiring the sponsor to obtain a right of reference from the original applicant. ANDA

98. What kind of application can be submitted as a 505(b) (2) application? New chemical entity (NCE)/new molecular entity (NME) Changes to previously approved drugs ANDA

99. SOME EXAMPLES OF 505(B) (2) APPLICATIONS Change in dosage form Change in route of administration Change in strength Change in dosage regimen Change in formulation (excipient) Change in active ingredient like use of different salt of same drug New molecular entity i.e. is prodrug of previously approved drug product Substitution of an active ingredient in a combination product Combination product: An application for a new combination product in which the active ingredients have been previously approved individually. Rx/OTC switch OTC monograph. Naturally derived or recombinant active ingredient. Bioinequivalence: ANDA

100. WHAT CAN'T BE SUBMITTED AS 505(B) (2) APPLICATIONS? An application that is a duplicate of a listed drug and eligible for approval under section 505(j). An application in which the only difference from the reference listed drug is that the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than the listed drug. An application in which the only difference from the reference listed drug is that the rate at which its active ingredient(s) is absorbed or otherwise made available to the site of action is unintentionally less than that of the listed drug ANDA

101. ANDA process with paragraph IV 103 ANDA submission FDA: Acceptable & Complete? FDA accepts for review 45 days NDA holder (TEVA) lawsuit for patent infringment 30 months stay or until court decision Patent infringement litigation If FDA accepts ANDA Momenta eligible for 180 days exclusivity July 2008 Dec 2008 Jan 2009 2011 2014 Patent expiration ANDA = Abbreviated New Drug Application