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- 1. PHARMACOVIGILANCE ITS ETHICAL TO DIE TO A DISEASE THAN TO A DRUG Presented by: Syed Kashif Department of Pharmacology AACP 1
- 2. CONTENTS Introduction Adverse event reporting Seriousness determination Sources of adverse event Disciplines of PV I. Risk management II. Casualty assessment III. Signal detection IV. Risk management plans V. Risk/benefit profile determination VI. Pharmacogenetics & pharmacogenomics 2
- 3. DEFINITION Pharmacovigilance (PV or PhV), also known as Drug Safety, is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical products pharmakon (Greek for drug) and vigilare (Latin for to keep watch). 3
- 4. AIMS To improve patient care and safety To improve public health and safety To contribute to the assessment of benefit, harm ,effectiveness and risk of medicines To promote education and clinical training To promote rational and safe use of medicines 4
- 5. RESPONSIBILITIES Timely collection of data ,recording and notification Appropriate assessments (data completeness , seriousness) Expedited and periodic reporting Creates appropriate structures for communication 5
- 6. 1.HUMANITARIAN CONCERN -Animal toxicology is often not a good predictor for human effects . -Evidence of safety from clinical trials is insufficient due to some limitations LIMITATIONS (phase 1-3): limited size , narrow population (age & sex specific), narrow indications (only specific disease) short duration 6
- 7. 2. SAFE USE OF MEDICINES it has been estimated that ADRs cause 5700 deaths per year in UK 4.PROMOTING RATIONAL USE OF MEDICINES 5.ENSURING PUBLIC CONFIDENCE 6.ETHICAL CONCERN not reporting serious reaction is unethical 7
- 8. PHARMACOVIGILANCE INSPECTION There are two types of inspections - 1.routine inspection 2.targeted inspection 1.ROUTINE INSPECTIONS - To make sure that pharmaceutical companies have the ability in performing Pharmacovigilance activities 8
- 9. 2.TARGETED INSPECTIONS a) inspections irrelevant to drug safety -companies that have not yet been inspected -companies that launch their first product -companies which are newly merged b) inspections relevant to drug safety -companies that delay or fail to take their obligations on safety monitoring -companies that delay to submit or submit incomplete periodic safety update reports -companies that failed to report drug safety related issues (like drug withdrawal with out reporting ) 9
- 10. Terms involved Adverse Drug Reaction is a side effect (non intended reaction to the drug) occurring with a drug where a positive (direct) causal relationship between the event and the drug is thought, or has been proven, to exist. Adverse event (AE) is a side effect occurring with a drug. By definition, the causal relationship between the AE and the drug is unknown. Benefits are commonly expressed as the proven therapeutic good of a product but should also include the patient’s subjective assessment of its effects. Causal relationship is said to exist when a drug is thought to have caused or contributed to the occurrence of an adverse drug reaction. 10
- 11. Clinical trial (or study) refers to an organised program to determine the safety and/or efficacy of a drug (or drugs) in patients. Control group is a group (or cohort) of individual patients that is used as a standard of comparison within a clinical trial Effectiveness is the extent to which a drug works under real world circumstances, i.e., clinical practice. Efficacy is the extent to which a drug works under ideal circumstances, i.e., in clinical trials. Dechallenge and Rechallenge refer to a drug being stopped and restarted in a patient, respectively Signal is a new safety finding within safety data that requires further investigation. There are three categories of signals: confirmed signals where the data indicate that there is a causal relationship between the drug and the AE; refuted (or false) signals where after investigation the data indicate that no causal relationship exists; and unconfirmed signals which require further investigation (more data) such as the conducting of a post-marketing trial to study the issue 11
- 12. Harm is the nature and extent of the actual damage that could be or has been caused. Triage refers to the process of placing a potential adverse event report into one of three categories: 1) non-serious case; 2) serious case; or 3) no case (minimum criteria for an AE case are not fulfilled). Individual Case Study Report (ICSR) is an adverse event report for an individual patient. 12
- 13. Adverse Event Reporting Adverse event (AE) reporting involves the receipt, triage, data entering, assessment, distribution, reporting (if appropriate), and archiving of AE data and documentation. The source of AE reports may include: spontaneous reports from healthcare professionals or patients (or other intermediaries); solicited reports from patient support programs; reports from clinical or post-marketing studies; reports from literature sources; reports from the media (including social media and websites); and reports reported to drug regulatory authorities themselves. 13
- 14. The "4 Elements" of an AE case One of the fundamental principles of adverse event reporting is the determination of what constitutes an adverse event case. During the triage phase of a potential adverse event report, the triager must determine if the "four elements" of an AE case are present: (1) an identifiable patient (2) an identifiable reporter (3) a suspect drug and (4) an adverse event. 14
- 15. Coding of Adverse Events Adverse event coding is the process by which information from an AE reporter, called the "verbatim", is coded using standardized terminology from a medical coding dictionary, such as MedDRA (the most commonly used medical coding dictionary). The purpose of medical coding is to convert adverse event information into terminology that can be readily identified and analyzed. 15
- 16. Seriousness Determination 16 An adverse event is considered serious if it meets one or more of the following criteria: 1. results in death, or is life-threatening; 2. requires inpatient hospitalization or prolongation of existing hospitalization; 3. results in persistent or significant disability or incapacity; 4. results in a congenital anomaly (birth defect); or is otherwise 5. "medically significant" —i.e., that it does not meet preceding criteria, but is considered serious because treatment/intervention would be required to prevent one of the preceding criteria.
- 17. SOURCES OF REPORTING AN ADVERSE EVENT 17
- 18. Expedited Reporting This refers to ICSRs that involve a serious and unlabelled event (an event not described in the drug's labeling) that is considered related to the use of the drug. In most countries, the time frame for reporting expedited cases is 15 calendar days from the time a drug company receives notification (referred to as "Day 0") of such a case . Within clinical trials such a case is referred to as a SUSAR (a Suspected Unexpected Serious Adverse Reaction). If the SUSAR involves an event that is life-threatening or fatal, it must be reported within 7-days. Cases that do not involve a serious, unlabelled event may be subject to non- expedited or periodic reporting. 18
- 19. Clinical Trial Reporting Also known as SAE (Serious Adverse Event) Reporting from clinical trials, safety information from clinical studies is used to establish a drug's safety profile in humans and is a key component that drug regulatory authorities consider in the decision-making as to whether to grant or deny market authorization (market approval) for a drug. SAE reporting occurs as a result of study patients (subjects) who experience serious adverse events during the conducting of clinical trials 19
- 20. Spontaneous reporting Spontaneous reports are termed spontaneous as they take place during the clinician’s normal diagnostic appraisal of a patient, when the clinician is drawing the conclusion that the drug may be implicated in the causality of the event. Spontaneous reporting system relies on vigilant physicians and other healthcare professionals who not only generate a suspicion of an ADR, but also report it. 20
- 21. Aggregate Reporting Aggregate, or periodic reporting plays a key role in the safety assessment of drugs. Aggregate reporting involves the compilation of safety data for a drug over a prolonged period of time (months or years), as opposed to single-case reporting which, by definition, involves only individual AE reports Worldwide, the most important aggregate report is the Periodic Safety Update Report (PSUR). This is a document that is submitted to drug regulatory agencies in Europe, the US and Japan (ICH countries), as well as other countries around the world PSUR was updated in 2012 and is now referred to in many countries as the Periodic Benefit Risk Evaluation report (PBRER) PBRER's focus is on the benefit-risk profile of the drug, which includes a review of relevant safety data compiled for a drug product since its development. 21
- 22. Other reporting methods Some countries legally oblige spontaneous reporting by physicians. In most countries, manufacturers are required to submit, through its Qualified Person for Pharmacovigilance (QPPV), all of the reports they receive from healthcare providers to the national authority Others have intensive, focused programmes concentrating on new drugs, or on controversial drugs, or on the prescribing habits of groups of doctors, or involving pharmacists in reporting. All of these generate potentially useful information. Such intensive schemes, however, tend to be the exception. 22
- 24. Risk Management Risk Management is the discipline within Pharmacovigilance that is responsible for signal detection and the monitoring of the risk-benefit profile of drugs. Other key activities within the area of Risk Management are that of the compilation of Risk Management Plans (RMPs) and aggregate reports such as the Periodic Safety Update Report (PSUR), Periodic Benefit Risk Evaluation Report (PBRER), and the Development Safety Update Report (DSUR). 24
- 25. Causality Assessment Causality refers to the relationship of a given adverse event to a specific drug. Causality determination (or assessment) is often difficult because of the lack of clear-cut or reliable data While one may assume that a positive temporal relationship might "prove" a positive causal relationship, this is not always the case This is due to the complexity of human physiology as well as that of disease and illnesses. By this reckoning, in order to determine causality between an adverse event and a drug, one must first exclude the possibility that there were other possible causes or contributing factors. In addition, if the patient is on a number of medications, it may be the combination of these drugs which causes the AE, and not any one individually 25
- 26. For instance, if a patient were to start Drug X and then three days later were to develop an AE, one might blame Drug X. However, before that can be done, the patient's medical history would need to be reviewed to look for possible risk factors for the AE This is because a patient on any drug may develop or be diagnosed with a condition that could not have possibly been caused by the drug. This is especially true for diseases, such as cancer, which develop over an extended period of time, being diagnosed in a patient who has been taken a drug for a relatively short period of time 26
- 27. Often the only way to confirm the existence of a causal relationship of an event to a drug is to conduct an observational study where the incidence of the event in a patient population taking the drug is compared to a control group If the incidence of an event is statistically significantly higher in the "active" group versus the placebo group (or other control group), it is possible that a causal relationship may exist to a drug, unless other confounding factors may exist 27
- 28. Signal Detection The WHO defines a safety signal as: “Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously”. Usually more than a single report is required to generate a signal, depending upon the event and quality of the information available. The data sources (databases) may be owned by a pharmaceutical company, a drug regulatory authority, or a large healthcare provider. Individual Case Safety Reports (ICSRs) in these databases are retrieved and converted into structured format, and statistical methods are applied to calculate statistical measures of association 28
- 29. If the statistical measure crosses an arbitrarily set threshold, a signal is declared for a given drug associated with a given adverse event. All signals that proved worthy of investigation, require further analysis using all available data in an attempt to confirm the signal. If the analysis is inconclusive, additional data may be needed such as a post-marketing observational trial. Ideally, the goal of SD is to identify ADRs that were previously considered unexpected and to be able to provide guidance in the product's labeling as to how to minimize the risk of using the drug in a given patient population. 29
- 30. Risk Management Plans A Risk Management Plan (RMP) is a documented plan that describes the risks (adverse drug reactions and potential adverse reactions) associated with the use of a drug and how they are being handled The overall goal of an RMP is to assure a positive risk-benefit profile once the drug is (has been) marketed. The document is required to be submitted, in a specified format, with all new market authorization requests within the European Union (EU) OR even in countries outside EU The risks described in an RMP fall into one of three categories: Identified Risks, Potential Risks, and Unknown Risks Since a drug, once authorized, may be used in ways not originally studied in clinical trials, this potential "off-label use", and its associated risks, is also described within the RMP. RMPs can be very lengthy documents, running in some cases hundreds of pages and, in rare instances, up to a thousand pages long. 30
- 31. In the US, under certain circumstances, the FDA may require a company to submit a document called a Risk Evaluation and Mitigation Strategies (REMS) for a drug that has a specific risk that FDA believes requires mitigation. While not as comprehensive as an RMP, a REMS can require a sponsor to perform certain activities or to follow a protocol, referred to as Elements to Assure Safe Use (ETASU), to assure that a positive risk-benefit profile for the drug is maintained for the circumstances under which the product is marketed. 31
- 32. Risk/Benefit Profile of Drugs Pharmaceutical companies are required by law in most countries to perform clinical trials, testing new drugs on people before they are made generally available. This occurs after a drug has been pre-screened for toxicity, sometimes using animals for testing. The manufacturers or their agents usually select a representative sample of patients for whom the drug is designed – at most a few thousand – along with a comparable control group. The control group may receive a placebo and/or another drug, often a so- called "gold standard" that is "best" drug marketed for the disease. 32
- 33. The purpose of clinical trials is to determine: if a drug works and how well it works if it has any harmful effects, and if it does more good than harm? If it has a potential for harm, how probable and how serious is the harm? Clinical trials do, in general, tell a good deal about how well a drug works and what potential harm it may cause. They provide information that should be reliable for larger populations with the same characteristics as the trial group - age, gender, state of health, ethnic origin, and so on. 33
- 34. Pharmacogenetics and Pharmacogenomics Pharmacogenetics is generally regarded as the study or clinical testing of genetic variation that gives rise to differing responses to drugs, including adverse drug reactions Pharmacogenomics, on the other hand, is the broader application of genomic technologies to new drug discovery and further characterization of older drugs. 34
- 36. contents Introductions Submissions Types Contents Review of DMFs Holder obligations Closure of a DMF 36
- 37. INTRODUCTION A DRug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. Typically, a DMF is filed when two or more firms work in partnership on developing or manufacturing a drug product. The DMF filing allows a firm to protect its intellectual property from its partner while complying with regulatory requirements for disclosure of processing details. 37
- 38. The submission of a DMF is not required by law or FDA regulation. The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), another DMF, an Export Application, or amendments and supplements to any of these. 38
- 39. Definitions 1. Agency means the Food and Drug Administration. 2 Agent or representative means any person who is appointed by a DMF holder to serve as the contact for the holder. 3. Applicant means any person who submits an application or abbreviated application or an amendment or supplement to them to obtain FDA approval of a new drug or an antibiotic drug and any other person who owns an approved application 4. Drug product means a finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients 39
- 40. 5. Drug substance means an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient (21 CFR 314.3 (b)). 6. Export application means an application submitted under section 802 of the Federal Food, Drug, and Cosmetic Act to export a drug that is not approved for marketing in the United States. 7. Holder means a person who owns a DMF. 40
- 41. 8. Letter of authorization means a written statement by the holder or designated agent or representative permitting FDA to refer to information in the DMF in support of another person's submission. 9. Person includes individual, partnership, corporation, and association. (Section 201(e) of the Federal Food, Drug, and Cosmetic Act.) 10. Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization (21 CFR 312.3 (b)). 41
- 42. Types of DMFs There are five types of DMF's: Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel Type II Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product Type III Packaging Material Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation Type V FDA Accepted Reference Information Each DMF should contain only one type of information and all supporting data. See Section IV.C of the guideline for more detailed descriptions of the kind of information desired in each type. Supporting information and data in a DMF can be cross referenced to any other DMF 42
- 43. SUBMISSIONS TO DRUG MASTER FILES Each DMF submission should contain a transmittal letter, administrative information about the submission, and the specific information to be included in the DMF as described in this section. The DMF must be in the English language. Whenever a submission contains information in another language, an accurate certified English translation must also be included. Each page of each copy of the DMF should be dated and consecutively numbered. An updated table of contents should be included with each submission. 43
- 44. A. Transmittal Letters Original Submissions Amendments B. Administrative Information Original Submissions Amendments C. Drug Master File Contents 44
- 45. A. Transmittal Letters The following should be included: A.1. Original Submissions a. Identification of submission: Original, the type of DMF and its subject. b. Identification of the applications, if known, that the DMF is intended to support, including the name and address of each sponsor, applicant, or holder, and all relevant document numbers. c. Signature of the holder or the authorized representative. d. Typewritten name and title of the signer. A. 2. Amendments a. Identification of submission: Amendment, the DMF number, type of DMF, and the subject of the amendment. b. A description of the purpose of submission, e.g., update, revised formula, or revised process. c. Signature of the holder or the authorized representative. d. Typewritten name and title of the signer. 45
- 46. B. Administrative Information Administrative information should include the following: B.1. Original Submissions a. Names and addresses of the following: (1) DMF holder. (2) Corporate headquarters. (3) Manufacturing/processing facility. (4) Contact for FDA correspondence. (5) Agent(s), if any. b. The specific responsibilities of each person listed in any of the categories in Section a. c. Statement of commitment. A signed statement by the holder certifying that the DMF is current and that the DMF holder will comply with the statements made in it. 46
- 47. B2. Amendments a. Name of DMF holder. b. DMF number. c. Name and address for correspondence. d. Affected section and/or page numbers of the DMF. e. The name and address of each person whose IND, NDA, ANDA, DMF, or Export Application relies on the subject of the amendment for support. f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies on the subject of the amendment for support, if known. g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that are affected, if known. 47
- 48. C. Types of Drug Master File 48
- 49. Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel A Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout. A Type I DMF is normally not needed to describe domestic facilities, except in special cases, such as when a person is not registered and not routinely inspected. The description of the site should include acreage, actual site address, and a map showing its location with respect to the nearest city. An aerial photograph and a diagram of the site may be helpful. Major equipment should be described in terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique. A diagram of major corporate organizational elements, with key manufacturing, quality control, and quality assurance positions highlighted, at both the manufacturing site and corporate headquarters, is also helpful. 49
- 50. Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product A Type II DMF should, in general, be limited to a single drug intermediate, drug substance, drug product, or type of material used in their preparation. (1) Drug Substance Intermediates, Drug Substances, and Material Used in Their Preparation Summarize all significant steps in the manufacturing and controls of the drug intermediate or substance. (2) Drug Product Manufacturing procedures and controls for finished dosage forms should ordinarily be submitted in an IND, NDA, ANDA, or Export Application. If this information cannot be submitted in an IND, NDA, ANDA, or Export Application, it should be submitted in a DMF. 50
- 51. Type III: Packaging Material Each packaging material should be identified by the intended use, components, composition, and controls for its release. The names of the suppliers or fabricators of the components used in preparing the packaging material and the acceptance specifications should also be given. Data supporting the acceptability of the packaging material for its intended use should also be submitted as outlined in the "Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics." Toxicological data on these materials would be included under this type of DMF. 51
- 52. .Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation Each additive should be identified and characterized by its method of manufacture, release specifications, and testing methods. Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document. Usually, the official compendia and FDA regulations for color additives, direct food additives , indirect food additives , and food substances may be used as sources for release tests, specifications, and safety. Guidelines suggested for a Type II DMF may be helpful for preparing a Type IV DMF. The DMF should include any other supporting information and data that are not available by cross reference to another document. 52
- 53. Type V: FDA Accepted Reference Information FDA discourages the use of Type V DMF's for miscellaneous information, duplicate information, or information that should be included in one of the other types of DMF's. If any holder wishes to submit information and supporting data in a DMF that is not covered by Types I to IV, a holder must first submit a letter of intent to the Drug Master File Staff FDA will then contact the holder to discuss the proposed submission. 53
- 54. Contents of DMF A. GENERAL INFORMATION 1. General properties 2. Structure 3. Nomenclature B. MANUFACTURE 1. Manufacture(s) 2. Description of Manufacturing Process and Process Control a) Flow Chart of Manufacturing Process b) Synthetic Route of Manufacturing Process c) Manufacturing Method. 3. Control of Material a) List of Materials. b) Specification and routine tests of the Raw Materials. 4. Control of Critical Steps and Intermediates. a) Critical Steps. b) Process Validation and/or evaluation. 5. Specifications and Test method for the Intermediates. 6. Manufacturing Process Development. 54
- 55. C. CHARACTERISATION 1. Elucidation of Structure and other characteristics. a) Elemental Analysis b) IR Spectrum of Drug Substance. c) NMR Spectrum of Drug Substance. d) Mass Spectrum of Drug Substance. e) U.V. Spectrum of Drug Substance. f) X-Ray Diffraction. g) Thermal Analysis. h) Comprehensive Illustration. 55
- 56. 2. Impurities a) Sources of Potential Impurities. b) Types of impurities. c) Test Procedure for determining impurities. 56
- 57. D. CONTROL OF DRUG SUBSTANCES 1. Specifications 2. Analytical procedure (STP) 3. Validation of Analytical procedure 4. Batch Analysis a) Description of Batches b) Certificate of Analysis 5. Justification of Specification 57
- 58. E. REFERENCE STANDARDS OF MATERIAL F. CONTAINER CLOSURE SYSTEM G. STABILITY 1. Stability summary and Conclusions 2. Post-Approval Stability protocol and Stability Commitment. 3. Stability data a) Accelerated Stability b) Long Term Stability Studies c) Forced Degradation Studies 58
- 59. H. MATERIAL DATA SAFETY SHEET I. APPENDICES 1. FACILITIES AND EQUIPMENTS a) Building and Utilities 2. EQUIPMENTS DESIGN AND LOCATION a. Equipment List b. Equipment Flow Chart 59
- 60. Format, Assembly, and Delivery An original and duplicate are to be submitted for all DMF submissions. Drug Master File holders and their agents/representatives should retain a complete reference copy that is identical to, and maintained in the same chronological order as, their submissions to FDA The original and duplicate copies must be collated, fully assembled, and individually jacketed. Each volume of a DMF should, in general, should not be more than 2 inches thick. For multivolume submissions, number each volume. For example, for a 3 volume submission, the volumes would be numbered 1 of 3, 2 of 3, and 3 of 3. U.S. standard paper size (8-1/2 by 11 inches) is preferred. Paper length should not be less than 10 inches nor more than 12 inches. However, it may occasionally be necessary to use individual pages larger than standard paper size to present a floor plan, synthesis diagram, batch formula, or manufacturing instructions. Those pages should be folded and mounted to allow the page to be opened for review without disassembling the jacket and refolded without damage when the volume is shelved. 60
- 61. The agency's system for filing DMF's provides for assembly on the left side of the page. The left margin should be at least three fourths of an inch to assure that text is not obscured in the fastened area. The right margin should be at least one half of an inch. The submitter should punch holes 8 1/2 inches apart in each page. See the page measurements shown in the following figure: 61
- 62. 62
- 63. Letter of Authorization to FDA Before FDA can review DMF information in support of an application, the DMF holder must submit in duplicate to the DMF a letter of authorization permitting FDA to reffer the DMF. If the holder cross references its own DMF, the holder should supply in a letter of authorization the information designated . The holder does not need to send a transmittal letter with its letter of authorization. The letter of authorization should include the following: The date. Name of DMF holder. DMF number. Name of person(s) authorized to incorporate information in the DMF by reference. Specific product(s) covered by the DMF. Submission date(s) Section numbers and/or page numbers to be referenced. Statement of commitment that the DMF is current and that the DMF holder will comply with the statements made in it. Signature of authorizing official. Typed name and title of official authorizing reference to the DMF. 63
- 64. Drug Master File submissions and correspondence should be addressed as follows: Drug Master File Staff Food and Drug Administration 5901-B Ammendale Rd. Beltsville, MD 20705-1266 64
- 66. Administrative Review After receipt, the original DMF undergoes an administrative review to determine whether it is administratively complete. This administrative review may take 2-3 weeks. If the DMF is acceptable from an administrative point of view, an Acknowledgement Letter will be issued, notifying the holder of the DMF number. At this point the DMF is "ACTIVE." If it is not acceptable from an administrative point of view, the holder will be notified of what deficiencies need to be corrected in order to make the DMF "Active". 66
- 67. Technical Review DMFs are subject to a complete review for technical information only under the following circumstances: 1. The DMF is ACTIVE. 2. The DMF holder submits a Letter of Authorization (LOA) in two copies (if a paper submission) to the DMF. This LOA should contain the DMF number. 3. The holder sends a copy of the LOA to the authorized party (customer). 4. The customer submits an application to the FDA that contains a copy of the LOA. 67
- 68. HOLDER OBLIGATIONS Any change or addition, including a change in authorization related to specific customers, should be submitted in duplicate and adequately cross referenced to previous submission(s). The reference should include the date(s), volume(s), section(s), and/or page numbers 68
- 69. A. Notice Required for Changes to a Drug Master File A holder must notify each affected applicant or sponsor who has referenced its DMF of any pertinent change in the DMF . Notice should be provided well before making the change in order to permit the sponsor/applicant to supplement or amend any affected application(s) as needed. B. Listing of Persons Authorized To Refer to a Drug Master File B.1. A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF . The holder should update the list in the annual update. The updated list should contain the holder's name, DMF number, and the date of the update. The update should identify by name (or code) the information that each person is authorized to incorporate and give the location of that information by date, volume, and page number. 69
- 70. B.2. Any person whose authorization has been withdrawn during the previous year should be identified under a suitable caption. B.3. If the list is unchanged on the anniversary date, the DMF holder should also submit a statement that the list is current. 70
- 71. C. Annual Update The holder should provide an annual report on the anniversary date of the original submission. This report should contain the required list as described in B.1., and should also identify all changes and additional information incorporated into the DMF since the previous annual report on the subject matter of the DMF. If the subject matter of the DMF is unchanged, the DMF holder should provide a statement that the subject matter of the DMF is current. Failure to update or to assure FDA annually that previously submitted material and lists in the DMF remain current can cause delays in FDA review of a pending IND, NDA, ANDA, Export Application, or any amendment or supplement to such application; and FDA can initiate procedures for closure of the DMF. 71
- 72. D. Appointment of an Agent When an agent is appointed, the holder should submit a signed letter of appointment to the DMF giving the agent's name, address, and scope of responsibility (administrative and/or scientific). Domestic DMF holders do not need to appoint an agent or representative, although foreign DMF holders are encouraged to engage a U.S. agent. 72
- 73. E. Transfer of Ownership To transfer ownership of a DMF to another party, the holder should so notify FDA and authorized persons in writing. The letter should include the following: Name of transferee Address of transferee Name of responsible official of transferee Effective date of transfer Signature of the transferring official Typewritten name and title of the transferring official. The new holder should submit a letter of acceptance of the transfer and an update of the information contained in the DMF, where appropriate. Any change relating to the new ownership (e.g., plant location and methods) should be included 73
- 74. CLOSURE OF A DRUG MASTER FILE A holder who wishes to close a DMF should submit a request to the Drug Master File Staff stating the reason for the closure. The request should include a statement that the holder's obligations as detailed in Section VII have been fulfilled. The Agency may close a DMF that does not contain an annual update of persons authorized to incorporate information in the DMF by reference and a list of changes made since the previous annual report. The holder will be notified of FDA's intent to close the DMF. 74
- 75. Reactivating a Inactive (Closed) DMF An Inactive DMF can be returned to ACTIVE status only by submission of a REACTIVATION, which should contain a complete resubmission of the DMF, updated to meet current Guidances. The cover letter must specify that the submission is a "REACTIVATION." 75
- 76. Drug Master File submissions and correspondence should be addressed as follows: Drug Master File Staff Food and Drug Administration 5901-B Ammendale Rd. Beltsville, MD 20705-1266 76
- 78. NDA 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. 78
- 79. GOALS 79 The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key decision 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. 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. The following resources provide summaries on NDA content, format, and classification, plus the NDA review process:
- 80. Guidance Documents for NDAs Guidance documents represent the Agency's current thinking on a particular subject. These documents are prepared for FDA review staff and applicants/sponsors to provide guidelines to the processing, content, and evaluation/approval of applications and also to the design, production, manufacturing, and testing of regulated products. 80
- 81. Guidance documents to help prepare NDAs include: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations(Issued 10/2000, Posted 10/27/2000). This guidance should be useful for applicants planning to conduct bioavailability (BA) and bioequivalence (BE) studies during the IND period for an NDA Container Closure Systems for Packaging Human Drugs and Biologics Format and Content of the Chemistry, Manufacturing and Controls Section of an Application. Format and Content of the Microbiology Section of an Application. Format and Content of the Clinical and Statistical Sections of an Application Format and Content of the Summary for New Drug and Antibiotic Applications. Formatting, Assembling and Submitting New Drug and Antibiotic Applications. 81
- 82. Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances. Submitting Documentation for the Stability of Human Drugs and Biologics. Submitting Samples and Analytical Data for Methods Validation. Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Products. NDAs: Impurities in Drug Substances Format and Content of the Human Pharmacokinetics and Bioavailability Section of an Application. Format and Content of the Nonclinical Pharmacology/Toxicology Section of an Application 82
- 83. Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. Describes the quantity of evidence, and the documentation of the quality of evidence necessary to support a claim of drug effectiveness. Drug Master Files. Qualifying for Pediatric Exclusivity. Certain applications may be able to obtain an additional six months of patent exclusivity. 83
- 84. Laws, Regulations, Policies and Procedures The mission of FDA is to enforce laws enacted by the U.S. Congress and regulations established by the Agency to protect the consumer's health, safety. The Federal Food, Drug, and Cosmetic Act is the basic food and drug law of the U.S. With numerous amendments, it is the most extensive law of its kind in the world. The law is intended to assure consumers that foods are pure and wholesome, safe to eat, and produced under sanitary conditions And that the drugs and devices are safe and effective for their intended use And also that cosmetics are safe and made from appropriate ingredients And that all labeling and packaging is truthful, informative, and not deceptive. 84
- 85. Abbreviated new drug application 85
- 86. ANDA An Abbreviated New Drug Application (ANDA) is an application for a U.S. generic drug approval for an existing licensed medication or approved drug. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost A generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use. All approved products, both innovator and generic, are listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). 86
- 87. Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical and clinical trial data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug). One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach thebloodstream in 24 to 36 healthy volunteers. This gives them the rate of absorption, or bioavailability, of the generic drug, which they can then compare to that of the innovator drug In cases of topically active drugs, the bioequivalence of a drug can be demonstrated by comparing drugs dissolution or transdermal drug absorption is compared with the innovator drug. In cases of systemically active drugs, active drug blood concentration of that drug is compared with the innovator drug. 87
- 88. The Hatch-Waxman act Using bioequivalence as the basis for approving generic copies of drug products was established by the Drug Price Competition and Patent Term Restoration Act of 1984, also known as THEHatch-Waxman Act. This Act increases the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials. At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDA's approval process. 88
- 89. SCHEDULE Y 89
- 90. What does it state Schedule Y refers to requirements and guidelines to be followed in order to attain permission of importing and/or manufacturing New Drugs to market or to undertake clinical trials in India. 90
- 91. 1) Application for a permit for importing or manufacturing new drug for sale or for a clinical trial. The requisites for the application are as follows: Chemical and Pharmaceutical ingredients and their related information; Animal Pharmacology & Toxicology Information. Human Pharmacology Information. Pharma Regulatory Status in other countries related to the drug, including restrictions imposed, if any, on the consumption of the drug in other countries, like dose limits, exclusion of certain age groups, adverse drug reactions,etc. Full prescribing information should be submitted as part of the new drug application for marketing. The prescribing information (package insert) shall include following details: generic name; composition; dosage form(s), indications; dose and method of administration; use in special populations (such as pregnant women, lactating women, pediatric patients, geriatric patients etc.) ; contra-indications; warnings; precautions; drug interactions; undesirable effects; overdose; pharmacodynamic and pharmacokinetic properties; incompatibilities; shelf-life; packaging information; storage and handling instructions. All package inserts, promotional literature and patient education material subsequently produced are required to be consistent with the contents of the approved full prescribing information. 91
- 92. Complete testing protocol(s) for quality control testing together with a complete impurity profile and release specifications for the product. Samples of the pure drug substance and finished product are also to be submitted when desired by the regulatory authority. If the drug under consideration is imported for the purpose of trial, test or analysis, the application for import of small quantities of drugs for such purpose should also be made. For drugs indicated in life threatening / serious diseases or diseases of special relevance to the Indian genetic conditions, the toxicological and clinical data requirements may be abbreviated, deferred or omitted, as seeked by the Regulatory Authority. 92
- 93. 2)CLINICAL TRAILS (a) Approval for Clinical Trial Clinical trials for any drug shall be initiated only after the permission granted by the Regulatory Authority, and the approval obtained from the respective ethics committee(s). The Regulatory Authority shall be informed of the approval of the respective institutional ethics comittee(s), and the trial initiated at each respective site only after obtaining such an approval for that site. All clinical trial Investigator(s) should possess appropriate qualifications, training and experience and should have access to such investigational and treatment facilities as are relevant to the proposed trial protocol. 93
- 94. (2) Responsibilities of Sponsor The clinical trial sponsor is responsible for implementing and maintaining quality assurance systems to ensure that the clinical trial is conducted and the data generated is documented and reported in compliance with the protocol and Good Clinical Practices (GCP) Sponsors are required to submit a status report on the clinical trial to the Regulatory Authority at regular intervals. In case of studies discontinued prematurely for any reason including lack of commercial interest in pursuing the new drug application, a summary report should be submitted within 3 months. In case of a serious adverse event (SAE) during a clinical trial, same should be reported promptly (within 14 calendar days) to the Regulatory Authority and to other investigators participating in the study. 94
- 95. (3) Responsibilities of the Investigator(s) The Investigator(s) is responsible for conducting the trial in accordance with the protocol and the GCP Guidelines. During a subject’s participation in the clinical trial, the investigator should ensure adequate medical care. Investigator(s) shall report all serious and unexpected adverse events to the Sponsor within 24 hours and to the Ethics Committee within 7 working days of their occurance. 95
- 96. (4) Informed Consent In all clinical trials, a freely given, informed, written consent is required to be obtained from each study subject. The Investigator must provide information about the study verbally as well as using a patient information sheet, in a language that is non- technical and understandable by the study subject. The Subject’s consent must be obtained in writing using an ‘Informed Consent Form’. Where a subject is not able to give informed consent (e.g. an unconscious person or a minor or those suffering from severe mental illness or disability), the same may be obtained from a legally acceptable representative (a legally acceptable representative is a person who is able to give consent for or authorize an intervention in the patient as provided by the law(s) of India). 96
- 97. (5) Responsibilities of Ethics Committee Ethics Committee reviews and accords its approval to a trial protocol to safeguard the rights, safety and well being of all trial subjects. Ethics Committee should make, at appropriate intervals, an ongoing review of the clinical trials for which they review the protocol(s). In case an ethics committee cancels its approval accorded to a trial protocol, it must record the reasons for doing so and at once communicate such a decision to the Investigator as well as to the Regulatory Authority 97
- 98. 3)Phases of clinical trails 98
- 99. a) Human Pharmacology (Phase I) Objective : To estimate safety and tolerability with the initial administration of an investigational new drug into human(s). Phase I clinical trials should preferably be carried out by Investigators trained in clinical pharmacology with access to the necessary facilities to closely observe and monitor the subjects. Studies conducted during phase I clinical trials, usually intend to involve one or a combination of the following objectives:- (a) Maximum tolerated dose: To determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected. (b) Pharmacokinetics, i.e., characterization of a drug's absorption, distribution, metabolism and excretion. (c) Pharmacodynamics: Depending on the drug and the endpoints studied, pharmacodynamic studies and studies relating to drug blood levels (pharmacokinetic/ pharmacodynamic studies) may be conducted in healthy volunteer Subjects or in patients with the target disease. (d) Early Measurement of Drug Activity: Preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective. 99
- 100. (b) Therapeutic Exploratory Trials (Phase II) The primary objective of Phase II trials is to evaluate the effectiveness of a drug for a particular indication or indications in patients with the condition under study and to determine the common short-term side-effects and risks associated with the drug. Additional objectives of Phase II studies can include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for further studies in Phase II or III. If the application for conducting clinical trials as a part of multi-national clinical development of the drug, the number of sites and the patients as well as the justification for undertaking such trials in India shall be provided to the Regulatory Authority. 100
- 101. (c) Therapeutic Confirmatory Trials (Phase III) Phase III studies have primary objective of demonstration or confirmation of therapeutic benefit(s). For drugs intended to be administered for long periods, trials involving extended exposure to the drug are ordinarily conducted in Phase III, although they may be initiated in Phase II. For new drugs approved outside India, Phase III studies need to be carried out primarily to generate evidence of efficacy and safety of the drug in Indian patients. The number of sites and patients as well as the justification for undertaking such a clinical trial in India should be provided to the Regulatory Authority along with the application. 101
- 102. (d) Post Marketing Trials (Phase IV) Post Marketing trials are studies (other than routine surveillance) performed after drug approval. These trials go beyond the prior demonstration of the drug’s safety, efficacy and dose definition. These trials may not be considered necessary at the time of new drug approval but may be required by the Regulatory Authority for optimizing the drug's use. They may be of any type but should have valid scientific objectives. Phase IV trials include additional drug-drug interaction(s), dose-response or safety studies and trials designed to support use under the approved indication(s), e.g. mortality/morbidity studies, epidemiological studies etc. 102
- 103. Post Marketing Surveillance Subsequent to approval of the product, new drugs should be closely monitored for their clinical safety once they are marketed. The applicants shall furnish Periodic Safety Update Reports (PSURs) in order to- Report all the relevant new information from appropriate sources; Relate these data to patient exposure; Summarize the market authorization status in different countries and any significant variations related to safety; and Indicate whether changes should be made to product information in order to optimize the use of the product. The PSURs shall be submitted every six months for the first two years after approval of the drug is granted to the applicant. For subsequent two years – the PSURs need to be submitted annually. 103
- 104. A PSUR should be structured as follows: A title page stating: Periodic safety update report for the product, applicant’s name, period covered by the report, date of approval of new drug, date of marketing of new drug and date of reporting; Introduction, Current worldwide market authorization status, Update of actions taken for safety reasons, Changes to reference safety information, Estimated patient exposure, Presentation of individual case histories, Studies, Other information, Overall safety evaluation, Conclusion, Appendix providing material relating to indications, dosing, pharmacology and other related information. 104
- 105. 4)Studies in special population Targets : geriatrics, pediatrics & pregnant/nursing women These studies are done to find out whether the drugs behave in the same manner as in non geriatric patients & in non pregnant women 1. Geriatrics : studies in this population are done when a) The disease that is to be treated with the test drug occurs in aged persons b) When there is a reason to expect that the drug will cause conditions which are likely to occur in elderly patients c) When the drug is likely to alter geriatric patients response when compared to non geriatric patients 105
- 106. 2) Pediatrics The studies are carried on this population when a) The disease being treated occurs more commonly in chidrens b) The drug has a potential use in pediatric population c) The reviewing ethics committee should have expert pediatricians 3) Pregnant women a) This is done when b) The drug is known to behave differently in pregnant women c) It is known to alter the hormonal balances in d) Known to pass placenta which may effect the foetus 106
- 107. SPECIAL STUDIES (i)For drugs approved elsewhere in the world and absorbed systemically, bioequivalence with the reference formulation should be carried out wherever applicable. These studies should be conducted under the labeled conditions of administration. Data on the extent of systemic absorption may be required for formulations other than those designed for systemic absorption. (ii)Evaluation of the effect of food on absorption following oral administration should be carried out. Data from dissolution studies should also be submitted for all solid oral dosage forms. (iii)Dissolution and bioavailability data submitted with the new drug application must provide information that assures bioequivalence or establishes bioavailability and dosage correlations between the formulation(s) sought to be marketed and those used for clinical trials during clinical development of the product. (iv)All bioavailability and bioequivalence studies should be conducted according to the Guidelines for Bioavailability and Bioequivance studies as prescribed. 107
- 108. Central Drugs Standard Control Organization (CDSCO) 108
- 109. Introduction 109 The Central Drugs Standard Control Organization (CDSCO) is the Central Drug Authority for discharging functions assigned to the Central Government under the Drugs and Cosmetics Act. CDSCO has six zonal offices, four sub-zonal offices, 13 port offices and seven laboratories under its control. Major functions of CDSCO: 1. Regulatory control over the import of drugs, approval of new drugs and clinical trials 2. Conduct meetings of Drugs Consultative Committee (DCC) and Drugs Technical Advisory Board (DTAB) 3. Approval of certain licences as Central Licence Approving Authority is exercised by the CDSCO hqrs.
- 110. Vision To Protect and Promote public health in India Mission To safeguard and enhance the public health by assuring the safety, efficacy and quality of drugs, cosmetics and medical devices 110
- 111. Strategies Initiate in framing of rules, regulations and guidance documents to match with the requirements of Drugs & Cosmetics Act 1940 and Rules 1945. Facilitate smooth conduct of the provisions of the Drugs & Cosmetics Act 1940 and Rules 1945. Function as Central license Approving Authority under the provisions of Drugs and Cosmetics Act 1945 and Rules 1945. Collaboration with other similar international agencies. Providing training to the Indian regulatory personnel 111
- 112. FUNCTIONS Central Authorities are responsible for approval of New Drugs, Clinical Trials in the country, Laying down the standards for Drugs Control over the quality of imported Drugs, Coordination of the activities of State Drug Control Organisations and providing expert advice with a view of bring about the uniformity in the enforcement of the Drugs and Cosmetics Act. 112
- 113. ZONAL OFFICES OF CENTRAL DRUGS STANDARD CONTROL ORGANISATION (CDSCO) The Central Government have established four zonal offices of the Central Drug Standard Control Organization at Mumbai, Kolkata, Chennai, and Ghaziabad. The Zonal Offices work in close collaboration with the State Drug Control Administration and assist them in securing uniform enforcement of the Drug Act and other connected legislations, on all India basis. 113
- 114. Central Drugs Laboratory (CDL) The Central Drugs Laboratory, Kolkata is the national statutory laboratory of the Government of India for quality control of Drug and Cosmetics and is established under the Indian Drug & Cosmetics Act, 1940. It functions under the administrative control of the Director-General of Health Services in the Ministry of Health and Family Welfare. 114
- 115. The functions of the Laboratory include: I. Statutory Functions: (a) Analytical quality control of majority of the imported Drug available in Indian market. (b) Analytical quality control of drug and cosmetics manufactured within the country on behalf of the Central and State Drug Controller Administrations. (c) Acting as an authority in matters of disputes relating to quality of Drug. II. Other Funtions: (a) Collection, storage and distribution of International Standard & International Reference Preparations of Drug and Pharmaceutical Substances. (b) Preparation of National Reference Standards and maintenance of such Standards. Maintenance of microbial cultures useful in drug analysis Distribution of Standards and cultures to State Quality Control Laboratories and drug manufacturing establishments. 115
- 116. (c) Training of Drug Analysts deputed by State Drug Control Laboratories and other Institutions d) To advise the Central Drug Control Administration in respect of quality and toxicity of drug awaiting licence. 116
- 117. Regional Drugs Testing Laboratory (RDTL) Central Drugs Testing Laboratory (CDTL) Chennai , Tamil Nadu Central Drug Testing Laboratory is one of the four National Laboratories in India engaged in the research and analysis of Drug and Cosmetics as per Drug and Cosmetics Act, 1940. Central Drugs Testing Laboratory (CDTL) Hyderabad, AP Central Drug Testing Laboratory is one of the Newly established Laboratories in the state of Andhra Pradesh, India engaged in testing , research and analysis of Drug and Cosmetics as per Drug and Cosmetics Act, 1940. 117
- 118. Guwahati The Regional Drugs Testing Laboratory Guwahati was established under the Indian Drugs & Cosmetics Act 1940 functioning under administrative control of the Drugs Controller General of India and sub ordinate officer Directorate General of Health Services, Ministry of Health & Family Welfare. The laboratory was set up in the year 2002 for entire North Eastern State including Sikkim and is housed in its own building at Guwahati. Functions a. Analytical quality control of drugs and cosmetic manufactured within the country on behalf of the Central and State Drugs Controller Administration. b. To assists the Central Drugs Standard Control Organization in the testing of Drugs and cosmetic. 118
- 119. Central Drugs Laboratory, CRI Kasauli Central Drugs Laboratory at Central Research Institute (CRI) Kasauli is a Central laboratory engaged in the testing of vaccines. It is a notified laboratory under the Drugs and Cosmetics Act, 1940 to function as Central Drugs Laboratory for testing of the following drugs or classes of drugs; i) Sera ii) Solution of serum proteins intended for injection iii) Vaccines iv) Toxins v) Antigens vi) Anti-toxins vii) Sterilized surgical ligature and sterilized surgical suture viii) Bacteriophages, including Oral Polio vaccine. The Director of CDL Kasauli is Dr.Arun Bhardwaj, Phone: 01792-272046, Fax: 01792 -272049 Email:nclkasauli@gmail.com 119
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- 121. Reference http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guida nces/ucm122886.htm http://www.cdsco.nic.in/forms/Default.aspx http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelo pedandApproved/ApprovalApplications/NewDrugApplicationNDA/ Nirali prakashan 121