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Biomedical Product Development

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Title: Biomedical Product Development


1
Biomedical Product Development
  • Start with the end in mind
  • Focus on areas of strength

2
US Package Insert Sections
  • Drug Abuse and Dependence
  • Overdosage
  • Dosage and Administration
  • How Supplied
  • Clinical Studies
  • References
  • Description
  • Clinical Pharmacology
  • Indications and Usage
  • Contraindications
  • Warnings
  • Precautions
  • Adverse Reactions

3
Paul Ehrlich 1854 - 1915
  • Immunologist
  • Tissue staining
  • 1908 Nobel Prize for Medicine
  • Magic Bullet
  • Salvarsan

4
Essentials
  • Paul Ehrlich All who are about to embark on
    developing a new drug must bring to the task four
    essentials
  • brains
  • persistence
  • capital
  • luck

5
Development Time Line
6
Research and Development
  • The term includes basic and applied research
    as well as development activities carried on or
    supported in the pharmaceutical, biological,
    chemical, medical, and related sciences,
    including psychology and psychiatry, if the
    purpose of such activities is concerned
    ultimately with the utilization of scientific
    principles in understanding diseases or in
    improving health.

7
Discovery
  • The term Discovery is used to describe the
    early phases of the overall biomedical discovery
    process, that is, the synthesis of or the search
    for compounds and the screening processes
    developed to identify lead compounds.

8
Idea sources
  • Where do ideas for new products originate?

9
The Process of Discovery
10
Prevalence and Cost of Uncured Disease in the US

11
National Institutes of Health
  • National Cancer Institute
  • National Heart, Lung and Blood Institute
  • National Institute on Aging
  • National Institute of Arthritis and
    Musculoskeletal and Skin Diseases
  • National Institute of Diabetes and Digestive and
    Kidney Diseases

12
Private Organizations
  • American Cancer Society
  • American Heart Association
  • Howard Hughes Medical Institute
  • Salk Institute for Biological Studies

13
Share of U.S. Ethical Pharmaceutical Market by
Product Class, 1995
14
The Process of Discovery
15
Strategic Plan
  • Select area of therapeutic or diagnostic interest
  • Establish long term (5 to 10 year) goals for
    program
  • Commit needed resources

16
Program Plan
  • Short term plans, 1 to 3 years
  • Identifies areas for discovery research
  • Allocates resources to carry out the plan
  • people
  • space
  • equipment
  • money

17
Technology Assessment
  • Discovery research
  • Marketing
  • Clinical research

18
Define the Target
  • Product
  • Market
  • Proprietary Aspects
  • Technologies used
  • Mechanism of action
  • Regulatory agencies involved
  • Clinical trials

19
Product Definition
  • Diagnostic
  • Therapeutic
  • Device
  • Combination

20
Know your market
  • Who will use the product?
  • What special needs does that group have?
  • Who will pay for the product?

21
Biomedical Research/Design
  • Basic Research
  • Feasibility
  • Explore research/design options
  • Lead candidate

22
Biotechnology Discovery Tools
  • Cloning
  • Protein purification
  • Monoclonal antibodies
  • Carbohydrate technology
  • In vivo genetic modification
  • Transgenic manipulation
  • Cell culture

23
The Screen
  • Tool to identify new drug candidates
  • Usually a subcellular component (enzyme,
    receptor, etc.) removed from a living system and
    studied in vitro
  • ACTIVES agents that stimulate or inhibit normal
    function

24
Receptors
  • Receptor any biological macromolecule which
    can be activated by a drug to cause a biological
    response or effect.

25
Agonists and Antagonists
  • Agonist a drug which binds to a receptor and
    elicits a biological response
  • Antagonist occupies (or blocks) a receptor but
    does not elicit a response
  • Intrinsic activity the measure of a drugs
    ability to elicit a response

26
Chemical Candidate Sources
  • Synthetic program
  • High through-put screening program
  • Compound libraries

27
Natural Product Sources
  • Fermentation/microbial sources
  • Plant/herbal sources
  • Arachnid and amphibian sources
  • Marine sources

28
High Through-put Screening
  • Tool to identify new drug candidates
  • Usually a subcellular component (enzyme,
    receptor, etc.) removed from a living system and
    studied in vitro

29
Active
  • An active is a substance that causes
    inhibition or stimulation in a screening model,
    thereby indicating the substance may have
    pharmacological effect.

30
Lead Compound
  • A compound that exhibits pharmacological
    properties which suggest its value as a starting
    point for drug development.

31
Optimization
  • The process of synthesizing chemical
    variations, or analogs, of a lead compound, with
    the goal of creating those compounds with
    improved pharmacological properties.

32
Neural Discovery
  • From WSJ Jan 27, 2000
  • Three teams of researchers have discovered a
    gene for a protein that appears to prevent nerves
    in the brain and spinal cord from growing back
    after being damaged by injury or disease.

33
So What?
  • By studying the protein, researchers hope they
    can design drugs that might help regenerate
    damaged nerves

34
The Next Steps
  • Scientist are looking for the receptor for the
    protein. Once it is found, drug companies may be
    able to design antagonists to block the effect of
    the protein, allowing damaged nerves to
    regenerate.

35
Safety Assessment
  • Ames Test
  • In vitro metabolism
  • microsomes
  • hepatocytes
  • liver slices

36
Candidate Flowchart
37
Quality Considerations
  • For every experiment the researcher should
    record
  • each item, source, lot number and quantity used
  • experimental conditions, e.g., times,
    temperatures, pressures, etc.
  • all calculations
  • sampling schedule, results

38
Product Review
  • Safety and Efficacy
  • Chemistry/Pharmacy
  • Clinical/Regulatory
  • Marketing/Legal
  • Potential Ups and Downs

39
Pitfalls of Research Stage
  • Process not well controlled nonreproducible
    results
  • Insufficient experience to adequately predict
    critical parameters
  • Process not scaleable as is
  • Documentation incomplete, poorly recorded, poorly
    organized, or does not support claims

40
Safety Assessment Candidate
  • Introduction and Summary
  • Assays
  • Chemistry
  • Pharmacy
  • Patents
  • Clinical Plan
  • Regulatory Affairs
  • Potential Liabilities
  • Competition
  • Candidate Potential
  • Safety
  • Recommendation

41
Research v. Development
42

Research v. Development
43
Research v. Development
44
Development Tasks
  • 1. Establish raw material specifications
  • 2. Scale-up production processes
  • 3. Establish critical process control parameters
  • 4. Establish final product specifications
  • 5. Validate analytical methods
  • 6. GLP preclinical studies
  • 7. Prepare clinical trial material
  • 8. Initiate stability/reliability studies
  • 9. Establish document systems

45
New Drug Entities
  • New Chemical Entities (NCE) or
  • New Molecular Entities (NME) - active
    ingredients never before used as drugs

46
Drug Substance or Active Pharmaceutical
Ingredient
  • The active ingredient intended to diagnose,
    treat, cure, or prevent disease or affect the
    structure or function of the body, excluding
    other inactive substances used in the drug
    product.

47
API Requirements
  • Identity normally two identity tests required
  • Strength/potency
  • Sensitivity
  • Specificity
  • Purity normally 98 for NCEs
  • Stability
  • Safety and efficacy

48
Drug Product
  • The finished dosage form (tablet, capsule,
    etc.) that contains a drug substance--generally,
    but not necessarily, in association with other
    active or inactive ingredients.

49
Raw Materials
  • Establish specifications and specification
    testing requirements for
  • identity
  • potency/strength
  • purity
  • stability

50
USP/NF
  • United States Pharmacopoeia and National
    Formulary - designated as the official compendia
    pursuant to federal and some state statutes, and
    containing enforceable standards and
    specifications for strength, quality, purity,
    packaging, labeling, and where applicable,
    bioavailability of drugs

51
Nonclinical Laboratory Study
  • Nonclinical laboratory study - in vivo or in
    vitro experiments in which test articles are
    studied prospectively in test systems under
    laboratory conditions to determine their safety.

52
Good Laboratory Practice (GLP)
  • Regulations established in the U.S. in 1976 to
    ensure the quality and integrity of bioresearch
    and animal test data submitted to the FDA

53
Good Laboratory Practice
  • Regulations on facilities and equipment
  • Regulations involved in tests and controls
  • Regulations on personnel and organization

54
GLP Objectives
  • Verify the quality and integrity of data
    submitted to FDA
  • Inspect nonclinical laboratories engaging in
    safety studies for regulated products
  • Audit ongoing and completed lab safety studies
  • Determine degree of compliance with GLP
    regulations

55
GLP Safety Studies
  • Toxicology
  • Acute toxicity
  • Subacute and chronic toxicity
  • Reproductive and developmental studies
  • Mutagenicity
  • Metabolism
  • Pharmacology
  • Tissue residue
  • Environmental

56
Pharmacokinetics
  • Study of how the drug is absorbed, distributed
    throughout the body, metabolized and excreted
    (ADME)
  • Determination of the rate constants (kinetics)
    for ADME

57
Project Team Tasks
  • Engineering Determine pilot plant requirements
    for preparation of clinical trial material
  • Clinical Affairs Begin the design of clinical
    studies to establish efficacy and tolerance of
    the new drug candidates in human beings
  • Regulatory Affairs
  • Prepare IND/IDE
  • Pre-IND/IDE meeting with the FDA to discuss plans
    for Phase I clinical trials

58
Development Phase Deliverables
  • Drug/Biologic/Component Characteristics
  • Description of actives, excipients, components,
    and solvents required for formulation or assembly
  • Analytical test methods
  • Process or assembly instructions
  • Processing equipment incompatibilities

59
Development Phase Deliverables
  • Regulatory Affairs
  • Regulatory status of drug substance and finished
    product
  • History or status of communications with FDA
  • World wide regulatory strategy

60
Development Phase Deliverables
  • Engineering
  • Equipment/environmental/facility requirements for
    manufacture
  • Special handling requirements

61
Pitfalls of Development
  • The scaled-up version of the product is
    ineffective or uncharacteristic when compared to
    the research version
  • Facilities are inadequate for aseptic handling of
    product, microbiological testing and/or quality
    control

62
Development Phase Deliverables
  • Quality specifications for raw materials, drug
    substance and processing intermediates
  • Stability of raw materials
  • Preliminary product specifications
  • Storage requirements

63
Development Phase Deliverables
  • Marketing and Medical
  • Product name
  • Initial dose levels
  • Packaging configurations
  • Projected initial market demand (units per month)

64
Development Phase Deliverables
  • Regulatory Affairs
  • Regulatory status of drug substance and finished
    product
  • History or status of communications with FDA
  • World wide regulatory strategy

65
Development Phase Deliverables
  • Engineering
  • Equipment/environmental/facility requirements for
    manufacture
  • Special handling requirements

66
Development Time Line
67
IND/IDE
  • Investigational New Drug Applications, or
  • Notice of Claimed Exemption for a New Drug

68
Pre-IND Meeting
  • Brief (1 - 2 hours) conference with FDA to get
    pre-submission feedback from FDA
  • Project Manager FDA staff person that serves as
    liaison between sponsor and FDA a Project
    Manager is assigned to each IND

69
IND Requirements
  • Preclinical testingPharm/tox data including
    ADME, carcinogenicity and mutagenicity screening
  • Protection of human subjects

70
IND Contents
  • General Investigational plans
  • Investigators Brochure
  • Clinical Protocols
  • Chemistry, Manufacturing and Controls
  • Animal Pharmacology and Toxicology
  • Previous Human Experience

71
IND Requirements
  • FDA review time 30 days
  • Submission size 4 to 10 (400 page) volumes

72
Human Clinical Trials

73
Clinical Trial
  • Any study in humans intended to
  • verify effects
  • identify adverse reactions
  • determine ADME
  • for an investigational drug

74
GCP
  • Good Clinical Practices
  • establish procedures to assure the quality and
    integrity of data obtained during clinical
    testing
  • protect the rights and safety of clinical trial
    subjects

75
Elements of GCP
GCP Requirements
Sponsor
Monitor
IRB
Investigator
Informed Consent
76
Declaration of Helsinki
  • In research on man, the interest of science and
    society should never take precedence over
    considerations related to the well-being of the
    subject
  • Biomedical research involving humans must be
    scientifically sound

77
Principles of GCP
  • Declaration of Helsinki
  • Benefits justify the risks
  • Preserve rights, safety, and well-being of
    subjects
  • Adequate information to support trial
  • Clear, detailed protocol
  • Prior IRB/IEC approval
  • Medical care by qualified physician

78
Principles of GCP
  • Qualified personnel
  • Informed consent
  • Record keeping
  • Confidentiality
  • GMP investigational products
  • Quality systems

79
Sponsor
  • An individual, company, institution, or
    organization that takes responsibility for the
    initiation, management, and/or financing of a
    clinical trial.

80
Responsibilities of Sponsor
  • Trial design
  • Trial management, Data handling and Recordkeeping
  • Independent Data Management Committee
  • Selecting Investigators
  • Financing

81
Responsibilities of Sponsor
  • selecting investigators and monitors
  • informing investigators
  • reviewing ongoing investigations
  • record keeping and record retention
  • ensuring disposition of unused drug supplies

82
Responsibilities of Sponsor
  • Quality Assurance/Quality Control
  • SOPs to assure compliance
  • access to sites and documents
  • data reliability
  • contracts with investigators
  • Contract Research Organization
  • Medical Expertise

83
Responsibilities of Sponsor
  • Notification/Submission to Regulatory Authorities
  • Confirmation of IRB Approval
  • Investigators Brochure
  • Clinical Trial Material
  • Ensuring disposition of unused drug supplies
  • Monitoring

84
Monitoring Clinical Trials
  • Sponsors must monitor trials to
  • ensure the quality and integrity of the clinical
    data
  • ensure that the rights and safety of human
    subjects involved in the clinical study are
    preserved

85
Monitoring
  • The act of overseeing the progress of a
    clinical trial, and of ensuring that it is
    conducted, recorded, and reported in accordance
    with the protocol, standard operating procedures
    (SOP's), GCP, and the applicable regulatory
    requirement(s).

86
Monitoring Responsibilities
  • selection of a monitor
  • written monitoring procedures
  • preinvestigation site visits
  • periodic site visits
  • review of subject records
  • record of on-site visits

87
Investigator
  • A person responsible for the conduct of the
    clinical trial at a trial site. If a trial is
    conducted by a team of individuals at a trial
    site, the investigator is the responsible leader
    of the team and may be called the principal
    investigator

88
Investigators Responsibilities
  • control of drug
  • record keeping and record retention
  • investigator reports
  • assurance of IRB review
  • handling of controlled substances

89
Investigators Responsibilities
  • Provide adequate resources
  • Medical care of Trial Subjects
  • Communication with the IRB
  • Compliance with the protocol
  • Control of investigational product
  • Informed Consent
  • Records and reports

90
Institutional Review Board (IRB)
  • An independent body constituted of medical,
    scientific, and nonscientific members, whose
    responsibility it is to ensure the protection of
    the rights, safety, and well-being of human
    subjects involved in a trial by, among other
    things, reviewing, approving, and providing
    continuing review of trials, of protocols and
    amendments, and of the methods and material to be
    used in obtaining and documenting informed
    consent of the trial subjects.

91
IRB/IEC Responsibilities
  • Institutional Review Board/Independent Ethics
    Committee
  • Minimize risk to subjects
  • Risk v. Benefit must be reasonable
  • Subject selection must be equitable
  • Informed consent
  • Adequate monitoring for safety
  • Subject Privacy

92
Informed Consent
  • A process by which a subject voluntarily
    confirms his or her willingness to participate in
    a particular trial, after having been informed of
    all aspects of the trial that are relevant to the
    subject's decision to participate. Informed
    consent is documented by means of a written,
    signed, and dated informed consent form.

93
Clinical Definitions
  • Adverse Drug Reaction (ADR) all noxious and
    unintended responses to a medicinal product
    related to any dose
  • Adverse Event (AE) any untoward medical
    occurrence in a patient or clinical investigation
    subject administered a pharmaceutical product and
    that does not necessarily have a causal
    relationship with this treatment.

94
IND Safety Reports
95
Phase I Clinical Trials
  • Number of Subjects
  • Length
  • Purpose
  • 20 to 80
  • Several months
  • Primarily safety

96
Phase I Subject Selection
  • FDA General Considerations for the Clinical
    Evaluation of Drugs
  • normal volunteers
  • generally, no concomitant drug therapy
  • generally excludes women of childbearing
    potential and children
  • pretreatment physical exams and follow-up studies

97
Clinical Protocols
  • objectives of study
  • investigator IRB approval
  • patient selection/exclusion
  • study designs
  • dosing schedules
  • description of observations and measurements
  • clinical procedures and lab tests

98
Phase I Data
  • metabolism
  • pharmacology
  • toxicology
  • dose ranging
  • side effects

99
Recording Phase I Data
  • Case Report Form
  • Baseline information on patients existing
    medical condition and personal characteristics
  • drug related changes e.g., blood pressure
  • adverse events (side effects)
  • patient feedback

100
Phase I Wrap-up
  • Evaluation of Phase I data for safety
  • Prepare Phase II Protocol
  • Update Investigators Brochure
  • Recruit Phase II clinical sites

101
Development Time Line
102
Developmental Pathways
  • Clinical trials
  • Formulation development/Stability
  • Chemical process development
  • Metabolism/ Pharmacokinetics
  • Toxicology

103
Phase 1 Assay Development
  • Well characterized drug substance
  • Broad specifications
  • Stability indicating assays developed
  • Start assay validations
  • Stability studies

104
Dosage Form Development
  • Preformulation
  • Formulation
  • Preliminary stability
  • Package selection
  • Formal stability
  • Manufacture and Packaging for clinical supplies
  • Technology transfer

105
Metabolism -1-
  • Pharmacokinetics - ADME
  • Duration of effect v. drug blood levels
  • Bioequivalency/bioavailability of alternate dose
    forms
  • Biotransformation of the drug

106
Metabolism -2-
  • Studies in special populations
  • Age
  • Gender
  • Hepatic/renal impaired
  • Metabolic interaction
  • Ethnic groups

107
Toxicology
  • Acute studies
  • Rangefinding studies
  • Subacute studies
  • Genetic Toxicity
  • Reproductive Toxicity
  • Chronic Toxicity (6 months, 1 year)
  • Carcinogenicity Studies (2 year dosing)

108
Phase 2 Clinical Trial
  • Number of patients
  • Length
  • Purpose
  • 100 to 300 patient volunteers
  • 2 years
  • Initial trials in patients to determine
    efficacy

109
Phase 2 Clinical Trial
  • Dose ranging to determine optimal effect
  • Strength
  • Frequency of administration
  • Acceptable level of side effects
  • Initial determination of risk-to-benefit ratio

110
Phase 2 Product Development
  • Pilot scale to larger scale-up batches
  • Start process validation
  • Assay Development
  • Set or tighten specifications as needed
  • Continue assay development
  • Continue stability studies
  • shelf-life
  • storage requirements
  • primary packing materials

111
End-of-Phase 2 Meetings
  • Determine the safety of proceeding to Phase 3
  • Evaluate Phase 3 plan and protocols
  • Identify any additional information necessary to
    support marketing application

112
Phase 3 Clinical Trials
  • Patients
  • Length
  • Purpose
  • 1,000 to 3,000 patient volunteers
  • 3 years
  • PIVOTAL
  • Verify safety and effectiveness
  • Monitor adverse reactions from long-term use

113
Phase 3 Differences
  • Larger patient pool
  • Genetic, lifestyle and physiologic diversity
  • Concomitant therapies and conditions permitted
  • Out-patient population, less rigorously monitored

114
Pivotal Studies
  • At least two pivotal (adequate and well
    controlled) studies are required to provide
    substantial evidence supporting claims of
    effectiveness for new drugs and antibiotics.

115
Criteria for Pivotal Studies
  • adequate size
  • must be a controlled trial
  • must have a blinded design (when practical and
    ethical)
  • must be randomized

116
Adequate Size Determinants
  • Degree of response sought
  • Desired assurance against false positive
  • Acceptable risk of failure to demonstrate
    response

117
Study Controls
  • Clear statement of objectives
  • Design that permits valid comparison with control
  • Method of subject selection that provides
    adequate assurance that subjects have the disease
    or condition being studied

118
Study Design
  • Adequate measures to minimize bias by subjects,
    observers and analysts of the data
  • Well-defined and reliable methods of assessment
    of subjects responses
  • Adequate analysis of the study results to assess
    the effects of the drug.

119
Discontinuance of a Study
  • Dangerous adverse effect is found
  • Drug lacks significant effects or has an effect
    less advantageous than that of an existing
    therapy
  • Drug has a significant effect, but that effect
    does not justify the risks associated with its
    use
  • Drug shows clear evidence of being safe and
    effective

120
Additional Phase 3 Components
  • Pharmacology/Toxicology Completion
  • Prescribing Information
  • Registration/Pricing
  • Sales Formulation
  • Marketing plan/support trials

121
Success Rate
  • 70 of INDs successfully complete Phase I
    Clinical Trials
  • 33 of INDs successfully complete Phase 2
    Clinical Trials
  • 27 of INDs successfully complete Phase 3
    Clinical Trials and continue to NDA

122
Development Time Line
123
Establishment of Commercial Scale Manufacturing

124
Technology Transfer
125
Early Development
  • Preformulation Report
  • Development Report
  • FMI, including packaging
  • Specifications
  • Pilot Scale stability
  • Preliminary process parameters
  • Specifications for dose form

126
Process Optimization
  • Biobatch (gt10 Full Scale)
  • Biobatch Qualification
  • Provisional Scale up
  • Full Scale Process Optimization
  • Provisional Scale up Report
  • Validation Protocol

127
Process Validation
  • Process Validation Batches (3)
  • Validation Activities
  • Preliminary Release Notification
  • Provisional Transfer Document
  • Full Scale Packaging
  • Full Scale Stability
  • Assessment of Bio-/Validation Batch Equivalence

128
Production Experience
  • Final Validation Report
  • Production Acceptance of the
  • Process (10 Batches or 1 Year)
  • Final Transfer Report
  • Pre-Approval Inspection

129
Validation
  • The defining and testing of processes,
    specifications and/or equipment used, and to
    prove the capability and suitability of achieving
    required results consistently
  • A requirement of GMPs for drugs and devices
  • Organized, documented common sense

130
Validation Protocol
  • A written plan stating how validation will be
    conducted, including test parameters, product
    characteristics. production equipment, and
    decision points on what constitutes acceptable
    test results.

131
Installation Qualification
  • Suitability of building
  • Services
  • Materials of construction
  • Suitability, positioning, accuracy and
    calibration of instruments

132
Operation Qualification
  • Consistent operation
  • System failsafes
  • Maintenance program
  • Equipment records
  • Equipment and system service records

133
Process Qualification
  • Demonstrate control of process within defined
    limits
  • Demonstrate consistent performance
  • Demonstrate consistent results

134
New Drug Application
  • FDA reviewers must determine
  • Whether drug is safe and effective for intended
    use
  • Whether benefits outweigh risks
  • Whether proposed labeling is appropriate
  • Whether manufacturing methods and controls are
    adequate

135
NDA Contents -1-
  • Application Form FDA-356h
  • Index
  • Summary
  • Pharmacologic Class, Scientific Rationale
  • Proposed Label
  • Foreign Marketing History

136
NDA Contents -2-
  • Chemistry, Manufacturing and Controls
  • Human Pharmacokinetics and Bioavailability
  • Nonclinical, Pharmacology, Toxicology
  • Microbiology (anti-infective)

137
NDA Contents -3-
  • Clinical Data Summary
  • List of Investigators
  • Background/Overview of Clinical Investigators
  • Clinical Pharmacology
  • Controlled Clinical Trials
  • Uncontrolled Clinical Trials

138
NDA Contents -4-
  • Clinical Data Summary
  • Integrated Summary of Effectiveness
  • Integrated Summary of Safety
  • Drug Abuse and Overdose
  • Benefits/Risks

139
NDA Contents -5-
  • Clinical Data Summary
  • Review of Literature for Analogs
  • Bibliography for Compound
  • Statistical Section
  • Case Report Forms and Tabulations

140
NDA Submission
  • 150 volumes
  • 50,000 pages
  • 12 to 48 months of review and negotiations
  • record 42 days

141
Pre-approval Inspection
  • Prior to NDA approval, the FDA will inspect
    the proposed manufacturing facility to assure
    that the conditions presented in the NDA do exist
    and have been adequately documented.

142
Records for PAI
  • CMC Section of NDA
  • Master Formula
  • specific manufacturing instructions for full
    scale commercial lots
  • in process specifications
  • product specifications
  • History section of NDA

143
Records for PAI
  • Raw materials
  • Laboratory
  • Equipment qualification
  • Cleaning validation
  • SOPs

144
Records for PAI
  • Batch record for first full scale production run
  • Validation protocols and reports
  • History of production
  • Failure investigation reports
  • All complaints
  • Microbiological data

145
PAI Documentation
  • Report to pilot plant detailing RD formulation
    development
  • Report covering pilot plant experiences during
    scale-up
  • Report setting product specification

146

US Package Insert Sections
  • Drug Abuse and Dependence
  • Overdosage
  • Dosage and Administration
  • How Supplied
  • Clinical Studies
  • References
  • Description
  • Clinical Pharmacology
  • Indications and Usage
  • Contraindications
  • Warnings
  • Precautions
  • Adverse Reactions

147
Description
  • proprietary name and established name
  • dosage form and route of administration
  • quantitative ingredient information
  • pharmacological or therapeutic class
  • chemical name and structural formula

148
Clinical Pharmacology
  • Actions of the drug in humans
  • Pharmacokinetic data (ADME)
  • Clinical Trial Results

149
Adverse Reactions
  • Clinical Adverse Experiences
  • Concomitant Therapy
  • Laboratory Abnormalities
  • Hypersensitivity Reactions

150
Dosage And Administration
  • General Recommendations
  • Dosage in Patients with Renal Insufficiency
  • National Drug Code

151
FDA Post Dug Approval Activities
  • Post-marketing surveillance
  • Prescription drug advertising and promotional
    labeling
  • Pharmaceutical industry surveillance
  • Drug shortages
  • Therapeutic inequivalence reporting
  • Medication errors

152
Post Market Surveillance
  • Phase 4 Clinical Trials
  • General Reporting Requirements
  • Field Alert Reports
  • Annual Reports
  • Adverse Drug Reaction Reporting (ADR)
  • Special reports
  • cGMP Requirements

153
Phase 4 Clinical Trials
  • Satisfy pre-approval FDA request
  • Evaluate safety and effectiveness in general use
  • Cost/benefit analysis
  • Augmentation of original indication
  • Marketing implications
  • Expansion of claim structure

154
Development Time Line
155
Success Rate
  • 70 of INDs successfully complete Phase I
    Clinical Trials
  • 33 of INDs successfully complete Phase 2
    Clinical Trials
  • 27 of INDs successfully complete Phase 3
    Clinical Trials and continue to NDA

156
New Drug Application
  • FDA reviewers must determine
  • Whether drug is safe and effective for intended
    use
  • Whether benefits outweigh risks
  • Whether proposed labeling is appropriate
  • Whether manufacturing methods and controls are
    adequate

157
Advisory Committee
  • Advisory Committee - a panel of outside
    experts convened periodically to advise FDA on
    safety and efficacy issues about drugs and other
    FDA-regulated products. FDA isnt bound to take
    committee recommendations, but usually does.

158
Preparing for the Panel
  • Learn as much as possible about the committee
    members
  • Fully understand the issues the review division
    presents
  • Understand how the committee functions
  • Dont over do the presentation keep it short

159
FDA Verdict
  • Approval letter
  • Approval letter
  • Not approvable letter

160
Success Rate
  • 20 of INDs result in successful NDAs

161
Development Time Line
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