Download Biomedical Product Development

Biomedical Product Development
Start with the end in mind
Focus on areas of strength
US Package Insert Sections
• Description
• Clinical
Pharmacology
• Indications and
Usage
• Contraindications
• Warnings
• Precautions
• Adverse Reactions
• Drug Abuse and
Dependence
• Overdosage
• Dosage and
Administration
• How Supplied
• Clinical Studies
• References
Paul Ehrlich 1854 - 1915
• Immunologist
• Tissue staining
• 1908 Nobel Prize for
Medicine
• “Magic Bullet”
• Salvarsan
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
Development Time Line
Stage
Discovery
The Screen
The Lead
Development
Safety Assess Cand
Patents
Dosage Form Dev
IND/IDE
Clinical Trials
Phase 1
Review Safety Data
Phase 2
End Phase 2 Clin Rev
Phase 3
NDA/BLA/PMA
FDA Review
Approval
Product Launch
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12
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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.
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.
Idea sources
Where do ideas for new products
originate?
The Process of Discovery
Prevalence and Cost of
Uncured Disease in the US
Approximate
Annual Prevalence
Cardiovascular
56,000,000
Approximate
Economic Cost
(billions)
$128
Cancer
10,000,000
$104
4,000,000
$100
Diabetes
16,000,000
$ 92
Arthritis
40,000,000
$ 65
Depression
17,400,000
$ 44
3,000,000
$ 30
28,000,000
$ 10
Uncured Diseases
Alzheimer’s
Stroke
Osteoporosis
National Institutes of Health
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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
Private Organizations
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American Cancer Society
American Heart Association
Howard Hughes Medical Institute
Salk Institute for Biological Studies
Share of U.S. Ethical Pharmaceutical
Market by Product Class, 1995
The Process of Discovery
Strategic Plan
• Select area of therapeutic or diagnostic
interest
• Establish long term (5 to 10 year) goals
for program
• Commit needed resources
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
Technology Assessment
• Discovery research
• Marketing
• Clinical research
Define the Target
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Product
Market
Proprietary Aspects
Technologies used
Mechanism of action
Regulatory agencies involved
Clinical trials
Product Definition
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Diagnostic
Therapeutic
Device
Combination
Know your market
• Who will use the product?
• What special needs does that group
have?
• Who will pay for the product?
Biomedical Research/Design
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Basic Research
Feasibility
Explore research/design options
Lead candidate
Biotechnology Discovery Tools
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Cloning
Protein purification
Monoclonal antibodies
Carbohydrate technology
In vivo genetic modification
Transgenic manipulation
Cell culture
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
Receptors
Receptor: any biological macromolecule
which can be activated by a drug to cause a
biological response or effect.
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
drug’s ability to elicit a response
Chemical Candidate Sources
• Synthetic program
• High through-put screening program
• Compound libraries
Natural Product Sources
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Fermentation/microbial sources
Plant/herbal sources
Arachnid and amphibian sources
Marine sources
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
Active
An active is a substance that causes
inhibition or stimulation in a screening
model, thereby indicating the substance
may have pharmacological effect.
Lead Compound
A compound that exhibits
pharmacological properties which
suggest its value as a starting point for
drug development.
Optimization
The process of synthesizing chemical
variations, or analogs, of a lead
compound, with the goal of creating
those compounds with improved
pharmacological properties.
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.
So What?
By studying the protein, researchers
hope they can design drugs that might
help regenerate damaged nerves
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.
Safety Assessment
Ames Test
In vitro metabolism
• microsomes
• hepatocytes
• liver slices
Candidate Flowchart
Compound from synthetic program,
combinatorial library, chemical library,
natural product source, etc.
In vitro evaluation - human/mammal
receptor/ enzyme assay; reporter
system
Active
No
Yes
Biochemical, tissue or animal model of
function
Active
Yes
Animal model of theraputic target
Pharmacokinetics, formulation, acute
toxicology
Approval for clinical development
No
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
Product Review
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Safety and Efficacy
Chemistry/Pharmacy
Clinical/Regulatory
Marketing/Legal
Potential Ups and Downs
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
Safety Assessment
Candidate
• Introduction and
Summary
• Assays
• Chemistry
• Pharmacy
• Patents
• Clinical Plan
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Regulatory Affairs
Potential Liabilities
Competition
Candidate Potential
Safety
Recommendation
Research v. Development
Overall
objective
Corporate
Mandate
Compounds
tested
Types of
studies
Research
Development
Select a
development
candidate
Broad, Loosely
defined
Many, diverse
Submit an NDA
Few
Narrow, focused
One
Many
Research v. Development
Research
Development
Regulatory
Little or none
Extensive
Timetable
Loose, flexible
Innovation
Strict,
constrained
Speed
Chaotic
Structured
Entrepeneurial
Interdependent
Recognition
Culture
Workstyle
Research v. Development
Research
Development
Quantity
µg  mg  g
g  kg
Safety
Ames, P450
1 w  105 w
Formulation
Capsule
Tablet, inject.
Metabolism
Radiolabeled
Assay
Budget
Departmental
Proj. Acct. No.
<$100,000
>$1,000,000
Costs
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
New Drug Entities
New Chemical Entities (NCE) or
New Molecular Entities (NME) - active
ingredients never before used as drugs
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.
API Requirements
• Identity: normally two identity tests
required
• Strength/potency
• Sensitivity
• Specificity
• Purity: normally 98+% for NCE’s
• Stability
• Safety and efficacy
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.
Raw Materials
Establish specifications and
specification testing requirements for:
• identity
• potency/strength
• purity
• stability
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
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.
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
Good Laboratory Practice
• Regulations on facilities and equipment
• Regulations involved in tests and
controls
• Regulations on personnel and
organization
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
GLP Safety Studies
• Toxicology
– Acute toxicity
– Subacute and chronic toxicity
– Reproductive and developmental studies
– Mutagenicity
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Metabolism
Pharmacology
Tissue residue
Environmental
Pharmacokinetics
• Study of how the drug is absorbed,
distributed throughout the body,
metabolized and excreted (ADME)
• Determination of the rate constants
(kinetics) for ADME
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
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
Development Phase Deliverables
Regulatory Affairs
• Regulatory status of drug substance
and finished product
• History or status of communications
with FDA
• World wide regulatory strategy
Development Phase Deliverables
Engineering
• Equipment/environmental/facility
requirements for manufacture
• Special handling requirements
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
Development Phase Deliverables
• Quality specifications for raw materials,
drug substance and processing
intermediates
• Stability of raw materials
• Preliminary product specifications
• Storage requirements
Development Phase Deliverables
Marketing and Medical
• Product name
• Initial dose levels
• Packaging configurations
• Projected initial market demand (units
per month)
Development Phase Deliverables
Regulatory Affairs
• Regulatory status of drug substance
and finished product
• History or status of communications
with FDA
• World wide regulatory strategy
Development Phase Deliverables
Engineering
• Equipment/environmental/facility
requirements for manufacture
• Special handling requirements
Development Time Line
Stage
Discovery
The Screen
The Lead
Development
Safety Assess Cand
Patents
Dosage Form Dev
IND/IDE
Clinical Trials
Phase 1
Review Safety Data
Phase 2
End Phase 2 Clin Rev
Phase 3
NDA/PLA/PMA
FDA Review
Approval
Product Launch
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IND/IDE
• Investigational New Drug Applications,
or
Notice of Claimed Exemption for a New
Drug
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
IND Requirements
• Preclinical testing:Pharm/tox data
including ADME, carcinogenicity and
mutagenicity screening
• Protection of human subjects
IND Contents
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General Investigational plans
Investigator’s Brochure
Clinical Protocols
Chemistry, Manufacturing and Controls
Animal Pharmacology and Toxicology
Previous Human Experience
IND Requirements
• FDA review time: 30 days
• Submission size: 4 to 10 (400 page)
volumes
Human Clinical Trials
Clinical Trial
Any study in humans intended to
– verify effects
– identify adverse reactions
– determine ADME
for an investigational drug
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
Elements of GCP
GCP
Requirements
Sponsor
Investigator
Monitor
Informed
Consent
IRB
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
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
Principles of GCP
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Qualified personnel
Informed consent
Record keeping
Confidentiality
GMP investigational products
Quality systems
Sponsor
An individual, company, institution, or
organization that takes responsibility for
the initiation, management, and/or
financing of a clinical trial.
Responsibilities of Sponsor
• Trial design
• Trial management, Data handling and
Recordkeeping
– Independent Data Management Committee
• Selecting Investigators
• Financing
Responsibilities of Sponsor
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selecting investigators and monitors
informing investigators
reviewing ongoing investigations
record keeping and record retention
ensuring disposition of unused drug
supplies
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
Responsibilities of Sponsor
• Notification/Submission to Regulatory
Authorities
• Confirmation of IRB Approval
• Investigator’s Brochure
• Clinical Trial Material
• Ensuring disposition of unused drug
supplies
• Monitoring
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
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).
Monitoring Responsibilities
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selection of a monitor
written monitoring procedures
preinvestigation site visits
periodic site visits
review of subject records
record of on-site visits
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
Investigators’ Responsibilities
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control of drug
record keeping and record retention
investigator reports
assurance of IRB review
handling of controlled substances
Investigators’ Responsibilities
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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
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.
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
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.
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.
IND Safety Reports
Unexpected, Fatal or
Life Threatening and
Associated with the Use
of the Drug
Serious, Unexpected
and Associated With
the Use of the Drug
Serious, Expected and
Nonserious
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To FDA by Telephone
Within 3 Working Days
To FDA and all
Participating
Investigators in a
Written Report Within
10 Working Days
To FDA in Next IND
Annual Progress Report
Written Report Within
10 Working Days
Written Report to all
Participating
Investigators
Phase I Clinical Trials
Number of
Subjects:
Length:
20 to 80
Purpose:
Primarily safety
Several months
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
Clinical Protocols
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objectives of study
investigator; IRB approval
patient selection/exclusion
study designs
dosing schedules
description of observations and
measurements
• clinical procedures and lab tests
Phase I Data
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metabolism
pharmacology
toxicology
dose ranging
side effects
Recording Phase I Data
Case Report Form
• Baseline information on patient’s
existing medical condition and personal
characteristics
• drug related changes e.g., blood
pressure
• adverse events (side effects)
• patient feedback
Phase I Wrap-up
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Evaluation of Phase I data for safety
Prepare Phase II Protocol
Update Investigator’s Brochure
Recruit Phase II clinical sites
Development Time Line
Stage
Discovery
The Screen
The Lead
Development
Safety Assess Cand
Patents
Dosage Form Dev
IND/IDE
Clinical Trials
Phase 1
Review Safety Data
Phase 2
End Phase 2 Clin Rev
Phase 3
NDA/PLA/PMA
FDA Review
Approval
Product Launch
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Developmental Pathways
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Clinical trials
Formulation development/Stability
Chemical process development
Metabolism/ Pharmacokinetics
Toxicology
Phase 1 Assay Development
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Well characterized drug substance
Broad specifications
Stability indicating assays developed
Start assay validations
Stability studies
Dosage Form Development
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Preformulation
Formulation
Preliminary stability
Package selection
Formal stability
Manufacture and Packaging for clinical
supplies
• Technology transfer
Metabolism -1• Pharmacokinetics - ADME
• Duration of effect v. drug blood levels
• Bioequivalency/bioavailability of
alternate dose forms
• Biotransformation of the drug
Metabolism -2• Studies in special populations
– Age
– Gender
– Hepatic/renal impaired
– Metabolic interaction
– Ethnic groups
Toxicology
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Acute studies
Rangefinding studies
Subacute studies
Genetic Toxicity
Reproductive Toxicity
Chronic Toxicity (6 months, 1 year)
Carcinogenicity Studies (2 year dosing)
Phase 2 Clinical Trial
Number of patients:
Length:
Purpose:
100 to 300 patient
volunteers
2 years
Initial trials in
patients to
determine efficacy
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
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
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
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 longterm use
Phase 3 Differences
• Larger patient pool
• Genetic, lifestyle and physiologic
diversity
• Concomitant therapies and conditions
permitted
• Out-patient population, less rigorously
monitored
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.
Criteria for Pivotal Studies
• adequate size
• must be a controlled trial
• must have a blinded design (when
practical and ethical)
• must be randomized
Adequate Size Determinants
• Degree of response sought
• Desired assurance against false
positive
• Acceptable risk of failure to demonstrate
response
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
Study Design
• Adequate measures to minimize bias by
subjects, observers and analysts of the
data
• Well-defined and reliable methods of
assessment of subject’s responses
• Adequate analysis of the study results
to assess the effects of the drug.
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
Additional Phase 3 Components
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Pharmacology/Toxicology Completion
Prescribing Information
Registration/Pricing
Sales Formulation
Marketing plan/support trials
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
Development Time Line
Stage
Discovery
The Screen
The Lead
Development
Safety Assess Cand
Patents
Dosage Form Dev
IND/IDE
Clinical Trials
Phase 1
Review Safety Data
Phase 2
End Phase 2 Clin Rev
Phase 3
NDA/PLA/PMA
FDA Review
Approval
Product Launch
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12
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Establishment of
Commercial Scale
Manufacturing
Technology Transfer
NDA
Phase 2
Early Development
Preformulation Report
Phase 3
Full Development
Process Optimization
Process Validation
Biobatch (>10% Full Scale Process Validation Batches
(3)
Development Report
Biobatch Qualification
Validation Activities
FMI, including packaging
Provisional Scale-up
Preliminary Release
Notification
Specifications
Full Scale Process
Optimization
Provisional Transfer
Document
Pilot scale stability
Provisional Scale-up Report
Full Scale Packaging
Preliminary process
parameters
Validation Protocol
Full Scale Stability
Specifications for dose form
Launch
Production Experience
Final Validation Report
Production Acceptance of
the Process (10 batches or
1 year)
Final Transfer Report
Pre-approval Inspection
Assessment of Bio/Validation Batch
Equivalence
Establish Technology Transfer Team
15 -23 Months
10 - 16 Months
10 Months
15 Months
Early Development
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Preformulation Report
Development Report
FMI, including packaging
Specifications
Pilot Scale stability
Preliminary process parameters
Specifications for dose form
Process Optimization
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Biobatch (>10% Full Scale)
Biobatch Qualification
Provisional Scale up
Full Scale Process Optimization
Provisional Scale up Report
Validation Protocol
Process Validation
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Process Validation Batches (3)
Validation Activities
Preliminary Release Notification
Provisional Transfer Document
Full Scale Packaging
Full Scale Stability
Assessment of Bio-/Validation Batch
Equivalence
Production Experience
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Final Validation Report
Production Acceptance of the
Process (10 Batches or 1 Year)
Final Transfer Report
Pre-Approval Inspection
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 GMP’s for drugs and
devices
• “Organized, documented common
sense”
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.
Installation Qualification
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Suitability of building
Services
Materials of construction
Suitability, positioning, accuracy and
calibration of instruments
Operation Qualification
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Consistent operation
System failsafes
Maintenance program
Equipment records
Equipment and system service records
Process Qualification
• Demonstrate control of process within
defined limits
• Demonstrate consistent performance
• Demonstrate consistent results
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
NDA Contents -1•
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Application Form FDA-356h
Index
Summary
Pharmacologic Class, Scientific
Rationale
• Proposed Label
• Foreign Marketing History
NDA Contents -2• Chemistry, Manufacturing and Controls
• Human Pharmacokinetics and
Bioavailability
• Nonclinical, Pharmacology, Toxicology
• Microbiology (anti-infective)
NDA Contents -3Clinical Data Summary
• List of Investigators
• Background/Overview of Clinical
Investigators
• Clinical Pharmacology
• Controlled Clinical Trials
• Uncontrolled Clinical Trials
NDA Contents -4Clinical Data Summary
• Integrated Summary of Effectiveness
• Integrated Summary of Safety
• Drug Abuse and Overdose
• Benefits/Risks
NDA Contents -5Clinical Data Summary
• Review of Literature for Analogs
• Bibliography for Compound
• Statistical Section
• Case Report Forms and Tabulations
NDA Submission
• 150 volumes
• 50,000 pages
• 12 to 48 months of review and
negotiations
• record: 42 days
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.
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
Records for PAI
•
•
•
•
•
Raw materials
Laboratory
Equipment qualification
Cleaning validation
SOPs
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
PAI Documentation
• Report to pilot plant detailing R&D
formulation development
• Report covering pilot plant experiences
during scale-up
• Report setting product specification
US Package Insert Sections
• Description
• Clinical
Pharmacology
• Indications and
Usage
• Contraindications
• Warnings
• Precautions
• Adverse Reactions
• Drug Abuse and
Dependence
• Overdosage
• Dosage and
Administration
• How Supplied
• Clinical Studies
• References
Description
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•
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•
proprietary name and established name
dosage form and route of administration
quantitative ingredient information
pharmacological or therapeutic class
chemical name and structural formula
Clinical Pharmacology
• Actions of the drug in humans
• Pharmacokinetic data (ADME)
• Clinical Trial Results
Adverse Reactions
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•
•
•
Clinical Adverse Experiences
Concomitant Therapy
Laboratory Abnormalities
Hypersensitivity Reactions
Dosage And Administration
• General Recommendations
• Dosage in Patients with Renal
Insufficiency
• National Drug Code
FDA Post Dug Approval
Activities
• Post-marketing surveillance
• Prescription drug advertising and
promotional labeling
• Pharmaceutical industry surveillance
• Drug shortages
• Therapeutic inequivalence reporting
• Medication errors
Post Market Surveillance
• Phase 4 Clinical Trials
• General Reporting Requirements
– Field Alert Reports
– Annual Reports
– Adverse Drug Reaction Reporting (ADR)
– Special reports
• cGMP Requirements
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
Development Time Line
Stage
Discovery
The Screen
The Lead
Development
Safety Assess Cand
Patents
Dosage Form Dev
IND/IDE
Clinical Trials
Phase 1
Review Safety Data
Phase 2
End Phase 2 Clin Rev
Phase 3
NDA/PLA/PMA
FDA Review
Approval
Product Launch
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12
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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
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
Advisory Committee
Advisory Committee - a panel of
outside experts convened periodically to
advise FDA on safety and efficacy
issues about drugs and other FDAregulated products. FDA isn’t bound to
take committee recommendations, but
usually does.
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
• Don’t over do the presentation; keep it
short
FDA Verdict
•
•
•
Approval letter
Approval letter
Not approvable letter
Success Rate
20% of IND’s result in successful NDA’s
Development Time Line
Stage
Discovery
The Screen
The Lead
Development
Safety Assess Cand
Patents
Dosage Form Dev
IND/IDE
Clinical Trials
Phase 1
Review Safety Data
Phase 2
End Phase 2 Clin Rev
Phase 3
NDA/PLA/PMA
FDA Review
Approval
Product Launch
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12
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