Drug discovery and development overview

 Description
 Clinical
Pharmacology
 Indications and
Usage
 Contraindications
 Warnings
 Precautions
 Adverse Reactions
 Drug Abuse and
Dependence
 Overdosage
 Dosage and
Administration
 How Supplied
 Clinical Studies
 References

 Immunologist
 Tissue staining
 1908 Nobel Prize
for Medicine
 “Magic Bullet”
 Salvarsan

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

Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12
Discovery
The Screen 
The Lead 
Development R R
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 

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.

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.

Uncured Diseases
Approximate
Annual Prevalence
Approximate
Economic Cost
(billions)
Cardiovascular 56,000,000 $128
Cancer 10,000,000 $104
Alzheimer’s 4,000,000 $100
Diabetes 16,000,000 $ 92
Arthritis 40,000,000 $ 65
Depression 17,400,000 $ 44
Stroke 3,000,000 $ 30
Osteoporosis 28,000,000 $ 10

 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

 American Cancer Society
 American Heart Association
 Howard Hughes Medical Institute
 Salk Institute for Biological Studies

 Select area of therapeutic or diagnostic
interest
 Establish long term (5 to 10 year) goals
for program
 Commit needed resources

 Short term plans, 1 to 3 years
 Identifies areas for discovery research
 Allocates resources to carry out the plan
› people
› space
› equipment
› money

 Discovery research
 Marketing
 Clinical research

 Product
 Market
 Proprietary Aspects
 Technologies used
 Mechanism of action
 Regulatory agencies involved
 Clinical trials

 Diagnostic
 Therapeutic
 Device
 Combination

 Who will use the product?
 What special needs does that group
have?
 Who will pay for the product?

 Basic Research
 Feasibility
 Explore research/design options
 Lead candidate

 Cloning
 Protein purification
 Monoclonal antibodies
 Carbohydrate technology
 In vivo genetic modification
 Transgenic manipulation
 Cell culture

 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

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

 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

 Synthetic program
 High through-put screening program
 Compound libraries

 Fermentation/microbial sources
 Plant/herbal sources
 Arachnid and amphibian sources
 Marine sources

 Tool to identify new drug candidates
 Usually a subcellular component
(enzyme, receptor, etc.) removed from a
living system and studied in vitro

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

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

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

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.

By studying the protein, researchers hope
they can design drugs that might help
regenerate damaged nerves

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.

Ames Test
In vitro metabolism
 microsomes
 hepatocytes
 liver slices

Compoundfromsyntheticprogram,
combinatoriallibrary,chemicallibrary,
naturalproductsource,etc.
Invitroevaluation-human/mammal
receptor/enzymeassay;reporter
system
Active
Biochemical,tissueoranimalmodelof
function
Active
Animalmodeloftheraputictarget
Pharmacokinetics,formulation,acute
toxicology
Approvalforclinicaldevelopment
Yes
Yes
No
No

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

 Safety and Efficacy
 Chemistry/Pharmacy
 Clinical/Regulatory
 Marketing/Legal
 Potential Ups and Downs

 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

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

Research Development
Overall
objective
Select a
development
candidate
Submit an NDA
Corporate
Mandate
Broad, Loosely
defined
Narrow, focused
Compounds
tested
Many, diverse One
Types of
studies
Few Many

Research v. Development
Regulatory Little or none Extensive
Timetable Loose, flexible Strict,
constrained
Recognition Innovation Speed
Culture Chaotic Structured
Workstyle Entrepeneurial Interdependent

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.
Costs <$100,000 >$1,000,000

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

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.

 Identity: normally two identity tests
required
 Strength/potency
 Sensitivity
 Specificity
 Purity: normally 98+% for NCE’s
 Stability
 Safety and efficacy

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

Establish specifications and specification
testing requirements for:
•identity
•potency/strength
•purity
•stability

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 - in vivo or in
vitro experiments in which test articles
are studied prospectively in test systems
under laboratory conditions to
determine their safety.

Regulations established in the U.S. in 1976
to ensure the quality and integrity of
bioresearch and animal test data
submitted to the FDA

 Regulations on facilities and equipment
 Regulations involved in tests and controls
 Regulations on personnel and
organization

 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

 Toxicology
› Acute toxicity
› Subacute and chronic toxicity
› Reproductive and developmental studies
› Mutagenicity
 Metabolism
 Pharmacology
 Tissue residue
 Environmental

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

 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

 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

Regulatory Affairs
 Regulatory status of drug substance and
finished product
 History or status of communications with
FDA
 World wide regulatory strategy

Engineering
 Equipment/environmental/facility
requirements for manufacture
 Special handling requirements

 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

 Quality specifications for raw materials,
drug substance and processing
intermediates
 Stability of raw materials
 Preliminary product specifications
 Storage requirements

Marketing and Medical
 Product name
 Initial dose levels
 Packaging configurations
 Projected initial market demand (units
per month)

Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12
Discovery
The Screen 
The Lead 
Development R R
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 

 Investigational New Drug Applications, or
Notice of Claimed Exemption for a New
Drug

 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

 Preclinical testing:Pharm/tox data
including ADME, carcinogenicity and
mutagenicity screening
 Protection of human subjects

 General Investigational plans
 Investigator’s Brochure
 Clinical Protocols
 Chemistry, Manufacturing and Controls
 Animal Pharmacology and Toxicology
 Previous Human Experience

 FDA review time: 30 days
 Submission size: 4 to 10 (400 page)
volumes

Any study in humans intended to
› verify effects
› identify adverse reactions
› determine ADME
for an investigational drug

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

GCP
Requirements
GCP
Requirements
Sponsor
MonitorInvestigator IRB
Informed
Consent

 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

 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

 Qualified personnel
 Informed consent
 Record keeping
 Confidentiality
 GMP investigational products
 Quality systems

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

 Trial design
 Trial management, Data handling and
Recordkeeping
› Independent Data Management
Committee
 Selecting Investigators
 Financing

 selecting investigators and monitors
 informing investigators
 reviewing ongoing investigations
 record keeping and record retention
 ensuring disposition of unused drug
supplies

 Quality Assurance/Quality Control
› SOPs to assure compliance
› access to sites and documents
› data reliability
› contracts with investigators
 Contract Research Organization
 Medical Expertise

 Notification/Submission to Regulatory
Authorities
 Confirmation of IRB Approval
 Investigator’s Brochure
 Clinical Trial Material
 Ensuring disposition of unused drug
supplies
 Monitoring

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

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).

 selection of a monitor
 written monitoring procedures
 preinvestigation site visits
 periodic site visits
 review of subject records
 record of on-site visits

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

 control of drug
 record keeping and record retention
 investigator reports
 assurance of IRB review
 handling of controlled substances

 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

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.

 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

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.

 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.

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
↓ ↓ ↓
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

Number of
Subjects:
Length:
Purpose:
20 to 80
Several months
Primarily safety

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

 objectives of study
 investigator; IRB approval
 patient selection/exclusion
 study designs
 dosing schedules
 description of observations and
measurements
 clinical procedures and lab tests

 metabolism
 pharmacology
 toxicology
 dose ranging
 side effects

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

 Evaluation of Phase I data for safety
 Prepare Phase II Protocol
 Update Investigator’s Brochure
 Recruit Phase II clinical sites

 Clinical trials
 Formulation development/Stability
 Chemical process development
 Metabolism/ Pharmacokinetics
 Toxicology

 Well characterized drug substance
 Broad specifications
 Stability indicating assays developed
 Start assay validations
 Stability studies

 Preformulation
 Formulation
 Preliminary stability
 Package selection
 Formal stability
 Manufacture and Packaging for clinical
supplies
 Technology transfer

 Pharmacokinetics - ADME
 Duration of effect v. drug blood levels
 Bioequivalency/bioavailability of
alternate dose forms
 Biotransformation of the drug

 Studies in special populations
› Age
› Gender
› Hepatic/renal impaired
› Metabolic interaction
› Ethnic groups

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

Number of patients:
Length:
Purpose:
100 to 300 patient
volunteers
2 years
Initial trials in patients
to determine
efficacy

 Dose ranging to determine optimal
effect
 Strength
 Frequency of administration
 Acceptable level of side effects
 Initial determination of risk-to-benefit
ratio

 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

 Determine the safety of proceeding to
Phase 3
 Evaluate Phase 3 plan and protocols
 Identify any additional information
necessary to support marketing
application

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

 Larger patient pool
 Genetic, lifestyle and physiologic
diversity
 Concomitant therapies and conditions
permitted
 Out-patient population, less rigorously
monitored

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

 adequate size
 must be a controlled trial
 must have a blinded design (when
practical and ethical)
 must be randomized

 Degree of response sought
 Desired assurance against false positive
 Acceptable risk of failure to demonstrate
response

 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

 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.

 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

 Pharmacology/Toxicology Completion
 Prescribing Information
 Registration/Pricing
 Sales Formulation
 Marketing plan/support trials

 70% of INDs successfully complete Phase
I Clinical Trials
2 Clinical Trials
3 Clinical Trials and continue to NDA

NDA
Phase 2 Phase 3
Launch
Full Development Production ExperienceEarly Development
Process Optimization Process Validation
Preformulation Report Biobatch (>10% Full Scale Process Validation Batches
(3)
Final Validation Report
Development Report Biobatch Qualification Validation Activities Production Acceptance of
the Process (10 batches or
1 year)
FMI, including packaging Provisional Scale-up Preliminary Release
Notification Final Transfer Report
Specifications Full Scale Process
Optimization
Provisional Transfer
Document
Pre-approval Inspection
Pilot scale stability Provisional Scale-up Report Full Scale Packaging
Preliminary process
parameters
Validation Protocol Full Scale Stability
Specifications for dose form Assessment of Bio-
/Validation Batch
Equivalence
Establish Technology Transfer Team
15 -23 Months 10 - 16 Months 10 Months 15 Months

 Preformulation Report
 Development Report
 FMI, including packaging
 Specifications
 Pilot Scale stability
 Preliminary process parameters
 Specifications for dose form

 Biobatch (>10% Full Scale)
 Biobatch Qualification
 Provisional Scale up
 Full Scale Process Optimization
 Provisional Scale up Report
 Validation Protocol

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

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

 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”

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.

 Suitability of building
 Services
 Materials of construction
 Suitability, positioning, accuracy and
calibration of instruments

 Consistent operation
 System failsafes
 Maintenance program
 Equipment records
 Equipment and system service records

 Demonstrate control of process within
defined limits
 Demonstrate consistent performance
 Demonstrate consistent results

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

 Application Form FDA-356h
 Index
 Summary
 Pharmacologic Class, Scientific
Rationale
 Proposed Label
 Foreign Marketing History

 Chemistry, Manufacturing and Controls
 Human Pharmacokinetics and
Bioavailability
 Nonclinical, Pharmacology, Toxicology
 Microbiology (anti-infective)

Clinical Data Summary
 List of Investigators
 Background/Overview of Clinical
Investigators
 Clinical Pharmacology
 Controlled Clinical Trials
 Uncontrolled Clinical Trials

 Integrated Summary of Effectiveness
 Integrated Summary of Safety
 Drug Abuse and Overdose
 Benefits/Risks

 Review of Literature for Analogs
 Bibliography for Compound
 Statistical Section
 Case Report Forms and Tabulations

 150 volumes
 50,000 pages
 12 to 48 months of review and
negotiations
 record: 42 days

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.

 CMC Section of NDA
 Master Formula
› specific manufacturing instructions for full
scale commercial lots
› in process specifications
› product specifications
 History section of NDA

 Raw materials
 Laboratory
 Equipment qualification
 Cleaning validation
 SOPs

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

 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

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

 Actions of the drug in humans
 Pharmacokinetic data (ADME)
 Clinical Trial Results

 Clinical Adverse Experiences
 Concomitant Therapy
 Laboratory Abnormalities
 Hypersensitivity Reactions

 General Recommendations
 Dosage in Patients with Renal
Insufficiency
 National Drug Code

 Post-marketing surveillance
 Prescription drug advertising and
promotional labeling
 Pharmaceutical industry surveillance
 Drug shortages
 Therapeutic inequivalence reporting
 Medication errors

 Phase 4 Clinical Trials
 General Reporting Requirements
› Field Alert Reports
› Annual Reports
› Adverse Drug Reaction Reporting (ADR)
› Special reports
 cGMP Requirements

 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

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 isn’t bound to take
committee recommendations, but
usually does.

 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

 Approval letter
 Approval letter
 Not approvable letter

20% of IND’s result in successful NDA’s

Drug discovery and development overview

Drug discovery and development overview

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