Introduction on
Drug Research and
Development (R & D) Process
in the USA
1
,Rock” Diagram of Drug Development Process
Targets
Scrrens
SAR
Discovery Pre-clinical Clinical Marketing
I II III
Toxicology
Pharmaco-
kinetics
Selection NDA
IND
2,000 cpds 20 6 3 2 1
1 year 1 1 2 3
50 Mill 50 100 200 400 800
2
Drug Development Process
(1),Discovery Stage
(2),Pre-clinical Stage
(3),Clinical Stage
(4),Marketing Stage
3
Major Steps in Discovery Stage
Target generation and selection
Compound Library
Combinatorial chemistry
Library chemistry
Natural products
{
Development
Method set-up
Method validation
Technique assesment
Automation
Optimization
}
High throughput screens
Lead confirmation and chemistry
In vivo functional tests
Assay development and validation
Preliminary PK investigation SAR
4
Target Generation and Selection
Screening
Target
based on
hypothesis
Target
associated
with disease
Target as
mechanism
of disease
Target
causing
disease
Copying others
(Fluoxetine and
olanzapine stories)
Schizophrenia Alzheimer Parkinson Genetics
(DA in Pfc) (Ab-42) (DA in Striatum) (Disease genes)
Market Analysis
5
Structure of Olanzapine and Other Anti-psychotics
6
Structure of Fluoxetine and Other Anti-depressants
7
Developments of Anti-depressants
(I),Monoamine related drugs
(A),Monoamine uptake inhibitors
(1),Selective 5-HT uptake inhibitors (SSRIs)
Astra Zimeldine (Withdrawn in 83)
Lilly Fluoxetine (Prozac)
Pfizer Sertraline (Zoloft)
GSK Paroxetine (Paxil)
Forest/Lundberg Citalopram (Celexa)
(2),Selective NE uptake inhibitors (SNRI) Reboxetine
(3),Selective DA uptake inhibitors Nomifensine
(4),Dual 5-HT/NE uptake inhibitors Duloxetine (Cymbalta)
(5),Dual DA/NE uptake inhibitors Bupropion
(6),Non-selective reuptake inhibitors,Tricyclic (TCAs),imipramine,desipramine,etc.
(B),Auto-receptor inhibitors to achieve rapid onset of actions
(1),5-HT1A antagonists Pindolol
(2),a2-adrenoceptor antagonists Napamezole
(C),Neurotransmitter releaser Fenfluramine
(D),Monoamine oxidase inhibitors (MAOI) Resagerine
(E),Specific receptors agents
(1),5-HT receptors Buspirone (5-HT1A partial agonist)
(2),NE receptor agent Modafinil (a1-adrenoceptor agonist)
(F),Combinations of SSRI with other mechanisms
(II),Non-monoamine related drugs
(1),NK-1 antagonists Aprpitant (MK-869,L-754030,stopped)
(2),PDE4 inhibitors MEM 1414 (preclinical)
(3),CRF1 antagonists Many compounds
(4),Other mechanisms St John’s Wort 8
Problems with Current Anti-depressants
Limitations in efficacy
? Efficacy between currently antidepressants and TCAs
TCAs
? Anti-cholinergic side effects
? CV side effects and orthostatic hypotension
SSRIs
? Nausea,headache,insomnia,agitation and sexual dysfunction,etc.
? Delayed onset of actions
MAOs
? Hypertensive crisis
Weight gain
? Weight gain could be a sign of improvement in depressive symptoms
? TCAs and MAOs are likely to cause weight gain than SSRIs
? Paroxetine may be more likely to cause weight gain (3.6% in 6 months)
9
Combinations of SSRIs and 5-HT1A Antagonists
5-HT
SSRI
T
5-HT5-HTP
5-HT1A
TRYP
(-)
WAY
(-)
(-)
Hypothesis:
Combination of SSRI and
5-HT1A antagonist may
overcome the delayed
onset of anti-depressant
action of SSRIs
10
Multiple Possibilities
for the Development of New Anti-depressants
5-HT
SSRI
5-HT3
Napamezole
DA
NET
E
G
5-HT ATP
cAMP
5-HT?
5-HTP
5-HT1A
TRYP
(-)
WAY
5-HT1B
5-HT1D
Ant
i-d
ep
res
sa
nt
Ac
tio
ns
(-)
(-)
a1
a2
Bupropion
(-)
(+)
NE
DA(+)
(-)
(-)
(-)
11
Animal Models for Depression Studies
Learned helplessness (increase escape behavior)
Forced swim/behavioral despair (increase the latency)
Tail suspension test (increase the latency)
Chick isolation (increase the latency)
Olfactory bulbectomy (increase learning and memory)
Differential reinforcement of low rates of response (DRL)
5-HTP induced head twitch (increase response)
Aggression behaviors (attenuate aggression)
Amphetamine self-administration (reduce response)
Activity wheel stress (reduce response)
12
Drug Development Process
(1),Discovery Stage
(2),Pre-clinical Stage
(3),Clinical Stage
(4),Marketing Stage
13
Major Steps in Pre-clinical Stage
General pharmacological studies
? Effects on various systems for safety evaluation
Comprehensive PK studies
? Absorption,distribution,metabolism and excretion (ADME)
Formulation development
? Further improve PK profiles of the final candidates
Scale-up and stability
? Prepare large quantity of the compounds for safety studies
Acute and chronic animal toxicological studies
14
Pre-clinical Safety and Toxicological Studies
(A),Safety Pharmacology Studies
(1) General pharmacology on major systems
(2) CNS safety
(3) CV safety hERG,APD,anaethetized dog,dog telemetric study
(4) GI motility
(5),Genetic Cytogenicity,Ames,mutagenic,etc.
(B),Toxicology Studies
(1),Study duration
Acute 1 day 1 wk 4 wks
Chronic 12 wks 6 mons 12 mons 2 years
(2) Animal species Rat Mouse Dog Monkey
(3) Doses 2 – 4 doses
(4) Administration route Usually oral,but sometimes ip,iv
(5) Goals To determine NOAEL,motility,
clinical pathology,histopathology,etc.
15
Drug Development Process
(1),Discovery Stage
(2),Pre-clinical Stage
(3),Clinical Stage
(4),Marketing Stage
16
Major Steps in Clinical Stage
Phase I studies in health volunteers
? Focus on drug safety and dosing range in humans
? Pre-IND meting with the authorities
? IND (Investigational New Drug) filing
Phase II studies in selective patient population
? Phase IIa,Proof-of-Concept studies
? Phase IIb,dose finding
? End of Phase II meeting with the authorities
Phase III studies in large patient population
? 2 adequate and well-controlled positive trials
? Need about $50 – 100 millions and 2 - 4 years
? New Drug Application (NDA) filing
17
Process of Clinical Trials
(1),Preparation for clinical studies
(2),Conduct of clinical studies
(3),Completion of clinical studies
18
Things to Do to Start Clinical Trials
? Develop CDP
? Consult the FDA and medical experts
? Develop protocol
? Develop Case Report Form (CRF)
? Select and initiate sites
? File IRB and other regulatory documents
? Select CROs
? Hold investigator meeting and site training
? Prepare drug supply
? Develop timeline and budget
19
Things to Do to Conduct Clinical Trials
? Visit sites to validate data recording
? Monitor patient enrollment
? Analyze baseline data
? Monitor safety and other issues during the trials
? Review patient profile
? Interim analysis to validate power calculation
? Execute site and patient payments
? Prepare data transfer from labs to sponsor
? Prepare database and statistic analysis plan
20
Things to Do to Complete Clinical Trials
? Review all patient profiles and issue queries
? Transfer out-site data to in-house database
? Clear and lock database
? Analyze data and produce tables and listings
? Prepare study report
? Communicate results with various functional areas
? Close sites and labs
? Complete all payments
? Retrive un-used study medication(s)
? Complete working relationship with the CROs
21
Clinical Development Plan (CDP)
(1),Background
Medical Need
Rationale for Development
Preclinical data summary
Efficacy,Pharmacokinetics and Toxicology Data
Formulation Development
Doses,Routes,and Schedules
Regulatory Review
Input from External Advisors
(2),Target Product Profile (TPP)
(3),Clinical Development Strategy
Approach to Characterization and Optimization of Therapy
Approach to Defining Efficacy and Safety
Approach to Non-registration Trials and Commercialization
(4),Potential Challenges
22
Target Product Profile (TPP)
? Indications and Usage
? Population
? Dose & Administration
? Efficacy
? Safety
? Contraindications and Precautions
? Clinical Pharmacology
? Outcomes Research
? Cost of Goods
23
Main Components of Investigator’s Brochure (IB)
Summary
Introduction
Research rationale and therapeutic indications
General evaluation approach,etc.
Physical and chemical properties and formulation
Non-clinical studies
Non-clinical Pharmacology
PK and metabolism in animals
Toxicology
Effects in Humans
PK and metabolism in humans
Safety and efficacy
Marketing experience
Guidance for the investigators
24
Protocol of Clinical Trials
(1),Background
Introduction about the disease and unmet medical needs
Overview of pre-clinical data of study drug
Rational for the development
(2),Study Objectives and Endpoints
(3),Study Design
(4),Patient Selection
(5),Schedule of Events
(6),Enrollment Procedures
(7),Treatments
(8),Assessments
Efficacy Assessments
Safety Assessments
Pharmacokinetic Assessment
(9),Statistical Methods
(10),Quality Control
(11),Data Handling and Record Keeping
(12),Others including ethics,references,appendices,etc.
25
Scales for Clinical Evaluation
Depression
Hamilton Depression Rating Scale (HAMS)
Montgomery-Asberg Depression Rating Scale (MADRS)
Beck Depression Inventory (BDI)
Schizophrenia
Brief Psychiatric Rating Scale (BPRS)
Positive and Negative Syndrome Scale (PANSS
Scale for the Assessment of Negative Symptoms (SANS)
Stroke
NIH Stroke Scale for severity
Glasgow Scale for disability
Barthel Index for functional evaluation
Parkinson’s disease
Unified Parkinson’s Disease Rating Scale (UPDRS)
Parkinson Dyskinesia Scale (PDS)
Hoehu and Yahr Scale
General
Clinical Global Impression (CGI)
Quality of Life Scale (QLS)
Medical Outcome Study 36-item Short Form Health Survey (SF-36)
26
Rough Estimate of Mean Sample Size
N = k (Z 1-b + Z 1-a)2 / (Effective size) 2
N,ITT patient number per group (total number should be larger to cover
dropouts)
Effective size = (mean difference between drug and placebo group) / Pooled SD
Pooled SD = square root of (SD12 + SD22)
SD = SEM times square root of N
k,enrollment factor (ratio of treatment groups]
k = 4 (for 2 groups) for an enrollment ratio of 1:1 [ (1/ 0.5) + (1/0.5) ]
k = 4.5 (for 2 groups) for an enrollment ratio of 2:1 [ (1/ 0.666) + (1/0.333) ]
b,power factor obtained from the Z table
If powered at 80%,a factor of 1 – 0.8 = 0.2 will be used for Z table [0.8416]
If powered at 90%,a factor of 1 – 0.9 = 0.1 will be used for Z table [1.28155]
a,P factor obtained from the P table [Z]
a = 0.05 for one dose or no multiple comparison [1.96,for 2-sided]
a = 0.025 for multiple comparison of 2 doses [2.24,for 2-sided]
a = 0.017 for multiple comparison of 3 doses
27
Donepezil (Aricept) Studies for Alzheimer’s Disease*
Study 1 Study 2
AD diagnosis NINCDS-ADRDA,DSM III-R NINCDS-ADRDA,DSM III-R
AD severity Mild-moderate (MMSE 10-26) Mild-moderate (MMSE 10-26)
Patients Randomized,473 Randomized,468
Treatment PBO PBO
Aricept,5 mg/day Aricept,5 mg/day
Aricept,10 mg/day Aricept,10 mg/day
Duration 30 wks (washout 6 wks) 15 wks (washout 3 wks)
Primary efficacy-1 ADAS-cog (cognitive) ADAS-cog (cognitive)
At wk24,diff vs PBO At wk12,diff vs PBO
5 mg,2.8,P<0.05 5 mg,2.7,P<0.05
10 mg,3.1,P<0.05 10 mg,3.0,P<0.05
Primary efficacy-2 CIBIS-Plus (global) CIBIS-Plus (global)
At wk24,diff vs PBO At wk12,diff vs PBO
5 mg,0.35,P<0.05 5 mg,0.36,P<0.05
10 mg,0.39,P<0.05 10 mg,0.38,P<0.05
(*From Aricept Approved Labeling Text)
28
Interactions with the FDA
(1),Pre-IND Safety study design (doses,duration,assessments,etc.)
(2),IND filing Answer to the possible FDA questions about the IND
IND number for clinical enter
(3),Pre-phase II FDA input on phase II protocol (<5% chance)
(4),End of phase II FDA input on phase III protocol
(5),Before NDA To make sure the data package is acceptable to the FDA
(6),NDA The process will take 6-9 months
Linked to a lot people’s bonus and company stock price
(7),AC meeting The AC will come up with a recommendation
The FDA usually follows the AC recommendation
4-6 months and >$1 millions to prepare for it
(8),Label What exactly will be included in the package insert
(9),Post-market Commitment to the FDA before approval
Safety issues after approval
Pediatric exclusivity (two trials in kids for 6 more months)
(10),Others FDA scientific meetings
FDA and CPMP guidelines for specific disease(s)
29
Investigational New Drug (IND) Application
Three IND types:
Investigator IND To be submitted by a physician
Emergency IND Emergency use of an experimental drug
Treatment IND Experimental drugs for life-threatening conditions
30 day waiting period
Possible FDA’s questions on safety
Pre-IND meeting with the FDA,Materials for the meeting include:
Purpose of the meeting
Specific questions
Product name and structure
Proposed indications
Dosage regimen and route of administration
Overview of the clinical development program
Clinical data summary
Non-clinical data summary
30
Main Components of an IND Application
(1) IND Application form (FDA form –1571) [21 CFR 312.23(a)(1)]
(2) Statement of Investigator (Form FDA 1572)
(3) Table of contents [21 CFR 312.23(a)(2)]
(4) Introduction and general plan [21 CFR 312.23(a)(3)]
(5) Investigator’s brochure (IB) [21 CFR 312.23(a)(5)]
(6) Protocols [21 CFR 312.23(a)(6)] (Focus on safety
(7) Chemistry,manufacturing and control information [21 CFR 312.23(a)(7)]
Drug substance Drug product
Placebo control Labels
(8) Animal pharmacology and toxicology information [21 CFR 312.23(a)(8)]
Pharmacology and drug distribution
Toxicology GLP certification
Full data for each animal toxicology study
(9) Previous human experience [21 CFR 312.23(a)(9)]
31
IND Application Process
32
New Drug Application (NDA) Filing
(A),Main Components of a NDA:
(1),Application Summary
(2),Final report for registration study 1
(3),Final report for registration study 2
(4),Integrated Summary of Efficacy (ISE)
(5),Integrated Summary of Safety (ISS)
(6),NDA Application Form FDA 356h
(B),The goals of the NDA are to reach the following key decisions:
(1),Whether the drug is safe and effective in its proposed use(s),and
whether the benefits of the drug outweigh the risks
(2),Whether the drug's proposed labeling (package insert) is appropriate,
and what it should contain
(3),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
33
NDA Review Process
34
Preparation for the FDA AC Meetings
(1),Briefing docu,A very good summary of the key data sets
(2),Speaker(s) Know about 90% of the data
Organize the talk and prepare the slides
Endless practice for presentation and Q & A sessions
(3),Advisory panel Comments and suggestions for improvement
Answer to any scientific questions
Opinion on key issues from a FDA point of view
Suggestions on what you can or cannot say to the FDA
(4),Consultants Provide trainings to the speakers
Develop slide category and database
FDA meeting format simulation
(5),Company team Careful review every single slide
Provide comments to the speaker about everything
(6) Q & A group Guess all possible questions the AC members might ask
Prepare sets of slides to answer all questions at different levels
Sort the slides and prepare the Q & A binder
Training and practice to pick up right slides in few seconds.
(7),Others,Public affairs,security,drills,gifts,parties,etc.
35
Top 10 Issues to Remember When Preparing for FDA Meetings
(1),Highlight the main points that you want the FDA agents to remember
(2),Get to your points quickly and finish meetings on time
(3),Give the FDA a short but good summary of your statement
(4),Listen to the comments of Advisory Committees
(5),Make sure you get right person from the right division in the meeting so a
decision can be made at end of the meeting
(6),Pay your attention to Project Managers,the messengers of the King
(7),Do not ask for meetings on Fridays
(8),Limit the number of person for the meeting
(9),Be clear if you are going to talk about non-scientific issues
(10),Make sure you know the exact location of the meeting room
36
General Considerations for Clinical Evaluation of Drugs
Institutional review
Patients,Informed consent
Design,Objectives Observation method
Number of patients Selection of patients
Randomization of patients Control,Placebo and/or active drug
Dosage consideration Patient compliance
Phase I studies
Subjects,usually normal volunteers
Investigators,skilled in initial evaluation for safety and efficacy
Additional considerations,ECG data,special tests,blood drug level
Phase II and III studies
Subjects,patients
Investigators,experts in the particular disease categories
Additional considerations,blood drug levels,etc)
Tests for safety
Women,Usually excluded from the earliest dose ranging studies
Male,Special consent forma if abnormalities occur in animal stud
Children,Not until there has been considerable experience in adults
37
Good Clinical Practice (GCP)
An international ethical and scientific quality standard for designing,conducting and reporting trials,The
goal is to protect public rights,safety and well-being,GCP covers the following areas of clinical study:
(1),Institutional review board (IRB) / independent ethics committee (IEC)
(2),Investigator
Qualification and resources Medical cares of trial subjects
Communication with IRB / IEC Compliance with protocol
Randomization procedures Informed consent
Records and reports Safety reporting
Termination or suspension of a trial Final report
(3),Sponsor
Quality control Trial design and management
Investigator selection Pay to subjects and investigators
Notification of regulatory authority Information on study products
Supplying and labeling product Adverse reaction reporting
Monitoring and audit
(4),Clinical trial protocol
(5),Investigator’s brochure (IB)
(6),Essential documents for the conduct of a clinical trial
? Before,IB,protocol,informed consent form,IRB approval,investigator CV,randomization list,etc.
? During,visit reports,adverse events,screening log,record of retained body fluids,etc.
? After,product accountability,audit certificate,close-out report,clinical study report,etc.
38
Drug Development Process
(1),Discovery Stage
(2),Pre-clinical Stage
(3),Clinical Stage
(4),Marketing Stage
39
Drug Development Process – Marketing Stage
Launch of new product
Costs $800 millions to reach peak sale
Further evaluation of long-tern safety in large patient population
Post-market clinical studies
Active isomer
New indications
Different patient populations
Commitment to the FDA before approval
Pediatric exclusivity
Two trials conducted in kids regardless the outcome of the studies
to get 6 more months of patent coverage
Medical outcome studies
Economic impact of your drug vs comparative drugs
40
Clinical Drug Development Procedure
Program Study Study Study Data Result NDA
Strategy Plan Design Conduct Analysis Report Filing
Discovery Ther area dir Statistics Clin Operation Statistics Med Writing Regulatory
In-licensing Clin Pharma Clin Supply Data Mgt Data Mgt Regulatory Med Affairs
Business Mgt Regulatory Data Mgt Safety Surveillance Programming Clin Data Std Marketing
Marketing IP Clin Planning Med Outcome Res Others
Project mgt Clin Operation Document Mg
Exp Medicine Quality Assurance
Finance / Adm Project mgt
Pharma Dlpt
Outsourcing (lab,ECG,recruitment,audit,data entry,randomization,etc.)
41
Clinical Operations Process
(1) Study planning Feasibility test
(2) Investigator selection Center screening and selection criteria
(3) Contract and grants
(4) Essential documents FDA 1572 and CVs,IRB,ICF,etc.
(5) Investigator meeting / coordinate training
(6) Study supplies Drugs,CRFs,etc.
(7) Study conduct Site monitoring,patient recruitment,etc.
(8) Data flow Data management,SAEs,etc.
(9) Clinical trial management system (CTMS)
(10) Clinical support center
(11) More,Central labs,etc.
42
Roles of Project Management in Clinical Development
(1),Develop an effective strategy for project management
(2),Establish realistic timelines and project budget
(3),Refine project management responsibilities
(4),Develop an effective project communication plan
(5),Develop a plan for project changes and risk management
(6),Implement best strategies for conflict management
(7),Effectively manage data reporting and adverse event reporting
(8),Review guidelines for compliance a quality assurance system
43
Thank You
Jiang-Xi Medical College,Nan-Chang
Prof,Wang,Chong-Wen and many others
Institute of Materia Medica,Chinese Academy of Medical Sciences
Prof,Zhang,Jun-Tian and his group
Karolinska Institute,Stockholm,Sweden
Prof,Kjell Fuxe and his group
Eli Lilly and Company
Ray Fuller
David Wong
And many others
44
Drug Research and
Development (R & D) Process
in the USA
1
,Rock” Diagram of Drug Development Process
Targets
Scrrens
SAR
Discovery Pre-clinical Clinical Marketing
I II III
Toxicology
Pharmaco-
kinetics
Selection NDA
IND
2,000 cpds 20 6 3 2 1
1 year 1 1 2 3
50 Mill 50 100 200 400 800
2
Drug Development Process
(1),Discovery Stage
(2),Pre-clinical Stage
(3),Clinical Stage
(4),Marketing Stage
3
Major Steps in Discovery Stage
Target generation and selection
Compound Library
Combinatorial chemistry
Library chemistry
Natural products
{
Development
Method set-up
Method validation
Technique assesment
Automation
Optimization
}
High throughput screens
Lead confirmation and chemistry
In vivo functional tests
Assay development and validation
Preliminary PK investigation SAR
4
Target Generation and Selection
Screening
Target
based on
hypothesis
Target
associated
with disease
Target as
mechanism
of disease
Target
causing
disease
Copying others
(Fluoxetine and
olanzapine stories)
Schizophrenia Alzheimer Parkinson Genetics
(DA in Pfc) (Ab-42) (DA in Striatum) (Disease genes)
Market Analysis
5
Structure of Olanzapine and Other Anti-psychotics
6
Structure of Fluoxetine and Other Anti-depressants
7
Developments of Anti-depressants
(I),Monoamine related drugs
(A),Monoamine uptake inhibitors
(1),Selective 5-HT uptake inhibitors (SSRIs)
Astra Zimeldine (Withdrawn in 83)
Lilly Fluoxetine (Prozac)
Pfizer Sertraline (Zoloft)
GSK Paroxetine (Paxil)
Forest/Lundberg Citalopram (Celexa)
(2),Selective NE uptake inhibitors (SNRI) Reboxetine
(3),Selective DA uptake inhibitors Nomifensine
(4),Dual 5-HT/NE uptake inhibitors Duloxetine (Cymbalta)
(5),Dual DA/NE uptake inhibitors Bupropion
(6),Non-selective reuptake inhibitors,Tricyclic (TCAs),imipramine,desipramine,etc.
(B),Auto-receptor inhibitors to achieve rapid onset of actions
(1),5-HT1A antagonists Pindolol
(2),a2-adrenoceptor antagonists Napamezole
(C),Neurotransmitter releaser Fenfluramine
(D),Monoamine oxidase inhibitors (MAOI) Resagerine
(E),Specific receptors agents
(1),5-HT receptors Buspirone (5-HT1A partial agonist)
(2),NE receptor agent Modafinil (a1-adrenoceptor agonist)
(F),Combinations of SSRI with other mechanisms
(II),Non-monoamine related drugs
(1),NK-1 antagonists Aprpitant (MK-869,L-754030,stopped)
(2),PDE4 inhibitors MEM 1414 (preclinical)
(3),CRF1 antagonists Many compounds
(4),Other mechanisms St John’s Wort 8
Problems with Current Anti-depressants
Limitations in efficacy
? Efficacy between currently antidepressants and TCAs
TCAs
? Anti-cholinergic side effects
? CV side effects and orthostatic hypotension
SSRIs
? Nausea,headache,insomnia,agitation and sexual dysfunction,etc.
? Delayed onset of actions
MAOs
? Hypertensive crisis
Weight gain
? Weight gain could be a sign of improvement in depressive symptoms
? TCAs and MAOs are likely to cause weight gain than SSRIs
? Paroxetine may be more likely to cause weight gain (3.6% in 6 months)
9
Combinations of SSRIs and 5-HT1A Antagonists
5-HT
SSRI
T
5-HT5-HTP
5-HT1A
TRYP
(-)
WAY
(-)
(-)
Hypothesis:
Combination of SSRI and
5-HT1A antagonist may
overcome the delayed
onset of anti-depressant
action of SSRIs
10
Multiple Possibilities
for the Development of New Anti-depressants
5-HT
SSRI
5-HT3
Napamezole
DA
NET
E
G
5-HT ATP
cAMP
5-HT?
5-HTP
5-HT1A
TRYP
(-)
WAY
5-HT1B
5-HT1D
Ant
i-d
ep
res
sa
nt
Ac
tio
ns
(-)
(-)
a1
a2
Bupropion
(-)
(+)
NE
DA(+)
(-)
(-)
(-)
11
Animal Models for Depression Studies
Learned helplessness (increase escape behavior)
Forced swim/behavioral despair (increase the latency)
Tail suspension test (increase the latency)
Chick isolation (increase the latency)
Olfactory bulbectomy (increase learning and memory)
Differential reinforcement of low rates of response (DRL)
5-HTP induced head twitch (increase response)
Aggression behaviors (attenuate aggression)
Amphetamine self-administration (reduce response)
Activity wheel stress (reduce response)
12
Drug Development Process
(1),Discovery Stage
(2),Pre-clinical Stage
(3),Clinical Stage
(4),Marketing Stage
13
Major Steps in Pre-clinical Stage
General pharmacological studies
? Effects on various systems for safety evaluation
Comprehensive PK studies
? Absorption,distribution,metabolism and excretion (ADME)
Formulation development
? Further improve PK profiles of the final candidates
Scale-up and stability
? Prepare large quantity of the compounds for safety studies
Acute and chronic animal toxicological studies
14
Pre-clinical Safety and Toxicological Studies
(A),Safety Pharmacology Studies
(1) General pharmacology on major systems
(2) CNS safety
(3) CV safety hERG,APD,anaethetized dog,dog telemetric study
(4) GI motility
(5),Genetic Cytogenicity,Ames,mutagenic,etc.
(B),Toxicology Studies
(1),Study duration
Acute 1 day 1 wk 4 wks
Chronic 12 wks 6 mons 12 mons 2 years
(2) Animal species Rat Mouse Dog Monkey
(3) Doses 2 – 4 doses
(4) Administration route Usually oral,but sometimes ip,iv
(5) Goals To determine NOAEL,motility,
clinical pathology,histopathology,etc.
15
Drug Development Process
(1),Discovery Stage
(2),Pre-clinical Stage
(3),Clinical Stage
(4),Marketing Stage
16
Major Steps in Clinical Stage
Phase I studies in health volunteers
? Focus on drug safety and dosing range in humans
? Pre-IND meting with the authorities
? IND (Investigational New Drug) filing
Phase II studies in selective patient population
? Phase IIa,Proof-of-Concept studies
? Phase IIb,dose finding
? End of Phase II meeting with the authorities
Phase III studies in large patient population
? 2 adequate and well-controlled positive trials
? Need about $50 – 100 millions and 2 - 4 years
? New Drug Application (NDA) filing
17
Process of Clinical Trials
(1),Preparation for clinical studies
(2),Conduct of clinical studies
(3),Completion of clinical studies
18
Things to Do to Start Clinical Trials
? Develop CDP
? Consult the FDA and medical experts
? Develop protocol
? Develop Case Report Form (CRF)
? Select and initiate sites
? File IRB and other regulatory documents
? Select CROs
? Hold investigator meeting and site training
? Prepare drug supply
? Develop timeline and budget
19
Things to Do to Conduct Clinical Trials
? Visit sites to validate data recording
? Monitor patient enrollment
? Analyze baseline data
? Monitor safety and other issues during the trials
? Review patient profile
? Interim analysis to validate power calculation
? Execute site and patient payments
? Prepare data transfer from labs to sponsor
? Prepare database and statistic analysis plan
20
Things to Do to Complete Clinical Trials
? Review all patient profiles and issue queries
? Transfer out-site data to in-house database
? Clear and lock database
? Analyze data and produce tables and listings
? Prepare study report
? Communicate results with various functional areas
? Close sites and labs
? Complete all payments
? Retrive un-used study medication(s)
? Complete working relationship with the CROs
21
Clinical Development Plan (CDP)
(1),Background
Medical Need
Rationale for Development
Preclinical data summary
Efficacy,Pharmacokinetics and Toxicology Data
Formulation Development
Doses,Routes,and Schedules
Regulatory Review
Input from External Advisors
(2),Target Product Profile (TPP)
(3),Clinical Development Strategy
Approach to Characterization and Optimization of Therapy
Approach to Defining Efficacy and Safety
Approach to Non-registration Trials and Commercialization
(4),Potential Challenges
22
Target Product Profile (TPP)
? Indications and Usage
? Population
? Dose & Administration
? Efficacy
? Safety
? Contraindications and Precautions
? Clinical Pharmacology
? Outcomes Research
? Cost of Goods
23
Main Components of Investigator’s Brochure (IB)
Summary
Introduction
Research rationale and therapeutic indications
General evaluation approach,etc.
Physical and chemical properties and formulation
Non-clinical studies
Non-clinical Pharmacology
PK and metabolism in animals
Toxicology
Effects in Humans
PK and metabolism in humans
Safety and efficacy
Marketing experience
Guidance for the investigators
24
Protocol of Clinical Trials
(1),Background
Introduction about the disease and unmet medical needs
Overview of pre-clinical data of study drug
Rational for the development
(2),Study Objectives and Endpoints
(3),Study Design
(4),Patient Selection
(5),Schedule of Events
(6),Enrollment Procedures
(7),Treatments
(8),Assessments
Efficacy Assessments
Safety Assessments
Pharmacokinetic Assessment
(9),Statistical Methods
(10),Quality Control
(11),Data Handling and Record Keeping
(12),Others including ethics,references,appendices,etc.
25
Scales for Clinical Evaluation
Depression
Hamilton Depression Rating Scale (HAMS)
Montgomery-Asberg Depression Rating Scale (MADRS)
Beck Depression Inventory (BDI)
Schizophrenia
Brief Psychiatric Rating Scale (BPRS)
Positive and Negative Syndrome Scale (PANSS
Scale for the Assessment of Negative Symptoms (SANS)
Stroke
NIH Stroke Scale for severity
Glasgow Scale for disability
Barthel Index for functional evaluation
Parkinson’s disease
Unified Parkinson’s Disease Rating Scale (UPDRS)
Parkinson Dyskinesia Scale (PDS)
Hoehu and Yahr Scale
General
Clinical Global Impression (CGI)
Quality of Life Scale (QLS)
Medical Outcome Study 36-item Short Form Health Survey (SF-36)
26
Rough Estimate of Mean Sample Size
N = k (Z 1-b + Z 1-a)2 / (Effective size) 2
N,ITT patient number per group (total number should be larger to cover
dropouts)
Effective size = (mean difference between drug and placebo group) / Pooled SD
Pooled SD = square root of (SD12 + SD22)
SD = SEM times square root of N
k,enrollment factor (ratio of treatment groups]
k = 4 (for 2 groups) for an enrollment ratio of 1:1 [ (1/ 0.5) + (1/0.5) ]
k = 4.5 (for 2 groups) for an enrollment ratio of 2:1 [ (1/ 0.666) + (1/0.333) ]
b,power factor obtained from the Z table
If powered at 80%,a factor of 1 – 0.8 = 0.2 will be used for Z table [0.8416]
If powered at 90%,a factor of 1 – 0.9 = 0.1 will be used for Z table [1.28155]
a,P factor obtained from the P table [Z]
a = 0.05 for one dose or no multiple comparison [1.96,for 2-sided]
a = 0.025 for multiple comparison of 2 doses [2.24,for 2-sided]
a = 0.017 for multiple comparison of 3 doses
27
Donepezil (Aricept) Studies for Alzheimer’s Disease*
Study 1 Study 2
AD diagnosis NINCDS-ADRDA,DSM III-R NINCDS-ADRDA,DSM III-R
AD severity Mild-moderate (MMSE 10-26) Mild-moderate (MMSE 10-26)
Patients Randomized,473 Randomized,468
Treatment PBO PBO
Aricept,5 mg/day Aricept,5 mg/day
Aricept,10 mg/day Aricept,10 mg/day
Duration 30 wks (washout 6 wks) 15 wks (washout 3 wks)
Primary efficacy-1 ADAS-cog (cognitive) ADAS-cog (cognitive)
At wk24,diff vs PBO At wk12,diff vs PBO
5 mg,2.8,P<0.05 5 mg,2.7,P<0.05
10 mg,3.1,P<0.05 10 mg,3.0,P<0.05
Primary efficacy-2 CIBIS-Plus (global) CIBIS-Plus (global)
At wk24,diff vs PBO At wk12,diff vs PBO
5 mg,0.35,P<0.05 5 mg,0.36,P<0.05
10 mg,0.39,P<0.05 10 mg,0.38,P<0.05
(*From Aricept Approved Labeling Text)
28
Interactions with the FDA
(1),Pre-IND Safety study design (doses,duration,assessments,etc.)
(2),IND filing Answer to the possible FDA questions about the IND
IND number for clinical enter
(3),Pre-phase II FDA input on phase II protocol (<5% chance)
(4),End of phase II FDA input on phase III protocol
(5),Before NDA To make sure the data package is acceptable to the FDA
(6),NDA The process will take 6-9 months
Linked to a lot people’s bonus and company stock price
(7),AC meeting The AC will come up with a recommendation
The FDA usually follows the AC recommendation
4-6 months and >$1 millions to prepare for it
(8),Label What exactly will be included in the package insert
(9),Post-market Commitment to the FDA before approval
Safety issues after approval
Pediatric exclusivity (two trials in kids for 6 more months)
(10),Others FDA scientific meetings
FDA and CPMP guidelines for specific disease(s)
29
Investigational New Drug (IND) Application
Three IND types:
Investigator IND To be submitted by a physician
Emergency IND Emergency use of an experimental drug
Treatment IND Experimental drugs for life-threatening conditions
30 day waiting period
Possible FDA’s questions on safety
Pre-IND meeting with the FDA,Materials for the meeting include:
Purpose of the meeting
Specific questions
Product name and structure
Proposed indications
Dosage regimen and route of administration
Overview of the clinical development program
Clinical data summary
Non-clinical data summary
30
Main Components of an IND Application
(1) IND Application form (FDA form –1571) [21 CFR 312.23(a)(1)]
(2) Statement of Investigator (Form FDA 1572)
(3) Table of contents [21 CFR 312.23(a)(2)]
(4) Introduction and general plan [21 CFR 312.23(a)(3)]
(5) Investigator’s brochure (IB) [21 CFR 312.23(a)(5)]
(6) Protocols [21 CFR 312.23(a)(6)] (Focus on safety
(7) Chemistry,manufacturing and control information [21 CFR 312.23(a)(7)]
Drug substance Drug product
Placebo control Labels
(8) Animal pharmacology and toxicology information [21 CFR 312.23(a)(8)]
Pharmacology and drug distribution
Toxicology GLP certification
Full data for each animal toxicology study
(9) Previous human experience [21 CFR 312.23(a)(9)]
31
IND Application Process
32
New Drug Application (NDA) Filing
(A),Main Components of a NDA:
(1),Application Summary
(2),Final report for registration study 1
(3),Final report for registration study 2
(4),Integrated Summary of Efficacy (ISE)
(5),Integrated Summary of Safety (ISS)
(6),NDA Application Form FDA 356h
(B),The goals of the NDA are to reach the following key decisions:
(1),Whether the drug is safe and effective in its proposed use(s),and
whether the benefits of the drug outweigh the risks
(2),Whether the drug's proposed labeling (package insert) is appropriate,
and what it should contain
(3),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
33
NDA Review Process
34
Preparation for the FDA AC Meetings
(1),Briefing docu,A very good summary of the key data sets
(2),Speaker(s) Know about 90% of the data
Organize the talk and prepare the slides
Endless practice for presentation and Q & A sessions
(3),Advisory panel Comments and suggestions for improvement
Answer to any scientific questions
Opinion on key issues from a FDA point of view
Suggestions on what you can or cannot say to the FDA
(4),Consultants Provide trainings to the speakers
Develop slide category and database
FDA meeting format simulation
(5),Company team Careful review every single slide
Provide comments to the speaker about everything
(6) Q & A group Guess all possible questions the AC members might ask
Prepare sets of slides to answer all questions at different levels
Sort the slides and prepare the Q & A binder
Training and practice to pick up right slides in few seconds.
(7),Others,Public affairs,security,drills,gifts,parties,etc.
35
Top 10 Issues to Remember When Preparing for FDA Meetings
(1),Highlight the main points that you want the FDA agents to remember
(2),Get to your points quickly and finish meetings on time
(3),Give the FDA a short but good summary of your statement
(4),Listen to the comments of Advisory Committees
(5),Make sure you get right person from the right division in the meeting so a
decision can be made at end of the meeting
(6),Pay your attention to Project Managers,the messengers of the King
(7),Do not ask for meetings on Fridays
(8),Limit the number of person for the meeting
(9),Be clear if you are going to talk about non-scientific issues
(10),Make sure you know the exact location of the meeting room
36
General Considerations for Clinical Evaluation of Drugs
Institutional review
Patients,Informed consent
Design,Objectives Observation method
Number of patients Selection of patients
Randomization of patients Control,Placebo and/or active drug
Dosage consideration Patient compliance
Phase I studies
Subjects,usually normal volunteers
Investigators,skilled in initial evaluation for safety and efficacy
Additional considerations,ECG data,special tests,blood drug level
Phase II and III studies
Subjects,patients
Investigators,experts in the particular disease categories
Additional considerations,blood drug levels,etc)
Tests for safety
Women,Usually excluded from the earliest dose ranging studies
Male,Special consent forma if abnormalities occur in animal stud
Children,Not until there has been considerable experience in adults
37
Good Clinical Practice (GCP)
An international ethical and scientific quality standard for designing,conducting and reporting trials,The
goal is to protect public rights,safety and well-being,GCP covers the following areas of clinical study:
(1),Institutional review board (IRB) / independent ethics committee (IEC)
(2),Investigator
Qualification and resources Medical cares of trial subjects
Communication with IRB / IEC Compliance with protocol
Randomization procedures Informed consent
Records and reports Safety reporting
Termination or suspension of a trial Final report
(3),Sponsor
Quality control Trial design and management
Investigator selection Pay to subjects and investigators
Notification of regulatory authority Information on study products
Supplying and labeling product Adverse reaction reporting
Monitoring and audit
(4),Clinical trial protocol
(5),Investigator’s brochure (IB)
(6),Essential documents for the conduct of a clinical trial
? Before,IB,protocol,informed consent form,IRB approval,investigator CV,randomization list,etc.
? During,visit reports,adverse events,screening log,record of retained body fluids,etc.
? After,product accountability,audit certificate,close-out report,clinical study report,etc.
38
Drug Development Process
(1),Discovery Stage
(2),Pre-clinical Stage
(3),Clinical Stage
(4),Marketing Stage
39
Drug Development Process – Marketing Stage
Launch of new product
Costs $800 millions to reach peak sale
Further evaluation of long-tern safety in large patient population
Post-market clinical studies
Active isomer
New indications
Different patient populations
Commitment to the FDA before approval
Pediatric exclusivity
Two trials conducted in kids regardless the outcome of the studies
to get 6 more months of patent coverage
Medical outcome studies
Economic impact of your drug vs comparative drugs
40
Clinical Drug Development Procedure
Program Study Study Study Data Result NDA
Strategy Plan Design Conduct Analysis Report Filing
Discovery Ther area dir Statistics Clin Operation Statistics Med Writing Regulatory
In-licensing Clin Pharma Clin Supply Data Mgt Data Mgt Regulatory Med Affairs
Business Mgt Regulatory Data Mgt Safety Surveillance Programming Clin Data Std Marketing
Marketing IP Clin Planning Med Outcome Res Others
Project mgt Clin Operation Document Mg
Exp Medicine Quality Assurance
Finance / Adm Project mgt
Pharma Dlpt
Outsourcing (lab,ECG,recruitment,audit,data entry,randomization,etc.)
41
Clinical Operations Process
(1) Study planning Feasibility test
(2) Investigator selection Center screening and selection criteria
(3) Contract and grants
(4) Essential documents FDA 1572 and CVs,IRB,ICF,etc.
(5) Investigator meeting / coordinate training
(6) Study supplies Drugs,CRFs,etc.
(7) Study conduct Site monitoring,patient recruitment,etc.
(8) Data flow Data management,SAEs,etc.
(9) Clinical trial management system (CTMS)
(10) Clinical support center
(11) More,Central labs,etc.
42
Roles of Project Management in Clinical Development
(1),Develop an effective strategy for project management
(2),Establish realistic timelines and project budget
(3),Refine project management responsibilities
(4),Develop an effective project communication plan
(5),Develop a plan for project changes and risk management
(6),Implement best strategies for conflict management
(7),Effectively manage data reporting and adverse event reporting
(8),Review guidelines for compliance a quality assurance system
43
Thank You
Jiang-Xi Medical College,Nan-Chang
Prof,Wang,Chong-Wen and many others
Institute of Materia Medica,Chinese Academy of Medical Sciences
Prof,Zhang,Jun-Tian and his group
Karolinska Institute,Stockholm,Sweden
Prof,Kjell Fuxe and his group
Eli Lilly and Company
Ray Fuller
David Wong
And many others
44
