Transcript ASENT _2008_06mar08

Phases of Therapeutic
Development
by
Virinder Nohria, MD, PhD
Presented at
ASENT Annual Meeting Symposium on
Neurotherapeutics
Arlington, VA
March 6, 2008
Contact Information: [email protected]; 1-828-349-0247
Agenda
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Definitions
Overview of Drug Development
Objectives of Drug Development Program
Contents of Package Insert
Strategy of Drug Development
Pre-clinical Testing
Phases of Clinical Development
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Definitions
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Sponsor – Organization sponsoring the study
CDER - Center for Drug Evaluation and Research
CBER – Center for Biologicals Evaluation and Research
CDRH - Center for Devices & Radiological Health
IND – Investigational New Drug
NDA – New Drug Application
BLA – Biological Licensing Application
510 (k) – Approval for devices etc.
IRB – Institutional Review Board
EMEA – European Medicines Evaluation Agency
ICH – International Commission on Harmonization
GCP – Good Clinical Practice (ICH – E6)
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An Overview of Drug Development
Idea Exploration
2 years
Strategy & Research
NDA Preparation
& Filing (6-9 months)
2-3 years
Lead Finding
Pharmacology
Lead Optimization
Synthesis, Toxicology
& ADME
IND Filing
Drug Candidate
3 months
Confirmation
6-12 months
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Therapeutic Confirmation
Phase III (Pivotal Studies)
1-2 years
Therapeutic Exploration
Phase II (Proof of Concept)
12-18 months
Human Pharmacology
Phase I
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Objectives of Development Program
 Gain regulatory approval
– support package insert
 Provide clinically meaningful information
– comparator data
– cost effectiveness
– clinical utility
• basic efficacy and safety
– quality of life (QOL)
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Package Insert Contents
 Highlights of Prescribing Information
 Full Prescribing Information
– Has 17 numbered sections referring to
detailed information
– This new format was proposed in 2006 and
is now being implemented for all new
approvals
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Full Prescribing Information (1)
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Indications and Usage
Dosage and Administration
Dosage Forms and Strengths
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
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Full Prescribing Information (2)
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Drug Abuse and Dependence
Overdosage
Description
Clinical Pharmacology
Non-clinical Toxicology
Clinical Studies
References
How Supplied/Storage and Handling
Patient Counseling Information
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Full Prescribing Information - Lyrica
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Corporate Strategy for Drug
Development
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Unmet medical need
Market size
Competitor advantage - franchise
Complexity and cost of development
program
Serendipity
Molecules looking for diseases
Niche markets - orphan drugs
Me too’s
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Generation of “Lead Candidate(s)”
 New understanding of pathophysiology designer drugs
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molecular biology,
computer modeling,
combinatorial chemistry
high through put screening
Structure activity relationship and pro-drugs
Serendipity
Partnership with academia (licensing-in)
Molecules looking for diseases
Reformulation
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Lead Optimization/Candidate
Confirmation
 Testing in in-vitro/in-vivo disease models
 Toxicology - acute and subacute
 Pharmacokinetics-pre-clinical - in-vivo
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absorption
distribution
metabolism
Excretion
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Investigational New Drug Application
(IND)
 2000-3000 page document containing
– investigators brochure
– ADME-preclinical
– Chemistry, manufacturing, & control
– Proof of concept (animals) - rationale
– toxicology - integrated summary
– proposed protocols
– previous human experience
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Phase I Studies
 Initial introduction of investigational new
drug to humans
 Determination of metabolism,
pharmacologic actions and side-effects
 Usually healthy volunteers, but may be
patients; e.g. development of oncolytics
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Objectives of Phase I Studies
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Human safety and tolerability
Pharmacokinetics (PK)
Pharmacodynamics
Correlation between PK & PD ( dose response curve)
 Drug interactions
 Maximum tolerated dose (MTD)
 Minimally effective dose (MED)
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Phase II Studies
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Carried out in patients
Establish PK & PD in patients
Determine MED and MTD in patients
Determine effective and safe dose range
– determine optimal dose
 Proof of concept studies
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Design of Early Phase II Studies
 Similar to phase I studies and often
carried out in major academic centers
(e.g GCRC) or purpose built units
 Primarily PK, safety & tolerability in
patients
 Often include efficacy measures
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Design of Late Phase II Studies
 These are usually proof of concept
studies
 Double-blind, placebo-controlled (may be
comparator controlled)
 Usually dose ranging – multiple dose
groups
 Strict inclusion/exclusion criteria
 Statistically water-tight - p < 0.05, 80-90%
power
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Design of Late Phase II Studies (2)
 Efficacy parameters - crisp & clinically
meaningful; may include surrogate
markers
 Plasma levels are monitored
 Usually requires 150-300 patients
 Treatment duration is 12-24 weeks
 Often have independent safety data
monitoring boards
 Phase II takes 12-24 months
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Phase III Studies
 Pivotal studies - need at least two
independent studies
 Confirm what was observed in phase II
studies
 Determine product label/primary
indication
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Design of Phase III Studies
 Double-blind, placebo-controlled (may be
comparator controlled), parallel group
 Multi-center, multi-national
 Broader inclusion/exclusion criteria
 Multiple doses, 100s of patients
 Statistically powered to show difference
from placebo (rarely from comparator)
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Design of Phase III Studies (2)
 Need to have long-term extensions in order to
accrue 300 patients exposed for 6 months and
100 patients exposed for 1 year (minimum long
term safety requirement by ICH agreement)
 Efficacy parameters should be clinically
relevant and accepted by the regulatory
authorities
 May include QOL scales
 Phase III takes 2-3 years
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Phase IV Studies
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Additional indications
Post marketing surveillance
Health economics
Clinical utility
Practice guidelines
Publication studies
Marketing studies
Safety studies
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Rate-limiting Steps in Drug
Development
 Lack of resources - human and financial
 Company bureaucracy and lack of
decision making and strategy
 Long-term toxicology studies
 IRB approvals/institutional bureaucracy
 Lack of study coordinators at sites
 Patient recruitment
 Data cleaning and harmonization
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Drug Development - Decision Points
and Milestones
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Lead generation
Identification of the candidate
Intellectual property protection
Scaling up of synthesis
Safety assessment - Toxicology
IND filing
Completion of phase I
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Drug Development - Decision Points
and Milestones (2)
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Marketable dosage form
Cost of manufactured goods
Completion of phase II
Clinical safety and efficacy review
Completion of phase III
NDA preparation and filing
Product launch
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Common Pitfalls in Drug Development
 Drug development is a process and there are
no short cuts
 However common pitfalls are
– Starting phase I/ phase II studies too late/ too early
– Not defining the dose range in well controlled phase
II studies before moving to phase III – too high a
dose leads to too many side effects and too low a
dose may lead to a negative study(ies) and the drug
not be approved
– Poor study designs (wrong endpoints, wrong
inclusion/exclusion criteria, wrong assumptions
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Common Pitfalls in Drug Development (2)
 Too many sites, too heterogeneous a patient
population leads to increased variability and
reduction/loss of effect size
 Inadequate investigator training
 Not listening to regulatory authorities – a
ongoing dialogue is important – e.g. pre-IND
meeting, EOP-2 meeting, pre-NDA meeting in
the US and similar meetings with other
authorities
 Emotion/investor driven development rather
than process driven development
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Mission Statement for a Drug
Development Program
Reduce Time to Market
by providing
Quality Data On Time (QDOT)
in order to bring
More Effective Therapies to
Patients while
Maximizing Shareholder Value
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