Transcript No Slide Title

Physician / Investigator
Update
Charles H. Pierce, MD, PhD
Consultant in
Pharmaceutical Medicine
Medical Research
Expected Mission:
“Quality You Can Count On”
Physician Update Topics
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“Phases” of Clinical research
“Good Clinical Practice”
“Quality Assurance”
“Adverse Events”
“Standard Operating Procedures”
“International Conference on
Harmonization”
Phases of Clinical Drug Development
FDA
Subjects
I
Healthy
Normals
IIa
First time
in Patients
IIb
Patients
III
Patients
Number
20 - 100
25 - 75
50 - 200
>300
>1,000
Efficacy,
Safety
Efficacy,
Safety
Efficacy,
Safety,
New uses
Measures
Value
Cost
(Millions)
Time
(Years)
Dosage,
Dose range,
MOA
Kinetics,
Efficacy,
Safety,
Safety
Equivalence
Kinetics,
Dynamics
Proof of
Concept
Confirm
Confirm
mechanism
usefulness
of action
Review
Approve or
disapprove
IV
Patients
Surveillance,
extend patent
expand market
$8
$12
$7
$43
?
Varies with
The drug and
its use
1 - 1.5
1
1 - 1.5
3-6
2-3
1-2
Phase I Clinical Studies
• First in man or normal healthy volunteer
studies?
• Designed to determine all critical clinical
safety issues for the drug.
– if you double the dose do you double the
blood concentration?
– effect of food
– differences between gender and age
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Phase IIa Clinical Studies
• Establish the science of the drug in the
patients for which the drug is intended
• Confirm the mechanism of action of the
drug in the target condition or disease
• Establish safety in patients with the
target condition or disease
• Determine the dosage range in patients
to manage the condition or disease
• Usually confined but not always
Drug Development Statistics
• Drug discoverers file patent
• Patent exclusivity (no generics) = 17 years
• Drug development time = 7 - 10 years
• Application review = 2 - 3 years
• Market exclusivity = 4 - 8 years
• Drug development cost = $250 M - $400M
• Target income/drug/year = $250 M - $1B
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Investigational New Drug
- IND • Key milestone in drug development!
• Signals that the company believes
the drug can safely be administered
to humans.
• Once an IND is filed with the FDA, the
company can start their first human
study in 30 days; unless the FDA
stops the study.
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Drug Development Standards
• Good laboratory practices (GLP)
- Non-clinical safety studies
• Good manufacturing practices (GMP)
- Production operations
- Drug Formulation Quality control
• Good clinical practices (GCP)
- Clinical studies Phases I to IV
Drug Development
• Expensive & time consuming
• Race to market
– patent life is 17 years (no competition)
– $1M - $3M /day for first to market
• Safety of the drug is thoroughly tested in
laboratory animals and people.
• Efficacy of the drug has to be statistically
proven efficacious in patients.
• MRO’s are important in this process.
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“Good Clinical Practice”
• Ethics: Informed Consent, IRB
• Operational Responsibilities
Investigator
Sponsor / Client
Study Manager etc.
• Adverse Events / Reactions
• Data Management & Statistics
• Quality Assurance
GCP - ICH Definition
A standard for the design, conduct,
performance, monitoring, auditing,
recording, analyses, and reporting of
clinical trials that provides assurance
that the data and reported results are
credible and accurate and that the
rights, integrity, and confidentiality of
trial subjects are protected.
ICH - GCP Glossary (Final draft, May 1996)
Good Clinical Practice
(An Operational View)
To: prevent
Careless errors
detect
Violations
correct
Fraud / Misconduct
document
Ethical problems
GCP - Objectives
• Ethics:
Rights of patients
• Safety:
Protection of patients
• Efficacy: Utility of the product
Registration Authorities
Notification
- Of starting
- Of stopping
- Adverse events
•Preparation of documents •Preparation of reports
•Pharmaceutical products
•Filing and archiving
•Data management
•Audit of systems and data
•Decisions on adverse events
Authorization
Sponsor
Monitor
Protocol, Inv. brochure
On site visits information
Clinical
Laboratory
- Equipment
- Personnel
- Certification
Quality
Amendments
to protocol
Investigator
- Availability
- Knowledge (product, protocol)
- Trained team
- Acceptance of monitoring
- Acceptance of audit & inspection
Product
Information
Ref: A. and T. Spriet, Good Practice of
Clinical Drug Trials, Karger, Ed. 1992
Consent
Compliance
with protocol
Patients
Severe
Adverse
Events
Written
Approval
Ethics Committee
- Independence
- Composition
- Written approval
- Documented
decision
GCP in Medical Research
Document ! Document ! Document !
“If it is not written,
it does not exist.”
Dr. Lisook (FDA)
Div. of Scientific Investigations
Office of Compliance
Adverse Events (AEs)
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Adverse experience (AE)
Adverse drug event (ADE)
Adverse drug reaction (ADR)
Adverse drug experience (ADE)
Adverse reaction (AR)
Side effect (SE)
Undesirable reaction (UR)
Unfavorable effect (UE)
But not identical !
Adverse Events
• Signs - findings eg. BP, temperature, skin
rashes or bruises etc.
• Symptoms - a change in function as abd.
Pain, nausea, headache, lightheadedness
• Laboratory Finding - incr. or decr. Abn.
• Inter-current Illness - cold, URI etc.
• Study Condition - caused by blood draw
or ambient temperature
Adverse Event (AE)
Defined
Any untoward medical occurrence in a
patient or clinical investigation subject
who is administered a pharmaceutical
product and which does not necessarily
have to have a causal relationship with
this treatment.
ICH - GCP Glossary
Draft 7 (March 31, 1995)
Adverse Experience vs.
Adverse Drug Reaction
(FDA Concept)
Adverse drug reaction (ADR) is an
adverse experience (AE) that is
probably / possibly / remotely a
reaction to a drug. (Concept of
drug-relation.)
Adverse Experience:
Attributes
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Frequent / Rare
Benign / Serious
Predictable* / Unpredictable
Expected / Unexpected
Early occurrence / Late
occurrence
* Related to pharmacology / class
Adverse Drug Reaction: Types
Type A
Type B
Pharmacologically predictable
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-
Dose-dependent
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Incidence and morbidity
High
Low
Mortality
Low
High
Adjust dose
Stop
Treatment
After M.D. Rawlins and J.W. Thompson
“Textbook of Adverse Drug Reactions”
Adverse Events
Severity
Severity
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Seriousness
Intensity of an event
(mild - moderate - severe)
Seriousness. Global evaluation of an
event in terms of major
consequences for life
Quality Assurance
All those planned and systematic
actions necessary to provide
adequate confidence that a product
or service will satisfy requirements
for “Quality You Can Count On”.
Quality Assurance
The goal of a QA is to
“minimize correction through
early detection”
by
Monitoring studies and forecasting QA
checkpoints to more efficiently utilize
resources and minimize delays
Standard Operating Procedures
“SOPs”
• What are they
• How are they defined
• How important are they
SOPs - Defined
• A set of pre-established written
procedures for:
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The organization,
The conduct,
The data collection,
The documentation, and
The verification ..…
of a clinical trial
SOPs - Defined
• A set of pre-established written
procedures to ensure that the rights
and integrity of the trial subjects
are thoroughly protected and to
establish the credibility of data and
to improve the ethical, scientific,
and technical quality of trials.
Standard Operating Procedures
“SOPs”
WHO does WHAT, WHERE, and WHEN
NOT
WHY or HOW
Policy
Instructions
Training
Standard Operating Procedures
• To establish consistency
• To optimize time / manpower
• To enhance teamwork
• To protect the subject / patient
• To assure compliance with GCP
• To assure worldwide acceptance
• To ensure quality of the data
International Conference
on Harmonization (ICH)
• What is it
• How does ICH affect what we do
ICH: Efficacy Groups (GCP)
(1)
E1A: Extent of population exposure for
clinical safety
E1B: Prospective/retrospective studies of
databases on population exposure
Clinical safety data management (ADE) :
• E2A: Expedited reporting: def./standards
• E2B: Expedited reporting: format of reports
• E2C: Periodic safety updates
ICH: Efficacy Groups (GCP)
(2)
E3: Clinical study reports:
format/contents
E4: Dose-response information
for registration
E5: Ethnic factors in acceptability of
foreign clinical data
E7: Clinical trials in special populations:
Geriatrics
ICH: Efficacy Groups (GCP)
(3)
E6: Good Clinical Practices:
consolidated guideline
E6A: Addendum: Investigator’s brochure
E6B: Addendum: Essential Documents
ICH: Efficacy Groups (GCP)
(4)
E8: General guidelines for clinical trials
E9: Biostatistical issues in planning,
analysis, and interpretation of clinical
trials to support efficacy and safety
E10: Choice of control groups in clinical
trials