1. Physician / Investigator Update
Charles H. Pierce, MD, PhD
Consultant in
Pharmaceutical Medicine

2. “Quality You Can Count On”
Medical Research
Expected Mission:
“Quality You Can Count On”

3. Physician Update Topics
“Phases” of Clinical research
“Good Clinical Practice”
“Quality Assurance”
“Adverse Events”
“Standard Operating Procedures”
“International Conference on
Harmonization”

5. 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

6. 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

7. Drug Development Statistics
Drug discoverers file patent
Patent exclusivity (no generics) = 17 years
Drug development time = years
Application review = years
Market exclusivity = years
Drug development cost = $250 M - $400M
Target income/drug/year = $250 M - $1B

8. 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.

9. 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

10. 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.

11. “Good Clinical Practice”
Ethics: Informed Consent, IRB
Operational Responsibilities Investigator
Sponsor / Client
Study Manager etc.
Adverse Events / Reactions
Data Management & Statistics
Quality Assurance

12. 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)

13. Good Clinical Practice (An Operational View)
To: prevent
detect
correct
document
Careless errors
Violations
Fraud / Misconduct
Ethical problems

14. GCP - Objectives Ethics: Rights of patients
Safety: Protection of patients
Efficacy: Utility of the product

15. Registration Authorities
Notification - Of starting - Of stopping - Adverse events
Authorization
Sponsor
Preparation of documents
Pharmaceutical products
Data management
Decisions on adverse events
Preparation of reports
Filing and archiving
Audit of systems and data
Monitor
Protocol, Inv. brochure
On site visits information
Amendments
to protocol
Clinical Laboratory
- Equipment
- Personnel
- Certification
Quality
Investigator
- Availability
- Knowledge (product, protocol)
- Trained team
- Acceptance of monitoring
- Acceptance of audit & inspection
Ethics Committee - Independence
- Composition
- Written approval
- Documented
decision
Severe
Adverse
Events
Written
Approval
Product
Information
Consent
Compliance
with protocol
Patients
Ref: A. and T. Spriet, Good Practice of Clinical Drug Trials, Karger, Ed. 1992

16. 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

17. Adverse Events (AEs) 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 !

18. 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

19. 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)

20. 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.)

21. Adverse Experience: Attributes
Frequent / Rare
Benign / Serious
Predictable* / Unpredictable
Expected / Unexpected
Early occurrence / Late occurrence
* Related to pharmacology / class

22. Adverse Drug Reaction: Types
Type A
Type B
Pharmacologically predictable
Dose-dependent
Incidence and morbidity
Mortality
Treatment +
High
Low
Adjust dose -
Low
High
Stop
After M.D. Rawlins and J.W. Thompson “Textbook of Adverse Drug Reactions”

23. Adverse Events Severity Seriousness . Severity Intensity of an event
(mild - moderate - severe)
Seriousness Global evaluation of an event in terms of major consequences for life .

24. 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”.

25. Quality Assurance “minimize correction through early detection”
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

26. Standard Operating Procedures “SOPs”
What are they
How are they defined
How important are they

27. SOPs - Defined A set of pre-established written procedures for:
- The organization, The conduct, The data collection, The documentation, and - The verification ..…
of a clinical trial

28. 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.

29. Standard Operating Procedures “SOPs”
WHO does WHAT, WHERE, and WHEN
NOT
WHY or HOW
Instructions
Training
Policy

30. 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

31. International Conference on Harmonization (ICH)
What is it
How does ICH affect what we do

32. 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

33. 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

34. ICH: Efficacy Groups (GCP) (3)
E6: Good Clinical Practices:
consolidated guideline
E6A: Addendum: Investigator’s brochure
E6B: Addendum: Essential Documents

35. 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