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Physician / Investigator Update

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Presentation on theme: "Physician / Investigator Update"— Presentation transcript:

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

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