FDA Clinical Investigator Training Course November 16 18, 2009 Silver Spring, MD

Monday November 16 7.30 8.30 Registration, distribution of course materials, breakfast National Labor College

Session 1. FDA and the Regulation of Clinical Trials 8.30 8.45

Purpose of the course. Housekeeping Review of Agenda FDA Structure (CDER/CBER/CDRH) An overview of numbers of approvals for drugs devices and biologics, numbers of product withdrawals, numbers of applications etc

Welcome.

Leonard Sacks, MD (OC, OCCP)

8.45 9.15

Overview and Introduction to Drug Regulation:

The role of FDA in the United States The origin of FDA and subsequent milestones. The FDC Act as the backbone of FDAs activities The importance of the clinical investigator in FDAs work. FDAs mandate in product development Value of investigator insight- on product indications, appropriate populations, relevance of study design to practice of medicine, vigilance in safety of new products Recruitment of appropriate study subjects and acquisition of high quality data to expedite product development Value of communication between FDA and investigators. Vision of well-qualified trialists. Engaging international investigators

Janet Woodcock, MD (CDER)

9.15 9.35

FDA Structure and Device Role:

What are devices? Unique aspects of the regulation and development of devices relevant to investigators. What is FDAs mandate in the regulation of devices? Challenges in the development of devices Challenges in combination products (drug/device/biologic) Data flow in FDA-role of centers and offices in channeling data

Daniel Schultz, MD (CDRH))

9.35 - 9.55

A vision for the future of clinical investigators in a new world of IT, biological science and communications
What is a biologic?- differences between biologics and drugs Challenges in the development of biologics Vaccines- a different paradigm for efficacy evaluation Manufacturing concerns and biosimilars Warnings from the past (examples)- predicting the dangers of biologics

Karen Midthun, MD (CBER)

9.55 10.15 10.15 11.00

Break Investigator responsibilities Regulation and clinical trials:

Why do we have regulations? Fraud (examples), subject protection (examples) ethics (Tuskeegee) What is the FDC act? What is the CFR? What is an FDA guidance? What is the 1572? Who is a clinical investigator? Investigator responsibility guidance. The intent of IDE and IND regulations-what products are covered (drugs, nutritional supplements, tobacco, medical diagnostics), when do these regulations apply? How they safeguard safety, mandate adverse event reporting. What is a clinical hold? (examples) NDA, BLA and Device applications- Intent of the regulations. Controlling the dispensing of, and trading in unlicensed (experimental) products. The need for informed consent in unlicensed products. The regulations on informed consent. Role of IRB in relation to FDA What is good clinical practice Retention of records. Access to source data

Rachel Behrman,MD (OC,OCCP)

11.00 11.40

Informed consent and ethical considerations in clinical trials Overview of the FDA Guidance Process

TBA

11.40 12.00

Susan Honig, MD (CDER)

12.00 1.00

Lunch

Session 2. Understanding the investigator brochure - Non-clinical and Phase 1 Studies

1.00 1.30

CMC and the investigator brochure (Drugs): Ensuring the quality of a drug being used in a clinical trial
What CMC concerns affect the efficacy of a drug? examples What CMC concerns affect the safety of a drug? examples Stability and shelf life- how do we determine shelf life? What happens to drugs that exceed their shelf lives? Examples How are the specs for quality selected What are impurities? Examples. What clinical problems do impurities cause? Examples What is chemical equivalence? Define drug product and drug substance Overview of the production and manufacturing of investigational drugs Drug patents-how long do they last? What do they protect? Sterility of injectables

Norman Schmuff, Ph.D. (CDER)

1.30 - 2.00

CMC and the investigators brochure (Biologics):

Ensuring the quality of biologics/devices being used in a clinical trial Eliminating transmissible agents Manufacturing Potency

Steven Kozlowski, MD (CDER)

2.00 2.45

Pharmacotoxicology in the Investigator Brochure: In vitro data, genotoxicity, carcinogenicity, mutagenicity Ames test etc Clinical examples correlating these test with adverse drug reactions What is the standard battery of animal testing? How many species are tested. Strengths and weaknesses of animal testing in the prediction of human safety. Examples of species specific issues- e.g. rabbits and quinolones Preclinical device testing Animal models: what they mean for man
Converting doses between species Differences in drug metabolism between animals and man Differences in drug absorption between animals and man Examples where animals failed to correlate with human outcomes Animal mysteries- phopholipoidosis Models of efficacy Models of safety

David Jacobson-Kram, Ph.D. (CDER)

2.45 3.00

Break

3.00 3.30

Overview of Phase 1 studies: purpose, guidance, design

Patricia Keegan, MD (CDER)

How to do a clinical study under IND regulationsadvice for new investigators How do we move into first in human trials?

3.30 - 4.15

Clinical pharmacology 1: What to look for in drugs being studied in Phase 1 studies and Early Drug development
Selecting the first human dose? Dose escalation, examples Repeat dosing, Examples ADME, drug distribution and penetration Drug elimination, accumulation p450 and drug metabolism Drug absorption, food, grapefruit juice (Routes of adinistration)

Sarah Robertson, Pharm. D. (CDER)

4.15 4.50

Clinical pharmacology 2: Phase 2 and Beyond

Bioequivalence Drug metabolism, drug interactions and the use of concomitant drugs in clinical trials. Genetics and drug metabolism Renal and hepatic dysfunction PK/PD Inferences for children and special populations

Kellie Reynolds, Pharm.D. (CDER)

4.50

Distribute Case Study assignments/Adjourn

Tuesday November 17 8.00 9.00 Review of Phase 1 Case Studies (1) Original IND Pharm/Tox issue (2) TGN1412. Session 3. The Clinical Trial Protocol 9.00 10.00 The design of clinical trials (Part I):
The folly of clinical anecdotes Standards of evidence and the RCT Basic concepts of trial design Sample size/Power Inclusion/exclusion criteria, enrichment Blinding

Discussants: 1. Owen McMaster, Ph.D. (CDER) 2. Barbara Rellahan, Ph.D.(CBER)

Robert Temple, MD (CDER)

10.00 10.20 10.20 11.00

Break The design of clinical trials (Part II)

Randomization Superiority vs. non-inferiority trials

Robert Temple, MD (CDER)

11.00 11.30

Clinical Trial Endpoints, including PROs:

Rigoberto Roca, MD (CDER)

11.30 12.00

Clinical Trial Endpoints: Biomarkers, surrogate endpoints Lunch

Jeffrey Murray, MD (CDER)

12.00 1.00

1.00 1.30

Issues in Clinical Trial Designs for Devices

Problems with small trials and device placebos/shams Control groups and valid scientific evidence Competing with off-label use What makes use of a device investigational

Bram Zuckerman, MD (CDRH)

1.30 2.00 2.00 2.45

Issues in Clinical Trial Designs for Diagnostics and Combination Products The analysis of investigator data, sources of bias and error
Superiority versus non-inferiority How noisy data supports to non-inferiority conclusions whereas precise data supports superiority-examples Getting comfortable with a NI margin-examples Subgroups and post hoc analyses Missing data-imputing data Loss to follow up

Sally Hojvat, Ph.D. (CDRH) David DeMets, Ph.D. University of Wisconsin

2.45 3.00

Break

Session 4. Safety of Clinical Trials and Special Populations 3.00 3.45 General issues in the Safety of Clinical Trials General principles: Frequent vs. infrequent Common vs. rare Attributability/backgrounds Toxicity scales Factorial designs Limitations of clinical trials to assess safety Differences in safety across trial types Can proper safety assessment in clinical trials affect the later withdrawal of drugs Personalized/Genomics and safety in clinical trials. Mwango Kashoki, MD (CDER)

3.45 4.30

Data quality: monitoring, inspection and fraud, common errors

Rationale for monitoring clinical trials Overview of different approaches Regulations on monitoring What is an FDA inspection? How is the inspection conducted? How are sites selected? What errors concern us at FDA? Types of citation and examples Fraud- examples, how it was detected, how FDA responds. What records are required? The data trail, the audit trail The future of central data analysis with algorithms to check variance and randomness etc. Electronic source data and electronic monitoring

Leslie Ball, MD (CDER)

4.30 5.00

Special populations and special considerations in Clinical Trials: Children, Elderly, Pregnant Women Distribute Case Study Assignments/Adjourn

Sandra Kweder, MD (CDER)

5.00

Wednesday November 18 8.00 9.00 Review of Case Studies (1) Spinal filler non-inferiority study (2) Cardiovascular endpoints/antiplatelet or plavix 9.00 9.30 Special safety concerns: CV safety issues: QT prolongation and valvulopathy. Special safety concerns: hepatotoxicity and life cycle safety analysis (including hepatic biomarkers). Break Discussants: 1. Ryan Kretzer, MD (CDRH) 2. Stephen Grant, MD (CDER) Norman Stockbridge, MD (CDER)

9.30 10.00

Mark Avigan, MD (CDER)

10.00 10.20

10.20 11.00 11.00 11.30

Ensuring the safety of clinical trials: AE reporting, DSMBs, IRBs Safety panel discussion/Q & A

Ling Chin, MD (NIH)

Session 5. Non-FDA Perspectives on Clinical Trials 11.30 - 12.15 A Pharmaceutical Industry Perspective on the Clinical Investigators Role in Drug Development. Lunch A Patient Advocates Perspective on Clinical Trials Personal experience Different types of trial- cancer versus headaches Exclusion criteria Informed consent Use of placebos Invasive procedures e.g. liver biopsy Privacy Retention and loss to follow up, sticks and carrots Patient reported outcomes What happens when the trial ends Patients say in the clinical trial design Session 6. Post Approval Activities and Future Developments 1.45 2.30 Beyond phase 3: Postmarket Safety Surveillance: A Medical Device Perspective What are the different types of postmarket surveillance When are postmarket studies needed When should physicians report an adverse event or device malfunction to FDA Thomas Gross, MD (CDRH) Marty Holland Briggs Morrison, MD (Pfizer)

12.15 1.15 1.15 1.45

2.30 3.15

New technologies: Genomics, proteonomics metabolomics, microarrays Impact on study inclusion exclusion criteria Impact on study endpoints Personalized medicine Wrap Up and Adjourn

Donna Mendrick, Ph.D. (NCTR)

3.15

Leonard Sacks, MD (OC, OCCP)