Outline

Principles of Clinical and Translational Research in Oncology

2 Credits, UMDNJ-GSBS

Course Coordinator/Director:

Robert Wieder, MD, PhD

Director, Clinical Research Office

NJMS-UH Cancer Center

Co-Course Coordinator (primary contact):

Gwendolyn Mahon, Ph.D.

Director, Research Program Planning and Development

NJMS-UH Cancer Center

2.25 hour classes, Mondays 6:00 – 8:15 PM, September 8 – December 8, 2008

1. September 8, 2008 - Principles of Cancer Therapy          

- Robert Wieder, MD, PhD

A. cancer biology, loss of tumor suppressor function, receptor and oncogene signaling, proliferation, metastasis, dormancy

B. Chemotherapy drugs, limits of detection, log growth, multiclonality, resistance, combination chemotherapy, log reduction, regrowth, remission, rationale for need for clinical research

2. September 15, 2008 - Human subjects protection Collaborative Institutional Training Initiative (CITI) training on the web

Students will use this week to take the online UMDNJ web-based course on human subjects protection.       

Students must present the certificate of completion before sitting for the first midterm exam.

3. September 22, 2008 - Overview of clinical research         

- Robert Wieder, MD, PhD

A. principles, aims, mechanisms of introducing drugs into patient testing, scientific consideration and principles, ethical consideration, financial consideration, regulatory considerations, FDA approval process, specific indications, secondary indications, impact on the practice of medicine

B. Ethics of clinical research, expected benefit for individual vs. human race, benefit to investigator physician, bias of physician in patient selection, independent study office, data safety monitoring boards

C. Financial costs of clinical trials, preparing a budget, institutional support for “loss leaders” eg. Cooperative groups, insurance coverage for standard of care

4. September 29, 2008 - Regulatory aspects of human subjects research              

- Tracie Saunders, RN, MS, CCRC, OCN

A. concept of informed consent, guiding principles of human subjects protection,  IRB’s, levels of risk and reviews, elements of a protocol- prospective plan – key to obtaining scientifically valid data, elements of consent forms, different types of consent, assent, vulnerable populations.

B. Writing an IRB application – study design, historical consideration, gap in knowledge or treatment, outlining study, statistical considerations, the involvement of an SRB, target study population, population size, sites of participation, inclusion and exclusion of subpopulations, involvement of minorities, children, vulnerable population, pregnant women and fetuses, inclusion criteria, exclusion criteria, protocol, data collection, data analysis, right to refuse or withdraw, length of keeping data, secure location of data storage, who has access to data, right to privacy, conflicts of interest, expected and unexpected toxicities, contact personnel and other issues.

C. Regulatory issues in clinical trials – documentation, data management, adverse event reporting, protocol deviations and reporting, surviving audits, protecting the integrity of the data and the study.

5. October 6, 2008 - Midterm  #1.

6. October 13, 2008 - Phase 1 studies

– Robert Wieder, MD, PhD

A. Preclinical phase – drug design, intelligent design, dose finding, mouse studies, larger mammal studies, good clinical practice, calculation of dose escalation, translation of animal doses to human doses, statistical considerations, financial considerations, careful selection of studies limited to obtaining data needed for FDA approval, decision to go forward to human testing or abandon.

B. Traditional phase I studies –dose finding studies for cytotoxic drugs, financial considerations, site qualification and selection,  study design, dose escalation, toxicity ratings by organ system, MTD, DLT, pharmacokinetics – plasma levels, AUC

C. Alternate designs in phase I studies, novel escalation algorithms, novel endpoints: biological, symptomatic, novel paradigms for phase II dose selection, efficacy recording.

7. October 20, 2008 - Phase II studies

– Robert Wieder, MD, PhD

A. Traditional phase II studies - study size calculations, historical controls, statistical considerations, phase I-II studies, toxicity data acquisition, efficacy determination, built in analysis and stopping points,  RECIST, response determinations and criteria, implications of response, decision to go forward to phase III studies.    

B. Targeted drug testing – study size calculations, pharmacodynamics and molecular endpoints, response determinations, toxicities as secondary endpoints, midcourse dose escalations, efficacy determinations, randomized phase II studies, traditional vs. alternate dose escalations, bias in accrual to successful arm.

8. October 27, 2008 - Phase III studies

– Robert Wieder, MD, PhD

A. Design of traditional phase III studies, study size determination, multi-institutional, randomized, double blind, cooperative groups, NCI support, site qualification, independent central data monitoring, primary and secondary end points, data collection, selection, randomization, patient selection, ethical and physician control consideration, data monitoring, release of results, study termination during interim analysis, total control by statisticians and statistical considerations guiding data release.

B. Design of targeted therapy phase III studies, subpopulation selection for genetic target, selection of sites, issues in efficacy determination, tissue and blood collection, handling and storage, laboratory facilities for special handling.

C. Post marketing studies – phase IV studies, additional indications, investigator initiated studies, combinations with other drugs.

A. Costs of development, preclinical studies, attrition of compounds through development, decision to move to clinical phase, selection of phase I, II, sites, elements of moving to phase III studies, licensing, patent limits.

B. Elements of the FDA approval process, data collection, avoidance of extraneous data, maintaining control of data available for FDA presentation, deciding when to seek approval.

C. Marketing costs, cost of competing drugs, becoming a “hot” drug, novel emergence of boutique drugs for genetically targeted population for efficacy.

10. November 10, 2008 - Midterm #2.

11. November 17, 2008 - Statistical considerations of clinical research

– Bart Holland, PhD

A. Study design, population selection, study size determination, power calculations, design of primary and secondary endpoints, build in interim analysis points.

B. data analysis, independent monitoring, interim analysis and termination, ethical issues of independent obligate statistical reasoning for study termination, determination of significant differences in primary and secondary endpoints.

12. November 24, 2008 - Additional types of clinical research in Oncology

– Robert Wieder, MD, PhD

A. Retrospective studies, population studies, quality of life and symptom management, prevention studies

B. Involvement of minorities in cancer research – statistics of cancer rates, or outcomes, of screening, of participation in clinical trials, issues of entering minorities onto clinical trials – consent, availability, vulnerable populations, later presentation, poverty, secondary medical conditions, The NIH Minority-Based CCOP system

13. December 1, 2008 - Publication of clinical research

– Robert Wieder, MD, PhD

              A. Ethical consideration of clinical research from the investigator’s point of view.

              Publish or perish, funding for research, drug company supported research and the right of            commenting on or delaying publication of the manuscript, enrolling the investigator’s             patients on studies, proposed NIH-managed clearing house for industry-sponsored trials.

              B. Issues of authorship, statistical issues of publication bias, and excess of false positives,             quality of published clinical research, critical evaluation of the literature, meta analyses.

14. December 8 - Final exam

Recommended options for references:

Clinical Trials in Oncology, Second Edition by Stephanie Green, Jacqueline Benedetti, and John Crowley, 2003, Chapman & Hall/CRC

Fundamentals of Clinical Trials by Lawrence M. Friedman, Curt D. Furberg, and David L. DeMets (Paperback - Dec 1999), Springer Science-Business Media