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Clinical Trials
Jame Abraham, M.D
Associate Professor of Medicine
Chief, Section of Hematology-Oncology
R word of academic medicine was
Research
R word of academic medicine is
RVU
The NIH defines a clinical trial as a prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices).
Clinical Trials; Definition
Web site; www.Grants.nih.gov/grants/funding/phs398
“A treatise of the scurvy” James Lind 1753
1990 - 5000 pharmacists and physicians conducted clinical trials of a new drug
2000- More than 60,000 medical professionals are principal investigators
• Phase I/II/III clinical Trial
• Behavioral medicine study
• Study of a new procedure
• Trial of new devices
Types of clinical Trials
Phase I Clinical Trial
• Phase I clinical trials test a new biomedical intervention in a small group of people (e.g., 20-80) for the first time to evaluate safety (e.g., to determine a safe dosage range and to identify side effects).
NIH definition
• Phase I Trial and Pharmacokinetic Study of BMS-247550, an Epothilone B Analog, Administered Intravenously on a Daily Schedule for Five Days
Jame Abraham, Manish Agrawal, Susan Bakke, Ann Rutt, Maureen Edgerly, Frank M. Balis, Brigitte Widemann, Louis Davis, Bharat Damle, Daryl Sonnichsen, David Lebwohl, Susan Bates, Herb Kotz, and Tito Fojo
National Cancer Institute, Bethesda, MD
JCO May 1 2003: 1866-1873.
Phase II Clinical Trial
• Phase II clinical trials study the biomedical or behavioral intervention in a larger group of people (several hundred) to determine efficacy and to further evaluate its safety.
• Phase II Clinical Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, in Metastatic and Locally Advanced Breast Cancer
• Jennifer A. Low, Suparna B. Wedam, James J. Lee, Arlene W. Berman, Adam Brufsky, Sherry X. Yang, Marianne S. Poruchynsky, Seth M. Steinberg, Nitin Mannan, Tito Fojo, Sandra M. Swain
• National Cancer Institute • JCO Apr 20 2005: 2726-2734.
Phase III trials
• Phase III studies investigate the efficacy of the biomedical or behavioral intervention in large groups of human subjects (from several hundred to several thousand) by comparing the intervention to other standard or experimental interventions as well as to monitor adverse effects, and to collect information that will allow the intervention to be used safely.
• Ixabepilone Plus Capecitabine for Metastatic Breast Cancer Progressing After Anthracycline and Taxane Treatment
• Eva S. Thomas, Henry L. Gomez, Rubi K. Li, Hyun-Cheol Chung, Luis E. Fein, Valorie F. Chan, Jacek Jassem, Xavier B. Pivot, Judith V. Klimovsky, Fernando Hurtado de Mendoza, Binghe Xu, Mario Campone, Guillermo L. Lerzo, Ronald A. Peck, Pralay Mukhopadhyay, Linda T. Vahdat, Henri H. Roché
• JCO Nov 20 2007: 5210-5217.
International study with 752 Patients
Phase III study
Ixabepilone with Capecitabine
Capecitabine
• From the M.D. Anderson, Houston, TX; Instituto Nacional de Enfermedades Neoplasicas; Lima, Peru; Veterans Memorial Medical Center, Quezon City, Philippines; Yonsei Cancer Center, Seoul, Republic of Korea; Centro de Oncologia Rosario, Sante Fe; Hospital de Oncologia ‘Maria Curie,’ Buenos Aires, Argentina; Medical University of Gdansk, Gdansk, Poland; C.H.U.Institut Claudius Regaud, Toulouse, France; Rajive Gandhi Instiute, New Delhi, India, Cancer Hospital –Chinese Academy of Medical Sciences, Beijing, China; and Weill Medical College of Cornell University, New York, NY
Oncology Drug Approval Process
Oncology Drug Advisory Committee
Food Drug Administration
Industry Bristol Myers Squibb
FDA Approval for Ixabepilone Brand name: Ixempra™On October 16, 2007, the U.S. Food and Drug Administration (FDA) approved ixabepilone for injection (Ixempra™, made by Bristol-Myers Squibb)
Drug discovery can cost up to 800 million to a billion dollars !
Phase III
Phase II
Phase I
Ixabepilone: A Novel Microtubule Stabilizing agent:Expert Reviews in Oncology ( in press)Gerald Higa and Jame Abraham
4,500 dollars for one infusion ofIxempra!!
Phase IV trial
• Phase IV studies are conducted after the intervention has been marketed. These studies are designed to monitor effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use
Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial
Robert S. Bresalier, M.D., Robert S. Sandler, M.D., Hui Quan, Ph.D., James A. Bolognese, M.Stat., Bettina Oxenius, M.D., Kevin Horgan, M.D., Christopher Lines, Ph.D., Robert Riddell, M.D., Dion Morton, M.D., Angel Lanas, M.D., Marvin A. Konstam, M.D., John A. Baron, M.D., for the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators
Volume 352:1092-1102 March 17, 2005 Number 11
Why Clinical Trials?
• Conventional-Dose Chemotherapy Compared with High-Dose Chemotherapy plus Autologous Hematopoietic Stem-Cell Transplantation for Metastatic Breast Cancer
Edward A. Stadtmauer, M.D., Anne O'Neill, M.S.,
• SCIENTIFIC MISCONDUCT:Cancer Researcher Sacked for Alleged Fraud
Michael HagmannScience 17 March 2000:Vol. 287. no. 5460, pp. 1901 - 1902
NEJM, Volume 342:1069-1076 April 13, 2000 Number 15
Investigator Initiated Clinical Trials
Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
Review Board
• Execution of the clinical Research
The first requirement…in practicing experimental medicine, is to be an observing physician and to start from pure and simple observations of patients made as completely as possible.
Claude Bernard (1813-1878)
“An Introduction to the Study of Experimental Medicine” 1865. He is considered as the "Father of Physiology”.
“Can chemotherapy affectmy memory?”
Adjuvant Breast Cancer Therapy Adjuvant Breast Cancer Therapy and Cognitionand Cognition
Unaffected by anxiety, depression, fatigue, and time since treatment
—
.013
—
6.4
28
12
39
34
CMF*
Controls
P-ValueOdds Ratio
Cognitive Impairment
(%)nTreatment Arm
Schagen SB, et al. Cancer. 1999;85:640-650.
*CMF = *CMF = cyclophosphamide cyclophosphamide + + methotrexate methotrexate + 5+ 5--fluorouracilfluorouracil..
Epo receptorsin the CNS
Erythropoietin inhibits apoptosis
Excellent question!!Valid pre-clinical Model
Cognitive impairment is a problem in patients receiving Chemotherapy
Erythropoietin may be an effective treatment!!
Selling points?
• Is it a novel idea?
• What is the relevance of the study?
• Is it a high priority study?
1. To study the Patho-physiology of cognitive dysfunction Using 15O Water PET Scan
2. Evaluate the effectiveness of the erythropoietin using 15O Water PET scan
Objectives of the study
In patients receiving adjuvant chemotherapy for breast cancer
Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
Review Board
• Execution of the clinical Research
Protocol development
• Collaboration• Design the study• Statistician• Writing the proposal
Naresh Gupta, M.DNuclear Medicine
Marc Haut, Ph.DBehavioural Medicine
Hiroto Kuwabara, M.D, PhDJohns Hopkins
Joyce O’shaughnessy M.DTexas Oncology
z = -5 z = 26 z = 21 z = 23
z = 47 z = 52 z = 40 z = 52
Anterior peaks
Posterior peaks
Solvent exposed Control subjects
t = 4.04 5 6 7
Study development
• Collaboration• Design the study• Statistician• Writing the proposal
24 patients
12 patients
12 patients
PET scanNPT
AC X 4 cycles
AC X 4 cycles
Placebo
Procrit
PET scanNPT
Schema of the study
Randomized
Prospective
Double blinded
Placebo controlled
Study development
• Collaboration• Design the study• Statistician• Writing the proposal
Study development
• Collaboration• Design the study• Statistician• Writing the proposal
Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
Review Board
• Execution of the clinical Research
Grant sources
http://grants1.nih.gov/grants/index.cfm
http://cdmrp.army.mil/
Grant writing
• Scientific part
• Budget Ms. Elsa Nadler
Office of the sponsored program (OSP)
Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
Review Board
• Execution of the clinical Research
Clinical Protocol
1. Protocol2. Consent 3. Budget
http://www.hsc.wvu.edu/mbrcc/ctru/
Clinical Trials Research Unit
Scientific Protocol Review Committee
(Protocol Review and Monitoring Committee – PRMC)
Institutional Review Board
Patient safety
Improving Protection for Research SubjectsRobert Steinbrook, M.D. Volume 346:1425-1430 May 2, 2002 New England Journal of Medicine
Johns Hopkins Admits Fault in Fatal Experiment
''Regardless of the fact that we are unlikely ever to know precisely how or why this happened, Hopkins takes full responsibility for what did happen,'' Dr. Edward B. Miller, the dean and chief executive of Johns Hopkins Medicine
July 17 2001
Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
Review Board
• Execution of the clinical Research
Erythropoietin, the FDA, and Oncology
Robert Steinbrook, M.D.
Volume 356:2448-2451 June 14, 2007
0
10
20
30
40
50
60
70
80
90
100
Digit Symbol
Patients
Controls
0.64
0.66
0.68
0.7
0.72
0.74
0.76
0.78
0.8
Genu Splenium
Patients
Controls
Abraham et al. Clinical Breast Cancer, Feb 2008
Cognitive impairment in rats receiving chemotherapy
Konat et. al Metabolic Brain Disease, Accepted for Publication
Research Team
Principal InvestigatorCo-Investigators
Research NurseStatisticianPharmacistData ManagerAccountant Collaborators
Clinical Trials UnitShannon Filburn Rebecca KellerLeah Darr
Angela PriceChristen Tringes
Cathy PatriarcaGerry Hobbs- Statistician
Marc HautGreg KonatWilliam PetrosAasim SehbaiMaria Moran Cliff Martin
Execution of Clinical Trial
• Patient recruitment
• Follow the protocol
• Be scientific and objective
• Maintain a highly ethical approach
Research RVU
Conflict of Interest• DOD Funding- 325,000 dollar• Ortho Biotech- 425,000 dollars• AstraZeneca – 110,000 dollars (not active)• Co-operative Groups
– NSABP
– ECOG
• Other Pharma– Pfizer
– Eli Lilly
Campbell E. N Engl J Med 2007;357:1796-1797
Frequency of Various Types of Physician-Industry Relationships
Conflict of Interest — or Conflict of Priorities?
Elizabeth G. Nabel, M.D.
Nex
t
Volume 355:2365-2367 November 30, 2006
Investigator initiated studies
• Choosing a Research Question
• Protocol Development
• Writing a grant
• Clinical Protocol and Institutional
Review Board
• Execution of the clinical Research
But why think, why not try the experiment?John Hunter, 1775
Thank you!!