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Clinical Trials Jame Abraham, M.D Associate Professor of Medicine Chief, Section of Hematology- Oncology.

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Presentation on theme: "Clinical Trials Jame Abraham, M.D Associate Professor of Medicine Chief, Section of Hematology- Oncology."— Presentation transcript:

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2 Clinical Trials Jame Abraham, M.D Associate Professor of Medicine Chief, Section of Hematology- Oncology

3 R word of academic medicine was Research

4 R word of academic medicine is RVU

5 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;

6 “A treatise of the scurvy” James Lind 1753

7 pharmacists and physicians conducted clinical trials of a new drug 2000-More than 60,000 medical professionals are principal investigators

8 Phase I/II/III clinical Trial Behavioral medicine study Study of a new procedure Trial of new devices Types of clinical Trials

9 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

10 Phase I Trial and Pharmacokinetic Study of BMS , 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 :

11 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.

12 Phase II Clinical Trial of Ixabepilone (BMS ), 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 :

13 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.

14 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 :

15 International study with 752 Patients Phase III study Ixabepilone with Capecitabine

16 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

17 Oncology Drug Approval Process Oncology Drug Advisory Committee Food Drug Administration Industry Bristol Myers Squibb

18 FDA Approval for Ixabepilone Brand name: Ixempra™ On October 16, 2007, the U.S. Food and Drug Administration (FDA) approved ixabepiloneixabepilone for injection (Ixempra™, made by Bristol-Myers Squibb)

19 Drug discovery can cost up to 800 million to a billion dollars ! Phase III Phase II Phase I

20 Ixabepilone: A Novel Microtubule Stabilizing agent: Expert Reviews in Oncology ( in press) Gerald Higa and Jame Abraham 4,500 dollars for one infusion of Ixempra!!

21 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

22 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: March 17, 2005March 17, 2005 Number 11

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24 Why Clinical Trials?

25 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 Hagmann Science 17 March 2000: Vol no. 5460, pp NEJM, Volume 342: April 13, 2000 Number 15April 13, 2000

26 Investigator Initiated Clinical Trials

27 Investigator initiated studies Choosing a Research Question Protocol Development Writing a grant Clinical Protocol and Institutional Review Board Execution of the clinical Research

28 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. C laude Bernard ( ) “An Introduction to the Study of Experimental Medicine” He is considered as the "Father of Physiology”.

29 “Can chemotherapy affect my memory?”

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31 Epo receptors in the CNS

32 Erythropoietin inhibits apoptosis

33 Excellent question!! Valid pre-clinical Model Cognitive impairment is a problem in patients receiving Chemotherapy Erythropoietin may be an effective treatment!!

34 Selling points? Is it a novel idea? What is the relevance of the study? Is it a high priority study?

35 1. To study the Patho-physiology of cognitive dysfunction Using 15 O Water PET Scan 2. Evaluate the effectiveness of the erythropoietin using 15 O Water PET scan Objectives of the study In patients receiving adjuvant chemotherapy for breast cancer

36 Investigator initiated studies Choosing a Research Question Protocol Development Writing a grant Clinical Protocol and Institutional Review Board Execution of the clinical Research

37 Protocol development Collaboration Design the study Statistician Writing the proposal

38 Naresh Gupta, M.D Nuclear Medicine Marc Haut, Ph.D Behavioural Medicine Hiroto Kuwabara, M.D, PhD Johns Hopkins Joyce O’shaughnessy M.D Texas Oncology

39 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 =

40 Study development Collaboration Design the study Statistician Writing the proposal

41 24 patients 12 patients PET scan NPT AC X 4 cycles Placebo Procrit PET scan NPT Schema of the study Randomized Prospective Double blinded Placebo controlled

42 Study development Collaboration Design the study Statistician Writing the proposal

43 Study development Collaboration Design the study Statistician Writing the proposal

44 Investigator initiated studies Choosing a Research Question Protocol Development Writing a grant Clinical Protocol and Institutional Review Board Execution of the clinical Research

45 Grant sources

46 Grant writing Scientific part Budget Ms. Elsa Nadler

47 Office of the sponsored program (OSP)

48 Investigator initiated studies Choosing a Research Question Protocol Development Writing a grant Clinical Protocol and Institutional Review Board Execution of the clinical Research

49 Clinical Protocol 1.Protocol 2.Consent 3.Budget

50 Clinical Trials Research Unit

51 Scientific Protocol Review Committee (Protocol Review and Monitoring Committee – PRMC)

52 Institutional Review Board Patient safety Improving Protection for Research Subjects Robert Steinbrook, M.D. Volume 346: May 2, 2002May 2, 2002 New England Journal of Medicine

53 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

54 Investigator initiated studies Choosing a Research Question Protocol Development Writing a grant Clinical Protocol and Institutional Review Board Execution of the clinical Research

55 Erythropoietin, the FDA, and Oncology Robert Steinbrook, M.D. Volume 356: June 14, 2007June 14, 2007

56 Abraham et al. Clinical Breast Cancer, Feb 2008

57 Cognitive impairment in rats receiving chemotherapy Konat et. al Metabolic Brain Disease, Accepted for Publication

58 Research Team Principal Investigator Co-Investigators Research Nurse Statistician Pharmacist Data Manager Accountant Collaborators

59 Clinical Trials Unit Shannon Filburn Rebecca Keller Leah Darr Angela Price Christen Tringes Cathy Patriarca Gerry Hobbs- Statistician Marc Haut Greg Konat William Petros Aasim Sehbai Maria Moran Cliff Martin

60 Execution of Clinical Trial Patient recruitment Follow the protocol Be scientific and objective Maintain a highly ethical approach

61 Research RVU

62 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

63 Campbell E. N Engl J Med 2007;357: Frequency of Various Types of Physician-Industry Relationships

64 Conflict of Interest — or Conflict of Priorities? Elizabeth G. Nabel, M.D. Next Next Volume 355: November 30, 2006November 30, 2006

65 Investigator initiated studies Choosing a Research Question Protocol Development Writing a grant Clinical Protocol and Institutional Review Board Execution of the clinical Research

66 But why think, why not try the experiment? John Hunter, 1775

67 Thank you!!


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