Clinical Trials

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

2. Rword of academic medicine was Research

3. R word of academic medicine is RVU

4. Clinical Trials; Definition 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). Web site; www.Grants.nih.gov/grants/funding/phs398

5. “A treatise of the scurvy” James Lind 1753

6. 1990 - 5000 pharmacists and physicians conducted clinical trials of a new drug 2000- More than 60,000 medical professionals are principal investigators

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

8. 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

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. International study with 752 Patients

15. 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

16. Oncology Drug Approval Process

17. 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)

18. Drug discovery can cost up to 800 million to a billion dollars !

19. 4,500 dollars for one infusion of Ixempra!! Ixabepilone: A Novel Microtubule Stabilizing agent: Expert Reviews in Oncology ( in press) Gerald Higa and Jame Abraham

20. 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

21. 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, 2005Number 11

23. Why Clinical Trials?

24. 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. 287. no. 5460, pp. 1901 - 1902 NEJM, Volume 342:1069-1076April 13, 2000Number 15

25. Investigator Initiated Clinical Trials

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

27. Claude Bernard (1813-1878) 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. “An Introduction to the Study of Experimental Medicine” 1865. He is considered as the "Father of Physiology”.

28. “Can chemotherapy affect my memory?”

30. Epo receptors in the CNS

31. Erythropoietin inhibits apoptosis

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

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

34. Objectives of the study In patients receiving adjuvant chemotherapy for breast cancer 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

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

36. Protocol development • Collaboration • Design the study • Statistician • Writing the proposal

37. 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

38. t = 4.04 5 6 7 Anterior peaks Solvent exposed Control subjects z = -5 z = 26 z = 21 z = 23 Posterior peaks z = 47 z = 52 z = 40 z = 52

39. Study development • Collaboration • Design the study • Statistician • Writing the proposal

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

41. Study development • Collaboration • Design the study • Statistician • Writing the proposal

42. Study development • Collaboration • Design the study • Statistician • Writing the proposal

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

44. Grant sources http://grants1.nih.gov/grants/index.cfm http://cdmrp.army.mil/

45. Grant writing • Scientific part • Budget Ms.Elsa Nadler

46. Office of the sponsored program (OSP)

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

48. Clinical Protocol • Protocol • Consent • Budget

49. Clinical Trials Research Unit http://www.hsc.wvu.edu/mbrcc/ctru/

50. Scientific Protocol Review Committee (Protocol Review and Monitoring Committee – PRMC)