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Research Methods: Clinical Trials and Lessons Learned

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Presentation on theme: "Research Methods: Clinical Trials and Lessons Learned"— Presentation transcript:

1 Research Methods: Clinical Trials and Lessons Learned
Kara Kelly, M.D. Associate Professor of Clinical Pediatrics Division of Pediatric Oncology Columbia University Medical Center New York

2 Research Challenges Many patients with cancer perceive a benefit to the use of CAM therapies Most have not been adequately tested for safety, efficacy, and interactions with chemotherapy and radiation ISSUE: CAM therapies are available over the counter without the regulatory oversight or quality controls that govern conventional medications

3 Research-Design Issues
Sufficient preclinical data often does not exist Adequate justification is needed beyond claiming that patients are already using a CAM therapy for a particular purpose Plausible data-based hypotheses about the possible clinical effects of the CAM therapy of interest are needed

4 Do the Ground Work First Before Initiating a Phase III Trial!

5 But How Do You Get Started with Clinical Research??
STEP 1: Develop plausible data-based hypotheses Assessment of Risk/Benefit Ratio Best Case Series Systematic Literature Reviews

6 Assess the Risk-Benefit Ratio
What is the known about the effectiveness of the CAM therapy? Is there any reported toxicity of the CAM therapy? How effective is the conventional anti-cancer therapy? Are there any known interactions?

7 NCI Best Case Series Program
Independent review of medical records and medical imaging from patients treated with unconventional cancer therapies Primary goal of this program is to obtain and review sufficient information to determine if NCI-initiated research on a specific intervention is warranted

8 What the NCI Best Case Series Program IS…
Retrospective data collection involving patients who receive an alternative therapy for the treatment of cancer that results in significant tumor reduction or complete tumor remission An opportunity to receive feedback on the quality of data submitted for review A pathway to possible NCI-initiated research and advances in scientific knowledge An avenue for cancer CAM therapies to gain scientific rigor supported by conventional medicine From

9 Systematic Reviews Synthesis of the results of multiple primary investigations by using strategies that limit bias and random error Comprehensive search of all potentially relevant articles using explicit, reproducible criteria in the selection of articles for review Primary research designs and study characteristics are appraised, data are synthesized, and results are interpreted Meta-analysis is a systematic review that uses statistical methods to combine the results of two or more studies Used to summarize existing data, refine hypotheses, estimate sample sizes, and help define future research agendas Cook, D. J. et. al. Ann Intern Med 1997;126:

10 Fig 1 Methodology for a systematic review of randomised controlled trials1
Greenhalgh, T. BMJ 1997;315: Copyright ©1997 BMJ Publishing Group Ltd.

11 Research Example: Antioxidant Supplementation During Chemotherapy
Improved Treatment Efficacy Tumor Protection

12 Antioxidant Use Increases with Diagnosis of Cancer
% Rock et al. J Nutr 2004;134:31948

13 Chemotherapy/Antioxidant Interactions
Patients with cancer frequently use antioxidant supplements in an effort to minimize side effects of chemotherapy or to have a direct effect on the tumor Although there is a lot of evidence from in vitro studies, there is limited evidence from clinical studies Anthracyclines Platinum-complexes High Alkylating agents Epipodophyllotoxins Camptothecins Purine/Pyrimidine Antimetabolites Low Taxanes Vinca alkaloids

14 Reasons for Antioxidant Supplements
Excessive chemotherapy or radiotherapy induced reactive oxygen species may prevent apoptotic death through interference with cell cycle Treatment related toxicity may necessitate chemotherapy or radiotherapy dosage reduction or treatment delays

15 Reasons Against Antioxidant Supplements
Protective mechanisms of antioxidants may not distinguish between normal and malignant cells Radiation and some chemotherapy agents rely on oxidative mechanisms for their antitumor effects Coagulation cascade may be affected by some antioxidants (e.g. vitamin E) increasing risk of hemorrhage

16 Conventional Protectants
Dexrazoxane Amifostine Mesna ASCO clinical guidelines are based on clinical trials showing evidence of improvement of specific side effects, with a lack of evidence of adverse impact on outcome

17 Antioxidants and Cancer Therapy: A Systematic Review
Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM Journal of Clinical Oncology 2004; 22(3):

18 Objective Systematic review of the published trials and observational studies investigating: The effects of conventional chemotherapy with or without radiation on antioxidant status The effects of antioxidant supplementation in combination with conventional chemotherapy with or without radiation on antioxidant status The effects of antioxidant supplementation on treatment-related toxicities and survival

19 Methods Human studies published in English were identified by repeated literature searches of MEDLINE and Cochrane database and reference lists from studies reviewed from July 2000 to January 2002 Keyword terms: antioxidants, supplements, vitamins, diet, nutrition, cancer, chemotherapy, chemotherapy toxicity, cancer survival Studies reporting vitamin C, E, selenium, or β-carotene (studies of other antioxidant nutrients not required from the diet were excluded)

20 Results > 100 citations reviewed; 52 met criteria 21 31

21 Only 6 of 21 Intervention Trials are RCTs
# Patients Enrolled

22 Observational Studies: The Effect of Cancer Therapy on Antioxidant Levels (n=31)
No specific chemotherapy treatment was associated with changes in individual antioxidant micronutrients

23 The Effect of Supplementation with Antioxidants in combination with Cancer Therapy on Antioxidant Levels (n=9)

24 Recurrence/Overall Survival
No effect (n=3) Vitamin E β-carotene Vitamin C, E, β-carotene Improved overall survival (n=2) Vitamin E, β-carotene, Selenium, Vitamin C Improved 1-year survival; No improvement in overall survival (n=1) Vitamin E, Vitamin C Do these results translate into absence of tumor protection? Study design issues preclude this conclusion at the present time

25 Conclusions Studies investigating changes in vitamins C and E, selenium, and beta carotene found no consistent patterns associated with chemotherapy Existing studies are too small and have too many variables to guide clinical practice Additional studies are needed

26 STEP 2: What Kind of Study Design?
Observational Studies Case-control studies Prospective cohort studies Intervention Trials Pilot studies Randomized controlled

27 Research Example: Antioxidant and Oxidative Status of Children on Treatment for ALL
Design: Prospective multi-center cohort study of newly diagnosed children with ALL followed for approximately 6 months Subjects: 103 newly diagnosed children with ALL between the ages of 1-18 years Measurements: Antioxidants: Plasma vitamin A, C, E, total carotenoids and lipids, ORAC, 8-oxo-dG adducts Dietary: Nutrient intake by YA FFQ and 24-hour recall; Intake of vitamins and herbs Clinical: Toxicity, QOL Am J Clin Nutr 79: , 2004 Integrative Cancer Therapies 3:301-9, 2004 Pediatric Blood and Cancer 44:1-8, 2005

28 Plasma Concentrations Vary By Phase of Therapy

29 Total Antioxidant Capacity Declines with Chemotherapy

30 Plasma Concentrations of Micronutrient Vitamins
% Children Deficient

31 Dietary Intakes of Micronutrient Vitamins
% Children Deficient

32 Associations with Clinical Outcomes
Lower antioxidant plasma levels were associated with increased risk of toxicity (dose reductions, infections, chemotherapy delays, days spent in the hospital, decreased quality of life) Lower dietary intake of antioxidants were associated with increased risk of toxicity (chemotherapy delays, infection, days spent in the hospital

33 Next Steps: DFCI ALL Consortium
Companion study to current Phase III trial (n=540) Objective: To investigate the association of dietary antioxidant micronutrient intake, including vitamin C, vitamin E, vitamin A, ß-carotene and total carotenoids with the rate of infections (episodes of bacteremia and disseminated fungal infections) during remission induction and continuation therapy

34 Intervention Trials Do we know enough from observational studies to move forward?

35 Product Issues: Standardization and Quality Control
Specify formulation: Capsule, powder, suspension Need to consider Placebo formulation Trials with Botanicals: Species Biologic variation Stability over course of the trial Quality assurance Independent testing preferred

36 Product issues: The Antioxidant Example
Type of antioxidant Natural vs Synthetic Class of Antioxidant Use of Single vs multiple antioxidants Route of Administration IV vs Oral Quality assurance Stability

37 Phase I and II Trials Phase I testing
MTD and Schedule of Administration: Dose and schedule tend to be based on traditional practice rather than experimental data MTD may not be achieved Effect on surrogate endpoint Need for sufficient preclinical data on mechanisms Risk of Supplement-chemotherapy/radiation interactions

38 Phase II Trial: Safety of Oral Antioxidants and IV Vitamin C During GYN Cancer Care
Intervention: IV and PO vitamin C; IV glutathione; PO carotenoids, vitamin A, and vitamin E with conventional chemotherapy and/or radiation therapy Non-Randomized Safety Study in 50 newly diagnosed and recurrent gynecologic cancer patients Primary Aim: Safety of adding high-dose antioxidants to chemotherapy Secondary Aims: Tumor response rate, Time to progression, Survival Study Status: Opened 9/2005; Expected closure 12/2008 PI: Jeanne Drisko, MD, Univ Kansas

39 Phase II Trial: Antioxidant Effects on the Outcome of Ovarian Cancer
Intervention: IV and PO vitamin C; IV glutathione; PO carotenoids, vitamin A and vitamin E with conventional chemotherapy Randomized, Double Blind, Safety/Efficacy Study in 40 patients with chemotherapy refractory stage III/IV ovarian cancer Primary Aim: Safety of adding high-dose antioxidants to chemotherapy Secondary Aims: Tumor response rate (CA-125), QOL Study Status: Opened 10/2002; Expected closure 1/2006 PI: Jeanne Drisko, MD, Univ Kansas

40 Phase III Trials Experimental arm
Selection of an adequate comparison group Work with a Statistician Estimates of effect sizes Determination of an adequate sample size Selection of appropriate outcome measures Analytic Plan

41 Phase III Trials Potential Pitfalls Use of self prescribed supplements
Compliance with the experimental therapy Reasonable timeline—Do you have enough patients?

42 Phase III Studies: Vitamin E in Preventing Chemotherapy-Induced Peripheral Neuropathy
North Central Cancer Treatment Group Concurrent chemotherapy: taxanes, platinum based Goal: 200 patients Primary Aim: Compare the incidence of chemotherapy-induced sensory peripheral neuropathy ≥ grade 2 in patients undergoing curative neurotoxic chemotherapy for cancer treated with vitamin E vs placebo. Secondary Aims: Compare the proportion of patients requiring dose reductions or cessation of chemotherapy secondary to sensory peripheral neuropathy Toxicity of vitamin E Study Status: Not yet recruiting

43 STEP 3: Practical Issues
Regulatory FDA Human Subjects Protection Clinical trials can be expensive Sources of funding

44 Product Regulatory Issues
IND application Animal Pharmacology and Toxicology Studies Manufacturing Information Clinical Protocols and Investigator Information

45 Research Pharmacy Manufacture, package, dispense and manage different dosage forms Blind and randomize (if appropriate) Manage drug ordering, inventory, accountability, multicenter drug distribution and return shipment for study drug products Fee usually associated with these services

46 Practical Issues Human Subjects Protection:
Institutional Review Board Approval Are there members on your institution’s IRB with expertise on reviewing CAM trials? Data Safety Monitoring Board Critical for Intervention trials List your trials on

47 Funding Institutional pilot funds Philanthropy Private foundations NIH
Industry Product Funds

48 Institute of Medicine Report January 2005
Healthcare should strive to be both comprehensive and evidence-based Hold conventional and complementary treatments to the same standards Use same general research principles in evaluating both types of treatments ABC codes Credentialing documents Pharm protocol Business plan/systems/working team Morgan/Medtronics/HMS commitment/Osher Enthusiasm of team members

49 Conclusions Further research of CAM therapies is greatly needed with the use of the same general research principles that are used in evaluating conventional treatments Strong research designs are necessary to evaluate CAM therapies and ultimately influence clinical practice and public awareness

50 Integrative Therapies Program
Judith Jacobson DrPH Stephen Sands PsyD Manuela Orjuela MD MSc Julia Glade Bender MD Olga Militano PharmD Ria Hawks RN MS PNP Kathy Taromina MS LaC (Acupuncturist) Diane Rooney MS LaC LMT (Acupuncturist, Massage Therapist) Elena Ladas MS RD Michael Weiner MD Deborah Hughes Christine Grimaldi PhD (Yoga/Movement Therapist)

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