1 The Chemoprevention of Sporadic Colorectal Cancer Issues Surrounding a Benefit/Risk Analysis in Clinical Trials Mark Avigan MD CM Medical Officer Division.

Slides:



Advertisements
Similar presentations
CT COLONOGRAPHY. CRC TRENDS  Incidence decreased by 7%  Mortality decreased by 20%  Five year survival rates increased by 12%
Advertisements

Breast cancer chemoprevention in the high-risk patient
Colorectal Cancer Screening and Surveillance FDA Advisory Committee March, 2002 David Lieberman MD Chief, Division of Gastroenterology Oregon Health Sciences.
Synopsis of FDA Colorectal Cancer Endpoints Workshop Michael J. O’Connell, MD Director, Allegheny Cancer Center Associate Chairman, NSABP Pittsburgh, PA.
TROPHY TRial Of Preventing HYpertension. High-normal BP increases CV risk Vasan RS et al. N Engl J Med. 2001;345: Incidence of CV events in women.
James Cross, MS Pharmaceutical Outcomes Research and Policy Program University of Washington Biobehavioral Cancer Fellows Day April 20, 2007 A risk-benefit.
Colorectal cancer: How do we approach health disparities? Marta L. Davila, MD, FASGE University of Texas MD Anderson Cancer Center.
Interpreting Adverse Signals in Diabetes Drug Development Programs Featured Article: Clifford J. Bailey, Ph.D. Diabetes Care Volume 36: 1-9 July, 2013.
Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 Overview of PK-PD in Drug Development Programs: FDA Perspective FDA/IDSA/ISAP Workshop.
Postmarketing Risk Assessment of Drug Products Division of Drug Risk Evaluation Office of Drug Safety Center for Drug Evaluation and Research.
Regulatory Background and Past FDA Approvals in Colorectal Cancer Amna Ibrahim M.D DODP, FDA.
The Effect of Celecoxib, a Cyclooxegenase-2 Inhibitor, In Familial Adenematous Polyposis Gideon Steinbach, M.D., Ph. D., Patrick Lynch, M.D., J.D., Robin.
SNDA : CELEBREX TM INDICATION Reduction and Regression of Adenomatous Colorectal Polyps in Familial Adenomatous Polyposis Patients FDA ODAC Presentation.
Prevention and Early Detection of Breast Cancer: Weighing the Risks and Benefits Kathy J. Helzlsouer, M.D., M.H.S. Prevention and Research Center, Women’s.
Taxane-pretreated metastatic breast cancer (MBC): investigational agents TTP = median time to disease progression OS = median overall survival.
Hormone Refractory Prostate Cancer A Regulatory Perspective of End Points to Measure Safety and Efficacy of Drugs Hormone Refractory Prostate Cancer Bhupinder.
TERIPARATIDE (r-hPTH 1-34) Endocrinologic and Metabolic Drugs Advisory Committee Holiday Inn, Bethesda MD July 27, 2001 Bruce S. Schneider, MD CDER FDA.
Oral Rivaroxaban for Symptomatic Venous Thrombroenbolism Group /06/11.
1 Kepivance™ (Palifermin) Basis for Approval and Pediatric Studies Kepivance™ (Amgen) Approved 12/15/04 Joseph E. Gootenberg, M.D. Office of Oncology Drug.
CLAIMS STRUCTURE FOR SLE Jeffrey Siegel, M.D. Arthritis Advisory Committee September 29, 2003.
DRAFT SLIDES FOR NDA ADVISORY COMMITTEE PRESENATIONS.
How to Analyze Therapy in the Medical Literature (part 2)
Best first ? The ATAC completed treatment analysis Professor Jack Cuzick Wolfson Institute of Preventive Medicine, London, UK.
1 Proton-Pump Inhibitor (PPI) Template for Pediatric Written Requests Pediatric Advisory Subcommittee of the Anti- Infective Drug Advisory Committee Hugo.
Orlistat 60 mg Joint Meeting Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committees January 23, 2006 Andrea Leonard-Segal, M.D.
Cardiovascular Risk and NSAIDs Arthritis Advisory Committee Meeting November 29, 2006 Sharon Hertz, M.D. Deputy Director Division of Analgesia, Anesthesia,
AA-2-1 Jerome D. Cohen, MD, FACC, FACP Professor of Internal Medicine / Cardiology Director, Preventive Cardiology Programs St. Louis University Health.
Safety of Cyclooxygenase-2 (COX-2) inhibitors, Valdecoxib and Parecoxib, versus Placebo for Post CABG Pain Management Presented at American College of.
CR-1 Everolimus Benefit/Risk Assessment Howard J. Eisen, MD Thomas J. Vischer Professor of Medicine Chief, Division of Cardiology Drexel University College.
Naotsugu Oyama, MD, PhD, MBA A Trial of PLATelet inhibition and Patient Outcomes.
Cost-effectiveness of Screening Tests Mark Hlatky, MD Stanford University.
Cardiovascular Risk and NSAIDs Arthritis Advisory Committee Meeting April 12, 2007 Sharon Hertz, M.D. Deputy Director Division of Analgesia, Anesthesia,
Arthritis Advisory Committee March 4, 2003 Update on the Safety of TNF Blockers Li-ching Liang, M.D. FDA / CBER/ OTRR Arthritis Advisory Committee March.
U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only.
1 Study Design Issues and Considerations in HUS Trials Yan Wang, Ph.D. Statistical Reviewer Division of Biometrics IV OB/OTS/CDER/FDA April 12, 2007.
1 PHOTOFRIN® PDT for High-grade Dysplasia in Barrett’s Esophagus Edvardas Kaminskas, M.D. Medical Officer, CDER, ODE III, DGCDP Milton Fan, Ph.D. Statistical.
Questions to the Committee. Question 1. The Agency has accepted durable responses in hematologic malignancies for approval for both chronic leukemias.
Cancers of the Digestive System November 19, 2007 NCDD Meeting Chair: John M. Carethers, MD Vice Chair: Robert Sandler, MD, MPH.
1 One Year Post Exclusivity Adverse Event Review: Sumatriptan Pediatric Advisory Committee Meeting November 18, 2005 Susan McCune, M.D. Medical Officer.
BIOSTATISTICS Lecture 2. The role of Biostatisticians Biostatisticians play essential roles in designing studies, analyzing data and creating methods.
Applying New Science to Drug Safety Janet Woodcock, M.D. Acting Deputy Commissioner for Operations April 15, 2005.
CT Colonography vs Colonoscopy for the Detection of Advanced Neoplasia David H. Kim, M.D., Perry J. Pickhardt, M.D., Andrew J. Taylor, M.D., Winifred K.
What about VIOXX?. Adenomatous Polyp Prevention on Vioxx (APPROVe) Vioxx (rofecoxib) versus Placebo Basic Clinical Trial Objective: Assess whether Vioxx.
Joanne Edwards Medical Information Manager ASCO Tech Assessment Update Commercial Implications & Promotional Guidance.
Regulatory Considerations for Endpoints Ann T. Farrell, M.D. FDA/CDER/DODP.
Small Bowel Toxicity of Nonselective NSAIDs Revealed by Capsule Endoscopy: Results From a Pivotal Clinical Trial Glenn M. Eisen, M.D., M.P.H. Associate.
1 A Randomized, Multi-Center Phase III Trial of Irinotecan in Combination with Three Different Methods of Administration of Fluoropyrimidine with Celecoxib.
Agency Review of sNDA SE-006 DOXIL for Ovarian Cancer Division of Oncology Drug Products Office of Drug Evaluation 1 Center for Drug Evaluation.
1 Clinical Overview Omeprazole Magnesium (Prilosec 1 TM ) June 21, 2002 Mark Avigan, MD CM Division of Gastrointestinal and Coagulation Drug Products CDER,
1 Risk Benefit and Conclusions George Sledge, MD Indiana University School of Medicine.
1 INTRODUCTION: Proposed Use of HBOC-201 * in the RESUS (Restore Effective SUrvival in Shock) Trauma Trial Laurence Landow MD, FRCPC Medical Officer, Clinical.
Surrogate Endpoints as Measures of Efficacy: Complexities & Limitations FDA Advisory Committee November 18, 2002 Michael D. Hughes, Ph.D. Professor of.
Vitrase (Hyaluronidase for Injection) Advisory Committee Meeting March 17, 2003 Jennifer D. Harris, MD Medical Officer Division of Anti-inflammatory, Analgesic,
Chemoprevention of cancer Dr Manal Kahwaji Cancer fighting day Feb 2, 2016.
Mok TS, Wu SL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361: Gefitinib Superior.
Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Colonoscopy Surveillance After Colorectal Cancer Resection: Recommendations of the US Multi-Society.
Once-Daily Celecoxib Effective for Preventing Sporadic Colorectal Adenomas Slideset on: Arber N, Rácz I, Spicak J, et al. Chemoprevention of colorectal.
Double-blind, randomized trial in 4,162 patients with Acute Coronary Syndrome
MA.17R: Reduced Risk of Recurrence With Extending Adjuvant Letrozole Beyond 5 Yrs in Postmenopausal Women With Early-Stage Breast Cancer CCO Independent.
FDA’s Role in the Risk Management of Opiate Analgesics Steven Galson, M.D., M.P.H. Deputy Center Director, Center for Drug Evaluation and Research Food.
Colonoscopic Polypectomy and Long-Term Prevention of Colorectal- Cancer Deaths N ENG J MED ;8 : Ann G. Zauber, Ph.D, Sidney J. Winawer,
The Stages of a Clinical Trial
VIOXX WITHDRAWAL: Learning valuable lessons from rofecoxib
Reasonable Assurance of Safety and Effectiveness: An FDA Division of Cardiovascular Devices Perspective Bram Zuckerman, MD, FACC Director, FDA Division.
Slide set on: McCarthy PL, Owzar K, Hofmeister CC, et al
Selection of NSAIDs for Osteoarthritis
Speeding access to therapies
Issues in TB Drug Development: A Regulatory Perspective
ASPIRE CLASS 6: Interpreting Results and Writing an Abstract
Presentation transcript:

1 The Chemoprevention of Sporadic Colorectal Cancer Issues Surrounding a Benefit/Risk Analysis in Clinical Trials Mark Avigan MD CM Medical Officer Division of Gastrointestinal and Coagulation Drug Products Center for Drug Evaluation and Research

2 Overview of Presentation Public health concerns Considerations for clinical trial design –Efficacy –Current treatment modalities, endpoints, duration –Safety Current treatment vs new therapy Criteria for FDA approval Unresolved issues to be addressed by Advisory Committee

3 Chemopreventive treatment should not replace colonoscopic screening and surveillance if CRC suppression is not as effective Patients who avoid colonoscopic examinations because of chemopreventive treatment may be increasing their CRC risk Risk attached to treatment of many may outweigh the benefit to few Public Health Concerns

4 Benefits for Different Uses ‘ Adjunctive’ CRC prevention (colonoscopy+drug) – An additive effect : reduction of risk for CRC and mortality – A relaxation of screening/surveillance guidelines ‘ Alternative’ CRC prevention (drug only) – Elimination of colonoscopy associated AEs, discomfort and cost – Drug safety profile superior to colonoscopy without compromising CRC risk reduction Treatment of non-compliant patients – CRC risk reduction must outweigh drug AEs

5 Efficacy Study Population Endpoints –Reduction in the frequency of: polyps, colon cancer, mortality Concomitant treatment modalities –Screening / surveillance colonoscopy –Medications with possible chemopreventive properties used by patients for other illnesses Duration of Rx –Expected occurrence interval –Durability of polyp suppression

6 Is Adenoma Recurrence a Useful Surrogate for CRC Risk? Most small adenomatous polyps do not progress to malignancy – Probability that a small adenoma contains high grade dysplasia/malignant changes in the US is small (< 1%) Average transition time from small adenoma to invasive cancer > 10 years In the National Polyp Study, the % of patients with recurrent small or medium adenomas was over 30% (N. Engl. J. Med., 1993)

7 Measurement of Efficacy Cumulative lifetime incidence of lesions FAP 100% (adenomas) 100% (CRC) Sporadic 60% (adenomas) 6% (CRC) Numbers Needed to Treat to detect a 50% reduction of lesions FAP 2,000 pt-yr (adenomas) 2,000 pt-yr (CRC) Sporadic 3,000 pt-yr (adenomas) >30,000 pt-yr (CRC)

8 Screening and Surveillance Colonoscopy (As Therapy) Incidence of CRC was reduced between 76% and 90% (Results of National Polyp Study) (N. Engl. J. Med., 1993) Approximately 95% of colonoscopies examine the entire colorectum Summary: Colonoscopy is benchmark for other CRC prevention modalities

9 Factors Influencing Efficacy Poor compliance during long-term chronic administration Lack of sufficient duration of treatment of patients Rebound of adenomatous neoplastic growth despite continued chemoprevention treatment Administration of ineffective doses or reversal of efficacy due to other concomitant medications or medical conditions

10 Safety Population Examples of chemopreventive agent safety issues – Aspirin – Cox-2 inhibitors Power calculations

11 Safety: Study Population Geriatric patient susceptibilities – Severe drug toxicity – Drug-drug interactions Potential for drug toxicity related to chronic administration Reduction of adenoma growth but dysplasia and CRC changes may continue

12 Aspirin – Serious upper GI complications after age 65: 16/10 4 pt-yr (Ann. Int. Med., 2001) – Prevention of cardiovascular events may be more important than possible chemoprevention Cox-2 inhibitors – VIGOR study: 5X MIs in patients treated with rofecoxib 50 mgs qd vs naproxen 500 mg bid: 74/10 4 pt-yr vs 15 /10 4 pt-yr (FDA Advisory Committee Meeting, Feb 2001) – Safety issues raised by VIGOR require further study Safety Issues: Aspirin and Cox-2 Inhibitors

13 Issues Surrounding Safety Incidence of drug-induced SAEs and mortality < chemopreventive benefit – Benefit related to reduction in CRC linked mortality Serious complications associated with colonoscopy Clinical studies should be powered to adequately study these effects

14 * Rate per 10,000 pt-yr

15 Number Needed to Treat (NNT) Chemoprevention –10,000/15 = 700 treated for one cancer prevented –700 healthy people at risk for each person who benefits Treatment of Disease (best case) –1 treated for one therapeutic effect –1 person at risk for each person who benefits

16 Ability to Detect Drug Toxicity: Low Background Rate If 10,000 pt-yr per group with no events, then risk < 3 in 10,000 Therefore risk (at worst) is comparable to benefit

17 Ability to Detect Drug Toxicity: High Background Rate If 10,000 pt-yr with 100 events per group –Difficult to detect drug effect –Confidence interval wide ( ± 14 per 10,000) –14 (extra AEs) ~ 15 (cancer prevented) Uninformative study –Can’t distinguish no harm from big harm –Need 70,000 pt-yr per group

18 Benefit/Risk CRC suppression limited to a small % of treated patients Since colonoscopy is effective the potential benefit of ‘adjunctive’ treatment is smaller Co-administered drugs (e.g. low dose aspirin) may also have chemopreventive effects Adequate safety powering must take into account background SAE rates and treatment duration

19 FDA Approved Chemopreventive Agents Tamoxifen Indicated for women at high risk for breast cancer Breast Cancer Prevention Trial randomized over 13, 000 women to 5 year treatment arms Approval granted for a 44% reduction in incidence of invasive breast cancer over median period of 4.2 years

20 Celecoxib Indicated for reduction of colorectal adenomas in FAP Granted Accelerated Approval status (21 CFR 314 Subpart H) –Serious or life-threatening illness –Meaningful therapeutic benefit over existing treatments –Surrogate endpoint acceptable if likely to predict clinical benefit Calculated benefits to treat FAP and sporadic CRC are very different

21 Unresolved Issues Significance of clinical benefits of treatment Clinical design requirements –Patient enrollment, role of adenomatous polyps as endpoints, duration of treatment and powering for safety Data analysis requirements –Approaches to study dropouts and uncontrolled safety information Benefit/risk analysis requirements