Background, Science & Potential Claims

Transcription

1 1. Background, Science & Potential Claims Kristian Rasmussen Cory Watson Crowder & DeGaris 2131 Magnolia Avenue Birmingham, AL (205)

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3 Chantix Overview Approval & Regulatory History Mechanism of Action Safety & Efficacy Profit Motive Over Promotion Potential Claims Pfizer s Defense 3

4 4. DRUG DETAILS Brand Name: CHANTIX Active Ingredient: varenicline Mechanism: both agonist & antagonist Approved Dose: 0.5mg / 1mg / 2mg Manufacturer: Pfizer, Inc. U.S. Approval Date: May, 2006 U.S. Launch: August, 2006

5 DRUG DETAILS 5

6 6 Purpose: aid to smoking cessation treatment Protect Profits and Prevent Loss of Market Share Mechanism: Combination of two actions Agonist: reduce nicotine craving and withdrawal symptoms Antagonist: reduce psychological rewards associated with smoking

7 7 Pfizer began marketing Chantix as the first new prescription treatment for smoking cessation in nearly a decade. APPROVAL: The FDA granted Chantix an accelerated review Chantix approved for use in the United States in May Market Launch in U.S. August, 2006 Sources: 1) July 20, 2006: Pfizer Corporate News, Pfizer Delivers Strong Second-Quarter 2006 Results, Driven By Performance Of Major In- Line And New Products,

8 8 LABEL CHANGES: Regulatory History After Approval Nov. 20, Modification of the Patient Package Insert: drug adverse effects related to sleep and dreaming disturbance, depression, agitation, suicidal thoughts, and problems with driving or operating machinery when beginning treatment.. - PRECAUTIONS: Information for Patients Section adverse drug effects relating to driving or operating machinery when beginning treatment. - ADVERSE REACTIONS: to address the potential for newly emergent psychiatric illness and the potential for exacerbation of underlying psychiatric illness that may occur following treatment with varenicline to attempt to quit smoking. Jan. 31, WARNINGS: a new paragraph that addresses neuropsychiatric symptoms, as described in reported adverse events. - PRECAUTIONS: to address these same neuropsychiatric symptoms.

9 9 MECHANISM OF ACTION Addiction Problem: Smokers receive bursts of nicotine when they inhale which, coincidentally, triggers an immediate increase of dopamine; thus creating the craving and perceived from smoking. Solution (Chantix Theory): - One Pill - Two Mechanisms - Diminish craving - Diminish perceived pleasure

10 10 MECHANISM OF ACTION Chantix Theory: 1. Regulate / Restrict Dopamine 2. Block Pleasure sensors / receptors (Alpha 4, Beta 2) Combine Two Actions: - Agonist: reduce nicotine craving and withdrawal symptoms - Antagonist: reduce psychological rewards associated with smoking Dopamine - Regulates the normal flux of emotion experienced by humans in daily life - Dopamine is produced in several areas of the brain and operates as a neurotransmitter. - Dopamine controls the receptors

11 11 MECHANISM OF ACTION Other Drugs With Similar Mechanism: - Cytisine (TABEX) - SSRIs (Pfizer: Prozac and Zoloft) - Rimonabant - Not FDA Approved - Intended for weight loss and smoking cessation

12 12 MOTIVE: Profit By Promotion Pursue Profits Over Patient Safety & Market Share Over Medicine Sept. 21, 2007: A survey headed by 6,040 doctors involved 332 professional advertisements in 11 therapeutic categories and the results of the survey declared a 2 page chantix ad, launched by Euro RSCG Life LM&P as the top advertisement in the general practice category ( Aug. 8, 2007: The global quit smoking market analysis and forecast report that examines the smoking cessation market in various countries such as UK, Spain, Australia, US, Japan, Canada et al reveals that the Pfizer's anti-smoking drug Chantix is slated to be the markets` blockbuster medicine. ( July 2007: Pfizer Corporate News released report describing Chantix as a key new product, deliver[ing] strong revenues May 2008: Pfizer CEO Jeffrey Kindler has been touting Chantix to help offset $12 Billion in sales that the company s Lipitor cholesterol medicine will begin losing to generic competition. Source: Bloomberg.com (5/28/08)

13 Pyramid Pfizer

14 Pfizer Profit and Rank

15 No1 in World

16 2007 Top Companies by U.S. Sales (IMS) - Pfizer Ranked #1 - $23.5 Billion (2007) - $26.8 Billion (2006) - $27.3 Billion (2005) - $31.1 Billion (2004) - $29.3 Billion (2003) - GSK Ranked #2 ($20.1 Billion 2007) - Merck Ranked #3 ($17.6 Billion 2007) 16

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18 18 PROFIT AND PRESCRIPTIONS Pfizer Total Revenue Declines: 2004: $51.9 Billion (Rank #1) 2006: $48.4 Billion 2007: $44 Billion Chantix Prescriptions June 15, 2007: 2.5 Million U.S. Patients (5 Months) June 17, 2008: 6 Million patients worldwide since launch Chantix Profit 2006: $101 Million 2007: $883 Million (increase 773%) $241 Million (3 rd Qtr alone) 2008: $1.1 Billion (analyst projection)

19 19 SAFETY AND EFFICACY Safety Risks: - Early Warning Signal from Derivative / Root Drug - Clinical Trials - High Number of Adverse Events - Intentional Effort to Avoid Detecting Signal - Clean Patient Population - No Safety Study of Suicide Risk or Similar AERs - Adverse Event Reports - Alarming Number of SAEs - Alarming Severity of Injuries Reported - Mechanism of Action Similar to Other Drugs

20 20 CHANTIX SAFETY RISKS Cytisine (Tabex): Early Warning Signal The active ingredient in Chantix is varenicline tartrate which was derived from cytosine. [1] [Cytosine] has been around for decades as a smoking cessation drug in Eastern European Countries. [2] What Pfizer knew or should have known is that reports have been documented as early as 1972 linking cytosine (the derivative of the active ingredient in Chantix) to cases of suicide and attempted suicide. [3] [1] Etter, Jean-Francois, Cytisine for Smoking Cessation Arch. Int. Med., Vol. 166, Aug. 14/28, [2] Id. [3] Stoyanov, S., Yanachkova, M., Tabex therapeutic efficacy and tolerance. Savr. Med. XXIII (6), 31-33

21 21 CHANTIX SAFETY RISK: CLINICAL TRIAL EVIDENCE Study Completed 6/28/06 and Published 2/8/08 - A woman in the varenicline group experienced suicidal ideation which resulted in hospitalization 11 days after completing the varenicline treatment. [She had no previously diagnosed mental and/or psychological disorder.] The study investigator considered this case to be attributable to the study drug. (Source: Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open label trial. Thorax published online 8 Feb 2008.) - Study (Pfizer Sponsored) Completed Feb and Published 7/5/06 - Patient Committed Suicide (Source: Tonstad, S., et al, Effect of Maintenance Therapy With Varenicline on Smoking Cessation A Randomized Controlled Trial, JAMA 296 no. 1, (July 5, 2006) 64-71) - Study (RCT) Completed March, 2005 and Published 7/5/06 - serious adverse events associated with varenicline including: acute psychosis, emotional liability, insomnia and abnormal dreams. (Source: Jorenby et al, Efficacy of Varenicline, an α4β2 Nicotinic Acetylcholine Receptor Partial Agonist, vs Placebo or Sustained-Release Bupropion for Smoking Cessation A Randomized Controlled Trial, JAMA 296, no. 1 (July 5, 2006)

22 22 CHANTIX SAFETY RISKS: DELAY IN PUBLISHING Pfizer has previously delayed publication of unfavorable study results. - Pfizer sponsored a study of one of its blockbuster Cox-2 inhibitor drugs Bextra (valdecoxib) which was completed in May, [1] The unfavorable results were not published until [2] - In 2004, investigative journalist, Jeanne Lenzer, reported Pfizer s delay in releasing the results of unfavorable safety data to the FDA and consumers. [3] [1] Ott et al., J Thorac Cardiovasc Surg 2003;125: [2] The safety analysis revealed, serious adverse events occurred twice as frequently in parecoxib/valdecoxib-treated patients than in control patients. Regarding individual serious adverse events, a greater incidence in sternal wound infection was found in the parecoxib/valdecoxib patients versus control patients. The incidences of other individual serious adverse events, including cerebrovascular complications, myocardial infarction, and renal dysfunction, were proportionally greater [in parecoxib/valdecoxib treated patients]. Error! Main Document Only.Ott et al., J Thorac Cardiovasc Surg 2003;125: [3] Jeanne Lenzer, Pfizer criticised over delay in admitting drug s problems. BMJ 2004:329 (23 Oct. 2004) 935.

23 23 CHANTIX SAFETYRISKS: INADEQUATE STUDIES Pfizer Intentionally Ignored the Safety Risks and Avoided Detecting any Safety Signal With Inadequate Studies - Patients In Clinical Trials Do Not Reflect Individuals Most Likely To Use The Drug - David Gonzales, co-director of Oregon Health & Science University s Smoking Cessation Center who led pivotal studies of Chantix, noted that patients in the trials are not terribly reflective of the population of smokers. - No Studies to Determine Risks of Suicide and/or Similar Adverse Events - Instead of Conducting Adequate Studies, Pfizer Requested and Received Accelerated Review and Approval

24 24 CHANTIX SAFETYRISKS: Inadequate Studies / Patients Excluded Pfizer excluded patients from clinical trials if they had previous history and/or diagnosis of mental / psychological disorders. [1] Pfizer admitted that [p]atients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the controlled clinical trial program. [2] Dr. Daniel Seidman, Director of Smoking Cessation Services, Columbia University Medical Center - When [Pfizer] tested the drug, the sample they chose simply isn t representative of people they re targeting. - By excluding drinkers, you re artificially inflating your results I run a clinic and two out of three [smokers] I see have a psychiatric or mood problem. None of these people have been part of the original trials. [1]Varenicline Study Group. Efficacy and Safety of the Novel Selective Nicotinic Acetylcholine Receptor Partial Agonist, Varenicline, for Smoking Cessation. Arch. Intern. Med. August 2006, Vol. 166, p ; Melinda Beck, Puff Power: Drug Warnings Speak to Nicotine s Sad Grip, Wall Street Journal, February 19, 2008, sec. D, p. 1; Deveraux, A., Mostafa, K., Laqueille, X., Efficacy of Varenicline for Smoking Cessation, JAMA 296 (December 6, 2006) 2555 [2] Pfizer Press Release, January 18, 2008.

25 25 CHANTIX SAFETYRISKS: Evidence From Adverse Event Reporting November 2007: Results of FDA Preliminary Investigation FDA specifically highlighted the number of reports noting: - the association between suicide and attempted suicide "within days to weeks of initiating Chantix treatment. - Many of the cases were reported for patients without any prior history of psychiatric illness. - Currently, government scientists are conducting further investigations into the drug and, specifically, the reports of suicide and suicidal ideation Source: Press Release, the FDA, Early Communication About an Ongoing Safety Review: Varenicline (marketed as Chantix) (Nov. 20, 2007)

26 26 CHANTIX SAFETY RISKS: FDA AER Database (4th quarter of 2007) Chantix accounted for 988 serious injuries More than any other drug in this time period. By comparison the FDA received a median of 5 reports of serious injury for 769 different drugs in the 4th quarter. Only 35 drugs accounted for 100 or more reports.

27 27 CHANTIX SAFETY RISKS: Timeline of Adverse Event Reports May 2006: Approval August 2006: Market Launch in U.S. 4 th Qtr 2006: Ranked with approx. 35 drugs accounting for 100 or more AERs 2 nd Qtr 2007: Ranked 3 rd Among All Drugs Receiving Most AERs 4 th Qtr 2007: Ranked First Chantix Received More AERs Than Any Other Drug

28 28 PFIZER S DEFENSE RE: Inadequate Studies / Excluding Patients: We were not negligent and/or ignoring the risk if anything we were being too careful. David Gonzales, co-director of Oregon Health & Science University's Smoking Cessation Center and who led the trials, told The AP that patients who reported schizophrenia and other mental illness were deliberately excluded from the trials so that adverse events could not be attributed to a pre-existing condition.

29 29 OTHER SAFETYRISKS: Evidence From FDA AER Database 173 Accidents and Injuries. 148 Vision Disturbance. 224 Heart rhythm disturbances. 327 Seizures (86) and abnormal muscle spasms or movements. 403 Moderate and Severe Skin Reactions (65) including TEN/SJS Reactions 544 Diabetes.

30 30 CHANTIX SAFETYRISKS: Evidence From European Medical Agency (EMEA) : 61-year-old man committed suicide less than a month after he finished taking Chantix. - The EMEA s report found Chantix had six times the number of serious adverse reactions as the smoking cessation drug Zyban (bupropion). - The EMEA reported receiving cases of suicidal ideation and suicide in July, October and November 2007.

31 31 OTHER EVIDENCE OF RISKS: High Number of AERs - Clinical Trials - Meta-Analysis - Retrospective Studies - HMO s (e.g. Kaiser) Also Note: Drugs With Similar Mechanism - SSRIs - Rimonabant)

32 32 CHANTIX EFFICACY? Key Points To Remember: - Long Term Quit Rate (1 yr. or more) - Dose of Chantix & Combining Data - Lack of Adequate Data - Rush to Market with Few Trials - No Study of Risk of Suicide or Similar Risks - No Depression Rating Scale Used - Dropout Rate of Study Participants - Many Patients Lost to Follow-up - AERs Occurring After Conclusion of Study - Statistical Significance of Studies Demonstrating Efficacy - Comparison to Risks

33 33 PFIZER S DEFENSE: CAUSATION You have the burden so even if we did do it you can t prove it! - Many statements to press re no proof of an association and/or causal link. - Response: We do have enough evidence to establish causation - Biologically Plausible Mechanism - Data from other similar drugs - Clinical Trial Data, Meta-Analysis, Etc.

34 34 PFIZER S DEFENSE June 5, 2008 (Ray Kerins: Pfizer VP of Media Relations) #1 Smoking is a serious health problem that kills people. (Shift the Focus: We The Cure Not The Problem) #2 Most of the adverse events that have been reported recently are already in the Chantix label. (This is tragic and sometimes mistakes happen but we are in the business of saving lives and as soon and we were notified of a problem we took action.) #3 Smokers who are trying to quit can be depressed and irritable. (Blame the patient not us. We are just trying to help people and I guess no good deed goes unpunished.) #4 Paying close attention to adverse-event reports helps the FDA and Pfizer enhance drug safety. (Nothing is perfect but we are doing everything in our power to make the system better.)

35 35 CHANTIX: Background, Science & Potential Claims Kristian Rasmussen Cory Watson Crowder & DeGaris 2131 Magnolia Avenue Birmingham, AL (205)