Presentation on theme: "For copyright notice see final page of this file"— Presentation transcript:
1 For copyright notice see final page of this file Chemistry 125: Lecture 30 Esomeprazole as an Example of Drug Testing and UsageThe chemical mode of action of omeprazole is expected to be insensitive to its stereochemistry, making clinical trials of the proposed virtues of a chiral switch crucial. Design of the clinical trials is discussed in the context of marketing. Otolaryngologist Dr. Dianne Duffey provides a clinician’s perspective on the testing and marketing of pharmaceuticals, on the FDA approval process, on the clinical trial system, on off-label uses, and on individual and institutional responsibility for evaluating pharmaceuticals.Synchronize when the speaker finishes saying “…talking about configuration - about handedness.” Synchrony can be adjusted by using the pause(||) and run(>) controls.For copyright notice see final page of this file
2 Sulfide Sulfoxide + Gives Racemate of Course O + d-vacant + + n + n •O+d-vacant•+•+•n+nperoxy acid*H+•Gives Racemate of Course
3 Blocking the Proton Pump ••+++nH+*H+H+ makes *C=N a lower LUMOomeprazole
4 Blocking the Proton Pump Enzyme- OH-+S- H++++s*•Enzyme-nPump enzymeis inactivated,slowing flow of HCl to stomach.At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min.(“enteric” coating postpones activation during initial passage through acid stomach)
5 Blocking the Proton Pump Should “Chiral Switch” to Single Enantiomer Help Omeprazole?Blocking the Proton Pump- H+ns*•Enzyme-+- OH-Pump enzymeis tied up.Slows flow of HCl to stomach.S+ACHIRAL !At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min.(“enteric” coating postpones activation during initial passage through acid stomach)
6 Should “Chiral Switch” to Single Enantiomer Help Omeprazole? No difference after omeprazole is “activated” by H+ to R-S-O-H (and rendered achiral).Still one enantiomer might be more effective in getting to the key stomach cells that produce acid.Need single enantiomer for laboratory and clinical testing.
7 Proton-Pump Inhibitor Use by Wellmark Members (1 Proton-Pump Inhibitor Use by Wellmark Members (1.75 M participants in IA/SD)>15% of Wellmark members>6108 worldwideChiralSwitch20032000RSS20021988
9 “Nexium Integrates Clinical, Commercial” Medical Marketing and Media (Dec, 2003) by Mark Tosh …Levine, executive director and develop-ment brand leader, adds the clinical and science proficiency as a research gastroenterologist.…as Levine and his staff put togetherclinical development plans, such as additional indications or line extensions, they get commercial input at every stage.
22 Perspectives from a Clinician I can remember sitting in organic chemistry at the University of North Carolina and fuming about the need to learn how to make paint…….when all I wanted to do was treat patients.I hope you realize how fortunate you are to have the insights and relevant applications provided by Professor McBride. It’s certainly my honor to be able to participate and share with you some of my observations and dilemmas experienced as a clinician.Dianne Duffey M.D., FACSSection of Otolaryngology, Department of SurgeryYale University School of Medicine
23 DisclosureI have no financial interest in any of the drugs or companies discussedI am not a consultant nor on any speakers’ bureaus for any companyI will discuss off label or experimental uses of compoundsThis slide gets longer and longer as we move forward in the current economic climate. Also, medical institutions are becoming much more aware and guarded about conflict of interest on the part of their faculty and medical providers. Even the appearance of COI will increase gastric acid production in institutional administrators.
24 DisclosureThe opinions stated are those of the presenter and are not meant to represent those of the Section of Otolaryngology, Department of Surgery or Yale School of Medicine.
25 Now, as you’ve heard testified here today: Prilosec fixes symptoms of GERD and Laryngopharyngeal Reflux.Or does it?
26 All we know is that his symptoms improved: in his body, eating his diet, and living his life.
27 Patient Variables Are we taking into consideration other factors? e.g. Diet: does Professor McBride take large amounts of herbal supplements that he didn’t tell us about?Did he take the prescribed medication on an empty stomach? (i.e. was he compliant?)
28 Clinical Trials design of a clinical trial Controlling variables Statistically sound
29 Biostatistics drive clinical trials design so that if differences are seen, it can be determined “with reasonable certainty” that differences observed are not due to chance
30 Duty - ManufacturerAre the pharma companies actually designing their studies so that they can make legitimate head-to-head comparisons between competitor compounds?
31 Duty - Physician evaluate the literature critically be able to ascertain the validity of research supporting our choices as clinicians.
32 Duty - Patient Be an educated consumer Direct to patient (DTP) marketing is ubiquitousVery effective
33 Specialty is Otolaryngology (ENT) Laryngopharyngeal Reflux (LPR)UnderdiagnosedSignificant source of morbidity and decreased quality of lifeFrequently associated with GERDGERD: Potential for premalignant disease in esophagus, significant public health problem
34 It is estimated that 4% to 10% of patients presenting to an otolaryngology practice have symptoms and/or findings related to LPR.Laryngopharyngeal reflux is increasingly recognized as a probable contributing factor to nonallergic asthma and many ear, nose, and throat complaints.Studies suggest that acid reflux is present in 50% to 80% of patients with asthma, % to 20% of patients with chronic cough, up to 80% of patients with difficult-to-manage hoarseness, and 25% to 50% of patients with globus sensation.Carrau et al; Arch Otolaryngol Head Neck Surg. 2005;131:
35 RefluxIt’s a big problemHence, much money to be made
36 LP Reflux Treatment: PPI, proton pump inhibitors Reality: PPI are FDA approved
37 Belafsky et al: ENT-Ear, Nose & Throat Journal Suppl 2,vol 81: September 2002.
38 Belafsky et al: ENT-Ear, Nose & Throat Journal Suppl 2,vol 81: September 2002.
39 Drug DevelopmentOnly 5 in 5,000 compounds entering preclinical testing make it to human testing1 in 5 agents in human testing may be safe and effective enough to gain FDA approval
41 FDA APPROVAL Prilosec OTC (2003) “We completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the agreed-upon labeling text.”[omeprazole magnesium delayed-release tablets, 20mg][for the treatment of frequent heartburn]
42 FDA APPROVAL Nexium Esomeprazole magnesium (Nexium) 1) Healing erosive esophagitis;2) Maintenance of healing of erosive esophagitis; and3) Treatment of symptomatic gastroesophageal reflux disease (2001)Approved for the Risk Reduction of NSAID associated Gastric Ulcers (2004)Treatment of pathological hypersecretory conditions including Zollinger-Ellison Syndrome (2006)
44 Clinical Trials - drug studies in humans Phase IPhase IIPhase IIIPhase IV
45 Clinical Trials - drug studies in humans Phase IHealthy volunteersEndpoint: side effectsDetermines metabolism and excretion of drugN=20-80Phase IIPhase IIIPhase IV
46 Endpoints AE - Adverse event, a side effect SAE - Serious adverse event; resulted in damage to patient, hospitalization, surgery etc.Reported to the FDA during trials
47 Clinical Trials - drug studies in humans Phase IPhase IIEffectivenessPreliminary data: effectiveness of drug for a particular disease or conditionComparison to placebo or to a different drugSafety and short-term adverse effects studiedN=dozens - 300Phase IIIPhase IV
48 Clinical Trials - drug studies in humans Phase IPhase IIPhase IIISafety and effectivenessStudy different populations; different dosages; combination with other drugsN=several hundred - 3,000Phase IV
49 Clinical Trials - drug studies in humans Phase IPhase IIPhase IIIPhase IVPostmarketing study commitmentsStudies required of or agreed to by a sponsorConducted after FDA approval receivedGathering additional information about product’s safety, efficacy or optimal use
50 Clinical Trials - drug studies in humans Phase 0Phase IPhase IIPhase IIIPhase IVClin Cancer Res 2008; 14(12), 2008
51 Clinical Trials - drug studies in humans Phase 0Exploratory, first-in-human trialsA.k.a. microdosing studiesDesigned to speed up development of promising agentsEstablishes very early on whether agent behaves in human subjects differently that expected from preclinical studiesSingle, subtherapeutic dose of drug, small number patients (n=10-15)Not targeting efficacy (dose too low for therapeutic effect)No potential benefit to patientEndpoint: pharmacodynamic and/or pharmacokinetic responseInterrogate and refine a target or biomarker assay for drug effectExpected effects at nontoxic doses and over short exposure durations (e.g. <7days)Clin Cancer Res 2008; 14(12), 2008
52 Reflux StudiesSustained resolution (>7days) of heartburn in patients with erosive esophagitisNo statistically significant difference between esomeprazole 20mg (n=620) and omeprazole 20mg (n=626)Chose omeprazole 20mg dose because it’s “the approved dose for this indication”
53 20mg esomeprazole (p<0.05) or 40mg esomeprazole (p<0.001) over However, healing of erosive esophagitis was statistically significantly better for20mg esomeprazole (p<0.05) or40mg esomeprazole (p<0.001) over20mg omeprazole (n = 656, 654, 650)Another study: no differenceEO 20mgO 20mg (n = 588, 588)Another study: statistically significantly better forEO 40mg (p<0.001) overO 20mg (n = 1216, 1209)EO 40mgO 20mg (n = 576, 572)
54 How are we able to use these drugs for LPR? Approximately 20% to 43% of patients with LPR experience heartburn, and 18% have esophagitis.How are we able to use these drugs for LPR?Carrau et al; Arch Otolaryngol Head Neck Surg. 2005;131:
55 “Off-label” Use of Marketed Drugs “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgement. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rational and on sound medical evidence, and to maintain records of the product’s use and effects.Use of a marketed product in this manner when the intent is the “practice of medicine” does not require the submission of an IND [Investigational New Drug] application, IDE [Investigational Device Exception] or review by an Institutional Review Board (IRB).
56 Duty - Physician evaluate the literature critically be able to ascertain the validity of research supporting our choices as clinicians.
59 Meanwhile, research investment in oncology has been growing steadily across the industry. Some view Indiana-based Eli Lilly's recent $6.5-billion bid for the biotechnology firm ImClone as a sign of increased demand for cancer drug candidates. Health-care insurance plans, too, have traditionally been more willing to pay high premiums for cancer therapies although there are signs that this attitude may be changing. And the pharmaceutical industry has recently embraced the drive towards genetically targeted, individual treatments in oncology a concept that once made companies cringe because it reduced the market for a given drug. That, says Conover, was before the industry realized that patients would pay tens of thousands of dollars for an expensive new drug. "All of a sudden," he says, "'market limiting' is OK.”Industry is shifting attention to Oncology (cancer), Immunology (e.g. rheumatoid arthritis), Neurology (Alzheimer’s)Nature News, Published online 4 November 2008 | Nature | doi: /456006a
60 Student Questions for Dr. Duffey 1) Who controls the number of warnings in TV drug commercials?2) Considering the recent case of Vioxx, do you think clinicaltrials should be longer?If off-label uses can’t be advertised, how do doctors learn about them?4) Do physicians take advantage of side-effects for off-label usage?