Obstacle handling

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<ul><li><p>Obstacles that we might face</p></li><li><p>FDA was delayed by 12 monthsZelmac was not granted FDA approval from in 2001. </p><p>Let me share the story</p></li><li><p>The reason for the Agencys request is a numerical imbalance between the treated and placebo groups with regard to abdominal surgeries and Gall Bladder Surgery</p><p>Delay in FDA : Granted July 02 Zelmac GroupPlacebo p Value n=2965 n=1740 Abdominal surgeries 0.3% 0.17% 0.37Gall Bladder surgery 0.16% 0.06% 0.22</p></li><li><p>FDA Granted July 2002The FDA approval was granted with following post-approval commitments:</p><p>Perform a gallbladder mechanistic study in healthy volunteers.Perform a placebo controlled study to evaluate the intermittent and long-term efficacy.Perform a post marketing surveillance study to evaluate the frequency of gallbladder surgeries and other abdominal and pelvic surgeries.</p></li><li><p>Zelmac indication is in women onlyWhat about male patients??? Is it safe ? Why does it not work in men?</p></li><li><p>Zelmac in malestegaserod lacks efficacy is inaccurateZelmac has shown significant improvement in bowel habit (number of bowel movements and stool consistencyNo evidence on primary end point (SGA score) due to relative small numbers of male patients investigated</p></li><li>SGA of Relief in individual studies: placebo subtracted values at endpoint , by genderStudyB 351Responder rate%P-value 11.6 13.70.007 0.003B 301B 3072FEMALEMALE Adjusted1 Unadjusted13.6 15.6</li><li><p>Percent change from baseline in number of bowel movements in males at endpoint Study Placebo4mg/d12mg/d% Therap. Gain(%) p-value % therap gain % p-valueB30133.3 47.1 13.8 0.00264.831.5 0.001B35110.7 36.4 25.7 0.016 37.7 27.0 0.060B307 34.6 56.2 21.6 0.053 43.6 9.0 0.027 </p></li><li><p>Comparison (%) of patients with adverse events, by gender and treatment (phase III database)Adverse eventfrequency of Adverse Events (percent)Tegaserod PlaceboMales FemalesMales FemaleN=260 N-2186N=130 N=1459Abdominal pain16 161212Diarrhea15 10 4 4Nausea9 8 5 7Flatulence7 7 2 6Dyspepsia4 5 6 4Headache14 1813 14Dizziness4 5 5 3Back pain5 5 1 4Upper respiratory 4 6 6 6 tract infection</p></li><li><p>Safety in MalesIn phase III studies 10% of the patients were male. The data suggests that there are no adverse event (AEs) suggesting difference in tolerability</p></li><li><p>How do we deal with the issue of Men?The number of men enrolled in clinical trials is around 10% , the small number is due to the natural distribution in IBS Ratio of 3:1Efficacy in men on endpoint (overall SGA relief) could not be achieved in the studies however Zelmac had a positive effect on Bowel movements and bowel consistencyThe safety and tolerability in males showed no difference with females- Our current data and indication cannot support use in males-</p></li><li><p>Incidence of Ovarian CystsI read/heard somewhere that Zelmac causes Ovarian Cysts??</p></li><li><p>Incidence of ovarian cyst: in clinical studies9 patients: 1 Placebo and 8 on tegaserodConfirmed after analysis in only 5 patients 2 of which had the diagnosis of OC before entering the study The other 3 had other diagnosis (pelvic adhesions, peritubal cysts etc)</p></li><li><p>How effective is Zelmac in patients with alternating symptoms?</p><p>A-IBS forms a substantial number of patients that can be seen in the clinics</p></li><li><p>Zelmac works best for female patients whose main symptom is constipation- we cannot recommend the use of Zelmac in alternating patients and we leave it to your medical judgment in patients currently experiencing diarrhea as a key symptom we do not advise use of Zelmac since it might result in intensifying this symptom </p></li><li><p>How should patients who experience diarrhea while taking Zelmac be managed?</p></li><li><p>Doctor , I understand this might be experienced by a few patientsDoctor, diarrhea can be a pharmacological response to therapy with Zelmac. Therefore, it is reasonable to expect that it could be a possible side effect.The majority of the patients taking Zelmac who reported diarrhea had a single episode. In most cases, diarrhea occurred within the first week of treatment. </p><p>Typically, the diarrhea resolved with continued therapy. Overall, the discontinuation rate from the studies due to diarrhea was low 1.6% - among the patients taking Zelmac.</p></li><li><p>Versus other medications.What advantages does Zelmac have over other treatments, such as Duspatalin? </p><p>Or: Have you conducted any studies comparing the efficacy of Zelmac against other treatments?</p></li><li><p>Response: no comparative studiesI believe this is a valid question with a new therapy such as ZelmacZelmac is a the first drug to be effective on all key symptoms of c-IBS and there has been no comparative data versus other medications . </p></li><li><p>The seriousness of IBSIs IBS really that important when compared with life-threatening diseases?</p></li><li><p>Two Key points to discussQOL of life of patients with IBS- lower than that of patients suffering with Diabetes Mellitus</p><p>So, doctor you can see that IBS has a significant impact on suffers lives. What do you think about it? </p><p>Patients have a significant impact on their life- such as work, traveling, socializing, eating etc </p></li><li><p>TachyphylaxisIs Tachyphylaxis a problem with Zelmac?</p><p>Because response rates in clinical trials did not decrease between Month 1 and Month 3, and actually increased slightly, Tachyphylaxis does not appear to be an issue with the administration of Zelmac.</p></li><li><p>Duration of Therapy and onset of effectZelmac has been studied for a duration of 12 weeks as agreed with FDA in terms of clinical study designOnset of action was fast in most patients, during 1 week for symptoms of pain and bloating and 1 day for symptoms of constipation It is recommended to evaluate response after a period of 4 weeks and to continue therapy to up to 12 weeks. </p></li><li><p>When can I re-challenge No available data on intermittent therapy however some post marketing studies are ongoing We have no data to support re-challenge however as with most chronic and acute syndromes clinical judgement is to be used</p><p>References (contd)Thompson WG, Creed F, Drossman DA, Heaton KW, Mazzacca G. Functional bowel disease and functional abdominal pain. Gastroenterol Int 1992;5:759. Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999;45(Suppl. II):437. Veldhuyzen van Zanten S, Talley N, Bytzer P, et al. Design of treatment trials for functional gastrointestinal disorders. Gut 1999;45(Suppl.II):6977.Whitehead WE, Crowell MD, Robinson JC, Heller BR, Schuster MM. Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared with subjects without bowel dysfunction. Gut 1992;33:82530.Zhou H, Horowitz A, Ledford P, et al. Tegaserod coadministration does not alter the pharmacokinetics of theophylline in healthy subjects. J Clin Pharmacol 2001;41:98793(a).Zhou H, Horowitz A, Ledford P, et al. The effects of tegaserod (HTF 919) on the pharmacokinetics and pharmacodynamics of digoxin in healthy subjects. J Clin Pharmacol 2001;41:11319(b).Zhou H, Walter Y, Hubert M, et al. Tegaserod (HTF 919) does not decrease the effectiveness of an oral contraceptive when co-administered to healthy female subjects. Gastroenterology 2000;118:4(Suppl. 2):A1207:5539.</p></li></ul>