1 Food and Drug Administration.doc

1 department of health and human services food and drug administration center for drug evaluation and research gastrointestinal drugs advisory subcommittee wednesday, july 14, 2004 8:30 a.m. acs conference room room 1066 5630 fishers lane rockville, maryland 2 participants ronald p. fogel, m.d., acting chair thomas h. perez, m.p.h., r.ph., executive secretary members: alan lewis buchman, m.d. byron cryer, m.d. alexander h. krist, m.d. john t. lamont, m.d. robert a. levine, m.d. david c. metz, m.d. weichung joe shih, ph.d. david b. sachar, m.d. jose m. vega, m.d., industry representative drug safety and risk management advisory committee (voting): brian l. strom, m.d., m.p.h. curt d. furberg, m.d., ph.d. arthur a. levin, m.p.h., consumer representative consultants (voting): ralph dagostino, ph.d. allen mangel, m.d., ph.d. federal employee (voting): maria h. sjogren, m.d. fda staff: robert justice, m.d., director, division of gastrointestinal and coagulation drug products robert prizont, m.d., medical officer garry dellazanna, d.o., m.sc., medical officer julie beitz, m.d., deputy director, ode iii 3 c o n t e n t s call to order, introductions, ronald fogel, m.d., 5 meeting statement, thomas h. perez, m.p.h. 8 opening comments, robert justice, m.d., director, division gastrointestinal and coagulation drug products 11 novartis presentation, zelnorm, nda 21-200: introduction, john r. cutt, ph.d., novartis executive director global head gi, drug regulatory affairs 14 chronic constipation: an unresolved problem for many patients, charlene m. prather, m.d., st. louis university school of medicine 20 zelnorm: efficacy and safety in chronic constipation, eslie dennis, m.d., novartis senior medical director, gi clinical develop and medical affairs 40 zelnorm: safety overview, bo joelsson, m.d., novartis senior medical director, clinical r&d 69 fatality cases, michael shetzline, m.d., ph.d., novartis senior medical director, u.s. clinical development and medical affairs 82 zelnorm: safety overview (continued), bo joelsson, m.d. 92 benefit/risk assessment, philip schoenfeld, m.d., university of michigan school of medicine 94 questions on presentation 116 fda efficacy presentation, robert prizont, m.d., medical officer, division of gastrointestinal and coagulation drug products 158 4 c o n t e n t s (continued) questions on presentation 173 fda safety presentation, gary dellazanna, m.sc., medical officer, division of gastrointestinal and coagulation drug products 199 questions on presentation 220 open public hearing: jeffrey d. roberts, b.sc., ibs self help group 229 constance hill 235 linda roepke 241 clarification of issues 249 discussion of questions 295 adjournement 364 5 p r o c e e d i n g s call to order, introductions dr. fogel: good morning. my name is ron fogel. i am acting chair for todays meeting of the gastrointestinal drugs advisory committee. todays meeting deals with the new drug application of zelnorm for the proposed indication of the treatment of patients with chronic constipation and relief of associated symptoms of straining hard or lumpy stools and infrequent defecation. there has been one change to todays agenda. the agenda has been pushed back half an hour so the tentative time of adjournment is five oclock. why dont we start by going around the table and introducing ourselves? if we could start on my far left? dr. vega: jose vega, from amgen in california. dr. levin: arthur levin. i am a member of the drug safety and risk management advisory committee. i am a consumer representative and i am a guest as a consumer representative here today. 6 dr. strom: brian strom, university of pennsylvania. i am a recent graduate of the drug safety and risk management advisory committee-i have already forgotten the name of the committee! i am here as a special government employee, though that is not what is says there. dr. furberg: i am curt furberg, from wake forrest university. i am an active member of the drug safety and risk management advisory committee. dr. dagostino: ralph dagostino, from boston university, statistician, consultant to the fda. dr. lamont: i am tom lamont. i am a member of the gidac. i work at beth israel hospital in boston and harvard medical school. dr. levine: i am bob levine, state medical university, syracuse, new york, and i am a member of the gi advisory committee. dr. metz: david metz, university of pennsylvania. i am on the gi drug advisory committee. dr. perez: tom perez, executive secretary 7 to this meeting. dr. fogel: ron fogel, henry ford health system, in detroit. dr. sachar: i am david sachar, from mount sinai school of medicine, in new york-my maiden voyage on the gi drug advisory committee. laughter dr. buchman: alan buchman, from northwestern university, in chicago, and this is also my first cruise with today as well. dr. mangel: allen mangel, research triangle institute. i am a special government employee. dr. cryer: i am byron cryer, from the dallas va medical center and ut southwestern medical school. i am a member of the gi advisory committee. dr. dellazanna: garry dellazanna, medical officer in the gi and coagulation drug product division. dr. justice: robert justice, director, division of gastrointestinal and coagulation drug 8 products. dr. beitz: julie beitz, deputy director in the office of drug evaluation iii. dr. fogel: thank you, all. at this point tom perez will read the meeting statement. meeting statement dr. perez: thank you and good morning. the following announcement addresses the issue of conflict of interest with regard to this meeting, and is made part of the record to preclude even the appearance of such at this meeting. based on the submitted agenda for the meeting and all financial interests reported by the committee participants, it has been determined that all interests in firms regulated by the center for drug evaluation and research present no potential for an appearance of a conflict of interest at this meeting, with the following exceptions: in accordance with 18 usc section 208(b)(3), full waivers have been granted to the following participants, dr. ronald fogel has been granted a waiver for serving as a member of the 9 sponsors speakers bureau. his lectures are unrelated to the matter at issue and he receives less than $10,001 per year. dr. ralph dagostino has been granted a waiver for serving on a competitors advisory board on unrelated matters. he receives less than $10,001 per year. dr. byron cryer has been granted a waiver under 21 usc 355(n)(4), amendment of section 505 of the food and drug administration modernization act, for ownership of stock in a competitor. the stock is worth less than $5,001. because this interest falls below the de minimis exemption allowed under 5 cfr 2640.202(a)(2) a waiver underlying 18 usc 208(b)(3) is not required. dr. david metz has been granted waivers under 18 usc section 208(b)(3) and 21 usc 355(n)(4) for his spouses ownership of stock in a competitor valued from $50,001 to $100,000. lastly, dr. allen buchman has been granted waivers under 18 usc section 208(b)(s) and 21 usc 355(n)(4) for owning stock in a competitor valued 10 from $25,001 to $50,000. a copy of the waiver statements may be obtained by submitting a written request to the agencys freedom of information office, room 12a-30 or the parklawn building. in the event that the discussions involve any other products or firms not already on the agenda for which an fda participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record. we would also like to note that dr. jose vega has been invited to participate as an industry representative, acting on behalf of regulated industry. dr. vega is employed by amgen, inc. with respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon. thank you. dr. fogel: thank you. at this time i will turn the meeting over to dr. justice, of the 11 fda, for opening comments. opening comments dr. justice: good morning. i would like to welcome everyone to todays meeting of the gastrointestinal drugs advisory committee, and i would especially like to welcome members of the committee and special government employees for taking the time to provide us with your advice. as you have heard, today we will be discussing the application for zelnorm tablets for the proposed indication of treatment of chronic constipation. before going on to the presentations, i would just like to briefly go through the questions so you will have them in mind as you listen to the discussions. the first item is that we would like you to discuss the appropriateness of a primary efficacy endpoint of an increase of equal to or greater than 1 complete spontaneous bowel movement per week versus a total of greater than 3 complete spontaneous bowel movements per week. the second question is, is the population 12 studied representative of patients with chronic constipation? if not, how do the populations differ? the third question is only 9 to 16 percent of subjects were greater than or equal to 65 years of age and the treatment effect was significantly smaller in older patients. are these data adequate for an indication that is common in the elderly? the fourth efficacy question is that only 9 to 14 percent of the subjects were male and the treatment effect was smaller in males than females. are these data adequate to support approval of zelnorm for use in the treatment of chronic constipation in males? the next question is are the clinical trial data adequate with respect to the population of non-irritable bowel syndrome patients with chronic constipation that is likely to be treated with zelnorm? the next efficacy question is, is zelnorm effective for the treatment of chronic constipation and associated symptoms? 13 as far as the safety questions, postmarketing access of ischemic colitis and serious complications of diarrhea were not limited to patients with irritable bowel syndrome. what are the implications of these adverse events from patients with chronic constipation? the next safety question is that the incidence of diarrhea and discontinuation due to diarrhea was higher in patients 65 years of age or older. is there sufficient information that zelnorm is safe for use in this age group? the next safety question is do the adverse event data from the clinical trials and postmarketing surveillance provide adequate evidence of safety of zelnorm for the treatment of chronic constipation? the next safety question is should the information on the postmarketing cases of ischemic colitis and intestinal ischemia be moved from the precautions section to the warning section of the package insert? then, the final question will be the 14 overall question of should zelnorm be approved for the proposed indication of the treatment of patients with chronic constipation and relief of associated symptoms of straining, hard or lumpy stools, and infrequent defecation? with that, i will turn it back over to dr. fogel for novartis presentation. dr. fogel: thank you very much. at this juncture i will turn the meeting over to dr. john cutt, global head of gi drug regulatory affairs for novartis, who will introduce the speakers and the presentations. thank you. novartis presentation introduction dr. cutt: thank you. first i would like to thank dr. beitz, dr. justice-dr. prizont is not here yet-and dr. dellazanna and the rest of the fda reviewers, and dr. fogel and the rest of the advisory committee, and say good morning to you. my name is john cutt. as dr. fogel said, i am the executive director and the global head for the gastrointestinal regulatory group at novartis, 15 and it is my pleasure to share with you today the clinical data on chronic constipation that we have generated. let me start out with the objectives, as we see them today for the meeting. we would like to share the zelnorm phase 3 clinical data in support of a new indication. dr. fogel read that before, i will read it again. zelnorm is indicated for the treatment of patients with chronic constipation and the relief of associated symptoms of straining, hard or lumpy stools, and infrequent defecation. the second topic that we are going to review today is the postm