Document 8OQJd67kq1Ndoy599eoQgJeqe

HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH ONCOLOGIC DRUGS ADVISORY COMMITTEE 48th Meeting Thursday, December 14, 1995 8:30 a.m. This transcript has not been edited or corrected, but appears as received from the commercial transcribing service. Accordingly, the Food and Drug Administration makes no representation as to its accuracy. Holiday Inn - Bethesda Versailles Room 8120 Wisconsin Avenue Bethesda, Maryland KO 0~t rv> t5 MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546--6666 jam PARTICIPANTS Paul A. Bunn, M.D., Chairperson (a.m.) David R. Parkinson, M.D., Chairperson (p.m.) Stephen Pollitt, P.A.-C, Executive Secretary VOTING MEMBERS Arlene Forastiere, M.D. Richard Gelber, Ph.D. James N. Ingle, M.D. James Krook, M.D. Judith Ochs, M.D. Robert Ozols, M.D., Ph.D. Sandra Swain, M.D. Patricia Abbitt, M.D. Michael D . Devous, S r ., Ph.D. Arnold Malcolm, M.D. Barry Siegel, M.D. Marilyn J. Siegel, M.D. CONSUMER REPRESENTATIVE E. Carolyn Beaman, M.H.S. PATIENT REPRESENTATIVE Barbara Sortino ' FDA (a.m.) Robert Delap, M.D., Ph.D. Lydia Larson, Pharm.D. Alison Martin, M.D. Robert Temple, M.D. (p.m.) Paul Botstein, M.D. Ira Berkower Patricia Keegan, M.D. George Mills, M.D. Jay Siegel, M.D. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 f > c/ic -CC.CG. Opening Statements 4 Open Public Hearing M s . Peggy McCarthy NDA 20-587 STERILE AEROSOL TALC Bryan Presentation: Mr. Frank Abrano ? Dr. John Beamis 8 15 17 FDA Presentation: Lydia Larson, Pharm.D. 46 Committee Deliberation (ODAC Discussants: Paul Bunn, M.D. and James Krook, M.D.) 79 PLA 94-0308, NR-LU-10 Karl Thomae Presentation: David Brill, Ph.D. 105 Darrell Salk, M.D. 1(39 Wil B. Nelp, M.D. 1*15 Darrell Salk, M.D. 125 Andrew Turrisi, M.D.131 FDA Presentation: Ira Berkower George Mills, M.D. 156 160 Committee Deliberation (ODAC Discussants: Hobert Ozols, M.D. and Barry Siegel, M.D.) 203 Adjournment 220 MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 r n x r? A a? C C C C . jam i. 1 2 3 4 PROCEEDINGS OPENING STATEMENTS MR. POLLITT: My name is Steve Pollitt. I am the 4 Executive Secretary of this Committee and I would like to 5 welcome you to the 48th Meeting of the Oncologic Drugs 6 Advisory Committee Meeting. At this time, I would like to 7 introduce Dr. Paul Bunn who is the Chairman of the 8 Committee. 9 CHAIRMAN BUNN: Thank you very much. I think we 10 will have a few introductions and then we will actually go 11 around the table and introduce ourselves. As hopefully 12 everyone knows, the ODAC has a patient representative at 13 every meeting. This morning, I would like to welcome 14 Barbara Sortino who is here as the Patient Representative 15 serving on the Committee for this session. 16 There is a new ODAC member who is a voting 17 Consumer Representative, Carolyn Beaman. Carolyn Beaman is 18 a permanent member of the Committee and we welcome you, 19 also. Perhaps, we will just go around quickly and introduce 20 ourselves. Even though I have introduced you, why don't you i 21 just say your name again and we will go this way. 22 MS. SORTINO: My name is Barbara Sortino. I am a 23 lung-cancer survivor. I am here representing patients. 24 MS. BEAMAN: I am Carolyn Beaman. I am the 25 Consumer Representative. I am a five-year breast-cancer MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 2 0 0 0 2 ( 2 0 2 ) 546-6666 5 1 survivor. 2 DR. KROOK: I am Jim Krook from Duluth, Minnesota, 3 medical oncologist. 4 DR. OZOLS: Bob Ozols from the Fox Chase Cancer 5 Center in Philadelphia, medical oncologist. 6 DR. SWAIN: Sandra Swain, medical oncologist from 7 Bethesda, Maryland. 8 DR. BUNN: I am Paul Bunn. I am a medical 9 oncologist from the University of Colorado. 10 MR. POLLITT: Steve Pollitt. I am the Executive 11 Secretary for the Committee. ' 12 DR. OCHS: Judy Ochs, now pediatrics and medical 13 oncology, Little Rock, Arkansas. 14 DR. FORASTIERE: Arlene Forastiere, medical 15 oncologist at Johns Hopkins, Baltimore. 16 DR. GELBER: Rich Gelber, biostatistician from 17 Boston. 18 19 DR. DELAP: Bob Delap, Oncology Division, FDA. DR. TEMPLE: Bob Temple. I am Associate Center 20 Director for Medical Policy. 21 DR. JUSTICE: Robert Justice, Division of 22 Oncology, FDA. 23 DR. LARSON: Lydia Larson, Division of Oncology, 24 FDA. 25 DR. MARTIN: Alison Martin, medical oncologist, MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 6 1 2 MR. POLLITT: I will now read the conflict-of3 interest statement for this meeting. 4 The following announcement addresses conflict-of5 interest issues associated with this meeting and is made a 6 part of the record to preclude even the appearance of a 7 conflict. 8 Based on the submitted agenda and information 9 provided by the participants, the Agency has determined that 10 all reported interests and firms regulated by the Center for 11 Drug Evaluation and Research present no potential for a . 12 conflict of interest at this meeting with the following 13 exceptions. 14 In accordance with 18 USC 208(b)3, full waivers 15 have been granted to Dr. Robert Ozols, Dr. Marilyn Siegel, 16 and Dr. Barry Siegel. The waivers permit them to 17 participate fully in the discussions and voting concerning 18 NR-LU-10 Fab. A copy of those waiver statements may be 19 obtained by submitting a written request to FDA's Freedom of 20 Information, Room 12A-30, of the Parklawn Building. 21 In addition, we would like to note that Dr. Ozols 22 and his employer, the Fox Chase Cancer Center, have 23 interests in the manufacture of a competing product, a 24 sterile aerosol talc, which are unrelated to the firm's 25 competing product. Although these interests do not MILLER REPORTING COMPANY, INC. , 507 C Street, N.E. Washington., D.C. 20002 (202) 546-6666 ?7 1 constitute a financial interest in the particular matter or 2 in the competing product within the meaning of 18 USC 3 Section 208, they could create the appearance of a conflict. 4 However, it has been determined, notwithstanding those 5 interests, that it is in the Agency's best interest to have 6 Dr. Ozols participate in the Committee's discussions 7 concerning sterile aerosol talc. He will, however, be 8 excluded from any vote related to this product. 9 Further, during the discussions of NR-LU-10, Dr. 10 Paul Bunn will step down as chairman. He will participate 11 in the discussions concerning NR-LU-Fab, however, he will, be 12 excluded from any vote related to the product. In the event 13 that the discussions involve any other products or firms not 14 already on the agenda for which an FDA participant has a 15 financial interest, the participants are aware of the need 16 to exclude themselves from such involvement, and their 17 exclusion will be noted for the record. 18 With respect to all other participants, we ask in 19 the interests of fairness that they address any current or 20 previous financial involvement with any firm whose product 21 they may wish to comment upon. I would also ask that anyone 22 who does ask questions or come up to speak, please speak 23 into a microphone, state your name first and who you 24 represent, and if you have any financial interests in the 25 product being discussed before the Committee. MILLER REPORTING COMPANY, INC. 507 c Street, N.E. Washington, D.C. 20002 ion-?.) 8 1 Thank you. 2 Dr. Bunn. 3 OPEN PUBLIC HEARING 4 CHAIRMAN BUNN: Thank you very much. 5 We now turn to the open public hearing, and we 6 e had one request, from Peggy McCarthy, to speak before 7 all. 8 Peggy, if you want to use this microphone, that 9 will be great. 10 m s . p e g g y Mc Ca r t h y 11 MS. MCCARTHY: I am Peggy McCarthy. I am Acting 12 Executive Director of the Alliance for Lung Cancer Advocacy, 13 Support and Education. 14 This group, ALCASE, is the only organization that 15 supports, advocates, and educates people with lung cancer. 16 It was founded in 1979 by a lung cancer survivor, Mort 17 Liebling, who started a group called Spirit and Breath, 18 after he had received his diagnosis of lung cancer and was 19 very discouraged when his physician told him, after Mort 20 complained of not feeling very well after his surgery and 21 his therapy, his physician said, well, Mort, you are either 22 going to die or you will eventually feel better, and Mort 23 went out and found ways to make himself feel better, 24 primarily through the use of exercise. He helped to learn 25 to re-breathe after losing a lot of his lung tissue, and he MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 i'?021 546-G6SS 9 1 started an organization that he shared with other people. 2 We found out about it a number of years ago and 3 jot to be friends with Mort, and prior to his passing away 4 two years ago, he asked my business if we would take over 5 the organization, make sure it continued. 6 We changed the name to ALCASE, as I mentioned, and 7 I am very pleased to be here representing the lung cancer 8 survivors who work with u s . 9 During the first half of the century, lung cancer 10 a very rare disease. According to epidemiologist, E.L. 11 Wynder, a patient who presented with lung cancer in a clinic 12 or a hospital became a teaching case for practicing 13 physicians and physicians in training. Today, however, lung 14 cancer kills more people than any other type of cancer. In 15 fact, each year, it kills more women than does breast 16 cancer. 17 Tobacco was identified as a major carcinogen in 18 the first Surgeon General's report published January 11, 19 1964, which linked smoking and lung cancer. Epidemiological 20 research over the past 40 to 50 years has revealed that 21 tobacco smoke is associated with 80 to 90 percent of all 22 lung cancers. Of course, other complicating risk factors 23 can be having a genetic predisposition for the disease and 24 exposure to other carcinogens, such as asbestos, radon, and 25 arsenic, to name a few. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 10 1 The increase in incidence is attributed to the 2 increase in smoking that occurred during World War I and 3 World War II when cigarettes were distributed to soldiers. 4 The subsequent and ever-increasing advertising campaigns by 5 cigarette manufacturers also contributes to this increase. 6 Today, the incidence of lung cancer is decreasing 7 in men but increasing in women. Deaths from lung cancer in 8 women have increased more than 400 percent in the last 30 9 years. Although overall, smoking has decreased among women 10 in the last decade, teenage smoking rates have not declined 11 appreciably since 1984, and, in fact, the incidence of 12 smoking in young adult women and teenagers is increasing. 13 A 1994 report by Dr. Joycelyn Elders, the Surgeon 14 General at that time, published in the American Journal of 15 Public Health stated that, among daily smokers, 71 percent 16 started smoking by the age of 18. We believe that the 17 increase in lung cancer incidence in women can be attributed 18 to cigarette advertising which exploits the adolescent and 19 woman's concerns about body image, popularity, success, and 20 fashion. 21 Despite the increasing prevalence of lung cancer, 22 early diagnosis is difficult. Many people are asymptomatic 23 until the disease has progressed significantly. The 24 symptoms may be vague or can be attributed to other physical 25 problems. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 11 1 By the time the disease has been diagnosed, it is 2 usually too advanced to be cured. There are many stories of 3 people whose lung cancers are misdiagnosed thereby delaying 4 treatment for months and even years. I would like to tell 5 you a few of these stories. These are case histories based 6 on people who have called in to ALCASE. 7 For example, there was a CPA from New York. She 8 was in her early forties. She called us back in 1994. She 9 had been treated for a year for back pain with analgesics 10 and heat by her family practice physician. She after a year 11 decided to consult a chiropractor because her pain wasn't,-12 getting any better. The chiropractor did an x-ray and found 13 lung cancer. She was diagnosed with Stage 3 non-small cell 14 lung cancer and died this past year. 15 Another woman, 39 years of age, called us 16 recently. She had been suffering from bronchitis and a 17 sinus infection all last winter, and was diagnosed with 18 many, many different diagnostic steps including an MRI of 19 her head to look at the sinuses. 20 She improved, was treated with antibiotics, 21 improved somewhat, and decided to take a road trip. During 22 her trip, she tripped and fell, and went to a hospital 23 emergency room where they x-rayed her for possible broken 24 ribs. She was diagnosed with Stage 3 non-small cell lung 25 cancer. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 12 1 A third woman, age 58, and her husband, age 68, 2 had scheduled physical exams by the same physician. The 3 doctor prescribed a chest x-ray for the man, and not for the 4 woman. Later she was given a colonoscopy and was diagnosed 5 via that with metastatic lung cancer. 6 These are many stories like these. Because lung 7 cancer has historically been a man's disease, physicians 8 forget to include it in the differential diagnosis for their 9 female patients. 10 While lung cancer is no longer an old man's 11 disease, neither is it an old woman's disease. More-and ; 12 more people in their 30's, 40's, and 50's are being 13 diagnosed with lung cancer every year. It is imperative 14 that health care professionals be educated about the changes 15 in lung cancer's epidemiological profile. 16 Improving diagnostic procedures can become a part 17 of that education. The May 1994 edition of a patient and 18 family guide published by the American Lung Association 19 stated that, "There is no benefit from yearly chest x-rays 20 with sputum cytology ... and that screening has not shown to 21 decrease the lung cancer death rate. In cases where lung 22 cancer was detected in its earlier stages, the data have not 23 shown any decrease in mortality." 24 This bleak outlook can become part of the 25 physician's beliefs about the efficacy of early detection MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 - 13 1 and aggressive proactive treatments. Yet, it cannot be 2 denied that a cure is possible when tumors localized in a 3 resectable site are surgically removed before they have 4 metastasized. 5 The American Cancer Society's Facts and Figures 6 for 1995 states, however, that although the five-year 7 survival rate for lung cancer is only 13 percent, it rises 8 to 47 percent for cases detected when the disease is still 9 localized. However, only 15 percent of lung cancers are 10 diagnosed in Stage 1 and 2. 11 In this light, we believe that the issue here is 12 not only treatment efficacy based on the current average 13 stage of tumor at diagnosis, the issue is promoting and 14 providing earlier diagnosis and improved diagnostic 15 techniques. 16 While it is true that the chest x-ray can miss a 17 tumor in its earliest stages and sputum cytology may yield 18 individual cells in numbers that are too small to be seen on 19 an x-ray, they are useful diagnostics and it is important to 20 make these and other tools available to all persons with 21 lung cancer risk factors. 22 We must educate the health care community to 23 reclaim the scientific heritage of their craft by 24 approaching patients with an open and investigative mind. 25 Then, we must provide the tools to make that investigative MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 17.07.) R46-S666 14 1 process fruitful and rewarding. 2 Finally, we must launch a whole-hearted and 3 vigorous campaign to combat the effect of cigarette 4 advertising, especially on our young women and men. And we 5 must not be afraid to tackle the difficult task of 6 eliminating the use of cigarettes in our culture. 7 I and the members of the Alliance for Lung Cancer 8 Support, Education, and Advocacy, also known as ALCASE, 9 thank you for this opportunity to speak. I am very glad to 10 be he r e . 11 CHAIRMAN BUNN: Thank you very much. . 12 Are there any questions or comments from Committee 13 members? 14 [No response.3 15 CHAIRMAN BUNN: Since I am interested in this 16 topic, I will give my points of view. 17 From the Surgeon General's report in 1964 until 18 1991, cigarette consumption as measured by the percentage of 19 adults who smoke went down, and over the last three years, 20 the data are that cigarette consumption is no longer 21 declining in the United States and more than 25 percent of 22 the adult population continues to smoke. 23 It is probably no accident that in the last 10 24 years, cigarette advertising expenditures have gone from $2 25 billion a year to $7 billion a year. Not only are they the MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 15 1 largest advertisers in the world, but they probably equal 2 everything else advertised in the world. 3 A couple of points of good news. Even though the 4 cure rate is only 13 percent in the United States, shortly 5 after the Surgeon General's report came out, it was 4 or 5 6 percent, and it is now 13 percent as you mentioned. In 7 Europe, the cure rate for lung cancer is still only 4 or 5 8 percent. So we seem to be doing something which may be 9 somewhat hard to identify. 10 We appreciate hearing from you. There has been 11 some controversy over whether the Comnjittee is interested- in 12 hearing from consumers, and I can assure you that we are. 13 We are also, as has been mentioned many times before, 14 interested in approving safe and efficacious drugs which 15 will improve the situation of cancer patients in our 16 country. 17 NDA 20-587 STERILE AEROSOL TALC 18 CHAIRMAN BUNN: So without further comment, then, 19 we will turn to NDA 20-587 sterile aerosol talc, and the 20 presentation will be given by Bryan Corporation. 21 MR. FRANK ABRANO 22 MR. ABRANO: My name is Frank Abrano and I hold 23 the position of Chief Executive Officer of Bryan 24 Corporation, which is a small, privately-owned medical 25 device company located outside of Boston. I am honored MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 16 1 today to have the opportunity to present Sclerosol, a 2 sterile aerosol talc for use in malignant pleural effusion. 3 I will begin by providing some background 4 information on Bryan Corporation. Bryan Corporation was 5 established in 1985, develops and promotes technology in the 6 field of diagnostic and therapeutic endoscopy. _ 7 This company began with the introduction of the 8 modified Dumon-Harrell Yag Laser Rigid Bronchoscope which 9 remains the number one bronchoscope in the world today. 10 Following this product, Bryan Corporation 11 introduced the first Baggish Continuous Flow Hysteroscope.in 12 the United States in 1988. This system was marketed by Week 13 Surgical under a license agreement with Bryan Corporation. 14 After working with Dr. Dumon and his colleagues in 15 Marseille, France, for a number of years, we realized that 16 the development of an aerosol talc addressed significant 17 clinical needs in the management of malignant pleural 18 effusion. 19 This is Bryan Corporation's first New Drug 20 Application. This is an unusual submission since it is 21 based on a literature search. 22 It gives me great pleasure to introduce to you 23 today Dr. John Beamis, the head of the Section of Pulmonary 24 and Critical Care Medicine at Lahey-Hitchcock Clinic in 25 Burlington, Massachusetts. Dr. Beamis was one of the first MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D .C . 20002 (202) 546-6666 17 1 individuals to assist Bryan Corporation in pioneering the 2 Dumon tracheobronchial stents. Today, Dr. Beamis will 3 present the clinical overview to Sclerosol sterile talc. 4 Thank you. 5 DR. JOHN BEAMIS 6 DR. BEAMIS: Thank you, Frank. 7 [Slide.] 8 Malignant pleural effusion is a condition that 9 occurs in many cancer patients. One estimate is that there 10 are 200,000 cases per year in the United States. This I 11 think is just an estimate from Dr. Light's book on pleural, 12 disease. It is the second most common cause of pleural 13 effusion next to congestive heart failure, and it is the 14 most common cause of exudate of pleural effusions. 15 [Slide.] 16 Lung cancer is the most common cause of malignant 17 pleural effusion followed by breast cancer, lymphomas, and a 18 number of other malignancies that can metastasize to the 19 lung or to the pleural space, producing a malignant pleural 20 effusion. 21 [Slide.] 22 Most patients with malignant pleural effusions are 23 symptomatic, and although these patients are usually 24 considered incurable because of the fact that they have 25 studding of their pleural cavity or certainly unresectable MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 On?.'* 18 1 disease, these patients do need palliation for the effusions 2 because they do produce symptoms primarily of dyspnea, some 3 chest pain, and usually, because of the dyspnea and the 4 extent of their cancers, they have significant systemic 5 symptoms. 6 [Slide.] 7 There are a number of treatment options for 8 malignant pleural effusions. Some small effusions can 9 simply be observed, at least for a number of weeks, 10 sometimes a number of months, although usually they 11 eventually become symptomatic. / 12 Simple thoracentesis and removing the fluid 13 occasionally suffices for therapy. Systemic therapy would 14 certainly be ideal. It certainly is helpful in many 15 patients with breast cancer who receive hormonal therapy or 16 chemotherapy, but in most patients with lung cancer, 17 systemic therapy does not control their effusion. 18 The last therapy that talc has been used for, for 19 a number of years, is pleurodesis or pleural sclerosis. 20 [Slide.] 21 The indications for pleurodesis for malignant 22 pleural effusions are symptomatic patients. Usually, one 23 should document that the patient's symptoms are improved by 24 removing the fluid. So every patient should have a standard 25 thoracentesis, removal of the fluid, and then a follow-up to MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 19 1 assure that there has been relief of symptoms. 2 One has to rule out trapped lung or bronchial 3 obstruction. It is most important that the lung re-expands 4 after the fluid is removed, so that pleural synthesis can be 5 achieved. Some authors feel that if a pH is very low, lower 6 than 7.2, that the chance of success of pleural sclerosis is 7 quite low. That hasn't been our experience, but that is 8 mentioned in the literature. 9 [Slide.] 10 The options for pleurodesis over the years have 11 included agents to produce inflammation and fibrosis of the 12 pleural surfaces. Tetracycline for many years, from 13 probably the mid-seventies until several years ago, was by 14 far the most commonly used agent, but intravenous 15 tetracycline, which is used through chest tubes, is no 16 longer available, so that other treatments have been used. 17 Doxycycline and minocycline have been used by a 18 number of institutions since then. They probably work as 19 well as tetracycline did, but there have not been good long 20 term studies on these. 21 Bleomycin, a chemotherapeutic agent, has been used 22 for pleurodesis for a number of years, probably producing 23 similar results to tetracycline. One concern from many 24 clinicians has been the expense of this medication. 25 Most studies in the literature show that these MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 1202) 546-6666 20 1 agents work approximately 70 to 75, 80 percent of the time, 2 out rarely approach success rates over 80 percent. 3 Talc has been available since the 1930's for 4 various indications to produce pleural synthesis. It has 5 been used either as a slurry, where it is suspended in 6 saline, or by insufflation. 7 In the literature, there are a number of series of 8 the use of talc for pleural sclerosis. Many of these have 9 been reported in the briefing documents that you have been 10 given. Many of these studies do show that the success rate 11 of talc for pleurodesis is over 90 percent, and in some ; 12 studies, approaches 100 percent. 13 [Slide.] 14 The advantages of using thoracoscopy for 15 pleurodesis is that one can achieve a rapid total drainage 16 of the pleural effusion, and this is most important to 17 achieve full lung expansion and adherence of the visceral 18 and parietal pleura. 19 One can also inspect the pleural space, do any 20 biopsies that might be indicated. Visual placement of the 21 chest tube I think is very important. In the thoracoscopy 22 cases that we have done and placed the chest tube visually, 23 you can assure that it is in the proper position going up in 24 the posterior gutter. Extra holes can be put in the chest 25 tube, again to make sure that the pleural cavity is drained MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 21 1 after suction is applied. 2 One can then confirm talc distribution if talc is 3 aerosolized or placed inside the cavity. 4 [Slide.] 5 For years, USP talc has been used in an atomizer, 6 which I will show in a minute, to insufflate talc into the 7 pleural cavity. It is very inexpensive. There are multiple 8 suppliers around the country evidently. It is supplied non- 9 sterily to hospitals, so that one must sterilize this and 10 package this locally. 11 That has been a problem in a number of ' 12 institutions in that there is no good standard on how to 13 sterilize this bulk talc, and one requires an insufflator to 14 do this. So the pharmacies must sterilize it, they must 15 prepare it and package it, and then store it in their 16 institution. 17 [Slide.] 18 This is the type of insufflator that has been used 19 through a thoracoscope to blow in insufflated talc. The 20 talc is usually placed in this either glass or plastic 21 container, and then there is an air bulb syringe that would 22 blow the talc through a thoracoscope. 23 [Slide.] 24 There are several methods to sterilize talc, dry 25 heat, ethylene oxide, and gamma irradiation, and most MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 22 1 hospitals have these two available to them, and there is 2 some debate about the exact temperature that should be used. 3 One author recommended this 130 degrees centigrade for six 4 hours. Some people recommend 12 hours. So the problem has 5 been the standardization of this. 6 Ethylene oxide also was used for some time. I 7 think the last I read it was going out of vogue. Gamma 8 irradiation may not be available for most hospitals. 9 [Slide.] 10 The Sclerosol agent sterilized talc that we are 11 discussing today is a can of 4 grams of Luzenac talc. This 12 is from France. It is a very fine asbestos-free talc powder 13 of very fine particle size. It is sterilized by gamma 14 irradiation, and it is in an aerosol canister that has a 15 propellant. 16 The talc is delivered through a catheter that 17 comes out of the container at a fairly fast rate. 18 [Slide.] 19 This just shows the container that we have used, a 20 sterile aerosolized talc, the plastic catheter that comes 21 off here, and the talc can then be delivered through a 22 thoracoscope. 23 [Slide.] 24 The technique that we have been using for 25 approximately a year now involves thoracoscopy performed by MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 54 6 - 6 6 6 6 23 1 a pulmonologist in a procedure room. This is not done in 2 the operating room. It is done under local anesthesia with 3 intravenous sedation. 4 We usually have the patient come in, in the 5 morning. Every patient has already had an established 6 diagnosis and has agreed to this procedure. We do a 7 thoracentesis of 3- to 500 cc's, and then just the opposite 8 of what we have been taught for many years, we actually try 9 to induce a pneumothorax. 10 We have the patient take about 10 deep breaths, 11 and they will suck air into the pleural cavity. We then : 12 send the patient to Radiology where we confirm that they 13 have a pneumothorax and that they have a large air space, so 14 that we can safely put in the thoracoscope. 15 Then, in the afternoons we have been doing the 16 thoracoscopy in the bronchoscopy room, I.V. sedation, 17 topical lidocaine, pretty much similar to the type of 18 anesthesia you would be using to put in a chest tube, being 19 at the bedside, possibly a little bit more of this. 20 We drain the remainder of the fluid. If we need 21 to, we obtain a biopsy. We then place the chest tube under 22 direct vision, so we are sure that it is not in a fissure, 23 that it is not overlying the diaphragm, and we have been 24 Using two cans of the Sclerosol, which is a total of 8 25 grams. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 24 1 Essentially, every patient has been discharged 2 after two to three days of drainage with this. 3 [Slide.] 4 This just shows the pneumothorax that has been 5 induced in the outpatient clinic in a patient that we did. 6 You can maybe see a little pleural thickening where there 7 was metastatic disease to the pleural surface. 8 This is a very safe procedure, putting a 9 thoracoscope in this type of a cavity, much different from 10 the video-assisted thoracic surgery that is done in the 11 operating room. ' 12 [Slide.] 13 This just shows the talc that is going through the 14 thoracoscope. Here is what is bringing this in. 15 [Slide.] 16 This may not show up too well, but this is a 17 patient who proved to have a mesothelioma, but this is an 18 adhesion to the chest wall. The lung is adhesed up here, 19 but certainly it is a large cavity that we could spray talc 20 out into. We usually don't try to cut these adhesions at 21 this point. 22 [Slide.] 23 This shows the talc after it has been sprayed in. 24 You can see it has coated the area quite well. Some of this 25 powder is so fine that you really can't see it too well on MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 . 25 1 the surface. It does concentrate in the areas probably 2 where that plastic catheter was aimed at. 3 [Slide.] 4 This just shows again the fine coating of the 5 pleural cavity by the talc. 6 [Slide.] 7 There aren't papers or a series on Sclerosol. It 8 is mentioned in one paper by Colt and Dumon, who had an 9 article in Chest in 1994, describing the development of this 10 spray canister. In their article, they mention that they 11 did treat 12 patients with malignant pleural effusions, and 12 11 out of 12 were successful. No specific follow-up is 13 given. There were no complications although 30 percent of 14 their patients did have a low grade fever. 15 We have recently submitted an abstract for the 16 American Thoracic Society annual meeting in May on the first 17 11 patients that we did. Ten of the 11 were successful. 18 The one patient required -- I think it probably would have 19 been successful. We became impatient after five days of 20 drainage and put some extra doxycycline in, and then his 21 drainage stopped and he has done fine since then. 22 We had no complications of the procedure. Again, 23 we noted transient fever in some of the patients in follow 24 up. 25 [Slide.] MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 26 1 I haven't reviewed all the papers and the 2 literature that was submitted with this application. All of 3 them concern the use of the standard USP talc, which has 4 been available for years. 5 I think some of these questions probably have been 6 answered, talc versus other pleural sclerosants. In 7 general, in the papers and the literature, the success of 8 talc is 90 percent or more, approaches, in some series it 9 has been 100 percent successful. 10 Most of the other sclerosants in the series give 11 you success rates anywhere from 70 to 80 percent, sometimes 12 even lower than that. So I think most clinicians and the 13 literature supports the fact that talc is probably the best 14 agent for pleural sclerosis. 15 The problem has been getting talc into the pleural 16 cavity. It does require a procedure. Thoracoscopy, I think 17 is an ideal way to apply this to the pleural cavity, but it 18 is a procedure that may not be available to a number of 19 institutions. 20 There is still some question of whether the talc 21 can be put in as a slurry or whether it has to be sprayed in 22 as a scope versus tube. There is, I think, an ongoing 23 study, a multicenter study, looking at this. I have 24 certainly not seen any data one way or the other. 25 Again, with talc, there is always the question how MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 27 1 much to use, and I think that has not been settled. People 2 say anywhere from 2 to 8 grams of talc. I don't think there 3 is a correct amount at this point in time. 4 We tried to visually coat the pleural cavity as 5 best we can. In our experience, it has taken two cans of 6 the Sclerosol. 7 Whether this should be used in benign disease is a 8 question. Certainly, classically, USP talc has been used 9 for many years to produce pleural synthesis in patients with 10 recurrent pneumothorax. We are not talking about that 11 today, but it certainly has been used for a long time for. 12 that indication. 13 Are there any long-term effects of this? This has 14 been studied primarily in patients who were treated for 15 benign disease with pneumothorax. There are papers in the 16 literature with 30-year follow-ups showing that talc 17 pleurodesis does not cause significant restrictive lung 18 disease, and now that we can be sure that there is no 19 asbestos fibers in the talc, I think the concern about 20 inducing mesothelioma, other malignancies, is not there 21 also. 22 [Photograph.] 23 I don't know if you can see this. I didn't have a 24 slide, but this is the snowstorm effect that takes place 25 when you put this talc in the cavity. When you blow the MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (U02) 546-6666 28 1 talc into the pleural cavity, it produces almost like a 2 snowstorm effect and that the talc distributes very finely 3 throughout the entire pleural cavity and deposits there. 4 I will be glad to take any questions. 5 CHAIRMAN BUNN: I think we will hold questions 6 until you are finished. 7 Do you have other speakers? 8 DR. BEAMIS: No. 9 CHAIRMAN BUNN: So you are not going to review any 10 of the literature studies? We will have questions then. 11 DR. BEAMIS: I will be glad to go over some of the 12 articles that are in the briefing documents. 13 CHAIRMAN BUNN: Dr. Krook? 14 DR. KROOK: Being an internist at heart and 15 working with chest physicians who don't necessarily enter 16 into the OR, have you put in the aerosol talc on -- I guess 17 I will use the word oncology units - - w e presently use the 18 slurry, but have you put the aerosol talc through just the 19 chest tube, or has it all been under a thoracoscope? 20 DR. BEAMIS: We haven't put it through a chest 21 tube, no. Our colleagues in France have said that you can 22 do this, but I think if the chest tube has a significant 23 amount of humidity in it or fluid, I am afraid that the talc 24 would congeal inside the chest tube. 25 It possibly could be done, but we haven't studied MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 29 1 that. 2 DR. KROOK: I would anticipate the response rate 3 or the decrease of fluid would be less, but on the other 4 side of the coin, there is a cost issue, and it is less 5 costly to do that. It will be interesting what happens 6 here. 7 DR. BEAMIS: We have done it in the procedure 8 room, not in the operating room. 9 CHAIRMAN BUNN: You mentioned that the goal of IO this is to relieve patients' symptoms, and when you say that 11 the success rate is 90 percent, and in your own series, 10 12 out of 11, is the success rate the absence of pleural 13 effusion or is it relief of symptoms? What evidence do you 14 have that the patients feel symptomatically better after 15 this treatment? 16 DR. BEAMIS: Well, we have done a thoracentesis 17 before the treatment to know that removing the fluid has 18 improved their symptoms of dyspnea, so that we wouldn't do 19 this on someone who isn't improved with thoracentesis. 20 Sometimes patients have lymphangiectic disease or 21 the lung involvement, so that even if you take the fluid 22 out, you don't palliate their dyspnea. 23 The follow-up that we have done has been both 24 symptomatic and radiographic. We have had patients come 25 back at monthly intervals. Certainly, if you can keep the MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 30 1 fluid out, the symptoms are relieved. The main symptom is 2 dyspnea, and I don't think there is any question if you can 3 keep their fluid controlled, the dyspnea is relieved. 4 CHAIRMAN BUNN: Let me be more succinct. When you 5 say 10 out of 11 cases, does that mean the patient has not 6 had a recurrence? 7 DR. BEAMIS: I would say both. That is 8 symptomatic and radiographic improvement, radiographic 9 control of the fluid and symptomatic improvement in dyspnea. 10 CHAIRMAN BUNN: When you were talking to this 11 company about developing something new, you mentioned that 12 tetracycline was pretty cheap and was removed from the 13 market. Why doesn't the company make tetracycline, would 14 that be cheaper than talc? 15 DR. BEAMIS: I have never quite figured out why 16 tetracycline was removed from the market. I think it has to 17 do with the availability of products to make the 18 tetracycline. It was made by one of the large 19 pharmaceutical companies worldwide, and they just stopped 20 making it. 21 CHAIRMAN BUNN: When you were talking about costs 22 there, as Dr. Krook just mentioned, doing these procedures, 23 whether it is VATS or thoracoscopy, putting the person in 24 the hospital for three or four days is pretty expensive. 25 Do you have any comparators of both costs and MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 31 1 efficacy compared to, for example, draining some effusion in 2 outpatient, putting something in as an outpatient compared 3 to, you know, your procedure that you presented here? 4 DR. BEAMIS: I don't have that. I think the 5 standard in my career has been to bring patients into the 6 hospital, put a chest tube in, drain them for several days 7 or more until the drainage decreases to the classic number 8 has been 150 cc's per day, and then.a pleural sclerosant is 9 inserted into the chest tube, and then you drain them again 10 for another X number of days until you get to that magic 150 11 cc's. ' 12 That, in my experience, usually is anywhere from a 13 seven- to a ten-day hospitalization. Using this technique, 14 there is no up-front hospitalization. The patients come in 15 the same day, and they are in the hospital two to three 16 days. 17 So I think compared to the standard 18 tetracycline/chest tube approach, this is a much short 19 hospitalization. I know now there is interest in especially 20 the interventional radiology field to put a tube in a 21 patient, send them home with a drainage until the drainage 22 decreases, and then have them come in, and quote, "put 23 something in." 24 I have heard anecdotal reports of that. I know it 25 is done in some institutions. I am not aware of the results MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 32 1 of that or the costs. ' 2 DR. KROOK: There are two interesting comments. 3 Since I live in the managed care world in Minnesota, we now 4 are an intelligent people putting chest tubes in and sending 5 them home the same day, and letting them manage at home. It 6 is happening. 7 DR. BEAMIS: It is happening with pneumothorax. 8 DR. KROOK: It is happening in malignant pleural 9 effusions also, and that is why I brought up the delivery 10 system. So there is other things that come into play at 11 least in the -- ' 12 DR. BEAMIS: I guess I am not sure I would want to 13 be sent home draining 5- or 600 cc's of fluid. 14 DR. KROOK: I hear you, but it's happening. 15 DR. BEAMIS: I know, but that doesn't mean it is 16 the right way to do i t . 17 DR. KROOK: Right. The second issue is I think 18 there is two things here that are of interest. One is the 19 substance which you used talc. Paul already brought up you 20 could have probably blown bleomycin in there, you probably 21 could have put mustard in the situation, and you chose talc 22 probably for reasons you can say. 23 But the other is, as I said, the delivery system. 24 It's different than what has been used before, so there is 25 really two things that are together here, and it fits. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 . 33 1 DR. BEAMIS: It is still an old technique. I mean 2 in recent years, video thoracoscopy has become more 3 popularized, but it is still a very old technique. 4 CHAIRMAN BUNN: Dr. Forastiere? 5 DP. FORASTIERE: I was wondering if you could say 6 how many of those 10 success patients did not have 7 reaccumulation of the fluid, say, within a three-month 8 period. 9 DR. BEAMIS: None of them had fluid at the end of 10 a month, all the ones that did well. By the end of three 11 months, some of them we haven't had follow-up on. We / 12 haven't had to admit anyone for more fluid management. They 13 have died of other aspects of their disease or have moved to 14 other areas. 15 So we don't have at this point complete three- and 16 six-month follow-up, but I know that at one month, none of 17 the patients had reaccumulation of fluid, and we haven't had 18 to re-treat patients for fluid management. 19 DR. FORASTIERE: So the symptomatic improvement - 20 DR. BEAMIS: That's right, but these patients were 21 at the late stages of their cancer, so they may be dyspneic 22 for other reasons three months after we do this procedure. 23 DR. FORASTIERE: One of the concerns or the 24 problems with the chest tube aspect of it, from my 25 understanding, is the distribution of the tetracycline or MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 34 1 whatever the slurry is, whatever you put in there, but this, 2 it would seem, then, it would have this advantage from 3 looking at the pictures of broader and perhaps even 4 distribution on the surfaces. 5 DR. BEAMIS: I think so. There has always been 6 that concern about moving the patient, especially, if there 7 are adhesions, if you put something into the chest tube, is 8 it well distributed/ is the slurry -- I have seen CT scans 9 of patients who have had talc slurry, and it all seems to be 10 congealed at the base of the lung rather than distributed. 11 DR. FORASTIERE: So you think that is what you . 12 would attribute the higher success rate that you have? 13 DR. BEAMIS: I think so. Talc is an excellent 14 sclerosant, and it seems that you can distribute it very 15 well with this technique. 16 DR. FORASTIERE: Thank you. 17 CHAIRMAN BUNN: Dr. Gelber. 18 D R . GELBER: We are going to be asked to take 19 information from the literature to judge the safety and 20 effectiveness of this agent. 21 DR. BEAMIS: I didn't hear the first part. 22 DR. GELBER: We are being asked on the Committee 23 to take information from the literature - 24 DR. BEAMIS: Yes. 25 DR. GELBER: - - t o judge the safety and MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 35 1 effectiveness of this agent, and you have told us about your 2 series of 11 patients and describing 10 as being successful. 3 It is still not exactly clear to me how you have 4 defined success, but I wonder if you can help us to 5 understand, in the papers that you have reviewed, whether 6 consistent definitions of success have been applied, and 7 whether the definitions for success rate through the 8 literature might match yours, and if you can give us some 9 insight into what success might mean. 10 DR. BEAMIS: I think most of the papers in the 11 literature that I have seen, success has been evaluated at 12 30 and 90 days, primarily based on the chest film, the lack 13 of reaccumulation of fluid. 14 Some of the studies also talk about control of 15 dyspnea, but most of the studies have been based on the fact 16 that the fluid doesn't come back radiographically. 17 DR. GELBER: Is there, in general, a time frame 18 within which the fluid does not come back or it does come 19 back? 20 DR. BEAMIS: I think if it hasn't come back by 90 21 days, it is unlikely that it is going to come back in that 22 space. If you just did a thoracentesis on a patient without 23 a pleural sclerosant, it invariably comes back within 30 24 days. 25 So I think if you can go 30 and 60, 90 days MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 36 1 without reaccumulation of fluid, I think you can attribute 2 that very realistically to your therapy. 3 DR. GELBER: Is there any limited follow-up that 4 you need for the patients? 5 DR. BEAMIS: In the literature, a number of the 6 patients have died within the first few weeks, usually of 7 their primary disease. So I don't think you could say that 8 those patients were necessarily a success of the therapy. I 9 think you would have to follow a patient for 30 days. 10 DR. GELBER: Just a few more? 11 CHAIRMAN BUNN: Let me just make one comment. : 12 This Committee recommended that the FDA approve bleomycin a 13 year or so ago, and the studies there were based on the 14 efficacy objective was a 30-day chest x-ray not showing a 15 recurrence of the pleural effusion. That was the primary 16 endpoint of the study which we accepted. 17 That study was purported to also show as a 18 secondary objective a 90-day chest x-ray, and it was 19 reported to this Committee that this agent reduced 20 recurrence rate at 90 days, as well. 21 However, the 90-day data were not statistically 22 valid in my recollection primarily because so many patients 23 had dropped out, not because of recurrent pleural effusion, 24 but because these are sick patients, and the median survival 25 is often only three or four months. So many of the patients MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 37 1 had had progressive disease elsewhere, and had dropped off 2 the study. 3 But the majority of what we were presented and the 4 majority of things in the literature used absence of 5 recurrence at 30 days and a chest x-ray as the primary study 6 endpoints. 7 There is a national trial going on, and I think 8 you alluded to it, and I believe the primary endpoint is 9 also 30-day chest x-ray. 10 DR. BEAMIS: Pleurodesis, insufflation versus 11 slurry? ' 12 CHAIRMAN BUNN: Dr. Dresler, do you want to tell 13 us about the national study that is going on? 14 DR. DRESLER: It is a Phase III randomized trial 15 looking at thoracoscopic talc versus insufflated talc, and 16 there are several endpoints to it, but the main therapeutic 17 one is looking at 30 days, but we are following the patients 18 out for six months in order to see if we can't capture the 19 three months or six months. 20 CHAIRMAN BUNN: Is it using this product? 21 DR. DRESLER: No, it is not. It was initially 22 written that it could use the product, but because of some 23 difficulty in obtaining the drug, there is many questions 24 that come up that are pertinent to the study, and you need 25 to, once the patient is randomized to go to the operating MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 38 1 room, they need to do it within 24 hours, so therefore, it 2 is difficult to get access to the drug within those 24 hours 3 because of current restrictions. 4 CHAIRMAN BUNN: Because it is not an approved drug 5 yet. 6 DR. DRESLER: Right. 7 DR. BEAMIS: The best study in the ones that we 8 submitted was a study by Hartman, et a l ., University of 9 Indiana, and they were not concurrent randomization, but 10 they did compare talc versus bleomycin and tetracycline. 11 Their endpoint was at 30 days and at 90 days. : 12 Talc was 97 percent successful based on the chest 13 x-ray at 30 days. Bleomycin was 64 percent. In their 14 study, tetracycline was quite low, only 33 percent. 15 DR. GELBER: Are the 11 patients you just 16 reported, all of the patients that you attempted the 17 procedure in? 18 DR. BEAMIS: Yes. 19 DR. GELBER: No dropouts from that number in your 20 series? 21 DR. BEAMIS: No. 22 DR. GELBER: You also reported to us two 23 additional studies, your own and another one that are not in 24 our literature review. 25 Are you aware of any other people who might have MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 39 1 done investigations of this agent, that for one reason or 2 another did not report out their results? 3 DR. BEAMIS: I am not aware. I think there will 4 be some reported later on by the FDA group, but I am not 5 aware of any other studies, and frankly, the paper by Colt 6 and Dumon from Chest, I had thought that they were just 7 describing the technique. I happened to take- another look 8 at it last week, and I saw they had mentioned the number of 9 patients in there, but they don't mention a lot about these 10 patients. They just said they treated 12 patients, and they 11 were all successful. ' 12 DR. GELBER: Twelve is about the average number in 13 most of the studies that are reported, so 12 is not an 14 insignificant number when doing an individual study. 15 DR. BEAMIS: I think you do 12 patients, and you 16 write a paper, I guess. 17 DR. GELBER: That is apparently what has been 18 happening, yes. 19 CHAIRMAN BUNN: Just to clarify, the particular 20 product, those two studies that he presented were with this 21 particular product. The other studies in the literature was 22 something almost identical, but they weren't necessarily 23 sterilized with the gamma irradiation by this company, and 24 they weren't necessarily in this particular type of can. 25 They could have been insufflated with the old style thing MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 40 1 he showed there. 2 DR. GELBER: I see. So the data that we have 3 reviewed are with a different product. 4 DR. BEAMIS: That's right. 5 DR. GELBER: But supposedly the same - 6 CHAIRMAN BUNN: More or less the same product, 7 just minor differences, right. 8 DR. GELBER: So the additional information that 9 you have just shown us might be even more important. 10 CHAIRMAN BUNN: It is with this particular 11 product, right. : 12 DR. GELBER: For this particular product. 13 DR. SWAIN: In the Colt study and your study, were 14 any of the patients breast cancer patients who received 15 systemic treatment also at the same time? 16 DR. BEAMIS: We did have some breast cancer 17 patients. I don't know about the Colt study. We had two 18 breast cancer patients. They had failed systemic therapy 19 already. 20 CHAIRMAN BUNN: Could I ask the president of the 21 company a couple of questions? 22 This product you get from some mine in France, and 23 it is stated that there is no asbestos in here. We are 24 pretty naive on the Committee here, we don't know much about 25 manufacturing, and so on, but how do you know that there is MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 - 41 1 not asbestos in there, and how do you know that what the 2 shovel digs out of the mine is the same from one canister to 3 another? . 4 MR. ABRANO: First of all, it is an interesting 5 question, but Talc Luzenac probably has the purest mine in 6 the world located in France. It is well known. They have a 7 U.S. distribution office here in Denver, Colorado. 8 The talc that is made for this procedure, the 9 particle size is very well regulated, and it has been 10 chemically tested for asbestos-free in Colorado through 11 their office and also Talc Luzenac in Europe. They are the 12 largest supplier of talc in the world. 13 I have never personally visited the mine, but I 14 understand from people who are in the business, have 15 indicated that their mine is very pure. 16 CHAIRMAN BUNN: So someplace, though, somebody is 17 testing it for asbestos and purity. 18 MR. ABRANO: Yes, it is done in France, and also 19 there is a certain number that is attached to this talc, and 20 this particular talc is also used in food processing in the 21 United States. So I would presume that the testing of the 22 asbestos has been regulated by the FDA since it is used in 23 food. 24 CHAIRMAN BUNN: Obviously, a concern would be that 25 this could cause mesothelioma or some other pleural disease. MILLER REPORTING: COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 <202) 546-6666 42 1 There wasn't much on the long-term side effects other than 2 it could be an issue. 3 Are you aware of any long-term complications from 4 the use of this, either another malignancy or infections, 5 empyema? 6 MR. ABRANO: I am not aware of any infections, and 7 it has been used in Europe for years in an aerosol 8 container, and we have asked about any clinical papers 9 indicating any irregularities at all. 10 DR. OCHS: Could you talk about the eligibility of 11 the patients to get the talc? Is this primarily a ' 12 palliative approach in Europe? 13 DR. BEAMIS: Oh, yes, it is definitely a 14 palliative approach. Talc is.not a chemotherapeutic agent. 15 People that have died after talc pleurodesis, that have had 16 post-mortem examinations, you can demonstrate that there are 17 tumor cells still within the pleural cavity, within the area 18 that is fibrosed. 19 So this is purely palliation. Certainly, if there 20 are other therapies that are available to the patient, we 21 would encourage them to have that, but many of the patients 22 with breast cancer have already failed systemic therapy. 23 The lung cancer patients, in general, they have failed other 24 therapies, too, or they just don't work as well. This is 25 purely local therapy for palliation. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 43 1 DR. OCHS: I think that needs to be clearly stated 2 because I saw in most of the studies, you have elderly 3 patients, but from personal experience, having had a 4 teenager with a pleural effusion that was given talc, who 5 turned out to be a newly diagnosed lymphoma patient, and 6 certainly in teenagers and young adults, where highly 7 curable lymphomas oftentimes the presenting symptom will be 8 a pleural effusion. I think that needs to be very clearly 9 understood. 10 DR. BEAMIS: I agree it is palliation. In some 11 ways that is one advantage of the thoracoscopy in that you 12 can be assured of the diagnosis. Patients often present 13 with a pleural effusion. If you do a thoracentesis, you 14 might get endocarcinoma cells and just stop there, but we 15 have had two of our series had that diagnosis, and on 16 thoracoscopy proved to have mesothelioma. 17 So I think the systemic therapy is much different 18 in endocarcinoma of the lung versus mesothelioma, so I think 19 it is important for one to know what the diagnosis is and to 20 make sure that they have benefitted from appropriate therapy 21 for that primary disease. 22 CHAIRMAN BUNN: I am going to ask you a question 23 that the FDA usually asks us. We have to approve or 24 recommend approval or disapproval based on whether a drug is 25 safe and efficacious, and we are supposed to determine MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546 - 6 6 6 6 44 1 whether it is safe and efficacious based on some study that 2 is deemed to be an adequate and well-controlled study. 3 For your own information, historical control can 4 be sufficient or well controlled, but in your own view, you 5 have obviously read these papers, obviously, they range in 6 size and quality considerably, do you in your own opinion 7 believe that some of these trials are adequate, well 8 controlled trials? 9 DR. BEAMIS: I think Hartman's trial is the best. 10 Some of the others I would say probably adequate. 11 Hartman's, I think is very good. Again, it is based on 12 historical controls. 13 I guess in my own mind I do feel that talc has 14 stood the test of time, I do feel that it is the best 15 agent. The question of delivery and availability of 16 thoracoscopy or getting into the pleural spaces will remain 17 even if this product is approved. 18 I think the safety issue has been, in all these 19 series, I think pretty well proven over the years. Many 20 patients have fever. It appears not to be related to 21 infection. 22 Although empyema is a problem, and it has been a 23 problem with the talc that is available over the years, I 24 know before we started using this agent, we had some USP 25 talc that was sterilized in our institution, and it had a MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 45 1 number -- over a six-month period - - a number of empyemas I 2 that we could never absolutely prove it was from the talc, 3 but when we stopped using our home-sterilized talc, the 4 empyemas didn't happen. 5 So I think there is always a question of sterility 6 of the agent, and it is very localized, there are no 1 standards, there appears to be no systemic distribution of 8 the talc when it is put in the pleural..cavity. 9 There have been some animal studies that have 10 shown talc in other organs, but I think as far as damage to 11 other organs of malignancy, restrictive lung disease, all: 12 these safety issues, I think have been pretty well shown in 13 these studies. 14 DR. GELBER: Thank you for the answer to that. 15 That was very helpful. I wonder what aspect of the Hartman 16 study in particular, if you have any ideas you can give us, 17 that selected that one as the one that you would say is the 18 most adequately controlled. 19 DR. BEAMIS: I think it had the largest numbers, 20 for one, and it is a well-respected institution. They had 21 had experience in all of the various areas. They were good 22 at thoracoscopy. I think they did the technique well. I 23 happen to know one of the authors. I am pretty sure -- but 24 I think the study was done correctly, having talked to them 25 about this, I think primarily it is because it has such MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 . (202) 5 4 6 - 6 6 6 6 46 1 large numbers compared to other studies. It is ;more_ than 12 2 patients. 3 CHAIRMAN BUNN: If there are no other questions, 4 thank you very much. 5 We will go on to the FDA presentation by Lydia 6 Larson. 7 FDA PRESENTATION 8 DR. LYDIA LARSON 9 [Slide.] 10 DR. LARSON: Good morning. I will be presenting 11 the review on NDA No. 20-587, Sclerosol, which is sterile- 12 aerosol talc. The sponsor is Bryan Corporation. 13 [Slide.] 14 The proposed indication for Sclerosol is for the 15 treatment of malignant pleural effusions secondary to 16 malignancies having spread to the pleural space. 17 [Slide.] 18 What I would like to do is take a moment and just 19 go over the trilaminate structure of talc. It has 20 alternating silicate and magnesium sheets, silicate and 21 magnesium, and then silicate again. And it acts as a 22 lubricant due to its planar properties, as you can see 23 across the difference crystals. 24 Now, cation impurities can result from cation 25 substitutions in the magnesium position. As I mentioned , . MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 5 4 6 - 6 6 6 6 47 1 earlier, this where your magnesium is positioned in the 2 crystalline structure. 3 These cation substitutions can consist of calcium, 4 aluminum or iron. Now, other contamination, for instance, 5 asbestos, can occur depending on where the product is mined. 6 [Slide.] 7 Talc is documented in the literature as early as 8 1935, when Bethune reported the first use of talc to create 9 pleural adhesions. Then, in the fifties, there was 10 documented use in England, as well as Europe, of talc being 11 used as a pleural sclerosing agent via poudrage, which is.12 insufflation or slurry. 13 In the sixties, talc (poudrage) was reported in 14 the U.S. as effective management of malignant pleural 15 effusions, however, it was used sporadically at that time, 16 and that was mainly due to the fact that tetracycline was 17 available then. 18 Then, injectable tetracycline no longer became 19 available, and there was increased use of video-assisted 20 thoracoscopy, both for diagnosing and treating pleural 21 diseases, and so poudrage became more viable, which led to 22 the increased use of talc. 23 [Slide.] 24 There is no approved talc product for the 25 treatment of malignant pleural effusions, in fact, USP MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 48 1 standards at this time do not require that talc be asbestos- 2 free or sterile. They are moving toward international 3 harmonization with the British, European, and Japanese 4 pharmacopeia. 5 In October of '93, the FDA Centers for Devices and 6 Drugs determined that talc could be approved for the 7 treatment of malignant pleural effusions if certain 8 conditions were met, mainly that it be asbestos-free and 9 sterile. 10 In March of '94, as a result of this, CDER did 11 send out to all talc distributors a letter inviting them to 12 submit an NDA, and Bryan Corporation was one of the few 13 companies that did submit an NDA. 14 Now, the Federal Food and Cosmetic Act does allow 15 a literature-based NDA, so the decision was made that it 16 would be acceptable, Bryan's NDA would be acceptable for 17 filing, however, it is subject to the criteria of adequate 18 and well-controlled trials or studies. 19 [Slide.] , 20 As I mentioned, this NDA is literature based, and 21 the three databases that the sponsor used were three of the 22 largest known today, namely, Medline, Biosis, and Embase. 23 Searched parameters were malignant pleural effusions, talc 24 pleurodesis, and chemical pleurodesis, and their results 25 were nine controlled trials (6 articles and 3 abstracts), MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 49 1 consisting of talc compared to chest tube only concurrent 2 control, that was one study; five active concurrent 3 controls, and three historical controls. 4 So the Agency verified the search and added the 5 next three largest databases, which are Cancerlit, 6 International Pharmaceutical Abstracts, and Derwent Drug 7 File, and found an additional three controlled trials, 8 however, they are abstracts. 9 They consisted of talc compared to active 10 concurrent| control, that is two studies, and one study is a 11 historical control. ' 12 So as you see it here, we have 12 studies, of 13 which 6 are articles and 6 are abstracts. However, one of 14 the abstracts that the sponsor submitted was an abstract by 15 Hartman in 1992, and that was a preliminary report of 16 Hartman's 1993 article. Therefore, we took it out. In 17 fact, that study was reported at the 72nd annual meeting of 18 the American Association of Thoracic Surgery in Los Angeles, 19 California, back in April of 1992'. 20 'So when you see this presentation, you are going 21 to notice that Hartman's abstract is not going to be 22 included, arid that is why. 23 [Slide.] 24 What I am going to do now is go over the articles 25 first, and then I will move on to the abstracts. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 . '202) 546-6.666 50 1 This is the study design of the concurrent control 2 articles, and I just wanted to orient you to these tables, 3 because we are going to be seeing quite a few, and they are 4 all set up the same. 5 On the lefthand column, you will find the author 6 and patient numbers per arm, study design, whether 7 stratification did take place, treatment received and dose, 8 and the tumor type if it was reported. 9 I did want to state ahead of time that in all 10 these articles except for one -- and I will get into that 11 later -- a single dose was administered, whether it be the 12 control arm or the talc arm. 13 Now, in all four of these articles, they all four 14 were prospective and randomized. Two of the articles did 15 stratify according to the presence or the absence of 16 metastases requiring systemic chemotherapy. 17 The treatment received was via poudrage in three 18 of the articles, and one was via slurry, and the tumor type 19 in three of the articles was breast cancer, and in one of 20 the articles, in Sorensen's '84 article, it was a variety of 21 tumors, which included ovarian, prostate, mesothelioma, 22 breast, GI, and lung. 23 Now, in Sorensen's article, this was the chest 24 tube drainage with talc compared to chest tube drainage 25 alone, and they did control for the chest tube drainage time MILLER REPORTING COMPANY, INC. 507 C Street, N.E, Washington, D.C. 20002 t?n?) 51 1 equally in both arms, which was 72 hours. 2 I also wanted to mention that the tumor type in 3 Sorensen's was reported in both arms together, so there was 4 no way of separating tumor types. 5 In Hamed's article, '89, actually, one patient 6 received bleomycin in one lung and one talc in the other, 7 and then there were two patients that received bilateral 8 therapy. 9 I also wanted to quickly go over the doses of the 10 control arms. In Fentiman's '86 article, tetracycline was 11 administered at 500 milligrams of slurry. In Fentiman s .83 12 article, mustine was administered at 15 milligrams. In 13 Hamed's '89 article, bleomycin was administered at 1 14 milligram per kilogram. 15 [Slide.] 16 This particular slide is a characteristics of 17 success across the trials. So you have a number of 18 evaluable patients per number entered, definition of 19 evaluable patients, definition of success, method of 20 evaluating success, success in evaluable patients, the 21 results, an intent to treat analysis -- this is the Agency s 22 analysis -- response duration, and symptom relief. 23 In Sorensen's '84 article, definition of evaluable 24 patients was these patients, their lungs had to re-expand by 25 72 hours, otherwise, they were no longer considered MILLER REPORTING COMPANY, INC. 507 C Street,. N.E. Washington, D.C. 20002 (202) 546-6666 52 1 ^Vciluable. As you can see, d6f inition of s u c c e s s throughout 2 these four trials was no fluid reaccumulation on all follow 3 ups. Follow-up time did vary, though, anywhere from three 4 months to 12 months, and in Hamed's, they did say on all 5 follow-ups. 6 Method of evaluating success across the four 7 trials was by chest x-ray, with three of them identifying it 8 at one-month interval, and then two articles did evaluate 9 success every three months after that. 10 As far as success in evaluable patients are 11 concerned, in the talc arm, we had a range of anywhere from 12 90 to 100 percent, and in the controls, the range was 13 anywhere from 33 to 58 percent. 14 Now, if we were to apply an intent-to-treat 15 analysis, the results would have ranged anywhere from 61 to 16 78 percent in the talc arm, and 39 to 43 percent in the 17 control arms. As you see here, we were not able to apply an 18 intent-to-treat analysis in this particular study, Hamed's 19 '89 study. The reason for that is that once they did report 20 their patients, after that, their success rate was reported 21 as procedures, and there was no way of assessing how many 22 patients actually did experience success. So an intent-to23 treat analysis was not possible at that time from that point 24 on. 25 Response duration was, in Sorensen's trial, until MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 ( 202) 546-6666 53 1 death in both arms with 10-month median duration, 12 months 2 in Fentiman's '86 trial, 6 months in Fentiman's '83 trial in 3 both arms or until death, and it was not provided in Hamed's 4 '89 article. 5 Symptom relief was described in Sorensen's '84 6 trial. It was 9 out of 9 in the chest tube and talc arm, 7 and chest tube only arm experienced 6 out of 7, and those 8 are evaluables or rather success patients. Symptom relief 9 for the talc arm was described as relief of dyspnea, and in 10 the control arm, they defined it as subjective improvement, 11 but they didn't describe it any further. 12 You have a small fraction here in Hamed's '89 13 article, and basically, that is to remind me to tell you 14 that 2 of the patients in the bleomycin group, 2 of the 15 patients that failed on bleomycin went on to receive talc, 16 and 1 out of the 2 did experience relief of symptoms, 17 however, they didn't describe it any further than that. 18 [Slide.] 19 On this slide are historical-controls articles. 20 In addition to the possible publication biases, the controls 21 are historical in nature and further bias can be introduced. 22 In Adler's study, '67, the study was retrospective in nature 23 with a historical review group. They weren't really 24 historical controls. The medication that was used, the 25 sclerosing agent that was used, was a variety of agents to MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 5 4 6 - 6 6 6 6 54 jam 1 include thiotepa, nitrogen mustard, radioactive phosphate, ' 2 radioactive gold, quinacrine. As you can see in both studies, they did 3 administer talc via poudrage, and there was a variety of 4 tumor in both studies, tumor types, that were actually 5 6 accepted onto the study. 7 In Adler's study, the tumor type in the talc arm 8 consisted of mesothelioma, bronchogenic carcinoma, and 9 breast. In the historical review group, the tumor type 10 1 consisted of breast, lung, lymphoma, and ovarian. 11 I did want to mention that they did compare age. 12 tumor type, response, chest tube drainage time, also pleural 13 fluid, amount of pleural fluid drained, but they made no 14 conclusions and no comparisons beyond that. 15 In that particular study, the patients were from a 16 1previous multicenter study that had taken place at the 17 | investigator's institution, which was Buffalo General 18 Hospital, and also another institution, which was Roswell 19 Park Memorial Institute. 20 Basically, the objective of this study was to 21 I introduce a new aerosolized unit of talc, and they actually 22 I reported experience with four patients in that particular 23 study. 24 Now, in Hartman's '93 article, this was a 25 Iprospective nonrandomized study, and the patients that MILLER REPORTING COMPANY, INC. I > 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 55 1 participated were from a multicenter study, but it was 2 unclear if the principal investigator's institution was one 3 of them. 4 The dose administered in the control arm consisted 5 of either bleomycin or tetracycline at 60 units or 1 gram 6 respectively, and the tumor type consisted of lung, breast, 7 or ovarian in the talc arm, and they just stated that in the 8 control arm, the tumor type was the same. 9 [Slide.] 10 In Hartman's trial, there were some patient number 11 discrepancies. They had higher success rates at 90 days ; 12 versus 30, and didn't further describe that, but I wanted to 13 -- excuse me, let me jump back a moment. 14 They evaluated their patients at 30 days and at 90 15 days, and that is why you have two different figures here, 16 and also they went ahead and reported success rates at both 17 time points for talc, as well as bleomycin, as well as 18 tetracycline. 19 Definition of success was defined in Hartman's 20 article as no fluid reaccumulation, and the method of 21 assessing success was via chest x-ray at one month and then 22 every three months after that. Response duration was not 23 reported in either trial. 24 [Slide.] 25 Now, there is much less information in these MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 5 4 6 - 6 6 6 6 56 1 studies because they are abstracts. Remember I mentioned 2 earlier that all of the studies administered one dose. 3 There was one study, Muir's '87 study, where talc was 4 compared to doxycycline, where they administered more than 5 one dose of the control drug, and it was slurry, repeated 6 lavage drainage at 20 milligrams per kilogram. 7 They actually did this until "pleural drainage was 8 at a minimum," and they didn't describe it any further. 9 However, four of the studies were prospective in nature, 10 three were randomized, and in Jones '89 study, the patients 11 were allocated to the tetracycline arm if they were 12 identified as a high operative risk patient. 13 Poudrage was the method of administering talc in 14 all four of the active concurrent control studies. Tumor 15 type was identified in one. In Lantos' study, it is 16 uncertain whether this study was prospective or 17 retrospective in nature, however, they did have a control to 18 compare talc to. 19 [Slide.] 20 Evaluables were described in two studies as 21 survival greater than or equal to one month post-procedure. 22 In Boutin's '85 study, the patients had to survive for six 23 months, and in Jones', they did not describe what an 24 evaluable patient was, but as you can see, success in the 25 talc arms in these four studies ranged anywhere from 92 to MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 . 57 1 100 percent, and in the controls, it ranged anywhere from 53 2 to 95 percent. 3 Success was defined in two studies. Method of 4 evaluating success was described in one, response duration 5 described in one study, and symptom relief was not 6 identified in any of these four abstracts. 7 [Slide.] 8 In Lantos' study, '94, it was unclear whether 9 these were actually patient numbers or cases, because they 10 used cases and patients interchangeably throughout the 11 entire abstract, but as you can see, success in the talc arm 12 was 96 percent, and in the controls being oxytetracycline 13 and doxycycline, of 87 and 92, respectively. 14 [Slide.] 15 There were also 24 noncomparator studies that were 16 submitted by the sponsor, and this is the results of 17 efficacy regarding these 24 studies. Total patient numbers 18 were 1,756, which included 1,548 malignant pleural effusion 19 patients. There were also some benign pleural effusion 20 patients, pneumothorax patients, and one study, there was no 21 way of separating patients out. They reported them as 22 benign pleural effusion, pneumothorax, or other, to include 23 empyema or chylothorax patients. 24 Response data per procedure, there were 1,535 25 evaluable procedures of which, as you can see, there was a MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 58 1 90 percent success rate in all the reported malignant 2 pleural effusion patients, and a 93 percent success rate in 3 a study where malignant pleural effusion and benign pleural 4 effusion, I was unable to separate the two out. 5 Definition of success was provided in 9 studies, 6 and there was no reaccumulation of pleural fluid for a 7 minimum period of 30 to 90 days. 8 I did want to mention one thing. I did say that 9 there were 24 articles, however, 3 articles were taken out 10 because there were 3 articles that were a series of 11 articles, so 2 were taken out for fear of double counting; 12 and they did report that it was a series of articles, so we 13 left 1 in, and 2 were taken out, and then 1 article we had 14 to take out because patient numbers were reported as greater 15 than 40, success rate war reported as greater than 100 16 percent. So that particular article was not counted in the 17 final analysis. 18 [Slide.] 19 Now, we have no way of assessing the completeness 20 of reporting. This is a summary of safety from the 21 published literature, and this is to include controlled, as 22 well as noncomparator studies. 23 As you can see, fever and pain were the most 24 frequently reported adverse events. About 23 percent of the 25 patients did experience fever and pain. Following were MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 59 1 adverse events including infection in nature, respiratory 2 disorders, and as you can see, the range is anywhere from 1 3 to 0.09 percent. 4 [Slide.] 5 This is the continuation of the previous slide. 6 Also, some of the adverse events that were reported were 7 cardiac in nature, and then there were some that we went 8 ahead and put under Other. As you can see, the range in 9 those, the reporting range was 0.2 percent to 0.09 percent. 10 [Slide.] 11 What I wanted to do was focus on the serious of12 life-threatening toxicities that were described. This is 13 from controlled and uncontrolled trials. There were four 14 reported cases of adult respiratory distress syndrome and 15 two were fatal. They were at a dose of 10 grams, and it was 16 delivered as a slurry. 17 Four cases of pulmonary embolism were reported, 18 and these patients had an underlying malignancy, one 19 resulted in fatality. There were three cases of myocardial 20 infarction. One was fatal. This was in a patient with 21 severe cardiac disease, that died about three months after 22 receiving talc pleurodesis. The patient had received 23 quinacrine first and then talc bilaterally within a few days of one another. There were two cases of asystole reported, and MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 ' 60 1 this was while under general anesthesia with.complete 2 resuscitation. 3 [Slide.] 4 As far as clinical experience with Bryan 5 Corporation's talc, you have already heard Dr. Beamis' 6 presentation, and I don't want to bore you with the results 7 of Colt and Dumon's study, because Dr. Beamis was very 8 thorough in describing i t . 9 While this particular NDA has been undergoing 10 review, Bryan Corporation has made their product available 11 through individual patient INDs, and I am going to go ahead 12 and describe those results at this time. 13 The Agency, in order to gain more experience with 14 Bryan's product, went ahead and collected data on these 15 individual INDs. 16 [Slide.] 17 There were 69 individual patient INDs that were 18 issued for malignant pleural effusion from May 18, 1995 to 19 October 22nd of this year, and that is when we censored the 20 data, so that we could have a one-month follow-up. 21 Out of those 69, we actually received results on 22 38 patients, so we got 38 patient results back, and 3 were 23 lost to follow-up, there were 7 deaths, and 3 failures due 24 to no lung re-expansion. 25 So out of those 38, we had 30-day follow-up on 25 MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 patients, 21 of which had no recurrence, 1 is unknown, and 3 patients had recurrence. So then out of those 21 patients, we received 12, 60-day follow-up forms back, 2 deaths, 1 recurrence, and 9 no recurrence, and then out of those 9, we received 5, 90-day follow-up forms back, 4 no recurrences, and 1 recurrence. The dose that was used in these individual INDs was 1 to 2 cans, which would be 4 to 8 grams. [Slide.] In conclusion, there are both strengths and weaknesses to this NDA. The weaknesses are that it is ; literature-based, therefore, there could be publication bias, there was incomplete data, and it was difficult to maintain quality assurance. Sample sizes were small, and in many situations, there was no way to tell the source or the purity of the talc that was used. There was variability and unspecified dose of talc, and as you know, achieving pleural synthesis Iis procedure-dependent and may impact on adverse Iexperiences, as well as success. I i want to go back to variability of the dose. 1What I did very quickly was I summarized the doses that were used in the controlled and uncontrolled trials, and what I I am going to do is go over the controls first. I There were four studies that actually reported a MILLER REPORTING COMPANY, INC. II 507 C Street, N.E. I Washington, D.C. 20002 (202) 5 4 6 - 6 6 6 6 62 1 dose in the control trials. Two reported a dose of 5 2 milliliters, did not provide a concentration. One specified 3 a dose of 3 to 10 grams, and one study they used 10 grams. 4 Then, in the noncomparator studies, there were 10 5 that reported a dose of talc. Seven studies reported using 6 1 to 5 grams, three studies reported using 10 to 10 1/2 7 grams. As I mentioned earlier, in our experience, the 8 individual patient INDs, it was anywhere from 4 to 8 grams. 9 Now, as far as the strengths are concerned, we did 10 have four prospective randomized trials that were reported. 11 There was a response definition in those four, with ; 12 objective measure via chest x-ray. 13 There was consistency of results over time, 14 institution, and despite different comparator arms. 15 Sclerosol is asbestos-free and it is sterile, therefore, 16 this would be an option for treatment. And it appears from 17 the preclinical data and the clinical experience today that 18 talc is not systemically absorbed. 19 Are there any questions? 20 CHAIRMAN BUNN: Questions? Dr. Krook. 21 DR. KROOK: I really don't have any. I think it 22 is a nice review, and I thank you. 23 CHAIRMAN BUNN: Dr. Ingle? 24 DR. INGLE: Obviously, the Agency has considered 25 the heterogeneity of talc issue. The two randomized . . MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 63 1 clinical trials of talc that are ongoing -at the present 2 time, the two intergroup studies, as I remember in seeing 3 those studies, there is a variety of talc preparations that 4 are permissible for those studies. 5 One assumes that the findings from those studies 6 will be applicable to talc in general, I guess the principle 7 all talc is created "approximately" equal, is that a 8 reasonable statement, that the clinical trials that are 9 ongoing will, in fact, relate to this product? 10 DR. LARSON: I am not certain of that. Dr. Martin 11 or Dr. Justice? 12 DR. MARTIN: Since we are using the body of 13 literature that has used a variety of talc to support a 14 particular product, that by extension, we would have to 15 assume that the variety that is being used in the two 16 intergroup studies could also be applied. 17 CHAIRMAN BUNN: Would the FDA recommend to the 18 people doing those studies if this product should get 19 approved, that perhaps this product should be incorporated 20 into those studies? 21 DR. JUSTICE: We have suggested that already. 22 CHAIRMAN BUNN: It would seem reasonable. 23 It is interesting that there are so many abstracts 24 that haven't been published, and these abstracts were 25 largely reported 10 years ago or so. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6556 64 1 Do you have any idea what happened to these 2 abstracts, why they weren't published? 3 DR. LARSON: As I said earlier, our literature 4 base, when we did our search, we actually used six of the 5 largest literature bases that we know of today, we came up 6 with about 400 articles, and this is it. 7 CHAIRMAN BUNN: I personally, I mean it might have 8 been interesting to call them, but I mean I personally 9 wouldn't view these abstracts as is, I would rule them out 10 as being adequate and well controlled, because they have not 11 been peer reviewed. 12 DR. GELBER: Could I make a comment on that? 13 CHAIRMAN BUNN: Yes. 14 DR. GELBER: It relates to one of the things you 15 mentioned, which is publication bias, and it was an 16 interesting example looking at the studies that were 17 reviewed, that the largest difference was in the 18 historically controlled, and the next largest were the 19 randomized trials that were able to be published, that 20 editors decided were important enough, and if you look at 21 the abstracts that haven't been published that we saw, the 22 differences were less remarkable. 23 So there might be an example right here of the 24 tendency to be as an example of publication bias, and one of 25 the reasons not to push those abstracts forward is they MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-S666 - 65 1 weren't as interesting as the ones that the editors decided 2 to accept, so people lost enthusiasm for publishing. That, 3 by definition, is publication bias. 4 Your point about the question of going to the 5 authors of the abstracts, and even the published reports, to 6 find out do they have information about cither series that 7 were done, or what other information to corroborate what is 8 already in the literature, I think would be a pretty trivial 9 thing to at least start to try to do, and get some more 10 information about some of the studies that were inadequately 11 reported. \ 12 CHAIRMAN BUNN: Dr. Ozols. 13 DR. OZOLS: Of the 69 individual patient INDs, 14 were those done out of many institutions? The collection 15 rate on that data is pretty low. About half of them you 16 received the forms back. 17 DR. LARSON: You mean as far as the response rate 18 that we got back? 19 DR. OZOLS: Right, returned forms. 20 DR. LARSON: We were rather disappointed also. It 21 was only 55 percent of what we actually did send out. 22 DR. OZOLS: How did people know about the 23 availability, how representative are these 69 patients? 24 DR. LARSON: I am going to defer that question to 25 Dr. Martin. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 66 1 DR. MARTIN: I am not sure how they knew about it. 2 I assume they called Bryan Corporation first and then they 3 contacted us to issue an IND. 4 That 55 percent of the forms that were returned 5 was despite numerous phone calls by our project manager, 6 Debbie Catterson, who called them repeatedly and asked for 7 the forms with chest x-rays. So I would say that probably 8 without that diligence, we would have gotten 10 percent of 9 the forms, even though initially, when we issued the IND, we 10 sent them the forms and asked them to sign to show that they 11 would follow through with all of the 90-day forms. : 12 CHAIRMAN BUNN: But that is not unusual, right, 13 for treatment IND. Does the company want to say how people 14 found out about these treatment INDs, did you make this 15 known in some way or somehow people just found out? 16 MR. ABRANO: I would believe that people became 17 aware of the talc through the article that was published by 18 Dr. Dumon and Dr. Colt, and it has certainly been word of 19 mouth. I mean we receive a lot of calls daily waiting for, 20 you know, inquiring about the approval or where we stand 21 with the talc. 22 DR. OZOLS: But this is not just one or two 23 institutions, these 69 patients are throughout the country? 24 MR. ABRANO: Yes, they were throughout the 25 country. They are at various institutions, and if they did / MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 67 1 one institution at first, they were using the same IND, but 2 that was eliminated, and if they called in again, they had 3 to use a new IND. 4 DR. MARTIN: It represented, to my recollection, 5 at least 20 different places, oftentimes private practice 6 and occasionally some tertiary referral centers from the 7 intergroup studies. 8 CHAIRMAN BUNN: That was quite a new review that 9 you did. It obviously took a lot of work. This might not 10 be fair, but you are going to ask us whether we think any of 11 these are adequate. So I will take the liberty of making;a 12 little editorial comment, and then asking you a question. 13 Certainly, Dr. Sorensen's article was 14 prospectively randomized, gave a dose, gave a definition of 15 efficacy, reported data on that efficacy, which included 16 both chest x-ray and symptom relief. 17 Certainly, Dr. Hartman's article also gave a dose, 18 had a definition of efficacy, reported the efficacy at 19 various time points. 20 Would you consider those particular articles to be 21 adequate? 22 DR. LARSON: Slide No. 7, please. 23 CHAIRMAN BUNN: You anticipated my question. 24 DR. LARSON: This is an opinion. 25 CHAIRMAN BUNN: That is what I am asking for. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202). 546-6666 68 1 DR. EARSON: These, in our opinion, are what we 2 thought were adequate and well-controlled trials, the 3 reasons being, number one, they stated an objective, mainly 4 to prove talc superiority in the treatment of malignant 5 pleural effusion; number two, these described their trial 6 design, and in Sorensen's, it was rather nice, because they 7 went ahead and also controlled for chest tube drainage time 8 equally in both arms. 9 Stratification did take place in two of the 10 studies, so they did attempt at stratifying patients, and 11 the tumor type was also described. I realize that the dose 12 was not given, but it was available in enough of the 13 studies, we felt, where it actually wouldn't make a 14 difference in these particular four studies. 15 They also described the treatment that was 16 actually given as far as talc is concerned and the control 17 arms. 18 CHAIRMAN BUNN: Well, you seem to have gotten some 19 questions on this. Dr. Temple. 20 DR. TEMPLE: The thing that you can't tell in the 21 literature usually is what happened to all the patients, or 22 you often can't tell. In a certain sense, the limited data 23 we got from the IND is better in that respect, because we 24 discovered that a number of patients died, therefore, they 25 probably weren't in the list of people who were evaluated, MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 69 1 and some of them were lost to follow-up, and they probably 2 weren't included. Usually, the literature is not so good at 3 that. 4 Do you have any impression from your review of the 5 studies whether that is addressed in them? Can you, for 6 example, tell how many people were given the therapy and 7 then how many patients they actually had data on or lived 8 long enough to reach the 30-day endpoint, and things like 9 that? That is just one element of whether a study is well 10 controlled. 11 DR. LARSON: Yes, in these particular four 12 studies, they did provide information on how many patients 13 were evaluable per patient center, and if I may veer off 14 just for a moment also, they also defined evaluable 15 patients, defined success and method of evaluating success, 16 and reported success in those four studies. 17 Even though Hamed's trial did report procedures, 18 they did report something there, and they attempted at 19 providing information regarding response duration. Also, 20 three of the studies, we were able to apply an intent to 21 treat analysis. 22 CHAIRMAN BUNN: Dr. Gelber. 23 DR. GELBER: I have a comment and then a question. 24 The comment is thank you very much for an excellent review. 25 I must say that if the Committee decides to vote approval, ., . MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 1 that it would be largely based on your efforts and the 2 efforts of the Agency, and this is another example of where 3 the Agency is not the bad guy in terms of the drug approval 4 process. 5 I also have to say that I am paid to be here by 6 the FDA. 7 [Laughter.] 8 DR. GELBER: The question relates to your next to 9 the last slide, and it is more something I am curious about, 10 because you did show the individual patient INDs. 11 DR. LARSON: Oh, yes, the flow chart? 12 DR. GELBER: The flow chart. 13 DR. LARSON: No. 19, please. 14 [Slide.] 15 DR. GELBER: Now, admittedly, there is a lot of 16 missing data there, but if these were the data we were to 17 look at, what would the success rate be? 18 CHAIRMAN BUNN: Thirty days, 21 out of 24. 19 DR. LARSON: Thirty days. 20 DR. GELBER: Twenty-one out of 25. 21 CHAIRMAN BUNN: Twenty-one of 24, or 21 of 25, 22 depending on - 23 DR. INGLE: The issue here is the 55 percent of 24 the forms returned. Is that a reflection of the drug, is it 25 a reflection of the FDA? My question is this. It seems MILLER REPORTING COMPANY, INC. . 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 71 1 strange to me, if I had. used an agent under IND, and the FDA 2 called me a couple of times, I think I would respond, and 3 this seems fairly casual, for 45 percent of the patients, 4 for you not to have any forms. 5 Now, I think you have to have your denominator be 6 the 69 patients. So I would like the FDA's help on that 7 question, is this a reflection of the drug or what? 8 \ DR. TEMPLE: You fundamentally can't know the 9 answer to that. I mean some people are more in awe of us 10 than others. 11 [Laughter.] : 12 DR. TEMPLE: We are grateful for your attitude, 13 and wish it were more widely shared. 14 I don't think it is safe to assume that there was 15 a lack of success in those. I mean the most conservative 16 impression would be, okay, the denominator is 69, and there 17 are 21 no recurrences, so the success rate is 33, but you 18 would know that that was almost surely an underestimate, but 19 it is one way of describing an conservative analysis. 20 But my guess is that failure to report has more to 21 do with how busy people are. 22 CHAIRMAN BUNN: I asked Alison about this before, 23 and this is typical, and I can just tell, you know, from my 24 own institution, this comes up a fair amount. In the cancer 25 center, the data managers are asked to do this, and then MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 72 1 they complain, and they say no one is giving us any money to 2 get these chest x-rays and fill out these forms, and why are 3 we doing this. 4 You say you are doing this because you have an 5 obligation to do it, do it, but I can guess that many 6 places, they don't have a cancer center director telling 7 them that they have to do this, and they had better do it or 8 they are not going to have a job, you know, there is not a 9 lot of incentive to return the data and get the chest x10 rays, and you are not getting paid. 11 I would guess this is actually pretty good data12 collection. 13 DR. MARTIN: Also, we had another methodologic 14 problem, which is oftentimes it was a thoracic surgeon or a 15 pulmonary doctor doing the procedure, and they released care 16 shortly after that procedure, and then we had to track down 17 the primary caregiver. 18 DR. GELBER: Even beyond that, I mean if you take 19 the 38 as the denominator, then, who do you consider 20 successes, what do you do with the 7 deaths, are the 3 no 21 lung re-expansion, failures of the procedure, and then the 22 final issue is do you stop at 30 days or do you want to look 23 at recurrences beyond that point, failure to maintain. 24 DR. JUSTICE: I don't think we have enough data to 25 answer the question precisely, but I think, at least in the MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 1202) 546-6666 73 1 literature, early deaths from disease are not considered 2 failures, they may be considered inevaluable. 3 If you were going to be consistent with the 4 literature - 5 CHAIRMAN BUNN: If you were doing it time to 6 recurrence, those people would be censored. 7 DR. GELBER: The point is, in fact, that intent to 8 treat is for one issue, and as you said, dropping out the 9 patients who died early, as long as it is recognized that 10 the success percentages are conditional percentages in terms 11 of the usefulness of the therapy, then, at least if that is 12 stated up-front, those are where the 90 to 100 come from. 13 It doesn't seem to me from the literature that 90 14 to 100 percent of the patients for whom you tried this 15 procedure were successfully treated with it. 16 DR. DELAP: The only other thing I would add is 17 please look at the data at the top, that it is from 5-18-95 18 to 10-22-95. This is a fairly recent innovation on our 19 part, and it is quite likely that we will get some further 20 forms returned on some of those patients, particularly for 21 the longer periods of follow-up where many of the patients 22 probably aren't even out that long yet. 23 CHAIRMAN BUNN: I think it is worth pointing out 24 for the public who are here that oftentimes there is a 25 misperception also that experimental agents or MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 iTnOl 74 1 investigational agents are not available to the public, and 2 oftentimes these agents are available to the public through 3 this mechanism, which is often used to provide drugs to 4 people, and it is a lot of work for the FDA and the people 5 that do it, but it makes these agents available, and people 6 should be aware that the consumer does often have access to 7 agents even before they are approved by the FDA with the 8 FDA's concurrence and with a lot of work by the FDA. 9 Are there any other questions? 10 What is the sense of the Committee? Do you want 11 to go to the questions or do you want to take a five-minute 12 break? Go to the questions? Okay. 13 DR. TEMPLE: I just want to say a couple of words 14 about the use of literature. I think actually he has 15 covered much of this. 16 As people probably remember, we have expressed a 17 lot of interest in getting new uses of drugs into the label 18 where possible, and have said that we are at least prepared 19 to look at the literature as a basis for those reviews. We 20 have never said that that is always going to win, but we 21 have said we would take a look. 22 i While this isn't a new use exactly, it is a sort 23 of validation of an established use, a lot of the situation 24 is the same. 25 The first question is why it is an issue. Most MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 , 2etf5K3lHBiC= 75 1 physicians learn about things from literature and trust it, 2 believe in peer review, and it is sort of the major method 3 of communication. Why would we be so skeptical? The answer 4 is the literature is usually very incomplete with respect to 5 details and methodology, with respect to what happened to 6 patients, who is included, who is not, and those kinds of 7 things, and we learn this every day when we compare the 8 reports of studies with what we see, and we have many 9 instances in which there are a significant disparity. 10 So we have a fairly strong, I would describe it as 11 experience-based preference for access to underlying data-, 12 and we are aware of publication bias. Nonetheless, despite 13 all that, we certainly legally can, and on a number of 14 conspicuous occasions have, relied primarily or even 15 entirely on a literature-derived database for approval. 16 Some of the examples are fairly conspicuous. The 17 approval of secretin for diagnosis of pancreatic function 18 was actually based entirely on the literature with no raw 19 data at all. The literature was absolutely fast. Secretin 20 was the first hormone, and people were sort of excited about 21 it. There were well over a thousand publications describing 22 what it did in animals and humans, and the approval was 23 based entirely on that. 24 The approval of propranolol for the treatment of 25 angina was actually based on the literature also. There MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 jam 76 1 were data submitted to us, but they were crumby, and the l 2 better data were in the publications. There were probably 3 20 controlled trials showing the effectiveness, so there was 4 a certain mass to it. 5 A controversial approval some years ago of 6 imipramine for the treatment of enuresis in children was 7 entirely based on the literature. The approval of 8 nitroprusside for treatment of bad hypertension included a 9 22-patient multicenter study, and a lot of vast literature 10 showing that nitroprusside lowered blood pressure. 11 Recently, actually, an important approval of : 12 coumadin for use in the post-infarction setting was at least 13 partly based on a paper published in Hong Kong actually. 14 It is worth thinking about what makes literature 15 persuasive versus what makes it unpersuasive. One critical 16 element is redundancy. When you can't check the actual 17 data, a great deal of consistency, including no exceptions, 18 is, relatively speaking, reassuring, and in certain 19 instances, data without a control group, but where you feel 20 you know what the natural history of the disease is 21 reasonably well can add to the accumulated sense. 22 It also helps to have access to some data. On a 23 number of occasions we have relied primarily on the UK, 24 literature and pursued one or more studies to reassure 25 ourselves that you could do that. So actually, to a degree, MILLER REPORTING COMPANY, INC. . 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 77 1 even the small data we are getting from the INDs is probably 2 helpful. 3 It is easier to believe in data that shows a very 4 robust effect. I mean 90 and 100 percent response rates are 5 more persuasive than 20 percent response rates. 6 It also helps if the measurements are not too 7 exotic and seem like the sorts of things people can 8 reasonably well do without a great deal of quality control. 9 So that is probably a favorable situation here. 10 But I agree in a sense with what Rick Gelber says, 11 is you should maybe trust abstracts more because they are; 12 not subject to publication bias. On the other hand, you 13 know so little about what is in them, that I guess they fail 14 my test for being able to rely on. 15 But in the end, it is a judgment that has to be 16 made that doesn't have terribly precise rules. It is a 17 feeling you get, and I guess I should add that we have been 18 able, where this was critical, to get the records even from 19 the fairly distant past. 20 So that needs to be kept in mind as an option if 21 the data were otherwise almost persuasive, but not quite, 22 you can do that. There is a fair amount of difficulty, and 23 it certainly has not always been considered necessary, but 24 it is a possibility, and we have gone back 15 years 25 sometimes to find data. We have not always been pleased MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 78 1 with the results, but we have done that. . 2 Anyway, there is no legal bar to doing so, and 3 th_LS does represent something of a model for us. As you all 4 know too well, there is a great many uses of drugs in 5 oncology that aren't in the label. 6 One possibility for getting them in there is a 7 robust published database. I think when we have looked, it 8 hasn't been as robust as we have hoped.most of the time, but 9 it is a possibility we need to consider. 10 CHAIRMAN BUNN: You left out -- I don't know what 11 the FDA has done with this recently, but this Committee did 12 hear another literature-based application for the same 13 indication, and the size of the studies and quality of the 14 data was probably quite similar, since it was the same 15 indication and it was pretty similar, and we did in that 16 instance, as a committee, recommend approval. 17 DR. TEMPLE: We had access to one of the studies 18 there. That is a small, perhaps important advantage. 19 CHAIRMAN BUNN: Yes. I think also the Committee, 20 of course, is very aware in this changing health care 21 environment that more and more managed care companies love 22 to not pay for drugs on some basis, and even though we 23 believe in the literature there is adequate reasons to use a 24 particular drug, that may not be good enough for them. 25 That, in my own experience, seems to be an increasing MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 /7031 - 79 1 popular way for insurance companies to try to save money, 2 and if that continues, we may see more of these, and it is 3 probably reasonable if that happens, that we do. 4 DR. TEMPLE: But we have been encouraging people 5 to at least take a crack at it, how to interpret them and 6 what we will eventually do still remains to be seen, but at 7 a minimum it is worth a try, and if the worst outcome is 8 that one of the studies has to be looked at more closely, 9 that is still a considerable decrease in effort compared to 10 starting from scratch. 11 DR. GELBER: Just a quick point of clarification. 12 Is this product approved for other purposes, then? Are we 13 talking about expanding a - 14 DR. TEMPLE: No. This is the first human drug 15 application for talc. It is a new molecular entity in our 16 terms. 17 COMMITTEE DELIBERATION 18 CHAIRMAN BUNN: We will turn to the questions. 19 There is a little bit of a preamble, but since we have set 20 ourselves up, the first question which the FDA has asked the 21 advisers to provide their advice on is: Which, if any, of 22 the clinical trials, which we have just had reviewed, are 23 adequate and well controlled? 24 D r . Krook. 25 DR. KROOK: I think it has already been stated MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 5 4 6 - 6 6 6 6 80 1 from what was presented by the FDA, the four trials which 2 were on the first slide, particularly the Sorensen trial, 3 although it be small, was controlled, and I think those are 4 the four that we have to accept as perhaps adequate and 5 reasonable controlled. I guess that is my use of the words, 6 and I would recommend to the Committee that this question be 7 answered yes, that there are trials that are. 8 CHAIRMAN BUNN: I will take a stab at this as the 9 other reviewer. Sometimes we have a question of what is 10 statistically relevant and what is clinically relevant, and 11 they are not always necessarily the same. ; 12 Oftentimes, in a particular clinical trial, the 13 statistical question that is being asked is, is one 14 treatment significantly better than another, and I suspect 15 that sometimes the statistical answer to whether some of the 16 trials are adequate is no. 17 On the other hand, as Dr. Temple was pointing out, 18 when you have something that is 90 percent effective all the 19 time, if the comparator is effective 80 percent of the time, 20 and those aren't statistically different, does that mean the 21 product isn't any good or the study isn't adequate to show 22 efficacy. 23 Of course, you get into the comparability issue, 24 and obviously, none of these trials are statistically 25 adequate to show comparability even if they are not MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 54S-66G6 jam , ' 1 statistically adequate to show superiority. 81 2 On the other hand, my own view is that these 3 studies are adequate for the question being asked, both in 4 terms of showing efficacy and safety. So I concur with Dr. 5 Krook. 6 DR. KROOK: One more comment which I hear our 7 thoracic people say, is that the chest tube alone, the first 8 trial has a chest tube arm alone although it is small, is 9 that that does control some without the talc. 10 CHAIRMAN BUNN: Does anyone, Dr. Gelber, since I 11 have made a distinction between clinically relevant and ; 12 statistically relevant -- 13 DR. GELBER: I would change really one thing you 14 said, Paul, when you said sometimes there are issues of 15 discussion between clinical and statistical. I would say 16 very often or quite frequently that is the case. 17 But I don't think necessarily that the issue is so 18 much statistical versus clinical for me here. It is more 19 the issue that Bob Temple brought out, that we ar^ really 20 being asked to answer a question that is clear in the 21 regulations, of the submitted clinical trials, whiqh ones of 22 the individual clinical trials are adequate and controlled, 23 and yet in Bob's very nice remarks, he used phrases like a 24 certain mass of the literature, a consistency, accumulated 25 evidence, and things like that, that are not present from a MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 'on?) fiR . 82 1 single individual trial. 2 So I think we are caught, as we are very often on 3 the Committee, between addressing the issue of single, 4 adequate, well-controlled trial that can be used. I think 5 that any one of the four studies that you mentioned, if we 6 only had one, there would be serious questions as to whether 7 that trial was adequate and well controlled even from a 8 clinical perspective. 9 Seeing the literature, seeing the four together, 10 seeing the supportive evidence, it is a certain mass of the 11 literature that we are voting on, but we have to answer this 12 question here about individual trials, and I think that is 13 really the dilemma we are in. 14 CHAIRMAN BU N N : D r . Temple. 15 DR. TEMPLE: I may not have been quite clear. The 16 presumption is that you are only talking about literature 17 trials that on their face appear to be well controlled. The 18 question then is, okay, there are a number of trials that 19 appear to be well controlled, should I believe this, and the 20 burden is greater, from our point of view anyway, than if we 21 actually have the data in hand. 22 With the data, we can be reasonably certain that 23 what is said is what happened. In the literature, you never 24 can actually do that directly, you have to take a fair 25 amount on faith, and experience tells you that some of the MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 fnr\n\ c/itz-cccc . 1 areas that you have to take on faith are disposition of 83 2 patients and a bunch of stuff like that. 3 So the presumption is -- there is a sort of first 4 step, which says are these by design and apparent reporting 5 well-controlled trials, and then collectively, does this 6 make a persuasive case, but sort of going in presumption is 7 that they have to look like well-controlled trials including 8 historically controlled trials, or you don't even think 9 about i t . 10 DR. GELBER: Can I just follow up on that with one 11 short phrase, which is I am less concerned about the aspect 12 of the well controlled in the four studies that have been 13 mentioned. I mean these were randomized prospective ' 14 studies. I am more concerned about the issue of adequate 15 for getting the information that we need as individual 16 trials. 17 Specifically, the Hartman report was mentioned as 18 the one that would be important because of its sample size, 19 but I would have problems indicating that as a well 20 controlled study because of the lack of understanding that I 21 had with respect to the control groups and how they were 22 assembled, and so on. 23 So you have the sample size adequacy in one study, 24 but that is not what I would consider well controlled, but 25 the four that were mentioned, I would consider to be well MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 ioaoA c/ic 84 1 controlled by design, but not really, or on the margin of 2 adequate as individual trials for demonstrating what we want 3 to show. 4 CHAIRMAN BUNN: Actually, the Hartman trial, I 5 actually sort of think it is adequate and well controlled, 6 not because of the control group in the study, but because 7 of historical controls, just looking at the 39 patients and 8 comparing them to historical. 9 DR. GELBER: Almost as a single-arm, Phase II 10 trial of effectiveness. 11 CHAIRMAN BUNN: Right. 12 Dr. Ingle. 13 DR. INGLE: Just one other requirement about how 14 much faith we put in the literature. Clearly, peer-reviewed 15 literature is essential. There are numerous publications 16 which are clearly sponsored by pharmaceutical firms or that 17 appear in the pseudo-literature, but if a study has stood 18 peer review, for instance, in one case, at a national 19 meeting and then showed up in the peer-reviewed literature, 20 I think that gives us much more, that is a requirement to 21 put any store in the quality of the study. 22 CHAIRMAN BUNN: We are being too kind to these 23 studies, because all of us would wish that some of the 24 studies had been a bit differently, the stratification, the 25 diseases studied, the dose, there is a number of issues in MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 f'yno'i 85 1 these studies that make them somewhat less than ideal. 2 But on the other hand, we do recognize that being 3 short of breath to the point where you can't walk is not 4 pleasant for patients, and we all know that an effusion goes 5 away, the people feel better, and we all know that taking a 6 chest x-ray and showing there is no effusion is a fairly 7 simple matter, and I think we are all biased by that, as 8 well, or influenced by that. 9 DR. TEMPLE: Some of the questions one would often 10 ask about things about stratification tend to go away when 11 the response rates are 90 percent plus. I mean stratify it 12 all you want, but 90 percent is 90 percent. 13 The controls, the no-treatment controls fairly 14 consistently come out in the 40 to 50 percent range, so 15 there obviously is a nonaccumulation rate of 30 days even if 16 you don't do anything, but that is a fairly large 17 difference. You know, if it were 60-50 or something like 18 that, I don't think we would be here. 19 CHAIRMAN BUNN: Well, I think we would actually. 20 If this worked 90 percent of the time, and they were asking 21 us to approve it, it wouldn't matter if there is something 22 else, 80 percent effective. It is just is this 90 percent 23 effective. 24 ... DR. TEMPLE: Well, if it was 90 and no treatment 25 at all was 80 -- MILLER REPORTING COMPANY, INC. 507 c Street, N.E. Washington, D.C. 20002 86 1 CHAIRMAN BUNN: Oh, well, yes. 2 D R . TEMPLE: Other than drainage. 3 CHAIRMAN BUNN: Yes. 4 DR. TEMPLE: Okay. 5 CHAIRMAN BUNN: So we have a motion that the 6 answer to Question 1 is that there are adequate and well 7 controlled trials, and they were identified by the FDA, and 8 we concur that these are adequate and-well-controlled, 9 studies. That was seconded. 10 Is there any further discussion? 11 [No response.] 12 CHAIRMAN BUNN: All in favor? 13 [Show of hands.] 14 CHAIRMAN BUNN: Dr. Ozols can't vote, so we have 15 seven in favor against one abstained, one abstention, 7-0-1. 16 DR. GELBER: Just an explanation on that is, as a 17 group, I would say that there is evidence, but, as phrased, 18 it asks for individual trials, and I have a problem with 19 that. 20 CHAIRMAN BUNN: The second question: Do the 21 identified trial(s) provide substantial evidence for 22 efficacy in the treatment of malignant ^pleural effusions? 23 We have somewhat beat this up, but Dr. Krook. 24 DR. KROOK: I would make the motion that the 25 identified trials using talc does provide substantial MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 87 1 evidence of efficiency in the treatment of malignant pleural 2 effusions. 3 CHAIRMAN BUNN: Thank you for not putting a 4 negative in there, which we always gets these double 5 negatives that confuse all of us. 6 I agree. I think, again, it is the mass of the 7 data. Every article essentially is showing something close 8 to a 90 percent efficacy rate, and I do view that as 9 efficacious. 10 I will also note that the surgeons will continue 11 to do this, because they believe it works whether we vote', 12 for this or not, but obviously, our surgical colleagues 13 believe it works as well. 14 DR. SWAIN: I would just like to make one comment. 15 I am a little concerned about using the numbers 90 to 100 16 percent efficacious. When you look at the intent to treat, 17 and you really read these papers, I think that is i 18 overstating it. 19 CHAIRMAN BUNN: Yes. If you censored patients, it 20 might be close to 90 percent, but certainly a lot of people, 21 this is a bad disease, and a lot of people die of other 22 causes, and so on. , 23 Dr. Ingle. 24 DR. INGLE: I would just like to support what Dr. 25 Swain said. Clearly, the two current randomized studies are MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 f3.02V 545-5666 jam 1 very important. 2 CHAIRMAN BUNN : Right. 3 Any other discussion? . 88 4 [No response.] 5 CHAIRMAN BUNN: All in favor of Dr. Krook'3 6 motion? 7 [Show of hands.] 8 CHAIRMAN BUNN: Eight. Opposed? Zero. 9 Abstained? Zero. 8-0-0. 10 The third question: Is the safety profile of a 11 single administration of 4 to 8 grams of talc acceptable?-. 12 D r . Krook. 13 DR. KROOK: Again, I would make the motion that 14 the safety profile of a single administration of 4 to 8 15 grams is acceptable. 16 The only comment I will have, as I reviewed the 17 literature, there were a couple of 10-gram doses which there 18 appeared as it went above 8, to be problems, as I remember 19 the data. So I think that 8 is the top. 20 CHAIRMAN BUNN: There were I think two fatalities. 21 DR. KROOK: Right. Whether they are related or 22 not -23 CHAIRMAN BUNN: Yes. Obviously, the serious side 24 effects were quite uncommon, and one of the things that 25 wasn't pointed out was most of those side effects were MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 , (202) 546-6666 89 1 probably due to the procedure, either the VATS or the 2 thoracoscopy and the anesthesia really rather than the agent 3 itself, and I think actually I would ask - - i t was commented 4 on that infections were pretty uncommon, empyema, a little 5 less than 1 percent, but we heard from the company that as 6 far as they knew, there weren't any infectious complications 7 from their product. 8 Alison, do you know, in those treatment INDs, were 9 there any infectious complications? 10 DR. MARTIN: The only serious complication that 11 was reported to us was intubation for a couple of days due 12 to re-expansion and pulmonary edema. We had no other 13 serious ADRs reported. 14 CHAIRMAN BUNN: So I second Dr. Krook's motion 15 that this is sufficiently safe. 16 Is there other discussion about safety? 17 DR. GELBER: Just one more question. Again, it is 18 an estimation of how safe, because it was pretty clear that 19 there is likely to be a lot of under-reporting in the large 20 series of uncontrolled studies. 21 So if your denominator is over 1,000, that is 22 being reported, then, your incidence of things is going to 23 be quite low. I just wonder, taking a number out of those 24 series, is reasonable or should be modified by the potential 25 to miss things. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 90 1 But overall, in terms of I guess serious 2 complications, there didn't seem to be anything reported. 3 CHAIRMAN BUNN: Some of the randomized trials, I 4 think should help also in sorting out complication rates 5 from procedures, as well as from the agent. Once again, if 6 one procedure has a lower incidence of side effects, that 7 would be important, but it is really not the issue here. 8 Any other discussion? 9 [No response.] 10 CHAIRMAN BUNN: All in favor of Dr. Krook's motion 11 that the safety profile is acceptable? ; 12 [Show of hands.] 13 CHAIRMAN BUNN: Eight. Opposed? Zero. 14 Abstained? Zero. 8-0-0. 15 Question 4 is: Is Sclerosol approvable for the 16 treatment of malignant pleural effusions? 17 D r . Krook. 18 DR. KROOK: I guess my comments here is that I 19 think aerosol talc is what we have seen or talc as it is, is 20 approvable. I think when we talk about Sclerosol, that 21 there is also a delivery system involved here, and I am not 22 sure we are asking -- maybe I am wrong, maybe FDA is asking 23 us to approve the delivery system also. 24 So my comment here is that I believe aerosol talc 25 is approvable for the treatment of malignant pleural MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 91 1 effusions rather than the brand name, although I have to 2 turn to my colleagues and say what are they asking. 3 I mean the studies are talc. We have a 12 -- am I 4 correct - - a 12-person study using Sclerosol. 5 CHAIRMAN BUNN: A 12 and an 11. 6 DR. KROOK: A 12 and an 11. 7 CHAIRMAN BUNN: A published 12 and an abstract 11. 8 DR. KROOK: And we have, if I am also correct, we 9 have the 69 individual INDs. That is my problem with that 10 question, and so if I were to be asked, I would say sterile 11 aerosol talc is approvable for malignant pleural effusions. 12 I am changing the question. 13 CHAIRMAN BUNN: Dr. Temple, do you want to comment 14 on this? I 15 DR. TEMPLE: We understand. We will have to reach 16 a judgment about -- well, you could help us on this -- about 17 how likely it is that any form that delivers -- I mean 18 sometimes with aerosols and things like that, you worry 19 about the spray pattern and things like that. 20 That seems less of a problem here than in many 21 cases, because you are sort of doing it under visualization, 22 but your point is certainly noted. I think we have to take 23 that into account. 24 We have certainly been thinking, though, that 25 aerosol data in general would be applicable to this product. MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 2 0 0 0 2 (202) 546-6666 92 1 CHAIRMAN BUNN: I just say actually, though, in 2 the company's presentation, you know, I think oftentimes a 3 picture is worth a thousand words, and the advantage of that 4 spray is that you can really say whether you have coated the 5 pleura or not, and I think that is a little bit easier to 6 control, so that I think it probably is easier to get a 7 fairly uniform distribution over the pleural surface with 8 that applicator. 9 The real difference from what you are saying is, 10 is the applicator reasonable, and we don't have a lot of 11 data. Twenty-three cases isn't a lot, but, you know, I was 12 impressed by the pictures, that you were able to get a 13 pretty uniform distribution over the pleura with that 14 particular applicator. 15 It wouldn't dissuade me from some other applicator 16 being acceptable, but I am fairly convinced that that 17 applicator seems fairly reasonable based on the pictures. 18 DR. GELBER: Just remember, we only saw one 19 picture of one instance. So, again, I agree with your point 20 that to make it more generic, those are the data we saw, and 21 to encourage review of the data that are coming in on the 22 particular product. 23 CHAIRMAN BUNN: We don't usually let the companies 24 talk, but, Dr. Beamis, do you want to make a comment about 25 whether you think that picture that you showed is fairly MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546 - 6 6 6 6 jam ' 93 1 representative of the type of uniformity of distribution you 2 can get with this applicator, and especially compared to 3 some other applicator? 4 DR. BEAMIS: We haven't used other applicators 5 with the Sclerosol. I have been to Marseille and seen other 6 people do talc applications with the powdered talc, USP 7 talc, and I think either applicator can do a good job. 8 The visual confirmation, I think is very 9 important, and all of our cases have been visually 10 confirmed. We tape each case, we are not the best 11 photographer through thoracoscope, but -- ' 12 CHAIRMAN BUNN: Obviously show you the best 13 pictures, but in other words, you think that usually, things 14 are pretty much like those pictures that you showed us? 15 DR. BEAMIS: That's right, yes. 16 CHAIRMAN BUNN: Dr. Ozols. 17 DR. OZOLS: I guess the problem of patient safety, 18 I think we should consider. I mean if we are talking about 19 not approving this particular product, other than USP, which 20 again raises the problems of individual pharmacies having to 21 sterilize it, and so forth, and it seems to me you are 22 caught in a bind if you just sort of approve it generically, 23 but there is no sort of approved other substitute. 24 D R . TEMPLE: But we have to deal with an 25 application for a particular product. Our current approval MILLER REPORTING COMPANY, INC, 507 C Street, N.E. Washington, D.C. 20002 94 1 won't be generic, even if your advice is, we will have to 2 interpret it . 3 CHAIRMAN BUNN: I don't know Robert's Rules of 4 Orders, but I would like to propose an amendment. I would 5 like to say that Sclerosol (sterile aerosol talc) is 6 approvable for the treatment of malignant pleural effusions. 7 We can have a discussion on that amendment and 8 vote on it. 9 DR. OCHS: Would you say palliative treatment 10 rather than treatment? Treatment rather implies, and it 11 really isn't, it's a palliative treatment. : 12 CHAIRMAN BUNN: Sure. 13 So we have a proposal to amend this to add the 14 word Sclerosol and to add the word palliative. 15 DR. KROOK: I guess my question again -- turning 16 to Bob Temple over here -- does that change it for you? I 17 mean instead of "sterile aerosol talc" or "sterile talc," 18 however you want, put the word Sclerosol? It's a brand 19 name. 20 DR. TEMPLE: Well, it is the particular product 21 that we are reviewing. I think we are content either way. 22 We understand. We understand what you are saying. 23 DR. KROOK: Then, I accept the amendment. 24 CHAIRMAN BUNN: We will just vote on the amendment 25 then. . MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 " 0 2 ) 546-6666 95 1 Any other discussion? 2 DR. TEMPLE: I guess before we leave that too 3 quickly, our probable assumption is that the ability to 4 visualize it won't interfere, the results won't be worse 5 that way than with methods that didn't give you as much 6 control. 7 So I would say that you should know our attitude 8 as reflecting that. 9 CHAIRMAN BUNN: I think that this agent is most 10 likely in the community going to be used via VATS or 11 thoracoscopy, and I think it is unlikely that people are ; 12 going to put this in through a thoracentesis, and it is 13 really, be definition, almost we are approving the 14 combination of thoracoscopy and VATS with this. But I think 15 that is fine. I can't imagine anybody giving this via a 16 thoracentesis. Physically, it wouldn't go in there. 17 I mean almost by definition, you are giving it in 18 a manner where you can see where it goes. I mean that is 19 just the way the techniques are done now. 20 So we have a vote on the amendment, which is to 21 make the motion be Sclerosol (sterile aerosol talc) is 22 approvable for the palliative treatment of malignant pleural 23 effusions. 24 All in favor of the amendment? 25 [Show of hands.] MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (202) 546-6666 96 1 CHAIRMAN BUNN: That is 8 to zero. 2 Now we will vote on the motion then. The motion 3 is that Sclerosol (sterile aerosol talc) is approvable for 4 the palliative treatment of malignant pleural effusions. 5 All in favor? 6 [Show of hands.] 7 CHAIRMAN BUNN: Dr. Gelber? 8 DR. GELBER: It just seems that the amendment and 9 the motion are exactly the same. 10 CHAIRMAN BUNN: They are. So it is 8 to 0, 8 in 11 favor, zero abstained, zero against. 12 Question 5. Does ODAC have advice for the FDA 13 regarding the acceptability of literature-based NDAs for 14 cancer therapeutics? For example: 15 a. What types of patient populations/clinical 16 indications could be considered as appropriate for a 17 literature-based NDA? 18 b. What types of products could be considered, 19 e.g., cytotoxic, hormonal, supportive care? 20 c. What should be required regarding the quality 21 and the quantity of data? 22 Since I have put Dr. Krook on the line, I will go 23 first on this. We have had some discussion of this already. 24 I think that literature-based NDAs are reasonable for cancer 25 therapeutics. I think if the changes in health care MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 (on OV . 97 1 continue to increase the number of denials by insurance 2 companies, particularly for approved products for 3 nonapproved indications, that this might become more 4 important. Actually, I personally hope that it isn't. 5 Historically, most insurers have relied on 6 physician expertise and the literature, and I think it is an 7 unfortunate thing where insurers are not relying on 8 physician expertise or the literature. If that becomes an 9 increasing problem, I hope that we will see increasing 10 literature-based NDAs, but I hope that doesn't happen. I 11 think that is a step backwards for health care in the United 12 States. 13 I personally believe that all types of products 14 listed here, cytotoxic, hormonal, supportive care, could be 15 considered. Regarding the quality and the quantity of the 16 data, obviously, the better the quality, the more the 17 quantity, the better. I would point out that this Committee 18 has gone on record as saying that randomized trials are 19 often easier to interpret than Phase II trials. 20 The cooperative group randomized trials often have 21 fairly good quality monitoring and quality assurance built 22 into the studies, both from an audit point of view and from 23 a statistical design point of view, and generally, I think 24 most people on the Committee feel that randomized studies 25 from cooperative groups are generally quite useful, but MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 f 0 0 'I 98 1 obviously, since we approved this without cooperative group 2. randomized trials, there are other ways with bulk of 3 evidence that can be used. 4 Dr. Krook. 5 DR. KROOK: My only thing to add, Paul, is I think 6 that under 5 (b), supportive care or palliative care I guess 7 I may change that to, maybe there is a fourth one, 8 palliative care, as Dr, Ochs has brought up, what we went 9 through today, the malignant pleural effusion certainly 10 falls into that, and I suppose supportive care can fall into 11 nausea questions, which aren't palliative care. I think 12 that particularly through literature-based ND A s . 13 I have a little more difficulty with cytotoxic. I 14 think you have got a little bit more commonly through a 15 literature. You have to have some controlled trials when 16 you increase th toxicity without a gain. 17 That is my only comment. I am saying the same 18 about quality and quantity as you are. 19 CHAIRMAN BUNN: Dr. Ingle. 20 DR. INGLE: This has already been mentioned. For 21 literature to be acceptable, there have to be strong 22 assurances of peer review and the minimizing of conflict of 23 interest, which can come from many sources. 24 ..... CHAIRMAN BUNN: There is a lot of debate going on 25 in the community. I have been involved in some of this from MILLER REPORTING COMPANY, INC. 507 C street, N.E. Washington, D.C. 20002 (202) 54^-6666 99 1 the insurers about what is standard treatment, and I 2 personally don't believe that the FDA should be the final 3 common denominator on what is adequate peer review of the 4 literature, and I think if every, you know, every indication 5 for every drug has to come back to the FDA for consideration 6 of is the literature adequate, again, I believe that is a 7 huge step backwards. 8 I believe that there are sensible people who 9 should be in the community, who can make those judgments 10 without bringing every indication for every approved drug to 11 this Committee and to the FDA, but again, that is my own / 12 bias. I think in certain instances, like this, this is very 13 useful, but I don't think every drug for every indication 14 should come here for a review of the literature. 15 DR. GELBER: I just wanted to add also that the 16 entire literature should be presented including abstracts to 17 allow the Committee to look at those data, as well, 18 especially because of the tendency not to publish abstracts 19 that are not as exciting as what is appearing - 20 CHAIRMAN BUNN: Again, I think we commend the FDA 21 for making sure that these literature searches are 22 completely thorough and as unbiased as possible. 23 DR. GELBER: And one last point is efforts that 24 could track down additional studies should be pursued and 25 the fact that arms-length literature by itself probably ' MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington., D.C. 20002 (202) 545-6666 100 1 would not be as persuasive as having some of the additional 2 information, for example, that was presented, the supportive 3 information about a consistency throughout, I think is very 4 important to a literature-based NDA. 5 CHAIRMAN BUNN: Dr. Temple. 6 DR. TEMPLE: Despite what some people think, we 7 don't think FDA-approved labeling ought to be the sole 8 determinant of practice either. At least part of the reason 9 for that is that sometimes you do things even before there 10 is decent evidence in support of them, and that is just one 11 of the exigencies of being out there. ; 12 I think our concern is that we don't want to put 13 things in the label as if they met a standard when they 14 haven't. So we are very sympathetic to the idea that there 15 is a real problem that insurers are not paying for things 16 that doctors think are important, but our immediate question 17 is what standard can we use to put things into labeling that 18 deserve to be there without compromising. 19 As this Committee pointed out repeatedly, there 20 have been many instances where close review of the actual 21 cases, where effectiveness depended on individual cases, 22 often revealed differences between one interpretation and 23 another, and for better or worse, peer review doesn't solve 24 that problem, because the peer reviewer rarely has access to 25 case reports. I have done my share of that, and you are MILLER REPORTING COMPANY, INC. 507 C Street, N.E. Washington, D.C. 20002 A202) 546-6666