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DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICAL EVALUATION AND RESEARCH
BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE
Friday, July 25, 1997
Holiday Inn Bethesda
8120 Wisconsin Avenue
Virginia C. Broudy, M.D., Acting Chairperson (Topic III)
Julie M. Vose, M.D., Chairperson (Topic IV)
William Freas, Ph.D., Executive Secretary
Hugh Auchincloss, Jr., M.D.
W. French Anderson, M.D.
Charles S. August, M.D.
Ellin R. Berman, M.D.
Richard A. Goldsby, Ph.D.
Pamela Hartigan, Ph.D.
Richard Hong, M.D.
Eugenie S. Kleinerman, M.D.
Paul R. McCurdy, M.D.
Carole B. Miller, M.D.
William M. O'Fallon, Ph.D.
Abbey S. Meyers
Christine Heinemann (Topic III)
Helaine R. Baruch (Topic IV)
Patricia Keegan, M.D.
Jay P. Siegel, M.D.
Karen Weiss, M.D.
C O N T E N T S
Opening and Administrative Remarks 5
Open Public Hearing
Kathryn Adams 7
OPEN COMMITTEE DISCUSSION: TOPIC III
BLA 97 0260
Rituximab, IDEC Pharmaceuticals
Presentation by IDEC Pharmaceuticals
Alice M. Wei 15
Scientific and Medical Summary of IDEC C2B8:
Antonio J. Grillo Lopez, M.D. 20
Antonio J. Grillo Lopez, M.D.
and Christine A. White, M.D. 48
Mark R. Brunswick, Ph.D. 77
Bernard W. Parker, 78
Committee Discussion 100
Open Public Hearing 131
OPEN COMMITTEE DISCUSSION: TOPIC IV
BLA, Supplement Reference 96 1136
Neupogen, Amgen, Inc.
Presentation by Amgen, Inc.
George Morstyn, MBBS, FRCP 132
Overview of Disease, Treatment and Study Design:
Alan Barge, MA, MBBS, MRCP 135
Results and Discussion of Efficacy:
James Matcham, MSc, C.Stat. 141
C O N T E N T S (Continued)
Discussion of Results Safety, Review of Published
Literature, Summary and Conclusions:
Alan Barge, MA, MBBS, MRCP 154
Henry Chang, M.D.
Committee Discussion 187
1 P R O C E E D I N G S
2 Opening and Administrative Remarks
3 DR. FREAS: Good morning and welcome. Again, I
4 apologize for the delay. I am Bill Freas. I am the
5 Executive Secretary for the Biological Response Modifiers
6 Advisory Committee and we would like to welcome you to the
7 second day of our meeting.
8 The good news is I do not have to read the
9 conflict of interest statement that was read into the public
10 record yesterday. The bad news, however, though, it still
11 applies to today's meeting. As a result, our Chair, Dr.
12 Julie Vose, has been excluded from today's topic and our new
13 Chair is Dr. Virginia Broudy.
14 I would like to go around the table and introduce
15 the members of the committee for those of you who were not
16 here yesterday. I will be starting down here at the end of
17 the table and if the members would raise their hands so the
18 people in the audience could identify who you are.
19 First we have Dr. French Anderson, Director, Gene
20 Laboratory, University of Southern California School of
21 Medicine. Next is Dr. Hugh Auchincloss, Associate Professor
22 of Surgery at Harvard Medical School. Next is Dr. Ellin
23 Berman, Associate Professor, Memorial Sloan Kettering Cancer
25 The empty seat will soon be filled with Dr.
1 Richard Hong, Professor, Vermont Cancer Center, University
2 of Vermont. Next is Dr. Eugenie Kleinerman, Professor,
3 University of Texas, M.D. Anderson Cancer Center. Next is
4 Dr. William O'Fallon, Chair, Department of Health Sciences
5 Research, Mayo Clinic.
6 Around the corner is Dr. Richard Goldsby,
7 Professor, Amherst College. Next is our Acting Chair for
8 this morning's topic, Dr. Virginia Broudy, Associate
9 Professor of Medicine, University of Washington School of
10 Medicine. Next is our patient rep, Christine Heinemann.
11 Next is our consumer advocate, Abbey Meyers, President and
12 Executive Director, National Organization of Rare Disorders,
13 New Fairfield, Connecticut.
14 Next is Dr. Charles August, Division of Hematology
15 and Oncology, Miami Children's Hospital. Next is Dr. Paul
16 McCurdy, Director, Blood Resources Program, Division of
17 Blood Diseases and Resources, NIH. Next is Dr. Carole
18 Miller, Assistant Professor of Oncology at the Johns Hopkins
19 University. Next is Dr. Pamela Hartigan, Senior
20 Biostatistician, Westhaven V.A. Medical Center.
21 At the table, we also have three members of FDA to
22 help coordinate the meeting. They are, continuing around
23 the table, Dr. Pat Keegan, Chief, Oncology Branch; Dr. Karen
24 Weiss, Director, Division of Clinical Trial Design and
25 Analysis; and Dr. Jay Siegel, Director, Office of
1 Therapeutics, Research and Review.
2 We were to have a voting patient representative at
3 this morning's meeting. At the very last minute, David Larr
4 contacted us and he was too ill to participate. His name
5 will be mentioned frequently throughout this morning because
6 he did receive the briefing materials and he does have some
7 comments to bring to the committee.
8 Fortunately, Christine Heinemann was contacted by
9 our Office of Special Health, and volunteered at the last
10 minute and I do mean at the last minute to join the
11 panel as a non voting patient representative.
12 Normally the patient representative has a vote,
13 however, at the last minute we were unable to process the
14 paperwork through the chain to get the vote approved on the
15 advisory committee, but we would like to welcome to the
16 table Christine, who at the last minute did manipulate her
17 schedule to join us here this morning.
18 At this time I would like to turn the microphone
19 over to our Chair, Dr. Broudy.
20 Open Public Hearing
21 DR. BROUDY: The first item on the agenda is the
22 open public hearing.
23 DR. FREAS: Dr. Broudy, if you don't mind, let me
24 just read the responses or address the responses that we
25 received from the advertisement that we placed in the
1 Federal Register notice about requesting members of the
2 public to speak at the open public hearing.
3 We have received one request, and that is from
4 Kathryn Adams from the Cure for Lymphoma Foundation.
5 Kathryn, would you please come to the microphone
6 this morning and make your statement, and also at the close
7 of the statement, please, in the interest of fairness,
8 address any affiliations that you may have with any of the
9 products that you may wish to comment upon.
10 MS. ADAMS: My name is Kathryn Adams. I am Vice
11 President of the Cure for Lymphoma Foundation based in New
12 York City.
13 The Cure for Lymphoma Foundation is a nationwide
14 not for profit organization dedicated to funding research
15 and to providing support and education for those whose lives
16 have been touched by Hodgkin's disease and non Hodgkin's
17 lymphoma. I am here today to represent the Foundation and
18 two our patients we know and love.
19 David Larr, who had planned to be a member of this
20 panel this morning, could not be here. He is very
21 enthusiastic about rituximab and asked me to pose the
22 following question.
23 After pursuing the material sent to him by the
24 FDA, his question is this: Since there is only a 1 percent
25 HACA response from the patient's own immune system, does
1 this mean that the patient can be retreated many times?
2 There was no information regarding retreatment in his
4 It seems as if a patient may be able to be
5 retreated on a chronic basis, with a so called "booster"
6 shot every year. It would mean that a low grade non
7 Hodgkin's lymphoma could be considered then a chronic
9 I would also like to read a statement faxed to me
10 late last night by Dr. Wendy Harpham, who is actually on our
11 board and a non Hodgkin's lymphoma patient. It is
12 handwritten, so please bear with me.
13 It is entitled "C2B8 Life and Hope." I am a
14 doctor of internal medicine, mother of three young children
15 and a seven year survivor of small cleaved cell follicular
16 non Hodgkin's lymphoma.
17 In 1990, I developed a rash, enlarging lymph
18 nodes, and excruciating pain in my groin and back. Two
19 surgeries disclosed disseminated low grade lymphoma. In
20 light of my debilitating symptoms, and the recent work
21 suggesting that more intensive therapies might increase the
22 durability of remission, and possibly effect a cure, I
23 received Promace MOPP chemotherapy.
24 My course was complicated by esophagitis,
25 phlebitis, colitis, and the usual host of side effects.
1 Needless to say, I was unable to care for my patients, and
2 could tend to my children only with major help from family
3 and friends.
4 Fatigue, persistent pain, colitis, and recurrent
5 infections slowed my recovery. Almost one year following
6 treatment, I was diagnosed with a local recurrence. It was
7 a devastating time, not because I had to close my beloved
8 medical practice but because, despite my being in a most
9 favorable subgroup at the beginning and end of chemotherapy,
10 I knew I wasn't cured.
11 Remission again achieved, I had my bone marrow
12 harvested. A few months later, the rash reappeared. Scans
13 appeared clear. In hopes of preventing the development of
14 measurable disease, I was started on interferon alpha.
15 After four long months of debilitating fatigue and nausea,
16 scans revealed disseminated disease.
17 As a physician patient, it was again a very
18 terrifying time. The pace of my disease suggested that I
19 would fall on the shorter end of the average life expectancy
20 after diagnosis. The fact that I had had a rapid and
21 complete response to chemotherapy but recurrence less than a
22 year later, and the new data coming in on recurrence of low
23 grade lymphoma after bone marrow transplants, made me
24 fearful that not only would transplant be a traumatic
25 experience, it may very well not provide a durable
2 I worried about the possible late effects of
3 repeated exposure to intensive chemotherapy. Since I had
4 never had a chance to recover from my first courses of
5 treatment before recurrent lymphoma was diagnosed, I worried
6 about feeling sick for the rest of my life, however long
7 that might be. And, most important of all, there was the
8 heart wrenching fear that I would not live to raise my
10 Balancing all the risks and benefits, short term
11 and long term, of all my treatment options, in 1993, I
12 entered the Phase I trial of IDEC anti CD20 MAB at Stanford.
13 Although I felt nauseated during the infusion, I fell back
14 to baseline when the infusion was over.
15 My husband and I went out to dinner and marveled,
16 "Can it really be working? It's not making me sick or
18 The single infusion resulted in a good partial
19 remission, during which time I regained all the weight I had
20 lost on interferon, wrote most of my second book, "After
21 Cancer: A Guide To Your New Life," and raised my children.
22 Eight months later, the remaining disease
23 progressed, the same month that, for the first time since
24 the antibodies were infused, my peripheral B cell count was
25 rising, indicating less of an effect of the IDEC Mab.
1 I then entered a Phase I/II trial and received
2 four infusions. Ill effects were minor and transient. The
3 infusions gave me another partial remission and eight more
4 months of good quality of life, and delayed further exposure
5 to toxic chemotherapies.
6 In December of 1994, the remaining lymphoma
7 progressed. The next trial of antibodies wasn't open, so I
8 did nine months of I can't read this based
9 chemotherapy. Although I did not lose my hair, the fatigue
10 was debilitating. At the end of the treatment, there were
11 minimal abnormalities on the scans, which continued to
12 improve over the subsequent few months.
13 In May of this year, scans revealed progressive
14 disseminated lymphoma. Biopsy confirmed the same SCCFNHL.
15 In June 1997, I received four weekly infusions of C2B8. As
16 far as I know, I am the first person ever to receive the
17 IDEC Mab three times.
18 I had more flu like symptoms for a couple of days
19 after the first doses, and a six day bout of diffuse
20 tenosynovitis after the second dose. None of these problems
21 required hospitalization or intervention other than oral
23 The first set of scans, done four weeks after the
24 last dose, were obtained 7 18 and showed just this recent
25 July 18 and showed dramatic improvement in all areas.
1 After living with this disease for seven years,
2 through seven various courses of treatment, here is what
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