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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

NINETEENTH MEETING


Friday, July 25, 1997

8:15 a.m.


Holiday Inn Bethesda

8120 Wisconsin Avenue

Bethesda, Maryland


2


PARTICIPANTS

Virginia C. Broudy, M.D., Acting Chairperson (Topic III)

Julie M. Vose, M.D., Chairperson (Topic IV)

William Freas, Ph.D., Executive Secretary

MEMBERS

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.

CONSUMER REPRESENTATIVE

Abbey S. Meyers

PATIENT REPRESENTATIVE

Christine Heinemann (Topic III)

Helaine R. Baruch (Topic IV)

FDA

Patricia Keegan, M.D.

Jay P. Siegel, M.D.

Karen Weiss, M.D.


3

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

Opening Remarks:

Alice M. Wei 15

Scientific and Medical Summary of IDEC C2B8:

Antonio J. Grillo Lopez, M.D. 20

Discussion:

Antonio J. Grillo Lopez, M.D.

and Christine A. White, M.D. 48

FDA Perspective:

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.

Introduction:

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


4

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

FDA Perspective:

Henry Chang, M.D.

174

Committee Discussion 187


5

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

24 Center.

25 The empty seat will soon be filled with Dr.


6

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


7

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


8

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


9

1 this mean that the patient can be retreated many times?


2 There was no information regarding retreatment in his

3 packet.

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

8 condition.

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.


10

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


11

1 remission.


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

9 children.

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


17 bald."

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.


12

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


22 Tylenol.

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.


13

1 After living with this disease for seven years,


2 through seven various courses of treatment, here is what
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